Pharmaceutical composition and application thereof in blood glucose reducing and weight losing medicines

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a pharmaceutical composition and application thereof in drugs for reducing blood glucose and reducing weight. The pharmaceutical composition disclosed by the invention comprises the GLP-1 / GCG dual-receptor co-excited polypeptide derivative or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliary materials. The pharmaceutical composition provided by the invention can be stably stored under the storage condition of 2-8 DEG C, meanwhile, the degradation speed is slowed down, and the pharmaceutical composition has excellent stability, effectiveness and safety.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a pharmaceutical composition and its application in hypoglycemic and weight-loss drugs. Background Technology

[0002] Type 2 diabetes mellitus (T2DM), formerly known as noninsulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes, is characterized by hyperglycemia, relative insulin deficiency, and insulin resistance. Currently, the main medications used clinically to treat type 2 diabetes include biguanides, sulfonylureas, thiazolidinediones, DPP-4 receptor inhibitors, SGLT-2 receptor inhibitors, and GLP-1 derivatives. Among these, GLP-1 derivatives are gradually becoming a major treatment for type 2 diabetes and a hot research topic due to their insulin-like hypoglycemic effect, minimal risk of hypoglycemia, weight loss benefits, and cardiovascular protective functions.

[0003] GLP-1 (glucagon-like peptide-1) is a glucose-dependent hypoglycemic polypeptide hormone secreted by L cells in the terminal jejunum, ileum, and colon. It exerts its hypoglycemic effect after specifically binding to the GLP-1 receptor. A major advantage of GLP-1 is its glucose-dependent incretin secretion, avoiding the risk of hypoglycemia often present in diabetes treatment. Besides regulating blood sugar, GLP-1 can also prevent pancreatic β-cell degeneration and stimulate β-cell proliferation and differentiation, thus improving the progression of diabetes at its source. Furthermore, GLP-1 also inhibits gastric acid secretion, delays gastric emptying, and suppresses appetite, resulting in some weight loss effects. However, to achieve significant weight loss, higher doses are generally required. High doses of GLP-1 derivatives can easily cause gastrointestinal side effects and often result in a narrow therapeutic window due to poor tolerability.

[0004] Glucagon (GCG) is a hormone produced in the α cells of the pancreas. Under stress conditions such as cold or hunger, it acts on the liver, breaking down glycogen and raising blood glucose levels. GCG also promotes fat degradation, fat oxidation, and estrogen production in the body (Diabetologia, 2017, 60, 1851 1861). Long-term administration can increase energy metabolism, resulting in weight loss. However, these beneficial effects of GCG on energy metabolism are not fully utilized due to its inherent glycemic effect.

[0005] Therefore, dual-target co-agonists possessing both GLP-1 and GCG receptor activating activity can utilize GCG to promote lipid degradation and lipid oxidation in vivo, achieving a significant enhancement in weight loss efficacy compared to GLP-1 single-target agonists. Currently, numerous patent documents have been published regarding peptide-based GLP-1 / GCG dual-receptor co-agonists, but no such dual-agonists have yet been commercialized.

[0006] GLP-1 / GCG can be administered orally or by injection. Injection refers to the preparation of a sterile solution (including emulsions and suspensions) for injection into the body, as well as sterile powders or concentrated solutions prepared as solutions or suspensions immediately before use. Injectable preparations act rapidly and reliably, are unaffected by pH, enzymes, or food, have no first-pass effect, and can exert systemic or localized effects. They are suitable for patients who cannot take oral medications. Injectable preparations generally include the active pharmaceutical ingredient (API), excipients, and solvents. The manufacturing process typically includes steps such as API preparation, formulation, filling, sterilization, and packaging. Excipients are generally used to increase the efficacy, safety, and stability of the injection. However, due to the low content of the API, if too many types and large amounts of excipients are added, greater consideration needs to be given to the efficacy and safety of the components.

