Method for treating insulin resistance, enhancing insulin sensitivity, providing glycemic control or treating insulin resistance-related disease

Abstract

Disclosed is a method for treating insulin resistance, enhancing insulin sensitivity, providing glycemic control or treating insulin resistance-related diseases, comprising: administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof:

Description

Method for treating insulin resistance, enhancing insulin sensitivity, providing glycemic control or treating insulin resistance-related diseaseCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of filing date of U. S. Provisional Application Serial Number 63 / 556,602, entitled “Methods for providing glycemic control, treating insulin resistance and treating insulin resistance- related disease” filed February 22, 2024 under 35 USC § 119(e)(1).BACKGROUND OF THE INVENTION

[0002] Field

[0003] The present invention relates to methods for treating insulin resistance, enhancing insulin sensitivity, providing glycemic control or treating insulin resistance-related disease. More specifically, the present invention relates to methods for treating insulin resistance, enhancing insulin sensitivity, providing glycemic control or treating insulin resistance-related disease by use of a glucagon receptor antagonist.

[0004] Description of Related Art

[0005] Prediabetes (intermediate hyperglycaemia) is a high-risk state for diabetes that is defined by glycaemic variables that are higher than normal, but lower than diabetes thresholds. 5-10% of people per year with prediabetes will progress to diabetes, with the same proportion converting back to normoglycaemia. Prevalence of prediabetes is increasing worldwide and experts have projected that more than 470 million people will have prediabetes by 2030. Prediabetes is associated with the simultaneous presence of insulin resistance and 0-cell dysfunction-abnormalities that start before glucose changes are detectable. Observational evidence showsassociations between prediabetes and early forms of nephropathy, chronic kidney disease, small fibre neuropathy, diabetic retinopathy, and increased risk of macrovascular disease. Multifactorial risk scores using non-invasive measures and blood-based metabolic traits, in addition to glycaemic values, could optimize estimation of diabetes risk.

[0006] For example, doctors most often use a fasting blood glucose (FPG) test or an A1C test to diagnose prediabetes. Doctors rarely use oral glucose tolerance tests (OGTT), which are more expensive and difficult to perfonn.

[0007] The A1C test reflects average blood sugar over the past 3 months.FPG and OGTT show blood glucose value at the time of the test. The A1C test is not as sensitive as other tests. In some people, the OGTT may miss possible prediabetes. The OGTT can detennine how body handles blood sugar after a meal, usually before fasting blood sugar values become abnormal. Doctors often use the OGTT to check for gestational diabetes, a type of diabetes that occurs during pregnancy.

[0008] The following test results show prediabetes.A1C - 5.7% to 6.4%FPG - 100 to 125 mg / dL (milligrams per deciliter)OGTT - 140 to 199 milligrams / deciliter

[0009] People with prediabetes have a 50% chance of developing diabetes within the next 5 to 10 years. Some steps may be used to control prediabetes and prevent type 2 diabetes. For prediabetic individuals, lifestyle modification is the cornerstone of diabetes prevention, with evidence of a 40-70% relative-risk reduction. Accumulating data also show potential benefits from pharmacotherapy.

[0010] On the other hands, strategies for the effective management of cardiovascular risk factors in patients with the metabolic syndrome (MS) ortype 2 diabetes mellitus (T2DM) are essential to help reduce cardiovascular morbidity and mortality. Treatment strategies should be multifactorial and include the promotion of therapeutic lifestyle changes, as well as pharmacologic therapies to treat individual risk factors according to current guidelines.

[0011] Some study indicates the importance of atherogenic dyslipidemia as a risk factor for the development of cardiovascular disease in patients with MS or T2DM. Current treatment options for managing this characteristic form of atherogenic dyslipidemia are limited and tend to be only moderately effective.

[0012] Therefore, it is desirable to provide novel strategies in clinical development.SUMMARY OF THE INVENTION

[0013] The present invention relates to methods for treating insulin resistance, enhancing insulin sensitivity, providing glycemic control or treating insulin resistance-related disease by use of a glucagon receptor antagonist, ALP001E.

[0014] An aspect of the present invention is drawn to a method for treating insulin resistance to a subject, comprising: administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of formula (I) (ALP001E), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof:

[0015] Another aspect of the present invention is drawn to a method for enhancing insulin sensitivity to a subject, comprising: administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of the above formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof.

[0016] Another aspect of the present invention is drawn to a method for providing glycemic control to a subject, comprising: administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of the above formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof.

