Method for reducing insulin resistance, or enhancing insulin sensitivity

Abstract

This disclosure provides a method for treating insulin resistance, enhancing insulin sensitivity, providing glycemic control, or treating insulin resistance-related diseases, comprising: administering a pharmaceutical composition to a subject, 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

[Technical Field]

[0001] This invention relates to methods for treating insulin resistance, enhancing insulin sensitivity, providing glycemic control, or treating insulin resistance-related diseases. More specifically, this invention relates to methods for using glucagon receptor antagonists to treat insulin resistance, enhance insulin sensitivity, provide glycemic control, or treat insulin resistance-related diseases. [Previous Technology]

[0002] Prediabetes (intermediate hyperglycemia) is a high-risk condition for diabetes, defined by a blood glucose level higher than normal but lower than the diabetes threshold. Each year, 5-10% of people with prediabetes will develop diabetes, and the same percentage will return to normal blood glucose levels. The global prevalence of prediabetes is increasing, and experts predict that more than 470 million people will have prediabetes by 2030. Prediabetes is associated with the coexistence of insulin resistance and abnormal β-cell function, which begin to appear before detectable changes in glucose. Observational evidence suggests an increased risk of prediabetes associated with early nephropathy, chronic kidney disease, small fiber neuropathy, diabetic retinopathy, and macrovascular disease. In addition to blood glucose levels, multivariate risk scoring using non-invasive measurements and blood-based metabolic traits can optimize the estimation of diabetes risk.

[0003] For example, physicians most commonly use fasting blood glucose (FPG) tests or A1C tests to diagnose prediabetes. Physicians rarely use oral glucose tolerance tests (OGTT), as these tests are more expensive and difficult to perform.

[0004] The A1C test reflects the average blood sugar level over the past 3 months. FPG and OGTT show the blood sugar level at the time of testing. The A1C test is not as sensitive as other tests. For some people, the OGTT may miss potential prediabetes. The OGTT can determine how the body processes postprandial blood sugar, usually before fasting blood sugar levels become abnormal. Doctors often use the OGTT to check for gestational diabetes, a type of diabetes that occurs during pregnancy.

[0005] The following test results indicate prediabetes.

[0005] A1C -5.7% to 6.4%

[0005] FPG - 100 mg / dL to 125 mg / dL (milligrams per deciliter)

[0005] OGTT - 140 mg / dL to 199 mg / dL

[0006] People with prediabetes have a 50% chance of developing diabetes within the next 5 to 10 years. Several steps can be taken to manage prediabetes and prevent type 2 diabetes. For individuals with prediabetes, lifestyle changes are the cornerstone of diabetes prevention, with evidence showing a relative risk reduction of 40%-70%. Cumulative data also demonstrate the potential benefits of medication.

[0007] On the other hand, strategies for effectively managing cardiovascular risk factors in patients with metabolic syndrome (MS) or type 2 diabetes mellitus (T2DM) are crucial to helping reduce cardiovascular morbidity and mortality. Treatment strategies should be multifactorial, including promoting therapeutic lifestyle changes and administering pharmacological therapy according to current guidelines to treat individual risk factors.

[0008] Some studies have shown the importance of atherogenic dyslipidemia as a risk factor for cardiovascular disease in patients with MS or T2DM. Currently, treatment options for this characteristic atherogenic dyslipidemia are limited and often have limited efficacy.

[0009] Therefore, it is hoped that new strategies can be provided in clinical development. [Summary of the Invention]

[0010] This invention relates to a method of using the glucagon receptor antagonist ALP001E to treat insulin resistance, enhance insulin sensitivity, provide glycemic control, or treat insulin resistance-related diseases.

[0011] One aspect of the present invention relates to a method for treating insulin resistance, comprising: administering a pharmaceutical composition to a subject, 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:

[0011]

[0012] Another aspect of the present invention relates to a method for enhancing insulin sensitivity, comprising: applying a pharmaceutical composition to a subject, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of formula (I) above, a pharmaceutically acceptable salt thereof, a solvate thereof, or a crystalline form thereof.

[0013] Another aspect of the present invention relates to a method for providing blood glucose control, comprising: applying a pharmaceutical composition to a subject, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of formula (I) above, a pharmaceutically acceptable salt thereof, a solvate thereof, or a crystalline form thereof.