[0007] Therefore, this invention provides an injectable formulation of a long-acting GLP-1 / GCG dual receptor co-agonist polypeptide derivative, which exhibits excellent stability, efficacy, and safety. Summary of the Invention

[0008] To address the aforementioned technical problems, this invention provides a pharmaceutical composition and its application in hypoglycemic and weight-loss drugs. The pharmaceutical composition provided by this invention can be stably stored at 2-8°C, does not precipitate under long-term and accelerated conditions, and simultaneously slows down degradation, exhibiting excellent stability, efficacy, and safety.

[0009] In a first aspect, the present invention provides a pharmaceutical composition comprising a GLP-1 / GCG dual receptor co-activating polypeptide derivative or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0010] The GLP-1 / GCG dual receptor co-activating polypeptide derivative described in this invention is the GLP-1 receptor and GCG receptor co-activating polypeptide derivative disclosed in patent CN202211323777.2, as detailed below:

[0011] The derivative is an acylated GLP-1 / GCG dual receptor co-activating polypeptide with a fatty acid side chain, and the amino acid sequence of the polypeptide is shown below:

[0012] H-Aib-HGTFTSDYSSYLDARAAHEFVKWLLEGGPSSG (SEQ ID NO. 1);

[0013] The fatty acid side chain is HOOC(CH2). 16 CO-γ-Glu-(AEEA)2-, which is linked to the ε-aminoacylation of amino acid K in the above-mentioned polypeptide;

[0014] The specific structural formula of the derivative is shown below:

[0015]

[0016] The excipients include stabilizers, which are selected from any one or more of amino acids, polyols, sugars, or metal ions.

[0017] The amino acids include arginine, glycine, histidine, etc.; the polyols include glycerol, etc.; the sugars include lactose, etc.; and the metal ions include calcium ions, etc.

[0018] Stabilizers are added to the pharmaceutical compositions of the present invention to ensure the stability of the pharmaceutical formulation.

[0019] The pharmaceutical composition provided by this invention can be stored under long-term conditions for at least 24 months, and can also be stored at room temperature for at least 7 days during clinical use. Specifically, 2℃-8℃ represents the proposed storage conditions for the pharmaceutical composition of this invention, i.e., long-term conditions; 25℃ represents accelerated storage conditions; and 40℃ represents high-temperature conditions.

[0020] As a preferred embodiment of the present invention, the stabilizer is selected from amino acids.

[0021] As a preferred embodiment of the present invention, the stabilizer is selected from any one or more of arginine, histidine, or glycine.

[0022] As a preferred embodiment of the present invention, the stabilizer is selected from arginine, and the resulting pharmaceutical composition exhibits optimal stability.

[0023] As a preferred embodiment of the present invention, the pharmaceutical composition is in the form of a liquid formulation.

[0024] As a preferred embodiment of the present invention, the concentration of the GLP-1 / GCG dual receptor co-activating polypeptide derivative or its pharmaceutically acceptable salt in the pharmaceutical composition is 0.05-10 mg / mL, for example 0.05 mg / mL, 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 4 mg / mL, 6 mg / mL, 8 mg / mL, 10 mg / mL, etc., preferably 0.5-10 mg / mL, more preferably 0.5-5 mg / mL, and even more preferably 1 mg / mL or 2 mg / mL.

[0025] The pharmaceutical composition of the present invention is in liquid form, and within the above-mentioned suitable concentration range, product stability and safety are ensured.

[0026] As a preferred embodiment of the present invention, the concentration of the stabilizer in the pharmaceutical composition is 0.2-25 mg / mL, for example 0.2 mg / mL, 0.5 mg / mL, 0.92 mg / mL, 1 mg / mL, 1.97 mg / mL, 3.9 mg / mL, 9.8 mg / mL, 19.7 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, etc.

[0027] The concentrations of the GLP-1 / GCG dual receptor co-activating polypeptide derivative or its pharmaceutically acceptable salt and stabilizer described in this invention, within the aforementioned range, can effectively improve the stability and manufacturing operability of the pharmaceutical composition. Too low a concentration can lead to adsorption and loss of the active ingredient (GLP-1 / GCG dual receptor co-activating polypeptide derivative or its pharmaceutically acceptable salt), while too high a concentration can cause aggregation and precipitation, interfering with manufacturing feasibility.

