GLP-1 receptor stimulant sublingual buccal preparation as well as preparation method and application thereof

Abstract

The invention provides a sublingual sublingual preparation of a GLP-1 receptor stimulant as well as a preparation method and application of the sublingual sublingual preparation, and belongs to the technical field of biological medicines. According to the sublingual oral preparation of the GLP-1 receptor stimulant prepared by utilizing a lipid formula, the GLP-1 receptor stimulant can be delivered into sublingual veins in a sublingual oral manner and then enters blood circulation, so that first-pass metabolism of gastrointestinal digestive tracts and livers is avoided, the biological activity of the GLP-1 receptor stimulant is preserved, the bioavailability is improved, and the medication cost is reduced. The sublingual sublingual preparation of the GLP-1 receptor stimulant is used for sublingual sublingual, can quickly enter blood circulation within 2-5 minutes, and is beneficial to blood sugar control or weight control.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and in particular relates to a GLP-1 receptor agonist sublingual preparation and a preparation method and application thereof. Background Art

[0002] Diabetes is a metabolic disease caused by an absolute or relative lack of insulin secretion, resulting in uncontrolled elevated blood sugar. As the disease progresses, it can lead to a variety of serious complications. Glucagon-like peptide-1 (GLP-1) is mainly used to treat type II diabetes. It is mainly a functional short peptide secreted by intestinal L cells and binds to pancreatic β-cell receptors to promote insulin secretion, inhibit insulin secretion, and lower blood sugar, but it does not cause hypoglycemia. At the same time, GLP-1 can delay gastric emptying rate, slow down postprandial glucose absorption, and reduce patient weight. However, GLP-1 receptor agonists are easily hydrolyzed by digestive enzymes through the gastrointestinal tract, resulting in loss of biological activity. Therefore, the currently approved GLP-1 peptide drugs, such as exenatide, semaglutide, liraglutide and tirpotide, are mainly used for subcutaneous injection. In addition, GLP-1 peptide drugs have poor solubility and are difficult to be absorbed by the intestinal mucosa. At present, the only oral GLP-1 receptor agonist approved in China is Novo Nordisk's semaglutide oral tablets. It needs to pass through multiple barriers in the gastrointestinal tract and liver to be absorbed, and its bioavailability is low. The maximum oral dose of semaglutide is 14 mg / day, which is far higher than the maximum subcutaneous dose of semaglutide of 4 mg / week. At present, there are no reports on sublingual preparations of GLP-1 peptide drugs. Summary of the invention

[0003] The purpose of the present invention is to provide a GLP-1 receptor agonist sublingual preparation and a preparation method and application thereof.

[0004] The present invention provides a sublingual preparation of a GLP-1 receptor agonist, comprising a GLP-1 receptor agonist and a lipid material; the lipid material comprises a first lipid material and a second lipid material; the first lipid material comprises one or more of cholesterol, lecithin, polyethylene glycol, distearoylphosphatidylethanolamine polyethylene glycol and N-acetylmethionine; the second lipid material comprises one or more of fatty acid, fatty acid glycerol, distearoylphosphatidylglycerol, caprylylglycerol and oleic acid; the GLP-1 receptor agonist comprises one of exenatide, semaglutide and liraglutide.

[0005] Preferably, the mass ratio of the GLP-1 receptor agonist, the first lipid material and the second lipid material is 4:25:20.

[0006] Preferably, the sublingual preparation of the GLP-1 receptor agonist further comprises a phosphate buffer solution and an organic solvent; the organic solvent comprises ethanol or methanol.

[0007] Preferably, the GLP-1 receptor agonist is exenatide; the first lipid material includes lecithin, N-acetylmethionine and polyethylene glycol; and the second lipid material includes distearoylphosphatidylglycerol and oleic acid.

[0008] Preferably, the GLP-1 receptor agonist is semaglutide; the first lipid material includes cholesterol, N-acetylmethionine and distearoylphosphatidylethanolamine polyethylene glycol; and the second lipid material includes fatty acids glycerol, caprylylglycerol and oleic acid.

