A GLP-1 analog oral delivery composition

Abstract

The present application relates to the field of medicine, and specifically, to a GLP-1 analog oral delivery composition. The GLP-1 analog oral delivery composition provided in the present application includes a GLP-1 analog and a delivery agent, and the delivery agent includes lauroyl-L-carnitine and sodium caprate. The composition shown in the present invention has excellent oral bioavailability. The composition shown in the present invention has good hypoglycemic and weight loss effects, and can be used to prepare drugs for treating or preventing diabetes or obesity. The preparation process of the composition shown in the present invention is simple, which is conducive to industrial production.

Description

Technical Field

[0001] The present application relates to the field of medicine, and in particular, to a GLP-1 analog oral delivery composition. Background Art

[0002] With the improvement of social economic level and living conditions, the incidence of diabetes is increasing day by day. Type 2 diabetes has become the third non-communicable disease threatening human health and life after cardiovascular disease and tumors.

[0003] One of the main causes of T2DM is obesity. Obesity significantly increases the risk of cardiovascular disease, diabetes, musculoskeletal diseases and certain cancers. In addition, an increase in BMI (Body Mass Index) also increases the risk of certain non-communicable diseases. Faced with the increasing number of overweight and obese people and the potential complications brought by obesity, obesity has become a public health issue in my country.

[0004] Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone secreted by L cells in the colon and distal small intestine. It has the advantages of strong blood sugar-lowering effect in a blood sugar-dependent manner, no increased risk of hypoglycemia, weight loss, and cardiovascular benefits. In recent years, a variety of GLP-1 receptor agonists (GLP-1RA) have been approved for marketing, including short-acting preparations such as exenatide and liraglutide for daily injection, and weekly preparations such as exenatide microspheres and semaglutide. Among them, semaglutide was once hailed as the "best diabetes drug in history" due to its excellent blood sugar-lowering, weight-loss effects, and cardiovascular protection, and it has been developed for the treatment of obesity. Most of the GLP-1 receptor agonists currently on the market still require subcutaneous injection, which has defects such as inconvenience and pain, which greatly limits their widespread application.

[0005] Oral administration is currently the most widely used route of administration, which can greatly improve patient compliance. Due to the high technical barriers and development difficulties of oral peptide drugs, the only oral GLP-1 receptor agonist on the market is Novo Nordisk's oral semaglutide tablets (trade name: Rybelsus TM ). Rybelsus TM The success of the drug lies in the use of the absorption enhancer N-(8-(2-hydroxybenzoyl)amino) caprylate (SNAC), which increases the pH value of the gastric mucosal surface in a short period of time, causing pepsin to lose its activity. At the same time, it increases the local lipophilicity of the stomach, improves the solubility of the main drug, and makes semaglutide easier to pass through the cell membrane and enter the blood. In addition, oral semaglutide tablets are in clinical trials for weight loss indications and Alzheimer's disease.

[0006] Lauroyl-L-carnitine ((2R)-3-carboxy-N, N, N-trimethyl-2-[(1-oxododecyl)oxy]-1-propylamine inner salt, LLC) and sodium decanoate (C10) are absorption enhancers used in the development of oral delivery of proteins and peptides. They increase the fluidity of the intestinal cell membrane and open tight junctions to increase transmembrane transport, making it easier for peptide drugs to enter the bloodstream, thereby improving their oral bioavailability. For example, Enteris BioPharma's investigational drugs oral leuprorelin and oral calcitonin both use LLC as an absorption enhancer; Merrion uses C10 as an enhancer, and its fatty chain mechanism of action needs to be further improved, so no product has been launched or entered key clinical trials. So far, there have been no reports of LLC alone or in combination with C10 for oral GLP-1RA. Summary of the invention

[0007] In view of the shortcomings of the prior art mentioned above, in order to further improve the effects of oral GLP-1 analog drugs in the prior art, the present application has developed a GLP-1 analog oral delivery composition, which combines the delivery agents lauroyl-L-carnitine (LLC) and sodium caprate (C10). The preliminary results of pharmacokinetic and pharmacological studies show that the GLP-1 analog drug composition designed in the present application can improve the bioavailability and realize the oral administration of GLP-1 analog drugs.

[0008] To achieve the above objectives and other related objectives, the present application provides a GLP-1 analog oral delivery composition in a first aspect, comprising a GLP-1 analog and a delivery agent, wherein the delivery agent comprises lauroyl-L-carnitine and sodium caprate.

