Use of olmesartan medoxomil monotherapy and combination therapy thereof with sorafenib in prevention / treatment of diabetes

Abstract

Provided in the present invention is the use of olmesartan medoxomil or a derivative thereof in the preparation of a drug for protecting pancreatic islet β cells, a drug for protecting pancreatic islet β cells against inflammation, a drug for preventing and treating diabetes, and a drug for preventing and treating type 1 diabetes. Further provided in the present invention is the use of a combination therapy of olmesartan medoxomil and sorafenib in the treatment of type 1 diabetes.

Description

Application of olmesartan medoxomil monotherapy and combination therapy with sorafenib in the prevention / treatment of diabetes Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to new applications of olmesartan medoxomil, especially the application of olmesartan medoxomil monotherapy and combination therapy with sorafenib in the prevention / treatment of type 1 diabetes. Background Technology

[0002] Type 1 diabetes mellitus (T1DM), also known as autoimmune diabetes, is a typical autoimmune disease characterized by insulin deficiency and hyperglycemia. It is caused by a combination of genetic and environmental factors, leading to damage to pancreatic beta cells due to autoimmune attacks. T1DM is one of the most common chronic diseases in children and adolescents, and its incidence is rising globally. Although China has one of the lowest T1DM incidence rates globally, its large population means it ranks fourth in the world in the number of children and adolescents with T1DM, resulting in a growing disease burden. Currently, the main treatments for T1DM are insulin and pancreatic beta cell / stem cell transplantation. While these methods can alleviate symptoms, they do not fundamentally improve the immune environment, and pancreatic beta cells still suffer from immune attacks and die. To this day, T1DM remains incurable, making the development of new drugs based on its pathogenesis an urgent priority.

[0003] The depletion of pancreatic β-cells due to autoimmune activation dominated by immune cells is a key mechanism in the pathogenesis of type 1 diabetes mellitus (T1DM). Immunotherapy has long been considered a promising treatment option. Studies have shown that the destruction of pancreatic β-cells during T1DM pathogenesis is mainly mediated by autoreactive T cells; therefore, targeting autoreactive T cells offers new hope for T1DM treatment. The CD3 monoclonal antibody (teslizumab) is the first immunotherapy approved by the US Food and Drug Administration (FDA) for delaying the onset of T1DM. Its Phase II clinical data showed that two weeks of administration significantly delayed the onset of T1DM in high-risk children and adults, with a median delay of at least two years. This study demonstrates that immunotherapy targeting T cells is an effective means of delaying the onset of T1DM.

[0004] Th1 cell activation plays a crucial role in the pathogenesis of type 1 diabetes mellitus (T1DM). Therefore, Th1 cells are an important target for T1DM immunotherapy. Previously, using an in vitro cell model of Th1 cell differentiation induced by interleukin-12 (IL-12), we screened a library of FDA-approved tyrosine kinase inhibitors and identified an effective Th1 cell differentiation inhibitor—sorafenib. We demonstrated that sorafenib can reverse T1DM by inhibiting Th1 cells, thus improving pancreatitis in non-obese diabetic (NOD) mice. This research has been granted a national invention patent (patent number: ZL 202010812329.3).

[0005] In previous studies, sorafenib showed an efficacy rate of approximately 50% in treating type 1 diabetes mellitus (T1DM) NOD mice. However, in NOD mice with initially high blood glucose levels and near-complete destruction of pancreatic β-cells, sorafenib failed to reverse the persistently elevated blood glucose levels. This result suggests that improving the in vivo inflammatory environment cannot restore the function of severely damaged pancreatic β-cells. Therefore, the development of drugs that protect pancreatic β-cells is essential.

[0006] Based on the pathogenesis of T1DM, the combined treatment of T1DM with drugs that protect pancreatic β cells and immunotherapy has important practical significance. Summary of the Invention

[0007] In view of this, the present invention provides the use of olmesartan medoxomil or its derivatives in the preparation of a medicament for protecting pancreatic β-cells.