[0009] Preferably, the pH of the sublingual preparation of the GLP-1 receptor agonist is neutral.

[0010] The present invention also provides a method for preparing the GLP-1 receptor agonist sublingual preparation of the above scheme, comprising the following steps: first mixing the GLP-1 receptor agonist and a phosphate aqueous solution to obtain a GLP-1 receptor agonist solution; second mixing a first lipid material and a first organic solvent to obtain a first organic phase; third mixing a second lipid material and a second organic solvent to obtain a second organic phase; fourth mixing the GLP-1 receptor agonist solution and the first organic phase to obtain a fourth mixture; and fifth mixing the fourth mixture and the second organic phase to obtain a sublingual preparation containing the GLP-1 receptor agonist.

[0011] Preferably, the fifth mixing temperature is comprised between 50 and 60°C.

[0012] The present invention also provides the use of the sublingual GLP-1 receptor agonist preparation described in the above scheme or the sublingual GLP-1 receptor agonist preparation prepared by the preparation method in the preparation of products for lowering blood sugar, improving blood lipids or losing weight.

[0013] The present invention also provides the use of the sublingual GLP-1 receptor agonist preparation described in the above scheme or the sublingual GLP-1 receptor agonist preparation prepared by the preparation method in the preparation of a drug for treating type II diabetes.

[0014] The present invention provides a sublingual preparation of a GLP-1 receptor agonist, comprising a GLP-1 receptor agonist and a lipid material encapsulating the GLP-1 receptor agonist. The sublingual preparation of a GLP-1 receptor agonist prepared by the present invention using a lipid formula can deliver the GLP-1 receptor agonist into the sublingual vein by sublingual administration, and then enter the blood circulation, thereby avoiding first-pass metabolism in the gastrointestinal tract and the liver, preserving the biological activity of the GLP-1 receptor agonist, improving bioavailability, and reducing medication costs. The sublingual preparation of a GLP-1 receptor agonist of the present invention is used for sublingual administration, can quickly enter the blood circulation in 2 to 5 minutes, and is beneficial to blood sugar control or weight control. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0016] Figure 1 The graph shows the hypoglycemic effect of different groups on normal ICR mice;

[0017] Figure 2 This is a graph showing the effects of different groups on blood glucose in DIO obese mice;

[0018] Figure 3 This is a graph showing the effects of different groups on insulin secretion in normal C57BL / 6J mice;

[0019] Figure 4 This is a graph showing the effects of different groups on blood lipids in DIO obese mice;

[0020] Figure 5 This is a graph showing the effects of different groups on the body weight of DIO obese mice. DETAILED DESCRIPTION

[0021] The present invention provides a sublingual preparation of a GLP-1 receptor agonist, comprising a GLP-1 receptor agonist and a lipid material; the lipid material comprises a first lipid material and a second lipid material; the first lipid material comprises one or more of cholesterol, lecithin, polyethylene glycol (PEG400), distearoylphosphatidylethanolamine polyethylene glycol and N-acetylmethionine; the second lipid material comprises one or more of fatty acid, fatty acid glycerol, distearoylphosphatidylglycerol, caprylylglycerol and oleic acid; the GLP-1 receptor agonist comprises one of exenatide, semaglutide and liraglutide.

[0022] In the present invention, most of the GLP-1 receptor agonist is encapsulated in lipid materials.

[0023] In the present invention, the GLP-1 receptor agonist is a polypeptide drug with a certain positive charge, and it itself is lipid-modified. In the present invention, the first lipid material can enhance the lipid modification of the GLP-1 receptor agonist; the second lipid material, such as fatty acids and distearoylphosphatidylglycerol, can be lipoamidated with the amino group of the side chain of the GLP-1 receptor agonist to make the GLP-1 receptor agonist more stable. The sublingual preparation of the GLP-1 receptor agonist of the present invention is a nanopolymer.