[0009] The second aspect of the present application provides a preparation method for preparing the GLP-1 analog oral delivery composition of the first aspect, comprising the following steps:

[0010] 1) mixing a delivery agent, a lubricant, and a filler, and rolling and compressing the mixture to obtain first granules;

[0011] 2) mixing the GLP-1 analog, the binder, the filler, and the pH adjuster, and rolling and compacting the mixture to obtain the second granules;

[0012] 3) The first granules and the second granules are mixed with a lubricant and compressed to obtain a GLP-1 analog oral delivery composition.

[0013] The third aspect of the present application provides use of the GLP-1 analog oral delivery composition described in the first aspect in the preparation of a product for preventing or treating diabetes or obesity.

[0014] Compared with the prior art, the present invention has the following beneficial effects:

[0015] 1. The present invention provides a novel GLP-1 analog drug oral delivery composition, and the composition shown in the present invention has excellent oral bioavailability.

[0016] 2. The composition of the present invention has good blood sugar lowering and weight loss effects and can be used to prepare drugs for treating or preventing diabetes or obesity.

[0017] 3. The preparation process of the composition shown in the present invention is simple and is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is the blood glucose-time curve of the glucose-lowering test on db / db mice by prescriptions F3, F13-F17, F20-F21, F23-F26 and Rybelsus.

[0019] Figure 2 This is a graph showing the blood glucose-time curves of the glucose tolerance test of db / db mice using prescriptions F3, F13-F17, F20-F21, F23-F26 and Rybelsus.

[0020] Figure 3 This is a weight-time curve of the weight loss experiment on obese mice using prescriptions F3, F13-F17, F20-F21, F23-F26 and Rybelsus. DETAILED DESCRIPTION

[0021] In order to make the invention purpose, technical scheme and beneficial effect of the present invention clearer, the present invention is further described below in conjunction with examples. It should be understood that the examples are only used to explain the present invention and are not used to limit the scope of the present invention. The test methods used in the following examples are conventional methods unless otherwise specified, and those familiar with the technology can easily understand other advantages and effects of the present invention from the contents disclosed in this description.

[0022] After extensive exploration and research, the inventors of the present application have discovered a GLP-1 analog oral delivery composition, which uses the delivery agents lauroyl-L-carnitine (LLC) and sodium caprate (C10) in combination. The preliminary results of pharmacokinetic and pharmacological studies show that the GLP-1 analog drug composition designed in the present application can improve the bioavailability and achieve oral administration of GLP-1 analog drugs.

[0023] In one aspect, the present application provides a GLP-1 analog oral delivery composition, comprising a GLP-1 analog and a delivery agent, wherein the delivery agent comprises lauroyl-L-carnitine and sodium caprate.

[0024] In the GLP-1 analog oral delivery composition provided in the present application, the GLP-1 analog is selected from semaglutide, specifically N-ε 26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib 8 Arg 34 ]GLP-1(7-37). Further, based on the total mass of the GLP-1 analog oral delivery composition, the mass fraction of semaglutide is 0.5-15% (w / w); further, the mass fraction of semaglutide is 0.74-11% (w / w), etc.

[0025] In the GLP-1 analog oral delivery composition provided in the present application, the mass fraction of the delivery agent is 60 to 85% (w / w) based on the total mass of the GLP-1 analog oral delivery composition. Further, the mass fraction of the delivery agent is 64.85 to 83.6% (w / w) based on the total mass of the GLP-1 analog oral delivery composition.

[0026] In the oral delivery composition of the GLP-1 analog provided in the present application, the mass ratio of lauroyl-L-carnitine to sodium caprate is 1:0.125-8; specifically, it can be 1:0.125-0.25, 1:0.25-0.33, 1:0.33-4, or 1:4-8, etc. In some specific embodiments, the mass ratio of lauroyl-L-carnitine to sodium caprate is 1:0.33-4; specifically, it can be 1:0.33-0.5, 1:0.5-1, 1:1-2, 1:2-3, or 1:3-4, etc.

[0027] In the GLP-1 analog oral delivery composition provided in the present application, the mass ratio of the GLP-1 analog to the delivery agent is 1:0.01-100; further, the mass ratio of the GLP-1 analog to the delivery agent is 1:6-100.

