Long-acting liquid injection of tilpotide as well as preparation method and application of long-acting liquid injection

Abstract

The invention discloses a long-acting liquid injection of tilpotide as well as a preparation method and application of the long-acting liquid injection. According to the injection obtained by changing the existence form of the tirpotide and the preparation method of the injection, the problem of burst release of the tirpotide in the injection is solved, the action time is prolonged, and the administration frequency and toxic and side effects are reduced. The long-acting liquid injection of the tilpotitide has the advantages of excellent slow release effect, simplicity and convenience in administration, good needle dredging property, low administration frequency, simplicity and convenience in treatment management and the like.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a tirzepatide long-acting liquid injection and a preparation method and application thereof. BACKGROUND

[0002] Tirzepatide is a GLP-1 / GIP dual receptor agonist, which is mainly used for treating type 2 diabetes, obesity and diabetes-related cognitive impairment and the like, has the core advantages of single weekly administration, significant hypoglycemic weight loss, and positive effects on visceral fat, triglyceride and the like metabolic indicators. The tirzepatide molecule is a polypeptide composed of 39 amino acids, which is easy to degrade and difficult to avoid the first pass effect of the gastrointestinal tract. Therefore, the currently used dosage form is mainly a once-weekly subcutaneous injection (pre-filled injection pen form), which can be directly administered by the patient (self-administration). Weekly injection is easy to cause pain and inflammatory reaction at the injection site, and the early burst and blood drug fluctuation caused by weekly administration can cause adverse reactions such as nausea and vomiting.

[0003] Long-acting sustained-release technology can be used to overcome these shortcomings, such as microsphere preparations, which can embed pharmacologically active substances in degradable polymer microspheres. When subcutaneously or intramuscularly injected, the drug is released from the microspheres through the slow degradation of the polymer (such as PLGA), so as to achieve uniform drug release for one month or more. However, the microsphere preparation needs to be configured into a suspension for administration, which is complicated to prepare before administration and needs to be prepared and injected by a professional doctor, thereby reducing the accessibility of the drug. In addition, the microsphere preparation cannot be removed after injection, and cannot be interrupted at any time according to the needs of the patient.

[0004] Therefore, there is an urgent need to develop a ready-to-use long-acting tirzepatide liquid preparation with excellent sustained-release effect. SUMMARY

[0005] The injection provided by the application does not need to be mixed before injection, can be directly injected into the body to form an in-situ gel drug depot, and can maintain a long sustained-release time and a low burst level of the drug. Specifically, the application includes the following contents.

[0006] In a first aspect, the application provides a tirzepatide long-acting liquid injection, wherein the injection includes a tirzepatide-inorganic salt complex, a degradable polymer and a biocompatible organic solvent.

[0007] In some embodiments, the tirzepatide long-acting liquid injection according to the application, wherein the inorganic salt includes at least one of zinc acetate, zinc chloride, magnesium phosphate, magnesium carbonate, calcium phosphate, calcium carbonate, ferric chloride and aluminum phosphate.

[0008] In some embodiments, the long-acting liquid injection of telpeptide according to the present application, wherein the biodegradable polymer comprises at least one of poly(lactide-co-glycolide), poly(lactide-co-ethylene glycol), poly(lactide-co-glycolide-co-ethylene glycol), and sucrose acetate isobutyrate.

[0009] In some embodiments, the long-acting liquid injection of telpeptide according to the present application, wherein the poly(lactide-co-glycolide) has a molecular weight of 15-60 kDa, and a molar ratio of lactide to glycolide of 40:60 to 80:20.

[0010] In some embodiments, the long-acting liquid injection of telpeptide according to the present application, wherein the biocompatible organic solvent comprises at least one of dimethyl sulfoxide, N-methyl pyrrolidone, acetone, 2-pyrrolidone, and acetonitrile.

[0011] In some embodiments, the long-acting liquid injection of telpeptide according to the present application, wherein the biocompatible organic solvent has a mass ratio of 63%-79% in the injection.

[0012] In some embodiments, the long-acting liquid injection of telpeptide according to the present application, wherein the telpeptide-inorganic salt complex has a mass ratio of 2-20% in the injection.

[0013] In some embodiments, the long-acting liquid injection of telpeptide according to the present application, wherein the biodegradable polymer has a mass ratio of 20-40% in the injection.