[0014] Another aspect of the present invention relates to a method for treating insulin resistance-related diseases, comprising: applying a pharmaceutical composition to a subject, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of formula (I) above, a pharmaceutically acceptable salt thereof, a solvate thereof, or a crystalline form thereof.

[0015] In addition to the active ingredients of formula (I) above, pharmaceutically acceptable salts and solvates thereof are also covered in this invention, if applicable. Salts can be formed between anion and a positively charged group (e.g., an amino group) on the compound. Examples of suitable anions include chlorine, bromine, iodine, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumurate, glutamate, glucuronate, lactate, glutarate, and maleate. Salts can also be formed between a cation and a negatively charged group. Examples of suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium ions. Salts further include those containing a quaternary nitrogen atom. A solvate is a complex formed between an active compound and a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.

[0016] The pharmaceutical composition of the present invention can be administered to the subject orally, parenterally, via inhalation spray, topically, rectally, nasally, buccally, or via an implanted reservoir. The term "parentereal" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0017] In this 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 using spray drying technology, hot melt extrusion strategy, micronization, and nano milling technologies. Alternatively, the pharmaceutical composition can be a nasal spray or inhalation composition, which can be prepared using techniques known in the field of pharmaceutical dosage forms. Alternatively, the pharmaceutical composition of this invention can also be used in the form of suppositories for rectal administration.

[0018] In a sense, the excipients in a pharmaceutical composition must be "acceptable", compatible with the active ingredient of the composition (and preferably a stable active ingredient), and harmless to the subject of treatment.

[0019] The term "treatment" refers to the administration or application of an active ingredient to a subject for the purpose of curing, alleviating, resolving, altering, remedying, improving, or influencing a disease, symptom, or predisposition. "Effective amount" refers to the amount of active ingredient required to achieve the desired effect on the subject. As those skilled in the art will know, the effective amount can vary depending on the route of administration, the use of excipients, and the possibility of co-administration with other pharmaceutical treatments (such as the use of other active agents).

[0020] Unless otherwise stated, the term “weight percentage” (i.e., weight % and “wt%” and “w / w”) used herein is based on the total weight of the pharmaceutical composition.

[0021] Details of one or more embodiments of the present invention are described below, and other features, objects and advantages of the present invention will be apparent from the specification and the scope of the patent application. [Simplified Explanation of the Diagram]

[0022] Figure 1 is a graph showing the change in insulin resistance (HOMA2-IR) relative to baseline in the MAD study.

[0022] Figure 2 is a graph showing the correlation between the HOMA2-IR baseline and the improvement.

Implementation Method

[0023] The following discloses in detail a method for treating insulin resistance, comprising: administering a pharmaceutical composition to a subject, 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:

[0023] . Specifically, when the pharmaceutical composition of the present invention is applied, the subject is not treated with any other anti-diabetic drug.

[0024] Another method for enhancing insulin sensitivity is disclosed in detail below, comprising: administering a pharmaceutical composition to a subject, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of formula (I) above, a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof.

[0025] Another method for providing blood glucose control is disclosed in detail below, comprising: administering a pharmaceutical composition to a subject, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of formula (I) above, a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof.

[0026] The following discloses in detail another method for treating insulin resistance-related diseases, comprising: administering a pharmaceutical composition to a subject, wherein the pharmaceutical composition comprises: a therapeutically effective amount of a compound of formula (I) above, a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof.

[0027] In one embodiment, the pharmaceutical composition may comprise: 8 wt% to 30 wt% of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a crystalline form thereof; and one or more excipients present in an amount of 70 wt% to 92 wt%, comprising at least one solubilizer.

[0028] In one embodiment, the pharmaceutical composition comprises an excipient containing a solubilizer.

[0029] In one embodiment, the compound of formula (I), its pharmaceutically acceptable salt, its solvate, or its crystalline form may be 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 14.5 wt%. It is present in amounts of t% to 27wt%, 14.5wt% to 26wt%, 14.5wt% to 25wt%, 14.5wt% to 24wt%, 14.5wt% to 23wt%, 14.5wt% to 22wt%, 14.5wt% to 21wt%, 14.5wt% to 20wt%, 14.5wt% to 19wt%, 15wt% to 19wt%, 15wt% to 18.5wt%, or 15.5wt% to 18.5wt%.