[0024] In the present invention, the sublingual preparation of GLP-1 receptor agonist is a liquid preparation.

[0025] The present invention utilizes lipid materials to modify the GLP-1 receptor agonist to prepare a sublingual preparation of the GLP-1 receptor agonist. The sublingual preparation of the GLP-1 receptor agonist can be administered sublingually, can avoid the degradation of the GLP-1 receptor agonist by digestive enzymes when it is orally administered, avoids the first-pass metabolic effect, can improve the bioavailability of the GLP-1 polypeptide, and reduces the drug cost of the product.

[0026] In a specific implementation of the present invention, the mass ratio of the GLP-1 receptor agonist, the first lipid material and the second lipid material is 4:25:20.

[0027] In the present invention, the sublingual preparation of GLP-1 receptor agonist preferably further comprises a phosphate buffer solution and an organic solvent; the organic solvent preferably comprises ethanol or methanol, more preferably ethanol; the phosphate buffer solution is used to dissolve the GLP-1 receptor agonist; the mass of the GLP-1 receptor agonist to the volume of the phosphate buffer solution is 20 mg: 15 ml; the phosphate buffer is preferably Dulbecco's phosphate buffer (DPBS), with ddH2O as the solvent, and contains the following components by mass per liter: 8 g sodium chloride, 0.2 g potassium chloride, 1.15 g disodium hydrogen phosphate, 0.2 g potassium dihydrogen phosphate, 0. 1g and 0.1g of magnesium chloride containing 6 crystal waters; in the specific implementation process of the present invention, the DPBS is purchased from Thermo Fisher; the pH value of the phosphate buffer solution is 7.4; the organic solvent is used to dissolve the first lipid material and the second lipid material respectively; the organic solvent consists of a first organic solvent and a second organic solvent, wherein the first organic solvent is used to dissolve the first lipid material, and the second organic solvent is used to dissolve the second lipid material; the ratio of the mass of the first lipid material to the volume of the first organic solvent is 125mg:15ml; the ratio of the mass of the second lipid material to the volume of the second organic solvent is 100mg:10ml.

[0028] In the specific implementation of the present invention, the GLP-1 receptor agonist is exenatide; the first lipid material includes lecithin, N-acetylmethionine and polyethylene glycol; and the second lipid material includes distearoylphosphatidylglycerol and oleic acid.

[0029] In one embodiment of the present invention, the GLP-1 receptor agonist is exenatide; the first lipid material is composed of lecithin, N-acetylmethionine and polyethylene glycol; the mass ratio of lecithin, N-acetylmethionine and polyethylene glycol is 5:16:2; the second lipid material is composed of distearoylphosphatidylglycerol and oleic acid; the mass ratio of distearoylphosphatidylglycerol and oleic acid is 13:7.

[0030] In the specific implementation of the present invention, the GLP-1 receptor agonist is semaglutide; the first lipid material includes cholesterol, N-acetylmethionine and distearoylphosphatidylethanolamine polyethylene glycol; the second lipid material includes fatty acids glycerol, caprylylglycerol and oleic acid.

[0031] In another embodiment of the present invention, the GLP-1 receptor agonist is semaglutide; the first lipid material is composed of cholesterol, N-acetylmethionine and distearoylphosphatidylethanolamine polyethylene glycol; the mass ratio of cholesterol, N-acetylmethionine and distearoylphosphatidylethanolamine polyethylene glycol is 4:16:3; the second lipid material is composed of fatty acids glycerol, caprylglycerol and oleic acid; the mass ratio of fatty acids glycerol, caprylglycerol and oleic acid is 9:6:5.

[0032] In the present invention, the pH of the sublingual preparation of the GLP-1 receptor agonist is neutral.