[0014] In a second aspect, the present application provides a preparation method of the long-acting liquid injection of telpeptide according to the first aspect of the present application, comprising the following steps: (1) mixing the biodegradable polymer and the biocompatible organic solvent to obtain a sustained-release solution; (2) preparing the telpeptide-inorganic salt complex; (3) mixing the telpeptide-inorganic salt complex with the sustained-release solution to obtain the long-acting liquid injection of telpeptide.

[0015] In a third aspect, the present application provides use of the long-acting liquid injection of telpeptide according to the first aspect of the present application in the preparation of a drug for improving or treating diabetes, obesity, or a related disease.

[0016] The present application is directed to the problem of the burst release of organic solvents when preparing gels for biodegradable polymers as diluents, by designing the structure of the tipepitide so that it forms a complex with inorganic salts, thereby controlling the burst release of tipepitide in the injection solution, and thus prolonging the drug release time and action time, and reducing the number of doses and side effects. Compared with other non-in situ gel sustained-release systems (such as microsphere systems), the present application has the advantages of simple administration and good needle passability. In addition, the drug depot formed by the present application can be removed at any time by simple surgery, and has the advantage of being able to interrupt administration at any time, and can cope with the possible nausea, diarrhea and other gastrointestinal reactions and other side effects of tipepitide. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 In situ gel formed by injecting the tipepitide long-acting liquid injection solution of Example 1 into simulated body fluid.

[0018] Figure 2 In vitro release curve of Example 1 and Comparative Examples 1-10. DETAILED DESCRIPTION

[0019] The various illustrative embodiments of the present application will now be described in detail below, which should not be considered limiting on the present application, but rather as a description of certain aspects, features and embodiments of the present application.

[0020] It should be understood that the terms used in the present application are merely used to describe particular embodiments and are not intended to limit the present application. In addition, for numerical ranges in the present application, it should be understood that the upper limit and the lower limit of the range and every intermediate value between them are specifically disclosed. Every smaller range within the range of any stated value or stated range of values and between any other stated value or stated range of values is also included in the present application. The upper limit and the lower limit of these smaller ranges can be included or excluded independently from the range.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, the preferred methods and materials are described. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials in connection with which the documents are cited. In the case of conflict between the content of this specification and that of any document incorporated by reference, the content of this specification controls.

[0022] Teriparatide long-acting liquid injection In one aspect of the present application, a long-acting liquid injection of telopeptide is provided, which comprises a telopeptide-inorganic salt complex, a degradable polymer and a biocompatible organic solvent. The "long-acting injection" refers to an injection with excellent sustained release effect and without burst release phenomenon during long-term use. In one aspect of the present application, the telopeptide is changed into a complex with an inorganic salt, and in another aspect, the composition of the excipients and the ratio of the components are optimized, and a unique preparation process is further combined, thereby solving the burst release problem of telopeptide in the injection, achieving excellent sustained release effect of telopeptide, prolonging the action time, and reducing the frequency of administration and side effects.

[0023] In the present application, the inorganic salt in the telopeptide-inorganic salt complex is not particularly limited, and any inorganic salt that is beneficial to the sustained release of telopeptide can be used in the present application. The inorganic salt is particularly preferably a metal salt, and examples thereof include, but are not limited to, zinc acetate, zinc chloride, magnesium phosphate, magnesium carbonate, calcium phosphate, calcium carbonate, ferric chloride, aluminum phosphate and the like. In a preferred embodiment, the inorganic salt is zinc acetate, and the telopeptide-inorganic salt complex is a telopeptide-zinc acetate complex.

[0024] In the present application, the degradable polymer includes, but is not limited to, at least one of poly(lactide-co-glycolide), poly(lactide-co-ethylene glycol), poly(lactide-co-glycolide-co-ethylene glycol) and sucrose acetate isobutyrate. In a preferred embodiment, the degradable polymer is poly(lactide-co-glycolide), i.e., PLGA.

[0025] In order to achieve excellent sustained release effect of the telopeptide long-acting liquid injection and solve the burst release problem, the molecular weight of poly(lactide-co-glycolide) should not be too high or too low. In the present application, the molecular weight of poly(lactide-co-glycolide) is 15-60 kDa, preferably 15-58 kDa, more preferably 15-56 kDa, further preferably 15-54 kDa, more preferably 15-52 kDa, for example, 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 kDa. In a preferred embodiment, the molecular weight of poly(lactide-co-glycolide) is 18 kDa. In another preferred embodiment, the molecular weight of poly(lactide-co-glycolide) is 39 kDa.