[0008] Furthermore, the present invention also provides the use of olmesartan medoxomil or its derivatives in the preparation of medicaments for protecting pancreatic β-cells against inflammation, and in the preparation of medicaments for the prevention and treatment of diabetes, particularly in the treatment of type 1 diabetes.

[0009] Furthermore, the present invention also provides the use of a combination therapy of metarttan medoxomil or a derivative thereof with sorafenib or a derivative thereof in the preparation of a medicament for treating diabetes.

[0010] Olmesartan medoxomil for the preventive treatment of type 1 diabetes and the combination therapy of olmesartan medoxomil and sorafenib for the treatment of type 1 diabetes provide new treatment options for patients, offering more choices for clinicians and patients alike. For patients with type 1 diabetes, the preventive treatment with olmesartan medoxomil and the combination therapy of olmesartan medoxomil and sorafenib can provide oral medication treatment, avoiding the inconvenience of tislelizumab injections or even daily insulin injections.

[0011] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0012] The use of olmesartan medoxomil or its derivatives in the preparation of drugs that protect pancreatic β-cells.

[0013] Olmesartan Medoxomil is a prodrug that is absorbed and hydrolyzed in the gastrointestinal tract to form olmesartan. Olmesartan is a selective angiotensin II type 1 receptor (AT1) antagonist, blocking the vasoconstrictive effect of angiotensin II by selectively blocking the binding of angiotensin II to AT1 receptors in vascular smooth muscle. Olmesartan Medoxomil is approved by the US FDA for the treatment of hypertension. It is a widely used first-line, long-acting antihypertensive drug in clinical practice. In addition to its significant antihypertensive effect, studies have shown that it also exerts anti-inflammatory effects in hypertensive patients, delaying the progression of microalbuminuria and coronary atherosclerosis, suggesting that olmesartan Medoxomil has multiple protective benefits. The safety of olmesartan Medoxomil has also been well verified in children and adolescents (6-16 years old). Furthermore, olmesartan Medoxomil is not metabolized by the hepatic cytochrome P450 system, improving the safety of combination therapy. Olmesartan medoxomil has the molecular formula C29H30N6O6, a molecular weight of 558.59, and its structural formula is shown in Formula I.

[0014] Furthermore, some embodiments of the present invention utilize pro-inflammatory factors interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) to treat mouse pancreatic β-cell line MIN6 cells, finding that the antihypertensive drug olmesartan medoxomil can resist inflammation and protect pancreatic β-cells. The present invention confirms the application of olmesartan medoxomil or its derivatives in the preparation of drugs that protect pancreatic β-cells against inflammation through cell experiments.

[0015] Furthermore, the present invention provides the use of olmesartan medoxomil or its derivatives in the preparation of medicaments for the prevention and treatment of diabetes.

[0016] In some embodiments of the present invention, NOD mice before the onset of type 1 diabetes were administered olmesartan medoxomil via gavage, and changes in blood glucose levels were monitored to observe the natural incidence of type 1 diabetes in the mice. The results showed that olmesartan medoxomil could prevent the development of type 1 diabetes in NOD mice.

[0017] Therefore, olmesartan medoxomil can be used to prevent the onset of type 1 diabetes. The use of olmesartan medoxomil or its derivatives in the preparation of medicines for the prevention and treatment of diabetes, particularly in medicines for the prevention and treatment of type 1 diabetes.

[0018] In some embodiments, the present invention combines olmesartan medoxomil and sorafenib in the gavage treatment of naturally occurring type 1 diabetic NOD mice for 7 weeks, and monitors changes in blood glucose levels. Results showed that the combination therapy of olmesartan medoxomil and sorafenib reversed hyperglycemia in type 1 diabetic NOD mice and maintained blood glucose levels within the normal range long-term after drug withdrawal.