[0028] As a preferred embodiment of the present invention, the pH value of the pharmaceutical composition is 7.5-8.5, such as 7.5, 7.6, 7.8, 8.0, 8.2, 8.5, etc., preferably 7.6-8.4, and more preferably 7.9-8.1.

[0029] The pharmaceutical composition of the present invention is in liquid form and is administered by subcutaneous injection. Its pH value must be controlled within the above-mentioned range.

[0030] In a preferred embodiment of the present invention, the pH is adjusted using a pH adjuster.

[0031] As a preferred embodiment of the present invention, the pH adjuster is selected from acids and / or bases. The present invention does not impose excessive limitations on the acids and / or bases. The acids and / or bases are those commonly used in the art for adjusting pH, such as hydrochloric acid, sodium hydroxide, etc.

[0032] As a preferred embodiment of the present invention, the auxiliary material further includes a buffer.

[0033] As a preferred embodiment of the present invention, the buffer is selected from any one or more of citric acid or its salt, tartaric acid or its salt, succinic acid or its salt, maleic acid or its salt, Tris hydrochloric acid or its salt, or disodium hydrogen phosphate.

[0034] As a preferred embodiment of the present invention, the buffer is selected from any one or more of citric acid or its salt, tartaric acid or its salt, succinic acid or its salt, and maleic acid or its salt.

[0035] The addition of a buffer to the pharmaceutical composition of the present invention can help maintain pH stability, and the stability of the pharmaceutical composition is good when the buffer is one of the above-mentioned components.

[0036] As a preferred embodiment of the present invention, the buffer is selected from a combination of citric acid and citrate, or a combination of tartaric acid and tartarate; more preferably, it is a combination of citric acid and citrate. When the buffer is a combination of citric acid and citrate, the chemical and physical stability of the pharmaceutical composition is optimal.

[0037] As a preferred embodiment of the present invention, the concentration of the buffer in the pharmaceutical composition is 0.5-5 mg / mL, for example 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, etc., preferably 1-3.1 mg / mL.

[0038] As a preferred embodiment of the present invention, the excipients further include an antibacterial agent.

[0039] In a preferred embodiment of the present invention, the antibacterial agent is selected from any one or more of phenol, m-cresol, or chlorobutanol, preferably phenol. When phenol is used as the antibacterial agent, the chemical and physical stability of the pharmaceutical composition is optimal.

[0040] As a preferred embodiment of the present invention, the concentration of the antibacterial agent in the pharmaceutical composition is 1-10 mg / mL, such as 1 mg / mL, 2 mg / mL, 4 mg / mL, 6 mg / mL, 8 mg / mL, 10 mg / mL, etc., preferably 5 mg / mL.

[0041] As a preferred embodiment of the present invention, the excipients further include an isotonic agent.

[0042] As a preferred embodiment of the present invention, the isotonic agent is selected from propylene glycol.

[0043] As a preferred embodiment of the present invention, the concentration of the isotonic agent in the pharmaceutical composition is 10-20 mg / mL, such as 10 mg / mL, 12 mg / mL, 14 mg / mL, 16 mg / mL, 18 mg / mL, 20 mg / mL, etc.

[0044] As a preferred embodiment of the present invention, the pharmaceutical composition further includes water as a solvent.

[0045] In a second aspect, the present invention provides a method for preparing the pharmaceutical composition described in the first aspect, the method comprising mixing and dissolving the active ingredient and excipients in a prescribed amount and filtering.

[0046] The active ingredient is the GLP-1 / GCG dual receptor co-activating polypeptide derivative or a pharmaceutically acceptable salt thereof.

[0047] In a preferred embodiment of the present invention, the excipient solution is prepared first, and then the active ingredient is added.

[0048] As a preferred embodiment of the present invention, the temperature during solution preparation is ≤26℃.

[0049] As a preferred embodiment of the present invention, the filtration process further includes filling, testing, and packaging.

[0050] As a specific embodiment of the present invention, the preparation method includes dissolving a buffer, an antibacterial agent, a stabilizer and an isotonic agent in water, adding a pH adjuster, adding the active ingredient, filtering and sterilizing using two 0.22μm PVDF capsule filters connected in series, filling into glass sleeves, pressing and capping, and packaging after quality inspection.