[0026] In order to achieve the excellent sustained-release effect of the long-acting liquid injection of telopeptide and solve the problem of burst release, the molar ratio of lactide and glycolide needs to be controlled in a suitable range. In the present application, the molar ratio of lactide and glycolide is 40:60 to 80:20, such as 50:50, 60:40, 65:35, 70:30, 75:25, etc.

[0027] In order to achieve the sustained-release effect of the long-acting liquid injection of telopeptide and solve the problem of burst release, a suitable biocompatible organic solvent needs to be selected. In the present application, the biocompatible organic solvent includes but is not limited to dimethyl sulfoxide, N-methyl pyrrolidone, acetone, 2-pyrrolidone, acetonitrile, etc. In a preferred embodiment, the biocompatible organic solvent is dimethyl sulfoxide.

[0028] In order to achieve the sustained-release effect of the long-acting liquid injection of telopeptide and solve the problem of burst release, the mass ratio of the biocompatible organic solvent in the injection needs to be controlled in a suitable range. In the present application, the mass ratio of the biocompatible organic solvent in the injection is 63%-79%, preferably 64%-78%, more preferably 65%-77%, such as 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%.

[0029] In the present application, the mass ratio of the telopeptide-inorganic salt complex in the injection is 2-20%, preferably 2-19%, more preferably 2-18%, further preferably 2-17%, more preferably 2-16%, such as 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%.

[0030] In the present application, the mass ratio of the degradable polymer in the injection is 20-40%, preferably 20-39%, more preferably 20-38%, further preferably 20-37%, more preferably 20-36%, such as 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%.

[0031] Preparation method In one aspect of the present application, a preparation method of the long-acting liquid injection of telopeptide is provided, which comprises the following steps: (1) mixing the degradable polymer and the biocompatible organic solvent to obtain a sustained-release solution; (2) preparing the telopeptide-inorganic salt complex; (3) The telpoeptide-inorganic salt complex is mixed with the sustained-release solution to obtain the telpoeptide long-acting liquid injection.

[0032] In a preferred embodiment, the preparation method of the present invention includes the following steps: (1) Take 55-75 parts by weight, preferably 56-74 parts by weight, even more preferably 57-73 parts by weight, and even more preferably 58-72 parts by weight, such as 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72 parts by weight of PLGA and 155-175 parts by weight, preferably 156-174 parts by weight, even more preferably 157-173 parts by weight, and even more preferably 158-172 parts by weight, such as 158, 159 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, and 172 parts by weight of DMSO are ultrasonically homogenized at 25-45°C, preferably 26-44°C, even more preferably 27-43°C, and more preferably 28-42°C, for example at 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, and 42°C, with a resonant acceleration of 60-90. The concentration of g is preferably 62-88 g, even more preferably 64-86 g, and more preferably 66-84 g, for example 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 g; the resonance time is 20-40 min, preferably 21-39 min, even more preferably 22-38 min, and more preferably 23-37 min, for example 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 min; and the solution is placed for 6-15 h, preferably 7-14 h, even more preferably 8-13 h, and more preferably 8-12 h, for example 8, 9, 10, 11, 12 h to obtain a sustained-release solution. (2) Dissolve telpotrepeptide powder without acetate in a 1-5% (w / w) (e.g., 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%) zinc acetate solution to obtain a mixture, wherein the molar ratio of zinc acetate to telpotrepeptide is (0.1-2):1, preferably (0.2-1.8):1, even more preferably (0.3-1.6):1, and more preferably (0.5-1.5):1, for example 0.5:1, 0.6:1, 0.7:1, 0.8:1. 1. Mixtures of 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, and 1.5:1 are incubated at 2-8°C (e.g., 2, 3, 4, 5, 6, 7, 8°C) for 16-30 hours, preferably 17-29 hours, even more preferably 18-28 hours, and more preferably 19-27 hours, for example 19, 20, 21, 22, 23, 24, 25, 26, 27 hours, followed by freeze-drying to obtain the telpoeptide-zinc acetate complex. (3) Take 5-15 parts by weight, preferably 6-14 parts by weight, even more preferably 7-13 parts by weight, and more preferably 8-12 parts by weight, for example 8, 9, 10, 11, or 12 parts by weight of the telpopeptide-zinc acetate complex, mix it with the sustained-release solution, and perform ultrasonic homogenization. The resonance acceleration is set to 50-80 g, preferably 52-78 g, even more preferably 54-76 g, and more preferably 56-74 g, for example 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, or 74 g. Homogenize for 20-40 min, preferably 21-39 min, even more preferably 22-38 min, and more preferably 23-37 min. For example, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 min, to obtain the long-acting liquid injection of telpoeptide.