[0019] Therefore, the combination therapy of olmesartan medoxomil and sorafenib can be used to treat type 1 diabetes.

[0020] In summary, this invention provides the use of olmesartan medoxomil or its derivatives in combination with sorafenib or its derivatives in the prevention / treatment of diabetes.

[0021] Furthermore, the present invention also provides the use of a combination therapy of olmesartan medoxomil or a derivative thereof with sorafenib or a derivative thereof in the preparation of a medicament for treating type 1 diabetes.

[0022] The weight ratio of olmesartan medoxomil or its derivatives to sorafenib or its derivatives is 2:5.

[0023] Preferably, the dosage of olmesartan medoxomil or its derivative is 20 mg / kg, and the dosage of sorafenib or its derivative is 50 mg / kg.

[0024] Furthermore, the medicament described in this invention also includes pharmaceutically acceptable excipients.

[0025] Furthermore, the dosage form of the drug described in this invention can be an oral formulation or an injectable formulation.

[0026] Each drug dosage form can be prepared by selecting appropriate and acceptable excipients according to the actual needs of that dosage form, which is a conventional dosage form preparation technique in this field. Examples include the preparation of capsules, tablets, and injectable powders.

[0027] As can be seen from the above technical solutions, this invention provides the application of olmesartan medoxomil or its derivatives in the preparation of drugs that protect pancreatic β-cells, drugs that protect pancreatic β-cells against inflammation, drugs for the prevention and treatment of diabetes, and drugs for the prevention and treatment of type 1 diabetes. Simultaneously, this invention also provides the application of olmesartan medoxomil and sorafenib combination therapy in the treatment of type 1 diabetes. The use of olmesartan medoxomil for the preventive treatment of type 1 diabetes and the use of olmesartan medoxomil and sorafenib combination therapy for the treatment of type 1 diabetes provide new treatment options for patients, offering clinicians and patients more choices. For patients with type 1 diabetes, the preventive treatment with olmesartan medoxomil and the combination therapy with olmesartan medoxomil and sorafenib provide oral medication treatment, avoiding the inconvenience of CD3 monoclonal antibody (teslizumab) injections or even daily insulin injections. Olmesartan medoxomil and sorafenib can be chemically synthesized, with lower costs than biological agents. Furthermore, they have been approved by the FDA and NMPA for clinical use. It has fewer and milder side effects, is well tolerated by clinical patients, and has a lighter burden on patients. Attached Figure Description

[0028] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0029] Figure 1 shows the results of flow cytometry detection of apoptosis protein- in MIN6 cells in Example 1.

[0030] Figure 2 shows the insulin content in MIN6 cells under low glucose (2.8 mM) and high glucose (16.7 mM) conditions detected by ELISA in Example 2.

[0031] Figure 3 shows the results of the type 1 diabetes prevalence analysis in mice of Example 3;

[0032] Figure 4 shows the therapeutic effects of olmesartan medoxomil and sorafenib alone on type 1 diabetic mice in Example 4.

[0033] Figure 5 shows the therapeutic effect of the combination of olmesartan medoxomil and sorafenib in type 1 diabetic mice in Example 5. Detailed Implementation

[0034] This invention discloses novel applications of olmesartan medoxomil and sorafenib. Those skilled in the art can refer to this document and appropriately modify the process parameters to achieve the desired results. It is particularly important to note that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments. Those skilled in the art will clearly be able to modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0035] Unless otherwise specified, all reagents involved in the embodiments of this invention are commercially available products and can be purchased through commercial channels.

[0036] Interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were all purchased from the market.

[0037] The present invention will be further illustrated below with reference to the embodiments.

[0038] Example 1: Olmesartan medoxomil protects pancreatic β-cells from inflammation-induced apoptosis.

[0039] I. Materials and Methods

[0040] 1. Cell line: The mouse pancreatic β cell line (MIN6 cells) was selected for experiments. The MIN6 cells of this invention were obtained from the ATCC cell bank in the United States.