[0051] Thirdly, the present invention provides the use of the pharmaceutical composition described in the first aspect in the preparation of a medicament for treating diabetes or for weight loss.

[0052] The technical solution provided by the embodiments of the present invention has the following advantages compared with the prior art:

[0053] The pharmaceutical composition provided by this invention can be stored stably at 2-8°C, does not precipitate under long-term and accelerated conditions, and slows down the degradation rate, thus exhibiting excellent stability, efficacy and safety. Detailed Implementation

[0054] To better understand the above-mentioned objectives, features, and advantages of the present invention, the solutions of the present invention will be further described below. It should be noted that, unless otherwise specified, the embodiments of the present invention and the features thereof can be combined with each other.

[0055] Many specific details are set forth in the following description in order to provide a full understanding of the invention, but the invention may also be practiced in other ways different from those described herein; obviously, the embodiments in the specification are only some embodiments of the invention, and not all embodiments.

[0056] Example 1

[0057] This embodiment explores the effect of different stabilizers on the pharmaceutical composition of the present invention.

[0058] 1. The pharmaceutical composition described in this embodiment is in liquid form. The solution is prepared according to the composition shown in Table 1. Each excipient is dissolved in ultrapure water, the pH is adjusted to 7.5, and then the active ingredient (GLP-1 / GCG dual receptor co-agonist polypeptide derivative) is added. The solution is then filtered and sterilized using two 0.22μm PVDF capsule sterile filters connected in series to obtain the pharmaceutical composition.

[0059] Table 1

[0060]

[0061] 2. The appearance, pH value and total impurity content of the pharmaceutical composition were measured after one month of storage at 25°C and 2-8°C, respectively, upon preparation.

[0062] The method for determining total impurities is as follows:

[0063] The total impurities in the pharmaceutical composition were determined by high performance liquid chromatography (HPLC). A biphenyl silica gel column (such as Phenomenex Kinetex Biphenyl, 2.6 μm, 4.6 mm × 150 mm) or other equivalent column was used. The mobile phase A was 80 mM sodium perchlorate-30 mM sodium sulfate (pH 2.8), and the mobile phase B was acetonitrile:ultrapure water = 4:1 (v / v). Gradient elution was performed, and the detection wavelength was 210 nm.

[0064] Drug compositions 1-5 to 1-7 all showed varying degrees of precipitation during storage, therefore they were not tested. The test results for drug compositions 1-1 to 1-4 are shown in Table 2.

[0065] Table 2

[0066]

[0067] The observations and Table 2 show that when the stabilizers are sugars (lactose), polyols (glycerol), or metal ions (calcium chloride), the drug composition exhibits varying degrees of precipitation during storage, resulting in relatively poor chemical stability. However, when the stabilizers are amino acids, especially arginine and glycine, the drug composition demonstrates the best chemical stability.

[0068] Example 2

[0069] This embodiment investigates the effect of buffers on pharmaceutical compositions.

[0070] 1. The pharmaceutical composition described in this embodiment is in liquid form. The solution is prepared according to the composition shown in Table 3. Each excipient is dissolved in ultrapure water, the pH is adjusted to 7.5 with sodium hydroxide, and then the active ingredient (GLP-1 / GCG dual receptor co-activating polypeptide derivative) is added. The solution is then filtered and sterilized using two 0.22μm PVDF capsule sterile filters connected in series to obtain the pharmaceutical composition.

[0071] Table 3

[0072]

[0073] 2. After preparation, the appearance, total impurity content, and high molecular weight protein (HMWP) content of the pharmaceutical composition were determined after one month of storage at 25℃ / 60%RH and 2-8℃.