[0028] The GLP-1 analog oral delivery composition provided in the present application also includes a pharmaceutically acceptable excipient. The term "excipient" used herein refers to any component other than the active therapeutic ingredient. Excipients may be inert substances, inactive substances and / or substances without medical activity. Excipients can be used for various purposes, such as as carriers, vehicles, fillers, adhesives, lubricants, glidants, disintegrants, flow control agents, crystallization retarders, solubilizers, stabilizers, colorants, flavor enhancers, surfactants, emulsifiers, pH regulators, to improve the administration and / or absorption of active substances. Those skilled in the art can select one or more of the above-mentioned excipients according to the specific desired performance of the solid oral dosage form through routine experiments and without any excessive burden. The amount of each excipient used can vary within the conventional range in the art. These substances are used as needed to help the stability of the formulation or to help improve the activity or its biological effectiveness or to produce an acceptable taste or smell in the case of oral administration.

[0029] Those skilled in the art can select a suitable formulation form according to the mode of administration. For example, the formulation form suitable for oral administration may include but is not limited to pills, tablets or coated tablets, chewable tablets, capsules, granules, drops or syrups, etc. For another example, the formulation form suitable for parenteral administration may include but is not limited to solutions, suspensions, reconstituted dry preparations or sprays, etc. For another example, the formulation form suitable for rectal administration may generally be a suppository.

[0030] In some specific embodiments of the present application, the auxiliary material includes a combination of one or more of a binder, a filler, a lubricant, and a pH adjuster.

[0031] In the oral delivery composition of the GLP-1 analog provided in the present application, the mass fraction of the binder is ≤5% (w / w) based on the total mass of the oral delivery composition of the GLP-1 analog; further, the mass fraction of the binder is 1-4% (w / w); specifically, it can be 1-2% (w / w), 2-3% (w / w), or 3-4% (w / w), etc. In some embodiments, the binder is selected from cellulose derivatives, povidone, or polyethylene glycol; further, the cellulose derivative is selected from conventional cellulose derivatives such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or sodium carboxymethyl cellulose. In a preferred embodiment of the present application, the povidone is selected from povidone K90.

[0032] In the GLP-1 analog oral delivery composition provided in the present application, the mass fraction of the filler is 10-35% (w / w) based on the total mass of the GLP-1 analog oral delivery composition; further, the mass fraction of the filler is 15-25% (w / w); specifically, it can be 15-18% (w / w), 18-20% (w / w), or 20-25% (w / w), etc. In some embodiments, the filler is selected from conventional fillers such as lactose, mannitol, calcium phosphate, starch, microcrystalline cellulose, or silicified microcrystalline cellulose.

[0033] In the GLP-1 analog oral delivery composition provided in the present application, the mass fraction of the lubricant is ≤5% (w / w) based on the total mass of the GLP-1 analog oral delivery composition; further, the mass fraction of the lubricant is 1-4% (w / w); specifically, it can be 1-2% (w / w), 2-3% (w / w), or 3-4% (w / w), etc. In some embodiments, the lubricant is selected from conventional lubricants such as stearic acid, metal stearate, micropowder silica gel, talc, polyethylene glycol, sodium lauryl sulfate, or hydrogenated vegetable oil. In a specific embodiment of the present application, the metal stearate is selected from conventional metal stearate such as calcium stearate, zinc stearate, or magnesium stearate.

[0034] In the GLP-1 analog oral delivery composition provided in the present application, the mass fraction of the pH adjuster is ≤15% (w / w) based on the total mass of the GLP-1 analog oral delivery composition; further, the mass fraction of the pH adjuster is 0.6-14% (w / w); specifically, it can be 0.6-1% (w / w), 1-5% (w / w), or 5-14% (w / w), etc. In some embodiments, the pH adjuster is selected from sodium bicarbonate.

[0035] On the other hand, the present application provides a preparation method for preparing the aforementioned GLP-1 analog oral delivery composition, comprising the following steps:

[0036] 1) mixing a delivery agent, a lubricant, and a filler, and rolling and compressing the mixture to obtain first granules;

[0037] 2) mixing the GLP-1 analog, the binder, the filler, and the pH adjuster, and rolling and compacting the mixture to obtain the second granules;

[0038] 3) The first granules and the second granules are mixed with a lubricant and compressed to obtain a GLP-1 analog oral delivery composition.