[0033] The present invention also provides a method for preparing the GLP-1 receptor agonist sublingual preparation of the above scheme, comprising the following steps: first mixing the GLP-1 receptor agonist and a phosphate aqueous solution to obtain a GLP-1 receptor agonist solution; second mixing a first lipid material and a first organic solvent to obtain a first organic phase; third mixing a second lipid material and a second organic solvent to obtain a second organic phase; fourth mixing the GLP-1 receptor agonist solution and the first organic phase to obtain a fourth mixture; and fifth mixing the fourth mixture and the second organic phase to obtain a sublingual preparation containing the GLP-1 receptor agonist.

[0034] The present invention first mixes a GLP-1 receptor agonist and a phosphate aqueous solution to obtain a GLP-1 receptor agonist solution.

[0035] The present invention has no special limitation on the first mixing, which is subject to the GLP-1 receptor agonist being fully dissolved in the phosphate aqueous solution. In the present invention, the first mixing is preferably ultrasonic mixing to promote the dissolution of the GLP-1 receptor agonist.

[0036] The present invention secondly mixes the first lipid material and the first organic solvent to obtain the first organic phase.

[0037] In the present invention, the second mixing is preferably stirring mixing. When the first lipid material includes lecithin, N-acetylmethionine and polyethylene glycol, the present invention sequentially adds lecithin, N-acetylmethionine and polyethylene glycol to the first organic solvent.

[0038] The present invention thirdly mixes the second lipid material and the second organic solvent to obtain a second organic phase.

[0039] In the present invention, the third mixing includes stirring and mixing, and the mixing is uniform.

[0040] After obtaining the GLP-1 receptor agonist solution and the first organic phase, the present invention performs a fourth mixing of the GLP-1 receptor agonist solution and the first organic phase to obtain a fourth mixture.

[0041] The present invention has no special limitation on the fourth mixing, as long as the mixing is uniform.

[0042] After obtaining the fourth mixture, the present invention fifthly mixes the fourth mixture with the second organic phase to obtain a sublingual preparation containing a GLP-1 receptor agonist.

[0043] In the present invention, the temperature of the fifth mixing is preferably 50-60° C., more preferably 56° C.; the fifth mixing is preferably performed in a water bath; and the fifth mixing is preferably performed by stirring.

[0044] After the fifth mixing, the present invention preferably further comprises cooling the material after the fifth mixing to room temperature (20-30° C.) and then adjusting the pH value to neutral.

[0045] The present invention also provides the use of the sublingual GLP-1 receptor agonist preparation described in the above scheme or the sublingual GLP-1 receptor agonist preparation prepared by the preparation method in the preparation of products for lowering blood sugar, improving blood lipids or losing weight.

[0046] In the present invention, the product includes a medicine; the dosage form of the medicine includes a sublingual dosage form. In the present invention, the users of the medicine include healthy people or animals, obese patients, and people or animals who need to lose weight.

[0047] The present invention also provides a method for lowering blood sugar or losing weight, comprising the following steps: a user sublingually takes an effective dose of the GLP-1 receptor agonist sublingual preparation according to the above scheme.

[0048] The present invention also provides the use of the sublingual GLP-1 receptor agonist preparation described in the above scheme or the sublingual GLP-1 receptor agonist preparation prepared by the preparation method in the preparation of a drug for treating type II diabetes.

[0049] In the present invention, the subjects of use of the medicine include patients with type II diabetes. In the present invention, the treatment of type II diabetes is achieved by promoting insulin secretion.

[0050] The present invention also provides a method for treating type II diabetes, comprising the following steps: the patient sublingually takes the above-mentioned effective dose of the sublingual preparation of GLP-1 receptor agonist before a meal. In the present invention, the sublingual time is preferably 5 minutes.

[0051] In order to further illustrate the present invention, a GLP-1 receptor agonist sublingual preparation provided by the present invention and its preparation method and application are described in detail below in conjunction with the accompanying drawings and examples, but they should not be construed as limiting the scope of protection of the present invention.

[0052] Example 1

[0053] 1. Select 20 mg of exenatide and dissolve it in 15 ml of phosphate buffer solution with a pH value of 7.4 to obtain a phosphate buffer solution of exenatide.