[0074] The method for determining the total impurity content is the same as in Example 1, and the method for testing the high molecular weight protein (HMWP) content is as follows:

[0075] The HMWP content was determined by size exclusion chromatography using a Waters Insulin HMWP column (10 μm, 7.8 mm × 300 mm or other equivalent column), with a phosphate solution containing 0.5 M sodium chloride as the mobile phase, a detection wavelength of 280 nm, and isocratic elution for 30 min. In the chromatogram, the ratio of the peak height of the polymer to the valley height between the polymer peak and the monomer peak should not be less than 2.0. In the chromatogram recorded from the main component reference solution, the relative standard deviation of the main component peak area should not exceed 5.0%.

[0076] The test results are shown in Table 4:

[0077] Table 4

[0078]

[0079] The experimental results in Table 4 surprisingly showed that drug composition 2-1 had better stability, exhibiting less degradation at 25°C, while drug composition 2-2 degraded abnormally at 25°C with no main peak detected. This indicates that the citrate buffer composed of citric acid and sodium citrate provides better stability for the active ingredient.

[0080] Example 3

[0081] This embodiment investigates the effect of the composition of the pharmaceutical composition on its stability.

[0082] 1. The pharmaceutical composition described in this embodiment is in liquid form. The solution is prepared according to the composition shown in Table 5. Each excipient (buffer, stabilizer, antibacterial agent, etc.) is dissolved in ultrapure water, and the pH is adjusted using hydrochloric acid or sodium hydroxide. Then, the active ingredient (GLP-1 / GCG dual-receptor co-agonistic polypeptide derivative) is added. The solution is then filtered and sterilized using two 0.22μm PVDF capsule-type sterile filters connected in series to obtain the pharmaceutical composition. The antibacterial agent is phenol, and the stabilizer is arginine.

[0083] Table 5

[0084]

[0085] 2. After preparation, the appearance, total impurity content and high molecular weight protein (HMWP) content of the pharmaceutical composition were determined after one month of storage at 25℃ / 60%RH and 2-8℃. The determination methods for total impurity content and HMWP were the same as in Example 2.

[0086] The test results are shown in Table 6:

[0087] Table 6

[0088]

[0089] Lower impurity content leads to better chemical stability, while lower HMWP content leads to better physical stability. Table 6 shows that drug composition 3-3 exhibits significant precipitation during storage, indicating poor stability and suggesting that disodium hydrogen phosphate has a poor stabilizing effect on the drug composition. Comparing drug compositions 3-1 to 3-3, composition 3-1 demonstrates the best stability, notably exhibiting significantly less degradation and appearance compared to other compositions at 25°C, indicating that citric acid / sodium citrate has a significant stabilizing effect on the active ingredient. Drug compositions 3-4 to 3-7 all show good stability, with compositions 3-4, 3-5, and 3-7 showing even better stability, exhibiting less degradation at 25°C, with composition 3-4 being the best. This indicates that citric acid / sodium citrate has the best stabilizing effect on the active ingredient, followed by tartaric acid / tartrate, then maleic acid, while succinic acid has the worst stabilizing effect.

[0090] Example 4

[0091] This embodiment investigates the effect of antibacterial agents on the stability of pharmaceutical compositions.

[0092] 1. The pharmaceutical composition described in this embodiment is in liquid form. The solution is prepared according to the composition shown in Table 7. The antibacterial agent is dissolved in ultrapure water, and then the active ingredient (GLP-1 / GCG dual receptor co-agonist polypeptide derivative) is added. The solution is then filtered and sterilized using two 0.22μm PVDF capsule sterile filters connected in series to obtain the pharmaceutical composition.

[0093] Table 7

[0094]

[0095] 2. After storing the pharmaceutical composition at 40°C for 7 days, the appearance, total impurity content, and high molecular weight protein (HMWP) content were determined. The methods for determining the total impurity content and HMWP were the same as in Example 2.

[0096] The test results are shown in Table 8:

[0097] Table 8

[0098]

[0099]

[0100] As shown in Table 8, drug composition 4-3 showed significant precipitation during storage. Among the other groups, drug composition 4-2 had the best stability, indicating that phenol had the best stabilizing effect on the drug composition, while trichlorobutylphenol had the worst stabilizing effect.

[0101] Example 5

[0102] This embodiment investigates the effect of active ingredient concentration on the composition.