[0039] In the preparation method provided by the present application, step 1) refers to mixing a delivery agent, a lubricant, and a filler, and rolling to obtain the first granules. In some embodiments, the delivery agent includes LLC and C10, which are first mixed, and the mixing time can be, for example, 2 minutes. Then, the delivery agent is first mixed with the lubricant, and the lubricant is mixed with the filler. When mixing respectively, equal volumes can be mixed first, and then the remaining raw materials are added and mixed together for easy mixing. The time for mixing respectively can be, for example, 4 minutes. Then, the products after mixing are mixed together, and rolled by a dry granulator to obtain the first granules.

[0040] In the preparation method provided in the present application, step 2) refers to mixing the GLP-1 analog, the binder, the filler, and the pH adjuster, and rolling to obtain the second granules. In some embodiments, the raw materials of the second granules can be added to the mixing container in the order of the added amount from high to low for reaction, and the mixing time can be, for example, 3 minutes, and then rolled by a dry granulator to obtain the second granules.

[0041] In the preparation method provided in the present application, step 3) refers to mixing the first granules, the second granules and the lubricant, and compressing to obtain a GLP-1 analog oral delivery composition. The mixing time can be, for example, 3 minutes, and the GLP-1 analog oral delivery composition is obtained by pressing into tablets. The preparation process of the composition of the present application is simple and is conducive to industrial production.

[0042] On the other hand, the present application provides the use of the aforementioned GLP-1 analog oral delivery composition in the preparation of a product for treating or preventing diabetes or obesity. The composition shown in the present invention has a more excellent oral bioavailability. The composition shown in the present invention has good hypoglycemic and weight loss effects and can be used to prepare a drug for treating or preventing diabetes or obesity. Among them, diabetes mainly refers to type 2 diabetes, and the present application can be used to treat type 2 diabetes by oral administration.

[0043] The invention of the present application is further described below by way of examples, but the scope of the present application is not limited thereby.

[0044] Example 1 Preparation of oral semaglutide solid composition

[0045] Table 1 Prescription of semaglutide tablet composition

[0046]

[0047] The tablet composition consists of first granules and second granules and an extragranular lubricant.

[0048] When preparing the first granule, LLC and C10, 70% (w / w) of the prescribed amount of microcrystalline cellulose, and 78% (w / w) of the prescribed amount of magnesium stearate were taken. The delivery agent was first mixed for 2 minutes, and an equal volume of the delivery agent and magnesium stearate were mixed for 60 seconds, and the mixture of magnesium stearate and delivery agent was mixed with the remaining delivery agent mixture for 4 minutes. The magnesium stearate delivery agent mixture with an equal volume of microcrystalline cellulose was mixed for 60 seconds, and then the above mixture was mixed with the remaining magnesium stearate delivery agent mixture for 4 minutes, and then the mixture was rolled and granulated by a dry granulator to obtain the first granule.

[0049] When preparing the second granules, semaglutide, povidone K90, 30% (w / w) of the prescribed amount of microcrystalline cellulose, and sodium bicarbonate are added to a mixing container in descending order, mixed for 3 minutes, and then the mixture is rolled and granulated by a dry granulator to obtain the second granules.

[0050] The first granules and the second granules were mixed for 5 minutes, the mixture was mixed with 22% of the prescribed amount of magnesium stearate for 2 minutes, and then the mixture was compressed into tablets.

[0051] The tablet composition was placed in 10 ml of artificial gastric juice to simulate the local microenvironment of the tablet composition in the stomach. The solution was shaken at 150 rpm / min for 30 min at 37°C. Then, samples were taken to detect the semaglutide content in the solution. The ability of different amounts of sodium bicarbonate to adjust pH in artificial gastric juice was investigated.

[0052] The experimental results are shown in the table:

[0053] Table 2 Results of semaglutide content detection

[0054]

[0055]

[0056] The research results of the present invention show that when the amount of sodium bicarbonate added is 6.7 mg / tablet, semaglutide in the tablet composition can be effectively protected from being decomposed by pepsin. When the amount of sodium bicarbonate is further increased to 60 mg / tablet, the content of semaglutide in artificial gastric juice does not increase significantly. Therefore, the amount of sodium bicarbonate added in subsequent studies is 6.7 mg / tablet.