[0041] 2. Cell preparation: MIN6 cells were prepared at a concentration of 1×10⁻⁶.5 Cells were seeded at a density of 100 cells / well in 24-well plates with 1 mL of complete culture medium (DMEM + 10% FBS + 100 U / mL penicillin / streptomycin) per well and incubated in a cell culture incubator for 2 days.

[0042] 3. Flow cytometry detection of MIN6 cell apoptosis—Annexin V staining:

[0043] Solvent preparation: DMEM and 0.1% bovine serum albumin were mixed evenly to obtain the solvent;

[0044] Preparation of inflammatory factor solvent: Interleukin-1β (IL-1β), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) are dissolved in the above solvent to prepare the inflammatory factor solvent.

[0045] Cells were divided into three groups: A, B, and C. Inflammatory factor solvents were added to the complete culture medium in groups B and C to achieve a final concentration of 20 ng / mL for interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). Olmesartan medoxomil was added to group C to a final concentration of 1 μM. The three groups (A, B, and C) were then treated with solvent to equal volumes. After 72 h of treatment, cells were collected into 1.5 mL EP tubes. After washing the cells with pre-cooled 1×PBS, Annexin V staining was performed, and the expression level of Annexin V was detected by flow cytometry. Each treatment group had three replicates, and the average value was taken. The results are shown in Figure 1 (in Figure 1, solvent, inflammatory factor mixture, and inflammatory factor mixture + 1 μM olmesartan medoxomil correspond to groups A, B, and C, respectively). * indicates significant differences between groups.

[0046] As shown in Figure 1, in group B, the expression level of the apoptotic protein Annexin V in MIN6 cells increased rapidly under the stimulation of inflammatory factors. The difference between group C and group B is that 1 μM olmesartan medoxomil was used. It can be seen that the expression level of the apoptotic protein Annexin V in MIN6 cells was significantly different from that in group B. Therefore, it can be seen that olmesartan medoxomil has the effect of resisting inflammation-induced pancreatic β-cell apoptosis.

[0047] Example 2: Olmesartan medoxomil protects the insulin secretion function of pancreatic β-cells in an inflammatory environment.

[0048] I. Materials and Methods

[0049] 1. Cell line: The mouse pancreatic β cell line (MIN6 cells) was selected for experiments. The MIN6 cells of this invention were obtained from the ATCC cell bank in the United States.

[0050] 2. Cell preparation: MIN6 cells were prepared at a concentration of 1×10⁻⁶.5 Cells were seeded at a density of 100 cells / well in 24-well plates with 1 mL of complete culture medium (DMEM + 10% FBS + 100 U / mL penicillin / streptomycin) per well and incubated in a cell culture incubator for 2 days.

[0051] 3. Divide the cells into three groups for glucose-stimulated insulin secretion experiments:

[0052] Solvent preparation: DMEM and 0.1% bovine serum albumin were mixed evenly to obtain the solvent;

[0053] Preparation of inflammatory factor solvent: Interleukin-1β (IL-1β), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) are dissolved in the above solvent to prepare the inflammatory factor solvent.

[0054] Cells were divided into three groups: D, E, and F. Inflammatory factor solvents were added to the complete culture medium in groups E and F to achieve a final concentration of 20 ng / mL for interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). Olmesartan medoxomil was added to group F to a final concentration of 1 μM. The three groups (D, E, and F) were then treated with solvent to achieve equal volumes. After 24 h of treatment, the culture medium was discarded, and adherent cells were washed twice with Krebs-Ringer bicarbonate buffer (KRB). Cells were then starved for 1 h using KRB solution containing 2.8 mmol / L low-concentration glucose and 0.3% BSA. Following starvation, the three groups of MIN6 cells were stimulated for 1 h with either 2.8 mmol / L low-glucose or 16.7 mmol / L high-glucose solutions. Insulin levels were detected by ELISA using cell culture supernatant, as shown in Figure 2 (in Figure 2, solvent, inflammatory factor composition, and inflammatory factor composition + 1 μM olmesartan medoxomil correspond to groups D, E, and F, respectively). Each treatment group had three replicates, and the average value was taken.