[0033] Application One aspect of the present invention provides the use of telpolide long-acting liquid injection in the preparation of medicaments for improving or treating diabetes, obesity, or related conditions. The related conditions include, but are not limited to, diabetic complications (e.g., but not limited to, related cognitive impairment, retinopathy, nephropathy, cardiovascular disease, cerebrovascular disease, osteoarthritis), and obesity-related complications (e.g., but not limited to, metabolic syndrome, dyslipidemia, hypertension).

[0034] Example 1 The following illustrates the preparation process of telpolide long-acting liquid injection.

[0035] (1) As shown in Table 1, weigh 65 mg of PLGA5050 (Mw=39 kDa) and 165 mg of DMSO into a mixing tank. Place the mixing tank in an acoustic resonance device and perform ultrasonic homogenization at 37°C (resonance acceleration of 75 g and resonance time of 30 min). After homogenization into a transparent and clear solution, let it stand overnight and mix thoroughly to obtain a sustained-release solution. (2) Add 10 mg of zinc acetate telpoeptide to the mixing tank (dissolve telpoeptide powder without acetate in 2% w / w zinc acetate solution, with a molar ratio of zinc acetate to telpoeptide of 1:1, incubate the mixture at 2-8℃ for 24 hours and then freeze dry to obtain powdered raw material). The total filling amount of all materials shall not exceed 60% of the container volume. Continue to place the mixing tank in the acoustic resonance device for ultrasonic homogenization. Set the resonance acceleration to 65 g and homogenize for 30 min to obtain long-acting injection.

[0036] Example 2 The following illustrates the preparation process of telpolide long-acting liquid injection.

[0037] (1) As shown in Table 1, weigh 130 mg of PLGA5050 (Mw=39 kDa) and 330 mg of DMSO into a mixing tank. Place the mixing tank in an acoustic resonance device for ultrasonic homogenization (resonance acceleration of 75 g and resonance time of 30 min). After homogenization into a transparent and clear solution, let it stand overnight and mix thoroughly to obtain a sustained-release solution. (2) Add 20 mg of zinc acetate telpoeptide to the mixing tank (dissolve telpoeptide powder without acetate in 2% w / w zinc acetate solution, with a molar ratio of zinc acetate to telpoeptide of 1:1, incubate the mixture at 2-8℃ for 24 hours and then freeze dry to obtain powdered raw material). The total filling amount of all materials shall not exceed 60% of the container volume. Continue to place the mixing tank in the acoustic resonance device for ultrasonic homogenization. Set the resonance acceleration to 65 g and homogenize for 30 min to obtain long-acting injection.

[0038] Example 3 The following illustrates the preparation process of telpolide long-acting liquid injection.

[0039] (1) As shown in Table 1, weigh 145 mg of PLGA7525 (Mw=18 kDa) and 365 mg of DMSO into a mixing tank. Place the mixing tank in an acoustic resonance device for ultrasonic homogenization (resonance acceleration of 75 g and resonance time of 30 min). After homogenization into a transparent and clear solution, let it stand overnight and mix thoroughly to obtain a sustained-release solution. (2) Add 60 mg of zinc acetate telpoeptide to the mixing tank (dissolve telpoeptide powder without acetate in 2% (w / w) zinc acetate solution, with a molar ratio of zinc acetate to telpoeptide of 1:1. After incubating the mixture at 2-8℃ for 24 hours, freeze-dry to obtain powdered raw material). The total filling amount of all materials shall not exceed 60% of the container volume. Continue to place the mixing tank in an acoustic resonance device for ultrasonic homogenization. Set the resonance acceleration to 65 g and homogenize for 30 min to obtain long-acting injection.

[0040] Table 1. Composition of the long-acting liquid injection solutions in Examples 1-3 Comparative Example 1 The following shows the preparation method of telpoeptide sustained-release microspheres.

[0041] Telpoeptide acetate and biodegradable polymer PLGA5050 (Mw=39 kDa) were dissolved in dichloromethane, an organic solvent, at a ratio of 20% of the theoretical drug loading to obtain an oil phase. A 0.5 wt% polyvinyl alcohol solution was used as the external aqueous phase for homogenization and emulsification. The resulting oil-in-water emulsion was further solidified into microspheres by stirring at 600 rpm. The solidified microspheres were repeatedly washed with pure water to remove residual polyvinyl alcohol, and then lyophilized to obtain Telpoeptide microspheres (drug loading of 11%).