[0030] In one embodiment, the solubilizer may be present in amounts of 70wt% to 92wt%, 70wt% to 91wt%, 71wt% to 91wt%, 72wt% to 91wt%, 72wt% to 90wt%, 72wt% to 89wt%, 72wt% to 88wt%, 72wt% to 87wt%, 73wt% to 87wt%, 73wt% to 86wt%, 73wt% to 85.5wt%, 74wt% to 85.5wt%, 75wt% to 85.5wt%, 76wt% to 85.5wt%, 77wt% to 85.5wt%, 78wt% to 85.5wt%, 79wt% to 85.5wt%, 80wt% to 85.5wt%, 81wt% to 85.5wt%, 81wt% to 85wt%, 81.5wt% to 85wt%, or 81.5wt% to 84.5wt%.

[0031] In one embodiment, the solubilizer may comprise hydroxypropyl methylcellulose acetate succinate, Kolliphor HS 15 (also known as polyethylene glycol 660 12-hydroxystearate, polyethylene glycol-15-hydroxystearate, or polyethylene glycol 15-hydroxystearate) or a combination thereof. In one embodiment, the solubilizer may comprise hydroxypropyl methylcellulose acetate succinate and Kolliphor HS 15. However, the invention is not limited thereto, and any other solubilizer may be used in the pharmaceutical compositions of the invention as needed.

[0032] In one embodiment, the amount of hydroxypropyl methylcellulose acetate succinate and Kolliphor HS 15 is not particularly limited and can be adjusted as needed. For example, in one embodiment, the weight ratio of hydroxypropyl methylcellulose acetate succinate to Kolliphor HS 15 can 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.

[0033] In one embodiment, the pharmaceutical composition may comprise: 15.77 wt% of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or its crystalline form; 76.97 wt% of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) MG; and 7.26 wt% of Kolliphor HS 15.

[0034] In one embodiment, the pharmaceutical composition may be formulated into a powder. Here, the method for preparing the powder of the pharmaceutical composition may be spray drying, but the present invention is not limited thereto. Methods for preparing the pharmaceutical composition can be found in US20230355591, the contents of which are incorporated herein by reference.

[0035] In one embodiment, the powder of the pharmaceutical composition may be placed inside a capsule. The capsule material may be, for example, gelatin.

[0036] In one embodiment, the powder of the pharmaceutical composition may be compressed into tablets, granules, or pellets. When the pharmaceutical composition is formulated into tablets, granules, or pellets, the pharmaceutical composition may further include a coating in which the active ingredient and excipients are contained.

[0037] In one embodiment, the pharmaceutical composition may be an oral pharmaceutical composition, which may be formulated as a powder, capsule, tablet or granule.

[0038] In one embodiment, the crystal form of the compound (I) is characterized by X-ray diffraction (XRD) patterns having peaks at 14.2°, 15.6°, 16.4°, 20.1°, 20.5°, and 21.2° ± 0.2° 2θ. In another embodiment, the XRD patterns of the crystal form of the compound (I) may further have peaks at 17.4°, 21.7°, or 23.7° ± 0.2° 2θ. An exemplary crystal form of the compound (I) is characterized by XRD patterns having peaks at 14.2°, 15.6°, 16.4°, 17.4°, 20.1°, 20.5°, 21.2°, and 21.7° ± 0.2° 2θ. Another exemplary crystalline form of the compound of formula (I) is characterized by XRD patterns having peaks at 14.2°, 15.6°, 16.4°, 17.4°, 20.1°, 20.5°, 21.2°, and 23.7° ± 0.2° 2θ. The preparation method of the crystal form of compound (I) can be found in US2023131180, the contents of which are incorporated herein by reference.

[0039] In one embodiment, the subject is resistant to other antidiabetic drugs. Examples of other antidiabetic drugs include, but are not limited to, sulfonylureas (e.g., glimepiride, glipizide, and glyburide), biguanides (e.g., metformin), thiazolidinediones (Tzd) (e.g., pioglitazone and Actos generic), alpha-glucosidase inhibitors (e.g., acarbose), and meglitinides (e.g., nateglinide).