[0055] As shown in Figure 2, olmesartan medoxomil can maintain the insulin secretion function of pancreatic β cells in an inflammatory environment.

[0056] Example 3: Olmesartan medoxomil can prevent the occurrence of type 1 diabetes in NOD mice.

[0057] 1. Mice: The classic mouse model for studying type 1 diabetes, namely the spontaneous type 1 diabetes mouse model—NOD mice—was selected. Since the incidence of spontaneous type 1 diabetes is much higher in female NOD mice than in male NOD mice, female NOD mice were used in this invention for experiments. All female NOD mice used in this invention were purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0058] 2. Drug preparation: Use sterile water as the solvent for olmesartan medoxomil: Before preparing the drug, autoclave the drinking water of the mice, dissolve the olmesartan medoxomil tablets in sterile water in a clean bench and store at 4°C to obtain the olmesartan medoxomil solution.

[0059] 3. Administration: The present invention uses gavage to administer the drug to mice, with the concentration of olmesartan medoxomil being 20 mg / kg body weight.

[0060] 4. Diagnosing type 1 diabetes by measuring blood glucose: Cut off about 1 mm from the tip of the mouse's tail, wipe away the first drop of blood with gauze, and when the second drop of blood flows out, use blood glucose test strips to collect and read the blood glucose level. If two consecutive blood glucose readings are greater than 250 mg / dL, type 1 diabetes can be diagnosed.

[0061] 5. Observation of the preventive effect of olmesartan medoxomil on spontaneous type 1 diabetes in NOD mice: Mice were divided into two groups, one group was given olmesartan medoxomil by gavage and the other group was given sterile water by gavage. When none of the mice participating in the experiment developed the disease, they were given gavage once a day for 12 consecutive weeks starting from 8 weeks of age. The natural incidence of type 1 diabetes in mice was observed and counted, and the results are shown in Table 1 and Figure 3.

[0062] Table 1. Disease prevalence in NOD mice

[0063] Five mice were administered the solution (sterile water) and six mice were administered olmesartan medoxomil. Survival curves were statistically analyzed at 30 weeks of age: * represents P < 0.05. At 17 weeks of age, the prevalence of type 1 diabetes was 16.7% in the olmesartan medoxomil group and 80% in the sterile water group. The preventive effect of olmesartan medoxomil on type 1 diabetes persisted after discontinuation of administration and continued until 30 weeks; this suggests that olmesartan medoxomil has a preventive effect against type 1 diabetes.

[0064] Example 4: The therapeutic effects of olmesartan medoxomil and sorafenib alone on type 1 diabetic mice.

[0065] 1. Mice: The classic mouse model for studying type 1 diabetes, namely the spontaneous type 1 diabetes mouse model—NOD mice—was selected. Since the incidence of spontaneous type 1 diabetes is much higher in female NOD mice than in male NOD mice, female NOD mice were used in this invention for experiments. All female NOD mice used in this invention were purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0066] 2. Drug preparation: Use sterile water as the solvent for olmesartan medoxomil: autoclave the drinking water of mice, dissolve olmesartan medoxomil tablets in sterile water in a clean bench and store at 4°C to obtain olmesartan medoxomil solution.

[0067] Use 1% carboxymethyl cellulose (CMC) as the solvent for sorafenib: autoclave the 1% CMC before dispensing, grind the sorafenib tablets into powder in a clean bench, weigh an appropriate amount of sorafenib powder, suspend it evenly in the solvent, and store it at 4°C to obtain a sorafenib suspension.

[0068] 3. Administration: The present invention uses gavage to administer drugs to mice. The concentration of olmesartan medoxomil is 20 mg / kg body weight, and the concentration of sorafenib is 50 mg / kg body weight.