[0042] Comparative Example 2 The preparation process of this comparative example of telpopritine injection differs from that of Example 1 only in that ethyl acetate is used as the organic solvent in this comparative example.

[0043] Comparative Example 3 The only difference between the preparation process of this comparative example of telpolide injection and that of Example 1 is that benzyl alcohol is used as the organic solvent in this comparative example.

[0044] Comparative Example 4 The preparation process of this comparative example of telpolide injection differs from that of Example 1 only in that this comparative example uses telpolide acetate (Hangzhou Gutuo Biotechnology Co., Ltd., GT-L007) as the active pharmaceutical ingredient.

[0045] Comparative Example 5 The only difference between the preparation process of this comparative example of telpolide injection and that of Example 1 is that this comparative example uses acetate-free telpolide (Harbin Jixianglong Biotechnology Co., Ltd.) as the active pharmaceutical ingredient.

[0046] Comparative Example 6 The preparation process of this comparative example of telpolide injection differs from that of Example 1 only in that the biodegradable polymer used in this comparative example is PLGA8515 (Mw=42 kDa).

[0047] Comparative Example 7 The preparation process of this comparative example of telpolide injection differs from that of Example 1 only in that the biodegradable polymer used in this comparative example is PLGA5050 (Mw=13kDa).

[0048] Comparative Example 8 The preparation process of this comparative example of telpolide injection differs from that of Example 1 only in that the amount of organic solvent DMSO is reduced to 120 mg.

[0049] Comparative Example 9 The preparation process of this comparative telpolide injection differs from that of Example 1 only in that the amount of organic solvent DMSO is increased to 285 mg.

[0050] Comparative Example 10 The preparation process of this comparative example of telpolide injection differs from that of Example 1 only in that the organic solvent is NMP.

[0051] Test case 1. Viscosity and in vitro release tests Viscosity testing method: The viscosity of the sustained-release gel injection was measured using a cone-plate rheometer at 25°C and a shear rate of 0.3 rpm. In vitro release testing method: The gel injection obtained by mixing the sterile-filtered sustained-release solution and the sterile-filtered lyophilized active pharmaceutical ingredient according to the aforementioned steps was injected into sterile phosphate-buffered saline (PBS). Release conditions were a 37°C constant temperature water bath, pH 7.4, and a shaking speed of 180 rpm. The PBS solution was replaced every two days, and the concentration of telpolide in the solution was measured at specified time points. The in vitro release method for the sterile microsphere injection was the same as above.

[0052] Examples 1-3 and Comparative Examples 7, 9, and 10 all yielded telpolide injection solutions that were colorless, transparent liquids with good flowability, which could be injected using a 24G needle. Comparative Examples 4 and 8 yielded long-acting injection solutions with poor flowability, requiring the use of a 22G needle. The long-acting injection solutions in these examples formed a gel-like solid upon injection into pH 7.4 phosphate buffer (e.g., ...). Figure 1 (As shown).

[0053] Viscosity and in vitro release tests were performed on the products provided in the examples and comparative examples, and the results are shown in Table 2.

[0054] Table 2 Viscosity and in vitro release data for the examples and comparative examples Test results show that the long-acting liquid injection of telpolide in Examples 1-3, when injected into in vitro pH 7.4 phosphate buffer, can achieve slow release of the drug at different doses over 28 days, effectively prolonging the duration of drug action.

[0055] Table 2 shows that in Comparative Example 7, the biodegradable polymer PLGA5050 with a weight-average molecular weight of 13 kDa was used, and the cumulative release of the resulting injection solution exceeded 15% in one day, indicating a high initial release rate. In Comparative Example 8, the amount of organic solvent was too low, and the active pharmaceutical ingredient could not be completely dissolved, resulting in particulate dispersion. During the release test, needle clogging occurred, and a 22G needle had to be used for injection. The overall release was also slow. Comparative Example 9 used a higher content of organic solvent, showing an excessively high burst release and an excessively rapid initial release. Comparative Example 10 replaced the organic solvent DMSO with NMP, and similarly showed an increased burst release compared to Examples 1-3, with an excessively rapid initial release.