[0054] 2. Add 25 mg of lecithin, 90 mg of N-acetylmethionine and 10 mg of polyethylene glycol to 15 ml of anhydrous ethanol solution in sequence, stir evenly to obtain the first organic phase.

[0055] 3. Mix the first organic phase obtained in step 2 with the phosphate buffer solution of exenatide obtained in step 1 to obtain a uniform mixture.

[0056] 4. Dissolve 65 mg of distearoylphosphatidylglycerol and 35 mg of oleic acid in 10 mL of anhydrous ethanol solution in turn and stir thoroughly to form a second organic phase.

[0057] 5. Stir the mixture obtained in step 3 and the second organic phase obtained in step 4 in a water bath at 56° C. to allow the mixture and the second organic phase to diffuse evenly to form a lipid preparation loaded with exenatide. After cooling to room temperature, adjust the pH value to neutral to obtain an exenatide sublingual preparation, which can be used immediately or stored in aliquots.

[0058] Example 2

[0059] 1. Select 20 mg of semaglutide and dissolve it in 15 ml of phosphate buffer solution (pH 7.4) to obtain a phosphate buffer solution of semaglutide.

[0060] 2. Add 20 mg of cholesterol, 15 mg of distearoylphosphatidylethanolamine polyethylene glycol and 90 mg of N-acetylmethionine to 15 ml of anhydrous ethanol solution in sequence, stir evenly to obtain a first organic phase.

[0061] 3. Mix the first organic phase obtained in step 2 and the phosphate buffer solution of semaglutide obtained in step 1 to obtain a uniform mixture.

[0062] 4. Dissolve 45 mg of fatty acid glycerol, 30 mg of caprylyl glycerol and 25 mg of oleic acid in 10 mL of anhydrous ethanol solution and stir thoroughly to form a second organic phase.

[0063] 5. Stir the mixture obtained in step 3 and the second organic phase obtained in step 4 in a water bath at 56° C. to allow the mixture and the second organic phase to diffuse evenly to form a lipid preparation loaded with semaglutide. After cooling to room temperature, adjust the pH value to neutral to obtain a semaglutide sublingual preparation, which can be used immediately or stored in aliquots.

[0064] Application Example 1 Experimental study on the effect of the sublingual exenatide preparation prepared in Example 1 on blood glucose in normal ICR mice

[0065] Fifteen male ICR mice aged 8 to 9 weeks were selected and randomly divided into three groups according to body weight after feeding for one week, namely group 1, group 2 and group 3, with 5 mice in each group. They were fasted but not watered overnight. Blood was collected from the tail vein of the mice the next morning, and the blood glucose level of the mice was measured using an ACCU-CHEK blood glucose meter. The blood glucose level 30 minutes before administration was measured.

[0066] The medication was administered according to the groups, as follows:

[0067] Group 1: intraperitoneal injection of normal saline (200 μl / mouse);

[0068] Group 2: Exenatide (raw materials purchased from MCE official website, CAS No.: 141758-74-9, 25 mg / bottle) intraperitoneal injection (calculated based on the exenatide content, 2.5 μg / kg);

[0069] Group 3: the sublingual exenatide preparation prepared in Example 1 (calculated based on the exenatide content, 2.5 μg / kg).

[0070] 30 minutes after administration, all mice were gavaged with glucose 2g / kg, and the blood glucose levels of mice were tested at 0min, 15min, 30min, 60min, 90min, 120min, and 150min after glucose gavage, and the blood glucose change curve of mice was drawn to evaluate the hypoglycemic effect of exenatide sublingual preparation on mice. Figure 1 As shown in Table 1, blood glucose reached a high level at 30 minutes after oral glucose gavage without drug treatment (Group 1), while blood glucose gradually decreased after 30 minutes after treatment with sublingual exenatide preparation (Group 3), and its effect was consistent with that of intraperitoneal injection of exenatide (Group 2).