[0040] In one embodiment, the subject has insulin resistance. In another embodiment, the subject has extreme insulin resistance, also known as severe insulin resistance. Severe insulin resistance syndrome can be defined as a severely impaired response to the biological effects of insulin, characterized by massive hyperinsulinemia, numerous metabolic abnormalities, impaired glucose response to both endogenous and exogenous insulin, and a variety of clinical manifestations and complications.

[0041] In one embodiment, the compound of formula (I), its pharmaceutically acceptable salt, its solvate, or its crystalline form may be administered in amounts ranging from about 1 mg / day to about 500 mg / day, for example, about 10 mg / day to about 400 mg / day, about 10 mg / day to about 350 mg / day, about 20 mg / day to about 350 mg / day, about 20 mg / day to about 300 mg / day, about 30 mg / day to about 300 mg / day, about 30 mg / day to about 250 mg / day, about 40 mg / day to about 250 mg / day, or about 40 mg / day to about 200 mg / day. The dosage of the compound of formula (I), its pharmaceutically acceptable salt, its solvate, or its crystalline form may be adjusted as needed. Furthermore, the pharmaceutical composition may be administered once daily (QD), twice daily (BID), three times daily (TID), or four times daily (QID), but this disclosure is not limited thereto, and the frequency of administration of the pharmaceutical composition may be adjusted as needed. For example, the frequency or dosage of administration can be adjusted based on the subject's physiological state, the severity of the subject's disease, and the route of administration.

[0042] In one embodiment, insulin resistance-related diseases may be prediabetes, metabolic syndrome, cardiovascular disease, or atherogenic dyslipidemia.

[0043] In one embodiment, the subject may be a mammal, such as a human, pig, horse, cow, dog, cat, mouse or rat.

[0044] The following embodiments are provided to clearly demonstrate the above and other technical contents, features, and / or effects of the present invention. Through the description of specific embodiments, one will further understand the technical means and effects adopted by the present invention to achieve the above objectives. Furthermore, the contents disclosed herein can be readily understood and implemented by those skilled in the art to which this invention pertains; therefore, all equivalent variations or modifications without departing from the concept of the present invention should be included in the appended claims.

[0045] Furthermore, in this specification, unless otherwise stated, a value may be interpreted as a range covering ±10% of that value, and more specifically, a range covering ±5% of that value; unless otherwise stated, a range may be interpreted as a subrange of a complex number defined by the smaller endpoint, the smaller quartile, the median, the larger quartile, and the larger endpoint.

[0046] Example

[0047] Without further detail, it is believed that those skilled in the art to which this invention pertains can utilize the invention to the fullest extent based on the above description. Therefore, the following specific embodiments should be interpreted as merely illustrative and not as limiting the remainder of this disclosure in any way. All publications cited herein are incorporated herein by reference in their entirety.

[0048] This disclosure is explained by way of the following embodiments, which are not intended to limit the scope of this disclosure. Unless otherwise stated, in the following embodiments, "%" as used herein is used to indicate the amount of contents or object, in weight percentage.

[0049] Example 1

[0050] The Phase 1 pharmaceutical product is a spray-dried powder (SDP) in manually filled hard gelatin capsules, composed of ALP001E active pharmaceutical ingredient. The oral capsules refer to white hard-shell gelatin capsules (OEL size) manufactured and supplied under Good Manufacturing Practice (GMP) conditions. ALP001E capsules for Phase 1 clinical studies are prepared and dispensed on-site under cleanroom conditions.

[0051] Table 1: Ingredients and composition of capsule formulations: 40mg ALP001E capsules in a phase I study

[0051]

[0052] Example 2

[0053] A randomized, double-blind, placebo-controlled phase I study was conducted 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. In the MAD portion, 16 patients with type 2 diabetes were randomized to receive either placebo (N=4) or ALP001E (N=12, 40 mg BID) for 14 days. In the MAD study, subjects had taken a stable dose of metformin for ≥12 weeks prior to randomization and had not used other antidiabetic medications for more than 3 weeks prior to randomization, and maintained this dose until the end of the study.