[0057] Example 2: Preparation of oral semaglutide solid composition

[0058] Table 3 Oral semaglutide solid composition

[0059]

[0060] Tablet compositions F8 to F18 were prepared according to the method of Example 1, wherein the amounts of delivery agents LLC and C10 were varied as shown in Table 3.

[0061] Example 3 Preparation of oral semaglutide solid composition

[0062] Table 4 Prescription of semaglutide tablet composition

[0063]

[0064] Tablet compositions F19 to F22 were prepared according to the method of Example 1, wherein the amounts of the delivery agents LLC and C10 were varied as shown in Table 4.

[0065] Example 4 Preparation of oral semaglutide solid composition

[0066] Table 5 Prescription of semaglutide tablet composition

[0067]

[0068]

[0069] Tablet compositions F23 to F26 were prepared according to the method of Example 1, wherein the amount of semaglutide added was varied as shown in Table 5.

[0070] Example 5: Pharmacokinetic (PK) study in SD rats

[0071] The purpose of this study was to determine the pharmacokinetic parameters and oral bioavailability of a series of formulations in SD rats.

[0072] Trial plan : 132 healthy male Sprague Dawley rats weighing 200-250 g were used and the drugs were administered according to the specific dosing regimen shown in Table 6:

[0073] Table 6 Pharmacokinetic study protocol for SD rats

[0074] Group Dosage Dosing volume Dosage Dosing frequency Number of animals Semaglutide 0.025mg / piece 0.2mL / piece Intravenous (iv) Single 6 Rybelsus 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F3 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F8 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F9 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F10 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F11 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F12 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F13 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F14 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F15 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F16 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F17 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F18 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F19 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F20 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F21 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F22 2.5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F23 1.1mg / piece 2mL / piece Intragastric administration (ig) Single 6 F24 5mg / piece 2mL / piece Intragastric administration (ig) Single 6 F25 9.0mg / piece 2mL / piece Intragastric administration (ig) Single 6 F26 18.0mg / piece 2mL / piece Intragastric administration (ig) Single 6

[0075] Blood sample collection time : Before administration, 0.083h, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, and 24h after administration.

[0076] Plasma preparation and sample analysis All blood samples were collected into tubes containing EDTA-K2, centrifuged at 2000g for 10 min, and plasma was separated and analyzed using an LC-MS / MS system. The lower limit of quantification in plasma was 0.5 ng / ml.

[0077] Pharmacokinetic calculations: The pharmacokinetic parameters were calculated using the non-compartmental model of Phoenix WinNonlin v 8.2 software. The peak concentration (C max ), area under the plasma concentration-time curve (AUC 0-t ), peak time (T max ), and calculated the absolute bioavailability (F), where F is the AUC obtained after oral administration 0-t / dose divided by the AUC obtained after i.v. administration 0-t / dose. The final data are expressed as mean ± standard deviation.

[0078] result : The results are shown in Tables 7 to 9.

[0079] Table 7 summarizes the pharmacokinetic parameters of semaglutide after single-dose administration of prescriptions F3, F8 to F18.

[0080] Table 8 summarizes the pharmacokinetic parameters of semaglutide after single-dose administration of formulations F19 to F22.

[0081] Table 9 summarizes the pharmacokinetic parameters of semaglutide after single-dose administration of prescriptions F23 to F26.

[0082] Table 7 Pharmacokinetic parameters of semaglutide after single administration of prescriptions F3, F8 to F18 (Mean±SD, n=6)

[0083]

[0084] Table 8 Pharmacokinetic parameters of semaglutide after single administration of prescriptions F19 to F22 (Mean±SD, n=6)

[0085]

[0086] Table 9 Pharmacokinetic parameters of semaglutide after single administration of prescriptions F23 to F26 (Mean±SD, n=6)

[0087]

[0088] In the prescription of the present invention, the dosage of the delivery agent is 200 mg to 450 mg (F3, F20 to F21 in Table 4 and Table 8), and the delivery agent LLC:C10 is used in combination in the range of 3:1 to 1:4 (Table 3 and Table 7, F3, F13 to F17), which can significantly improve the bioavailability of semaglutide.

[0089] When the total amount of the delivered agent was 300 mg and LLC:C10=1:3 remained unchanged (Table 5 and Table 9, F23-F26), the exposure of semaglutide (C max , AUC0-t ) and bioavailability increase with increasing dose.