[0071] Table 1 Hypoglycemic effects of different groups on normal ICR mice

[0072]

[0073]

[0074] Application Example 2 Experimental study on the hypoglycemic effect of the sublingual semaglutide preparation prepared in Example 2 on a high-fat diet-induced obese mouse model (DIO)

[0075] Fifteen male DIO obese mice aged 8 to 9 weeks purchased from Saiye Biotechnology Co., Ltd. were selected and randomly divided into three groups according to body weight after feeding for one week, namely Group 1, Group 2 and Group 3, with 5 mice in each group. They were fasted but not watered overnight before administration.

[0076] The medication was administered according to the groups, as follows:

[0077] Group 1: intragastric administration of normal saline;

[0078] Group 2: Semaglutide (purchased from MCE official website, CAS No. 910463-68-2, 50 mg / bottle) was administered intragastrically (calculated based on the Semaglutide content, 0.25 mg / kg);

[0079] Group 3: sublingual administration of semaglutide prepared in Example 2 (calculated based on semaglutide content, 0.25 mg / kg ) .

[0080] 30 minutes after administration, each group of mice was intraperitoneally injected with glucose at a dose of 1 g / kg, and then blood glucose was tested at 7 time points, including -30 minutes (30 minutes before administration), 0 minutes, 15 minutes, 30 minutes, 60 minutes, 90 minutes, and 120 minutes. GraphPad Prism was used to plot the blood glucose values ​​of each group against the corresponding time points, and the area under the blood glucose curve (AUC) from 0 to 120 minutes (relative to the 0% baseline) was calculated. The results are shown in the figure. Figure 2 As shown in Table 2, the blood glucose of mice in group 1 as the control group reached a peak at 15 minutes after intragastric administration of normal saline and could not return to the baseline level within 2 hours. The blood glucose of mice in groups 2 and 3 reached a peak at 15 minutes, but gradually returned to the baseline level within 1 hour, indicating that the sublingual preparation of semaglutide is beneficial to lowering blood glucose, which is similar to the effect of semaglutide tablets. AUC was calculated according to the following formula (0-2h) The difference indicates that the bioavailability of semaglutide sublingual preparation is 5.8%, while the bioavailability of semaglutide tablets by oral administration is 1.5%, which is better than that of semaglutide oral tablets.

[0081] Bioavailability F(%) = {[AUC (0-2h)组1 -AUC (0-2h)组3 ]×Dose 组2} / {[AUC (0-2h)组1 -AUC (0-2h)组2 ]×Dose 组3}×100%.

[0082] Table 2 Effects of different groups on blood glucose in DIO obese mice

[0083]

[0084]

[0085] Application Example 3: Effect of the Exenatide Sublingual Preparation Prepared in Example 1 on Insulin Secretion in Normal C57BL / 6J Mice

[0086] Eighteen adult female C57BL / 6J mice aged 8 to 9 weeks were randomly divided into three groups according to their body weight, with 6 mice in each group, namely Group 1, Group 2 and Group 3. The drugs were administered according to the groups, as follows:

[0087] Group 1: control group, intraperitoneal injection of normal saline;

[0088] Group 2: intraperitoneal injection of exenatide (calculated based on exenatide content, 2.5 μg / kg);

[0089] Group 3: sublingual exenatide prepared in Example 1 (measured based on exenatide content, 2.5 μg / kg).

[0090] Blood was drawn 30 minutes after administration to test insulin secretion levels. Figure 3 As shown in Table 3, compared with the control group (Group 1), the sublingual exenatide preparation (Group 3) and the exenatide injection (Group 2) had the effect of promoting insulin secretion.

[0091] Table 3 Effects of different groups on insulin secretion in normal C57BL / 6J mice

[0092]

[0093] Application Example 4: Long-term effects of the sublingual exenatide preparation prepared in Example 1 on blood lipids and body weight in DIO obese mice

[0094] Ten 10-week-old male DIO obese mice were selected and randomly divided into two groups, group 1 and group 2. The mice were anesthetized using a small animal anesthesia machine, and then the drugs were administered according to the groups, as follows:

[0095] Group 1: control group, sublingual administration of normal saline;

[0096] Group 2: the sublingual exenatide preparation prepared in Example 1 (calculated based on the exenatide content, 2.5 μg / kg).