[0054] Each patient underwent a 2-hour oral glucose tolerance test (OGTT) on day 0 (1 day prior to ALP001E initiation) and after 14 consecutive days of ALP001E initiation. Blood samples containing fasting blood glucose and fasting insulin were collected on day 0 (1 day prior to ALP001E initiation) after overnight fasting and after 14 consecutive days of ALP001E initiation. Insulin resistance was estimated by calculating HOMA2-IR using a HOMA calculator.

[0055] Figure 1 shows the change in insulin resistance (HOMA2-IR) relative to baseline in the MAD study, *p<0.05 (t-detection model).

[0056] The results showed that after 14 days of treatment, ALP001E reduced insulin resistance, represented by HOMA2-IR. The correlation between baseline HOMA2-IR and improvement was -0.95. In the treatment group, the improvement in HOMA2-IR was correlated with baseline HOMA2-IR (R=-0.95).

[0057] Figure 2 shows the correlation between the HOMA2-IR baseline and the improvement.

[0058] The results showed that, after 14 days of treatment, the improvement in HOMA2-IR changes in the treatment group was correlated with the baseline HOMA2-IR (R=-0.95).

[0059] In summary, pharmaceutical compositions containing ALP001E can be used to treat insulin resistance in subjects in need, enhance insulin sensitivity, provide glycemic control, or treat insulin resistance-related diseases.

[0060] All features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature having the same, equivalent, or similar purpose. Therefore, unless otherwise expressly stated, each feature disclosed is merely an example of a series of equivalent or similar features.

[0061] Furthermore, based on the above description, those skilled in the art to which this invention pertains can readily determine the essential features of this disclosure, and can make various changes and modifications to this disclosure to adapt it to various uses and conditions without departing from the spirit and scope of this disclosure. Therefore, other embodiments are also within the scope of the patent application.

Claims

1. The use of a pharmaceutical composition in the preparation of a drug for reducing insulin resistance, wherein, The pharmaceutical composition comprises: a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvation thereof; 2. The use as described in claim 1, wherein, The pharmaceutical composition comprises: 8 wt% to 30 wt% of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvation thereof; and one or more excipients present in an amount of 70 wt% to 92 wt%, comprising at least one solubilizer.

3. The use as described in claim 2, wherein, The pharmaceutical composition comprises: 15 wt% to 18.5 wt% of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvation thereof; and 81.5 wt% to 85 wt% of a solubilizer.

4. The use as described in claim 3, wherein, The solubilizer comprises hydroxypropyl methylcellulose succinate, Kolliphor HS 15, or a combination thereof.

5. The use as described in claim 1, wherein, This organism exhibits insulin resistance.

6. The use as described in claim 1, wherein, Compound of formula (I), its pharmaceutically acceptable salt, or its solvation may be administered in amounts ranging from 1 mg / day to 500 mg / day.

7. The use as described in claim 1, wherein, This drug treats insulin resistance-related diseases by reducing insulin resistance.

8. The use as described in claim 7, wherein, The insulin resistance-related diseases mentioned are prediabetes, metabolic syndrome, cardiovascular disease, or atherosclerotic dyslipidemia.

9. The use of a pharmaceutical composition in the preparation of a drug for enhancing insulin sensitivity, wherein, The pharmaceutical composition comprises: a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvation thereof; 10. The use as described in claim 9, wherein, The pharmaceutical composition comprises: 8 wt% to 30 wt% of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvation thereof; and one or more excipients present in an amount of 70 wt% to 92 wt%, comprising at least one solubilizer.

11. The use as described in claim 10, wherein, The pharmaceutical composition comprises: 15 wt% to 18.5 wt% of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvation thereof; and 81.5 wt% to 85 wt% of a solubilizer.

12. The use as described in claim 11, wherein, The solubilizer comprises hydroxypropyl methylcellulose succinate, Kolliphor HS 15, or a combination thereof.

13. The use as described in claim 9, wherein, This organism exhibits insulin resistance.

14. The use as described in claim 9, wherein, Compound of formula (I), its pharmaceutically acceptable salt, or its solvation may be administered in amounts ranging from 1 mg / day to 500 mg / day.

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