[0090] Example 6 Drug efficacy study in type II diabetic db / db mice

[0091] The purpose of this study was to evaluate the pharmacodynamic effect of the formulation of the present invention on the type 2 diabetes db / db mouse model by means of a glucose-lowering test (Study A) and a glucose tolerance test (Study B).

[0092] Study A: This study mainly used BKS-Lepr em2Cd479 / Nju strain, 84 db / db male mice about 7-8 weeks old, were used for the experiment after one week of adaptation. According to body weight and blood glucose, they were randomly divided into 14 groups, namely model control group, prescription F3, F13-F17, F20-F21, F23-F26 group and Rybelsus group, with 6 mice in each group. All animals were given oral administration, and the dosage of prescription F3, F13-F17, F20-F21 group and Rybelsus group was 0.15 mg / mouse, the dosage of F23 was 0.06 mg / mouse, the dosage of F24 was 0.30 mg / mouse, the dosage of F25 was 0.54 mg / mouse, and the dosage of F26 was 1.07 mg / mouse. The model control group was given PBS buffer, and the dosage volume of each group was 0.4 mL / mouse. All animals were fasted for 6 hours before and 0.5 hours after administration, and the blood glucose values ​​of all animals were measured before and 1, 2, 4, 6, 8, 12 and 24 hours after administration.

[0093] Study B: This study mainly used BKS-Lepr em2Cd479 / Nju strain, 84 db / db male mice about 7-8 weeks old, were used for the experiment after one week of adaptation. According to body weight and blood sugar, they were randomly divided into 14 groups, namely model control group, prescription F3, F13-F17, F20-F21, F23-F26 group and Rybelsus group, with 6 mice in each group. All animals were fasted for 18 hours and their fasting blood sugar was measured (recorded as -30min), and 30 minutes later, they were gavaged and given drugs (recorded as 0min). The dosage of prescription F3, F13-F21 group and Rybelsus group was 0.15mg / mouse, the dosage of F23 was 0.06mg / mouse, the dosage of F24 was 0.30mg / mouse, the dosage of F25 was 0.54mg / mouse, and the dosage of F26 was 1.07mg / mouse. The model control group was given PBS buffer, and the dosage volume of each group was 0.4mL / mouse. Blood glucose was tested 30 min after administration and glucose (2 g / kg) was injected intraperitoneally. Blood glucose was measured at 45, 60, 75, 90, 120, 150, 210, and 240 min after administration.

[0094] result: The results are shown in Tables 10 to 12 and Figures 1 to 3 shown.

[0095] Table 10 Blood glucose levels of prescriptions F3, F13-F17, F20-F21, F23-F26 and Rybelsus in the glucose-lowering test in db / db mice (mmol / L, Mean±SD, n=6)

[0096]

[0097]

[0098] Note: * and Δ indicate significant differences compared with the model control group and Rybelsus, respectively.

[0099] Table 11 Blood glucose levels of prescriptions F3, F13-F17, F20-F21, F23-F26 and Rybelsus in the glucose tolerance test of db / db mice (mmol / L, Mean±SD, n=6)

[0100]

[0101] Note: * and Δ indicate significant differences compared with the model control group and Rybelsus, respectively.

[0102] Figures 1-2 The results in Tables 10 to 11 show that the prescriptions F3, F13 to F17, F20 to F21, and F23 to F26 of the present invention can significantly reduce blood sugar and hyperglycemia after glucose loading in db / db mice.

[0103] Example 7 Drug efficacy study in diet-induced obese mice

[0104] The purpose of this experiment is to evaluate the therapeutic effect of the prescription of the present invention on obese mice induced by a high-fat diet.

[0105] Healthy male C57BL / 6N mice were fed a high-fat diet (D12492, Research Diet) from 5 weeks of age. All animals were weighed once a week during the modeling period. When most mice fed a high-fat diet weighed ≥40 g, 84 mice weighing about 40 g were screened and divided into 14 groups, namely the model control group, prescription F3, F13-F17, F20-F21, F23-F26 groups and Rybelsus groups, with 6 mice in each group. All animals were given oral administration, with prescription F3, F13-F17, F20-F21 groups and Rybelsus groups receiving 0.15 mg / mouse, F23 receiving 0.06 mg / mouse, F24 receiving 0.30 mg / mouse, F25 receiving 0.54 mg / mouse, and F26 receiving 1.07 mg / mouse. The model control group was given PBS buffer, and the administration volume of each group was 0.4 mL / mouse. The drug was administered once a day for 7 consecutive days, and the body weight of all mice was measured every day. The body weight at each test time point was subtracted from the body weight before the first administration to calculate the body weight change value (g). The results are shown in the following table and figure:

[0106] Table 12 Body weight changes of obese mice after repeated administration of prescriptions F3, F13-F17, F20-F21, F23-F26 and Rybelsus within 7 days (g, Mean±SD, n=6)

[0107]

[0108] Note: * and Δ indicate significant differences compared with the model control group and Rybelsus.

[0109] Figure 3 The results in Table 12 show that the prescriptions F3, F13-F17, F20-F21, and F23-F26 of the present invention can significantly reduce the body weight of diet-induced obese mice.

[0110] In summary, the GLP-1 analog drug oral delivery composition provided by the present application has excellent oral bioavailability. The composition shown in the present invention has good hypoglycemic and weight loss effects and can be used to prepare drugs for treating or preventing diabetes or obesity. The preparation process of the composition shown in the present invention is simple and is conducive to industrial production.

[0111] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. A GLP-1 analog oral delivery composition, characterized in that: It includes a GLP-1 analog and a delivery agent, wherein the delivery agent is lauroyl-L-carnitine and sodium decanoate, and the GLP-1 analog is semaglutide; based on the total mass of the GLP-1 analog oral delivery composition, the mass fraction of semaglutide is 0.5-15% (w / w); based on the total mass of the GLP-1 analog oral delivery composition, the mass fraction of the delivery agent is 60-85% (w / w), and the mass ratio of lauroyl-L-carnitine to sodium decanoate is 1:0.33-4.

2. The GLP-1 analog oral delivery composition according to claim 1, characterized in that The mass ratio of the GLP-1 analog to the delivery agent is 1:6-100.

3. The GLP-1 analog oral delivery composition according to claim 1, characterized in that The invention also comprises pharmaceutically acceptable excipients; the excipients include one or more combinations of adhesives, fillers, lubricants and pH regulators.

4. The GLP-1 analog oral delivery composition according to claim 3, characterized in that Based on the total mass of the GLP-1 analog oral delivery composition, the mass fraction of the binder is 1 to 4% (w / w); and / or, based on the total mass of the GLP-1 analog oral delivery composition, the mass fraction of the filler is 15 to 25% (w / w); and / or, based on the total mass of the GLP-1 analog oral delivery composition, the mass fraction of the lubricant is 1 to 4% (w / w); And / or, based on the total mass of the GLP-1 analog oral delivery composition, the mass fraction of the pH adjuster is 0.6-14% (w / w).

5. The GLP-1 analog oral delivery composition according to claim 4, characterized in that The binder is selected from one of cellulose derivatives, povidone, or polyethylene glycol, and the cellulose derivative is selected from one of methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or sodium carboxymethyl cellulose; and / or, the filler is selected from one of lactose, mannitol, calcium phosphate, starch, or microcrystalline cellulose; and / or, the lubricant is selected from one of stearic acid, metal stearate, micropowdered silica gel, talc, polyethylene glycol, sodium lauryl sulfate, or hydrogenated vegetable oil; and / or, the pH regulator is sodium bicarbonate.

6. The GLP-1 analog oral delivery composition according to claim 5, characterized in that The povidone is povidone K90; And / or, the metal stearate is selected from one of calcium stearate, zinc stearate, or magnesium stearate.

7. A preparation method for preparing the GLP-1 analog oral delivery composition according to any one of claims 1 to 6, comprising the following steps: 1) mixing a delivery agent, a lubricant, and a filler, and rolling and compressing the mixture to obtain first granules; 2) mixing the GLP-1 analog, the binder, the filler, and the pH adjuster, and rolling and compacting the mixture to obtain the second granules; 3) The first granules and the second granules are mixed with a lubricant and compressed to obtain a GLP-1 analog oral delivery composition.

8. Use of the GLP-1 analog oral delivery composition according to any one of claims 1 to 6 in the preparation of a product for preventing or treating diabetes.

9. Use of the GLP-1 analog oral delivery composition according to any one of claims 1 to 6 in the preparation of a product for preventing or treating obesity.

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