[0017] Another aspect of the present invention is drawn to a method for treating an insulin resistance-related disease, comprising: administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of the above formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof.

[0018] In addition to the active ingredient of the formula (I) described above, their pharmaceutically acceptable salts and solvates, where applicable, are also covered by the present invention. A salt can be formed between an anion and a positively charged group (e.g., amino) on a compound.Examples of a suitable anion include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumurate, glutamate, glucuronate, lactate, glutarate, and maleate. A salt can also be formed between a cation and a negatively charged group. Examples of a suitable cation include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. A salt further includes those containing quaternary nitrogen atoms. A solvate refers to a complex formed between an active compound and a pharmaceutically acceptable solvent. Examples of a pharmaceutically acceptable solvent include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.

[0019] The pharmaceutical composition of the present invention can be administered to a subject orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrastemal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0020] In the present invention, the pharmaceutical composition can be an oral pharmaceutical composition, which can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions. Oral solid dosage forms can be prepared by spray dried techniques; hot melt extrusion strategy, micronization, and nano milling technologies. Alternatively, the pharmaceutical composition can be a nasal aerosol or inhalation composition, which can be prepared according to techniques well known in the art of pharmaceutical formulation. Furtheralternatively, the pharmaceutical composition of the present invention can also be administered in the form of suppositories for rectal administration.

[0021] The excipient in the pharmaceutical composition must be “acceptable” in the sense that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject to be treated.

[0022] The term “treating”, “treat” or “treatment” refers to application or administration of the active ingredient to a subject with the purpose to cure, alleviate, relieve, alter, remedy, improve, or affect the disease, the symptom, or the predisposition. “An effective amount” refers to the amount of the active ingredient which is required to confer the desired effect on the subject. Effective amounts vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments such as use of other active agents.

[0023] The term “weight percentages” (i.e., "% by weight" and "wt %" and w / w) referenced herein, unless otherwise indicated, are based on the total weight of the pharmaceutical composition unless specified otherwise.

[0024] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.BRIEF DESCRIPTION OF DRAWINGS

[0025] FIG. 1 is a diagram showing change from baseline on insulin resistance (HOMA2-IR) in the MAD study.

[0026] FIG. 2 is a diagram showing correlation of H0MA2-IR baseline and improvement.DETAILED DESCRIPTION OF THE INVENTION

[0027] Disclosed in detail below is a method for treating insulin resistance to a subject, comprising: administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof:(I). In particular, the subject is not treated with any other anti-diabetic drugs when administering the pharmaceutical composition of the present invention.

[0028] Disclosed in detail below is another method for enhancing insulin sensitivity to a subject, comprising: administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of the above formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof.

[0029] Disclosed in detail below is another method for providing glycemic control to a subject, comprising: administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of the above formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof.

[0030] Disclosed in detail below is another method for treating an insulin resistance-related disease, comprising: administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of the above formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof.

[0031] In one embodiment, the pharmaceutical composition may comprise: 8 wt% to 30 wt% of the compound of the formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof or the crystalline form thereof; and one or more excipients at least including a solubilizer present in an amount of 70 wt% to 92 wt%.

[0032] In one embodiment, the pharmaceutical composition comprises one excipient including the solubilizer.

[0033] In one embodiment, the compound of the formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof or the crystalline form thereof may be present in an amount of 8 wt% to 30 wt%, 9 wt% to 30 wt%, 9 wt% to 29 wt%, 9 wt% to 28 wt%, 10 wt% to 28 wt%, 11 wt% to 28 wt%, 12 wt% to 28 wt%, 13 wt% to 28 wt%, 13 wt% to 27 wt%, 14 wt% to 27 wt%, 14.5 wt to 27 wt%, 14.5 wt% to 26 wt%, 14.5 wt% to 25 wt%, 14.5 wt% to 24 wt%, 14.5 wt% to 23 wt%, 14.5 wt% to 22 wt%, 14.5 wt% to 21 wt%, 14.5 wt% to 20 wt%, 14.5 wt% to 19 wt%, 15 wt% to 19 wt%, 15 wt% to 18.5 wt% or 15.5 wt% to 18.5 wt%.