[0056] Table 2 shows that the microspheres provided in Comparative Example 1 had an excessively high in vitro burst release, posing safety and tolerability risks. The in-situ gel prepared in Comparative Example 2 had an excessively high burst release, reaching 33% on the first day. The in-situ gel prepared in Comparative Example 3 had a slow release, insufficient initial efficacy, and only 1% release on the first day. Comparative Example 4 changed the active pharmaceutical ingredient (API) salt form to acetate form, showing that the API could not dissolve, causing needle clogging problems during release testing. A 22G needle was required for injection. The prepared in-situ gel showed a significant burst release, reaching 23% on the first day. Although the burst release of the in-situ gel prepared in Comparative Example 5 was lower than that of Comparative Example 4, it was still significantly higher than that of Examples 1-3, reaching 8% on the first day. Comparative Example 6 used a biodegradable polymer PLGA8515 with a weight-average molecular weight of 42 kDa and an LA:GA ratio of 85:15. The resulting sustained-release solution had a high viscosity. Although the initial release was similar to that of Example 1, the drug release was slow in the later stages, with a cumulative release of only 44% after 28 days.

[0057] 2. Assessment of removability within the injected fluid Test samples: Example 1 long-acting injection and comparative microsphere injection.

[0058] Sprague-Dawley rats (SPF grade), adult males weighing 250-300 g and aged 8-10 weeks, were selected. 0.5 mL of the long-acting injectable formulation from Example 1 and the microsphere suspension from Comparative Example 1 were subcutaneously injected into the scapular region of the rats' backs. Three parallel samples were taken from each group, and the average value was calculated. The implants were removed from the original injection site at different time points, and their length and width were measured. The results showed that the long-acting injectable formulation from Example 1 formed a gel with a complete skeletal structure in vivo and could be completely removed surgically. In contrast, the microsphere suspension from the comparative example remained dispersed in the skin tissue during this period and could not be removed individually. The gel solid formed by the long-acting injection in vivo had a length of 1.33 and a width of 1.06 at 0.25 days (6 hours), degraded to a length of 0.77 and a width of 0.63 by day 7, and was almost completely degraded by day 28. The remaining body measured a length of 0.18 and a width of 0.17, demonstrating that the long-acting liquid injection of telpolide has good surgical removability and biodegradability in vivo.

[0059] Table 3. Volume changes of in-situ gels at different time points Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. These modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A long-acting liquid injection of telpolide, characterized in that, This includes telpoeptide-inorganic salt complexes, biodegradable polymers, and biocompatible organic solvents.

2. The long-acting liquid injection of telpolide according to claim 1, characterized in that, The inorganic salt includes at least one of zinc acetate, zinc chloride, magnesium phosphate, magnesium carbonate, calcium phosphate, calcium carbonate, ferric chloride, and aluminum phosphate.

3. The long-acting liquid injection of telpolide according to claim 1, characterized in that, The biodegradable polymer includes at least one of the following: lactide-glycolic acid copolymer, polylactide-polyethylene glycol copolymer, polylactide-glycolic acid copolymer and sucrose isobutyrate.

4. The long-acting liquid injection of telpolide according to claim 3, characterized in that, The molecular weight of the lactide-glycolic acid copolymer is 15-60 kDa, and the molar ratio of lactide to glycolide is 40:60 to 80:

20.

5. The long-acting liquid injection of telpolide according to claim 1, characterized in that, The biocompatible organic solvent includes at least one of dimethyl sulfoxide, N-methylpyrrolidone, acetone, 2-pyrrolidone, and acetonitrile.

6. The long-acting liquid injection of telpolide according to claim 1, characterized in that, The biocompatible organic solvent accounts for 63%-79% of the mass of the injection solution.

7. The long-acting liquid injection of telpolide according to claim 1, characterized in that, The mass ratio of the telpoeptide-inorganic salt complex in the injection solution is 2-20%.

8. The long-acting liquid injection of telpolide according to claim 1, characterized in that, The biodegradable polymer accounts for 20-40% of the mass of the injection solution.

9. The method for preparing the long-acting liquid injection of telpolide according to any one of claims 1-8, characterized in that, Includes the following steps: (1) The biodegradable polymer and the biocompatible organic solvent are mixed to obtain a sustained-release solution; (2) Preparation of the telpoeptide-inorganic salt complex; (3) The telpoeptide-inorganic salt complex is mixed with the sustained-release solution to obtain the telpoeptide long-acting liquid injection.

10. The use of the telpolide long-acting liquid injection according to any one of claims 1-8 in the preparation of a medicament for improving or treating diabetes, obesity or related conditions.

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