[0097] The drug was administered once a day for 8 consecutive weeks. Body weight was recorded once a week. After 8 weeks, blood was collected from the tail vein, left to stand at room temperature for 2 hours, and centrifuged at 3000 rpm for 5 minutes to collect serum. The levels of four blood lipids in the serum were tested. The results are as follows Figure 4 , Figure 5 As shown in Tables 4 and 5, compared with the control group, the sublingual exenatide preparation improved blood lipids and significantly reduced the body weight of mice by 25.3%.

[0098] Table 4 Effects of different groups on blood lipids in DIO obese mice

[0099]

[0100] Table 5 Effects of different groups on body weight of DIO obese mice

[0101]

[0102] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A sublingual preparation of a GLP-1 receptor agonist, characterized in that: including a GLP-1 receptor agonist and a lipid material; The lipid material comprises a first lipid material and a second lipid material; The first lipid material comprises one or more of cholesterol, lecithin, polyethylene glycol, distearoylphosphatidylethanolamine polyethylene glycol and N-acetylmethionine; The second lipid material comprises one or more of fatty acids, fatty acid glycerol, distearoylphosphatidylglycerol, caprylylglycerol and oleic acid; The GLP-1 receptor agonist includes one of exenatide, semaglutide and liraglutide.

2. The GLP-1 receptor agonist sublingual preparation according to claim 1, characterized in that: The mass ratio of the GLP-1 receptor agonist, the first lipid material and the second lipid material is 4:25:

20.

3. The GLP-1 receptor agonist sublingual preparation according to claim 1, characterized in that: The sublingual preparation of the GLP-1 receptor agonist further comprises a phosphate buffer solution and an organic solvent; the organic solvent comprises ethanol or methanol.

4. The GLP-1 receptor agonist sublingual preparation according to claim 1, characterized in that: The GLP-1 receptor agonist is exenatide; the first lipid material includes lecithin, N-acetylmethionine and polyethylene glycol; and the second lipid material includes distearoylphosphatidylglycerol and oleic acid.

5. The GLP-1 receptor agonist sublingual preparation according to claim 1, characterized in that: The GLP-1 receptor agonist is semaglutide; the first lipid material includes cholesterol, N-acetylmethionine and distearoylphosphatidylethanolamine polyethylene glycol; the second lipid material includes fatty acids glycerol, caprylylglycerol and oleic acid.

6. The GLP-1 receptor agonist sublingual preparation according to claim 1, characterized in that: The pH of the sublingual GLP-1 receptor agonist preparation is neutral.

7. The method for preparing the sublingual GLP-1 receptor agonist preparation according to any one of claims 1 to 6, characterized in that: The following steps are involved: first mixing a GLP-1 receptor agonist and an aqueous phosphate solution to obtain a GLP-1 receptor agonist solution; secondly mixing the first lipid material and the first organic solvent to obtain a first organic phase; mixing the second lipid material and the second organic solvent to obtain a second organic phase; fourthly mixing the GLP-1 receptor agonist solution and the first organic phase to obtain a fourth mixture; The fourth mixture and the second organic phase are mixed fifthly to obtain a sublingual preparation containing a GLP-1 receptor agonist.

8. The preparation method according to claim 7, characterized in that: The fifth mixing temperature is comprised between 50 and 60°C.

9. Use of the sublingual GLP-1 receptor agonist preparation according to any one of claims 1 to 6 or the sublingual GLP-1 receptor agonist preparation prepared by the preparation method according to claim 7 or 8 in the preparation of products for lowering blood sugar, improving blood lipids or losing weight.

10. Use of the sublingual GLP-1 receptor agonist preparation according to any one of claims 1 to 6 or the sublingual GLP-1 receptor agonist preparation prepared by the preparation method according to claim 7 or 8 in the preparation of a medicament for treating type II diabetes.

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