[0034] In one embodiment, the solubilizer may be present in an amount of 70 wt% to 92 wt%, 70 wt% to 91 wt%, 71 wt% to 91 wt%, 72 wt% to 91 wt%, 72 wt% to 90 wt%, 72 wt% to 89 wt%, 72 wt% to 88 wt%, 72 wt% to 87 wt%, 73 wt% to 87 wt%, 73 wt% to 86 wt%, 73 wt% to 85.5 wt%, 74 wt% to 85.5 wt%, 75 wt% to 85.5 wt%, 76 wt% to 85.5 wt%, 77 wt% to 85.5wt%, 78 wt% to 85.5 wt%, 79 wt% to 85.5 wt%, 80 wt% to 85.5 wt%, 81 wt% to 85.5 wt%, 81 wt% to 85 wt%, 81.5 wt% to 85 wt% or 81.5 wt% to 84.5 wt%.

[0035] In one embodiment, the solubilizer may include hydroxypropyl methylcellulose acetate succinate, Kolliphor HS 15 (also called as polyethylene glycol 660 12-hydoxystearate, macrogol-15-hydroxy stearate or macrogoli 15 hydroxystearas), or a combination thereof. In one embodiment, the solubilizer may include hydroxypropyl methylcellulose acetate succinate and Kolliphor HS 15. However, the present invention is not limited thereto, and any other solubilizer may be used in the pharmaceutical composition of the present invention according to the need.

[0036] In one embodiment, the used amount of the methylcellulose acetate succinate and Kolliphor HS 15 are not particularly limited and may be adjusted according to the need. For example, in one embodiment, the weight ratio of the methylcellulose acetate succinate to Kolliphor HS 15 may be 15:1 to 1:15, 15: 1 to 1:10, 15:1 to 1:5, 15:1 to 1:1, 15:1 to 5:1, 13:1 to 5:1, 13:1 to 8:1, 12:1 to 8:1, 12:1 to 9:1, 11:1 to 9:1 or 11 :1 to 10:1.

[0037] In one embodiment, the pharmaceutical composition may comprise: 15.77 wt% of the compound of the formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof or the crystalline form thereof; 76.97 wt% of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) MG; and 7.26 wt% of Kolliphor HS15.

[0038] In one embodiment, the pharmaceutical composition can be formulated into powders. Herein, the method for preparing the powders of the pharmaceutical composition may be a spray drying method, but the present invention is not limited thereto. The method for preparing the pharmaceutical composition can be referred to the disclosure ofUS20230355591, and the subject matter of which is incorporated herein by reference.

[0039] In one embodiment, the powders of the pharmaceutical composition can be placed inside a capsule. The material of the capsule can be, for example, gelatin.

[0040] In one embodiment, the powders of the pharmaceutical composition can be compressed to fonn a tablet, a granule or a particle. When the pharmaceutical composition is formulated into the tablet, the granule or the particle, the pharmaceutical composition may further comprise a coating layer, wherein the active ingredient and the excipients are included within the coating layer.

[0041] In one embodiment, the pharmaceutical composition can be an oral pharmaceutical composition, which can be formulated into powders, capsules, tablets or granules.

[0042] In one embodiment, the crystalline form of the compound of the formula (I) is characterized by an X-ray diffraction (XRD) pattern having peaks at 14.2, 15.6, 16.4, 20.1, 20.5 and 21.2° ± 0.2° 20. In one embodiment, the XRD pattern of the crystalline form of the compound of formula (I) may further have peaks at about 17.4, 21 .7 or 23.7° ± 0.2° 20. An exemplary crystalline form of the compound of formula (I) is characterized by the XRD pattern having peaks at about 14.2, 15.6, 16.4, 17.4, 20.1, 20.5, 21.2 and 21.7° ± 0.2° 20. Another exemplary crystalline form of the compound of formula (I) is characterized by the XRD pattern having peaks at about 14.2, 15.6, 16.4, 17.4, 20.1, 20.5, 21.2 and 23.7° ± 0.2° 20. Another exemplary crystalline form of the compound of formula (I) is characterized by the XRD pattern having peaks at about 14.2, 15.6, 16.4, 20.1, 20.5, 21.2, 21.7 and 23.7° ± 0.2° 20. Another exemplary crystalline form of the compound offormula (I) is characterized by the XRD pattern having peaks at about 14.2, 15.6, 16.4, 17.4, 20.1, 20.5, 21.2 and 23.7° ± 0.2° 20. The method for preparing the crystalline form of the compound of formula (I) can be referred to the disclosure of US2023131180, and the subject matter of which is incorporated herein by reference.