[0069] 4. Diagnosing type 1 diabetes by measuring blood glucose: Cut off about 1 mm from the tip of the mouse's tail, wipe away the first drop of blood with gauze, and when the second drop of blood flows out, use blood glucose test strips to collect and read the blood glucose level. If two consecutive blood glucose readings are >250 mg / dL, type 1 diabetes can be diagnosed.

[0070] 5. Observe the therapeutic effects of olmesartan medoxomil and sorafenib alone on type 1 diabetic mice.

[0071] NOD mice were divided into three groups: a solvent group (sterile water + CMC), a group receiving olmesartan medoxomil via gavage, and a group receiving sorafenib via gavage. From the onset of type 1 diabetes diagnosis, mice were administered gavage once daily for three weeks, with blood glucose levels monitored weekly. Blood glucose values ​​are listed in Table 2, and the results after three weeks are compared in Table 3. The comparison is shown in Figure 4.

[0072] Table 2 Blood glucose levels in NOD mice after disease onset with single-drug administration

[0073] Table 3. Blood glucose levels in NOD mice 3 weeks after drug administration following disease onset.

[0074] Six mice were administered the solvent group (sterile water + CMC), eight mice were administered the olmesartan medoxomil group, and six mice were administered the sorafenib group. Three weeks after the onset of the disease, blood glucose levels were statistically analyzed in the olmesartan medoxomil group vs. the solvent group and the sorafenib group vs. the solvent group. Independent samples t-test was used for statistical analysis: NS (No significance) indicates no statistical difference, and * indicates P value < 0.05.

[0075] The results showed that, in Figure 4, a) was the change in blood glucose in type 1 diabetic mice after gavage administration of solvent (sterile water + CMC); b) was the change in blood glucose in type 1 diabetic mice after gavage administration of olmesartan; c) was the change in blood glucose in type 1 diabetic mice after gavage administration of sorafenib; and d) was the statistical analysis of blood glucose in the three groups of type 1 diabetic mice after gavage administration. The blood glucose of mice in the olmesartan monotherapy group was not different from that in the sterile water + CMC group, while the blood glucose of mice in the sorafenib monotherapy group was lower than that in the sterile water + CMC group. This suggests that olmesartan monotherapy cannot treat type 1 diabetes in NOD mice, while sorafenib has a certain therapeutic effect on type 1 diabetes.

[0076] Example 5: Olmesartan medoxomil combined with sorafenib for the treatment of type 1 diabetes in NOD mice

[0077] 1. Mice: The classic mouse model for studying type 1 diabetes, namely the spontaneous type 1 diabetes mouse model—NOD mice—was selected. Since the incidence of spontaneous type 1 diabetes is much higher in female NOD mice than in male NOD mice, female NOD mice were used in this invention for experiments. All female NOD mice used in this invention were purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0078] 2. Drug preparation: Use sterile water as the solvent for olmesartan medoxomil: autoclave the drinking water of mice, dissolve olmesartan medoxomil tablets in sterile water in a clean bench and store at 4°C to obtain olmesartan medoxomil solution.

[0079] Use 1% carboxymethyl cellulose (CMC) as the solvent for sorafenib: autoclave the 1% CMC before dispensing, grind the sorafenib tablets into powder in a clean bench, weigh an appropriate amount of sorafenib powder, suspend it evenly in the solvent, and store it at 4°C to obtain a sorafenib suspension.

[0080] 3. Administration: The present invention uses gavage to administer drugs to mice. The concentration of olmesartan medoxomil is 20 mg / kg body weight, and the concentration of sorafenib is 50 mg / kg body weight.

[0081] 4. Diagnosing type 1 diabetes by measuring blood glucose: Cut off about 1 mm from the tip of the mouse's tail, wipe away the first drop of blood with gauze, and when the second drop of blood flows out, use blood glucose test strips to collect and read the blood glucose level. If two consecutive blood glucose readings are >250 mg / dL, type 1 diabetes can be diagnosed.