[0103] 1. The pharmaceutical composition described in this embodiment is in liquid form. The solution is prepared according to the composition shown in Table 9. The buffer, antibacterial agent (phenol) and stabilizer (arginine) are dissolved in ultrapure water, and the pH is adjusted to 8.0 using hydrochloric acid or sodium hydroxide. Then, the active ingredient (GLP-1 / GCG dual receptor co-agonist polypeptide derivative) is added, and the solution is filtered and sterilized using two 0.22μm PVDF capsule sterile filters connected in series to obtain the pharmaceutical composition.

[0104] Table 9

[0105]

[0106] 2. After preparation, the appearance, total impurity content and high molecular weight protein (HMWP) content of the pharmaceutical composition were determined after one month of storage at 25°C and 2-8°C, respectively. The methods for determining the total impurity content and HMWP were the same as in Example 2.

[0107] The test results are shown in Table 10:

[0108] Table 10

[0109]

[0110] As shown in Table 10, when the concentration of the active ingredient is in the range of 0.5-10 mg / mL, the compositions using the components confirmed by the present invention all exhibit excellent stability.

[0111] In summary, the pharmaceutical composition prepared by this invention has excellent stability, efficacy, and safety.

[0112] It should be noted that, in this document, relational terms such as "first" and "second" are used merely to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0113] The above description is merely a specific embodiment of the present invention, enabling those skilled in the art to understand or implement the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the present invention is not to be limited to the embodiments described herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a GLP-1 / GCG dual receptor co-activating polypeptide derivative or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients; The derivative is an acylated GLP-1 / GCG dual receptor co-activating polypeptide with a fatty acid side chain, and the amino acid sequence of the polypeptide is shown below: H-Aib-HGTFTSDYSSYLDARAAHEFVKWLLEGGPSSG; The fatty acid side chain is HOOC(CH2). 16 CO-γ-Glu-(AEEA)2-, which is linked to the ε-aminoacylation of amino acid K in the above-mentioned polypeptide; The excipients include stabilizers, which are selected from any one or more of amino acids, polyols, sugars, or metal ions.

2. The pharmaceutical composition according to claim 1, characterized in that, The stabilizer is selected from amino acids, preferably any one or more of arginine, histidine, or glycine, and more preferably arginine.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The pharmaceutical composition is in liquid formulation; Preferably, the concentration of the GLP-1 / GCG dual receptor co-activating polypeptide derivative or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 0.05-10 mg / mL; Preferably, the concentration of the stabilizer in the pharmaceutical composition is 0.2-25 mg / mL.

4. The pharmaceutical composition according to any one of claims 1-3, characterized in that, The pH value of the pharmaceutical composition is 7.5-8.5, preferably 7.6-8.4, and more preferably 7.9-8.

1.

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The excipients also include buffers; Preferably, the buffer is selected from any one or more of citric acid or its salt, tartaric acid or its salt, succinic acid or its salt, maleic acid or its salt, Tris hydrochloric acid or its salt, or disodium hydrogen phosphate.

6. The pharmaceutical composition according to claim 5, characterized in that, The buffer is selected from a combination of citric acid and citrate or a combination of tartaric acid and tartarate, preferably a combination of citric acid and citrate; And / or, the concentration of the buffer in the pharmaceutical composition is 0.5-5 mg / mL.

7. The pharmaceutical composition according to any one of claims 1-6, characterized in that, The excipients also include antibacterial agents; Preferably, the antibacterial agent is selected from any one or more of phenol, m-cresol, or chlorobutanol, and is preferably phenol; Preferably, the concentration of the antibacterial agent in the pharmaceutical composition is 1-10 mg / mL.

8. The pharmaceutical composition according to any one of claims 1-7, characterized in that, The excipients also include an isotonic agent; Preferably, the isotonic agent is selected from propylene glycol; Preferably, the concentration of the isotonic agent in the pharmaceutical composition is 10-20 mg / mL.

9. The pharmaceutical composition according to any one of claims 1-8, characterized in that, The pharmaceutical composition also includes water as a solvent.

10. Use of the pharmaceutical composition according to any one of claims 1-9 in the preparation of a medicament for treating diabetes or for weight loss.

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