[0043] In one embodiment, the subject is resistant to other anti-diabetic drugs. Examples of other anti-diabetic drugs include, but are not limited to, sulfonylureas (such as glimepiride, glipizide and glyburide), biguanides (such as metformin), thiazolidinediones (Tzd) (such as pioglitazone and Actos generic), alpha-glucosidase inhibitors (such as acarbose) and meglitinides (such as nateglinide).

[0044] In one embodiment, the subject has insulin resistance. In one embodiment, the subject has extreme insulin resistance, also called as severe insulin resistance. Severe insulin resistance syndromes may be defined as a severely diminished response to insulin’s biological effects, and is characterized by substantial hyperinsulinemia, substantial metabolic abnonnalities, impaired glucose response to endogenous and exogenous insulin and a variety of clinical manifestations and complications.

[0045] In one embodiment, the compound of the formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof or the crystalline form thereof may be administered in an amount within a range from about 1 to about 500 mg / day, for example, about 10 to about 400 mg / day, about 10 to about 350 mg / day, about 20 to about 350 mg / day, about 20 to about 300 mg / day, about 30 to about 300 mg / day, about 30 to about 250 mg / day, about 40 to about 250 mg / day, or about 40 to about 200 mg / day. The administration amount of the compound of tire formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof or thecrystalline form thereof may be adjusted according to the needs. In addition, the pharmaceutical composition may be administered once a day (Q.D.), twice a day (B.I.D.), three times a day (T.I.D.) or four times a day (Q.I.D), but the present disclosure is not limited thereto and the administration times of the pharmaceutical composition may be adjusted according to the needs. For example, the administration times or the administration amount may be adjusted according to physiological status of the subject, disease severity of the subject, administration route and the like.

[0046] In one embodiment, the insulin resistance-related disease may be prediabetes, metabolic syndrome, cardiovascular disease or atherogenic dyslipidemia.

[0047] In one embodiment, the aforesaid subject may be mammal, for example, a human, a pig, a horse, a cow, a dog, a cat, a mouse or a rat.

[0048] The following embodiments are made to clearly exhibit the above- mentioned and other technical contents, features and / or effects of the present invention. Through the exposition by means of the specific embodiments, people would further understand the technical means and effects the present invention adopts to achieve the above-indicated objectives. Moreover, as the contents disclosed herein should be readily understood and can be implemented by a person skilled in the art, all equivalent changes or modifications which do not depart from the concept of the present invention should be encompassed by the appended claims.

[0049] Moreover, in the present specification, a value may be interpreted to cover a range within ±10% of the value, and in particular, a range within ±5% of the value, except otherwise specified; a range may be interpreted to be composed of a plurality of subranges defined by a smaller endpoint, asmaller quartile, a median, a greater quartile, and a greater endpoint, except otherwise specified.

[0050] Examples

[0051] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific examples are therefore to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications cited herein are incorporated by reference in their entirety.

[0052] The present disclosure is explained by the following embodiments, which are not used to limit the scope of the present disclosure. Unless specified otherwise, “%” used herein for indicating the amount of the contents or the objects in the following embodiments are weight percentage.

[0053] Example 1

[0054] The Phase 1 drug product was a spray dried powder (SDP) in a manually filled hard gelatin capsule consisting of ALP001E drug substance. Capsules for oral administration are white and hard-shell gelatin capsules (0EL size) manufactured and provided under Good Manufacturing Practices (GMP) conditions. ALP001E capsules for the Phase 1 clinical study were compounded and dispensed on-site under clean room conditions.

[0055] Table 1 : Components and composition of capsule formulation: 40 mg ALP001E capsule in phase 1 study

[0056] Example 2A phase 1 , randomized, double-blinded, placebo-controlled study to evaluate the safety, tolerability and pharmacokinetics of single and multiple ascending doses (MAD) of ALP001E in healthy subjects and patients with type 2 diabetes was conducted. In the MAD part, 16 patients with type 2 diabetes were randomized to placebo (N=4) or ALP001E treatment (N=12, 40 mg BID) for 14 days. In the MAD study, subjects were on a stable dose of metformin for >12 weeks without use of other antidiabetic medications for >3 weeks prior to randomization and maintain the dose until the end of the study;

[0057] Every patient proceeded with a 2-hour oral glucose tolerance test (OGTT) on day -1 prior to the beginning of ALP001E administration (day 0) and after 14 days consecutive ALP001E administration. Blood samples including fasting glucose and fasting insulin were collected after overnight fasting on day -1 prior to the beginning of ALP001E administration (day 0) and after 14 days consecutive ALP001E administration. Insulin resistance was estimated by calculating HOMA2-IR, using the HOMA Calculator.