[0082] 5. Observe the synergistic effect of olmesartan medoxomil and sorafenib in the treatment of type 1 diabetic mice.

[0083] NOD mice were divided into two groups: one group was administered olmesartan medoxomil + sorafenib, and the other group was administered sterile water + CMC. From the onset of the disease and diagnosis of type 1 diabetes, the mice were administered the medication once daily by gavage for 7 weeks. Blood glucose levels were monitored weekly, and the values ​​are listed in Table 4 (see Figure 5).

[0084] Table 4. Blood glucose levels in NOD mice after combined drug administration following disease onset.

[0085] Three mice were administered the solvent group (sterile water + CMC), and three mice were administered the olmesartan medoxomil + sorafenib group. Blood glucose levels were statistically analyzed in both groups at 16 weeks. The independent samples t-test was used for statistical analysis: *** represents P value < 0.001.

[0086] The results are shown in Figure 5. Figure a shows the blood glucose changes in type 1 diabetic mice administered via gavage in the solvent (sterile water + CMC) group; Figure b shows the blood glucose changes in type 1 diabetic mice administered via gavage in the olmesartan medoxomil + sorafenib group; Figure c shows the statistical analysis results of blood glucose in the two groups of type 1 diabetic mice administered via gavage. The results of Example 4 indicate that there was no difference in blood glucose levels between the olmesartan medoxomil monotherapy group and the sterile water + CMC group, while the blood glucose levels in the sorafenib monotherapy group were lower than those in the sterile water + CMC group. However, the results of Example 5 indicate that the blood glucose levels in the olmesartan medoxomil + sorafenib group were significantly lower than those in the sterile water + CMC group, and the therapeutic effect of the olmesartan medoxomil + sorafenib group on type 1 diabetes persisted for up to 16 weeks after discontinuation of gavage.

[0087] It can be seen that the efficacy of sorafenib alone in treating type 1 diabetes is not high, lower than that of the combination of olmesartan medoxomil and sorafenib for 3 weeks in Example 5. Furthermore, after 3 weeks, the therapeutic effect of sorafenib alone began to decline, and the treatment durability was inferior to that of the combination of olmesartan medoxomil and sorafenib. These results indicate that the combination therapy of olmesartan medoxomil and sorafenib significantly enhances the efficacy of sorafenib alone in treating type 1 diabetes in NOD mice.

[0088] The above description of the disclosed embodiments enables those skilled in the art to make or use 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 invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. The use of olmesartan medoxomil or its derivatives in the preparation of drugs that protect pancreatic β-cells.

2. The use of olmesartan medoxomil or its derivatives in the preparation of drugs that protect pancreatic β-cells against inflammation.

3. The use of olmesartan medoxomil or its derivatives in the preparation of drugs for the prevention and treatment of diabetes.

4. The use of olmesartan medoxomil or its derivatives in the preparation of drugs for the prevention and treatment of type 1 diabetes.

5. The use of olmesartan medoxomil or its derivatives in combination with sorafenib or its derivatives in the preparation of drugs for the treatment of diabetes.

6. The use of olmesartan medoxomil or its derivatives in combination with sorafenib or its derivatives in the preparation of medicaments for the treatment of type 1 diabetes.

7. The drug as described in claim 5 or 6, characterized in that: The weight ratio of olmesartan medoxomil or its derivatives to sorafenib or its derivatives is 2:

5.

8. The drug as described in claim 7, characterized in that: The dosage of olmesartan medoxomil or its derivatives is 20 mg / kg, and the dosage of sorafenib or its derivatives is 50 mg / kg.

9. The application as described in any one of claims 1-8, characterized in that, The drug also includes pharmaceutically acceptable excipients.

10. The application as described in any one of claims 1-8, characterized in that, The drug is available in oral or injectable form.

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