[0058] FIG. 1 is a diagram showing change from baseline on insulin resistance (HOMA2-IR) in the MAD study, * p< 0.05 (t-test model).

[0059] The results indicate that, after 14 days treatment, ALP001E reduced insulin resistance represented by HOMA2-IR. Correlation of HOMA2-IRbaseline and improvement (R=-0.95).The improvement of H0MA2-IR change correlates with H0MA2-IR baseline in treatment group (R=-0.95).

[0060] FIG. 2 is a diagram showing correlation of HOMA2-IR baseline and improvement.

[0061] The results indicate that, after 14 days treatment, the improvement of HOMA2-1R change correlates with HOMA2-1R baseline in treatment group (R=-0.95).

[0062] In conclusion, the pharmaceutical composition comprising ALP001E may be used to treat insulin resistance, enhance insulin sensitivity, provide glycemic control, or treat an insulin resistance-related disease of a subject in need thereof.

[0063] All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

[0064] Further, from the above description, one skilled in the art can easily ascertain the essential characteristics of the present disclosure, and without departing from the spirit and scope thereof, can make various changes and modifications of the disclosure to adapt it to various usages and conditions. Thus, other embodiments are also within the claims.

Claims

Claims1. A method for treating insulin resistance to a subject, comprising: administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof:

2. The method of claim 1 , wherein the pharmaceutical composition comprises: 8 wt% to 30 wt% of the compound of the formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof or the crystalline form thereof; and one or more excipients at least including a solubilizer present in an amount of 70 wt% to 92 wt%.

3. The method of claim 2, wherein the pharmaceutical composition comprises: 15 wt% to 18.5 wt% of the compound of the formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof or the crystalline form thereof; and 81.5 wt% to 85 wt% of a solubilizer.

4. The method of claim 3, wherein the solubilizer includes hydroxypropyl methylcellulose acetate succinate, Kolliphor HS 15, or a combination thereof.

5. The method of claim 1, wherein the subject has insulin resistance.

6. The method of claim 1 , wherein the compound of the fonnula (I), the pharmaceutically acceptable salt thereof, the solvate thereof or the crystalline fonn thereof is administered in an amount within a range from about 1 to about 500 mg / day.

7. A method for enhancing insulin sensitivity to a subject, comprising: administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of fonnula (I), a pharmacally acceptable salt thereof, a solvate thereof or a crystalline form thereof:

8. The method of claim 7, wherein the pharmaceutical composition comprises: 8 wt% to 30 wt% of the compound of the formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof or the crystalline form thereof; and one or more excipients at least including a solubilizer present in an amount of 70 wt% to 92 wt%.

9. The method of claim 8, wherein the pharmaceutical composition comprises: 15 wt% to 18.5 wt% of the compound of the formula (1), the pharmaceutically acceptable salt thereof, the solvate thereof or the crystalline form thereof; and 81.5 wt% to 85 wt% of a solubilizer.

10. The method of claim 9, wherein the solubilizer includes hydroxypropyl methylcellulose acetate succinate, Kolliphor HS 15, or a combination thereof.

11. The method of claim 7, wherein the subject has insulin resistance.

12. The method of claim 7, wherein the compound of the fonnula (I), the pharmaceutically acceptable salt thereof, the solvate thereof or the crystalline fonn thereof is administered in an amount within a range from about 1 to about 500 mg / day.

13. A method for treating an insulin resistance-related disease, comprising: administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof:

14. The method of claim 13, wherein the pharmaceutical composition comprises: 8 wt% to 30 wt% of the compound of the formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof or the crystalline form thereof; and one or more excipients at least including a solubilizer present in an amount of 70 wt% to 92 wt%.

15. The method of claim 14, wherein the pharmaceutical composition comprises: 15 wt% to 18.5 wt% of the compound of the formula (1), the pharmaceutically acceptable salt thereof, the solvate thereof or the crystalline form thereof; and 81.5 wt% to 85 wt% of a solubilizer.

16. The method of claim 15, wherein the solubilizer includes hydroxypropyl methylcellulose acetate succinate, Kolliphor HS 15, or a combination thereof.

17. The method of claim 13, wherein the insulin resistance-related disease is prediabetes, metabolic syndrome, cardiovascular disease or atherogenic dyslipidemia.

18. The method of claim 13, wherein the compound of the formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof or the crystalline formthereof is administered in an amount within a range from about 1 to about 500 mg / day.

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