Use of compounds and pharmaceutical compositions thereof in the preparation of a medicament for the treatment of myopia

Abstract

This disclosure relates to the use of compounds and pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of myopia. The compounds disclosed herein are medicaments for treating diabetes, selected from at least one of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, insulin sensitizers, or dipeptidyl peptidase-4 inhibitors. This disclosure provides novel compounds for the prevention and / or treatment of myopia, and to further improve efficacy, this disclosure also provides pharmaceutical compositions comprising said compounds.

Description

Technical Field

[0001] This disclosure relates to the pharmaceutical field, and more particularly to the use of compounds and pharmaceutical compositions thereof in the preparation of medicaments for the treatment and / or prevention of myopia. Background Technology

[0002] Myopia, the most common refractive error, refers to a refractive state in which, in a relaxed state of accommodation, parallel light rays, after refraction by the eye's refractive system, focus in front of the retina. Currently, myopia is one of the most serious public health problems globally. Early literature indicated that in 2010, the number of people with myopia worldwide approached 1.84 billion, accounting for 27% of the world's total population at that time. Among them, 170 million people had high myopia, accounting for 2.8%. Particularly in East Asia, such as China, Japan, South Korea, and Singapore, the prevalence of myopia is close to 50%, far higher than in Australia, Europe, and the Americas. It is projected that by 2050, the global prevalence of myopia will reach over 50%. The incidence of myopia among children and adolescents aged 6 to 18 in my country is particularly severe. Therefore, the prevention and treatment of myopia has become an important topic in medical research and public health.

[0003] Currently, methods for controlling and slowing the progression of myopia mainly include optical correction, environmental intervention, and drug therapy. Among these, drug therapy has received increasing attention in recent years due to its non-invasive nature and wide applicability. In the field of drug therapy, antimuscarinic drugs (such as atropine sulfate) are considered one of the current means of controlling myopia progression. However, the use of antimuscarinic drugs has certain limitations, such as the potential for long-term side effects like photophobia and decreased accommodative function. At present, the drugs available on the market for treating myopia are relatively limited and not suitable for all myopic individuals. Therefore, there is an urgent need to develop new drugs to prevent, control, or treat myopia to meet the clinical needs of different populations. Summary of the Invention

[0004] In view of this, this disclosure provides the use of compounds and pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of myopia, with the aim of providing novel medicaments for the prevention and / or treatment of myopia.

[0005] According to one embodiment of this disclosure, a compound, or a tautomer, stereoisomer, enantiomer, diastereomer, racemic mixture, solvate, isotope derivative, basic form, prodrug, acidic form, metabolite, ester, pharmaceutically acceptable salt, or solvate thereof, is provided for use in the preparation of a medicament for the prevention and / or treatment of myopia, wherein the compound is a medicament for treating diabetes, the medicament for treating diabetes being selected from at least one of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, insulin sensitizers, or dipeptidyl peptidase-4 inhibitors.

[0006] According to one embodiment of the present disclosure, the use of a pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of myopia is provided, wherein the pharmaceutical composition comprises a compound and a pharmaceutically acceptable excipient, the compound being a medicament for treating diabetes, the medicament for treating diabetes comprising at least one of a glucagon-like peptide-1 receptor agonist, a sodium-glucose cotransporter 2 inhibitor, an insulin sensitizer, or a dipeptidyl peptidase-4 inhibitor.

[0007] The compounds and drug combinations disclosed herein offer new ideas and options for the prevention and / or treatment of myopia, meeting more clinical needs of the public.

[0008] The above description is merely an overview of the technical solution disclosed herein. In order to better understand the technical means of this disclosure and to implement it in accordance with the contents of the specification, and to make the above and other objects, features and advantages of this disclosure more apparent and understandable, specific embodiments of this disclosure are described below. Detailed Implementation

[0009] Unless otherwise stated, all figures used in this specification and claims to represent content, concentration, proportion, weight, particle size, percentage, technical effect, etc., should in any instance be understood to be modified by the terms “about” or “approximately”. Therefore, unless indicated to the contrary, the numerical parameters listed in the following specification and appended claims are approximate values. Unless otherwise stated, the terminology used herein has its common meaning as understood by one of ordinary skill in the art. It may vary for those skilled in the art depending on the desired properties and effects sought through this disclosure, and each numerical parameter should be interpreted according to the number of significant figures and conventional rounding methods or as understood by those skilled in the art.

[0010] Although the numerical ranges and parameters described in this disclosure are approximate, the values ​​presented in the specific embodiments are provided as precisely as possible. However, any numerical value will inherently contain some errors, which are necessarily caused by the standard deviation found in its corresponding test measurements. Each numerical range given in this specification will include every narrower numerical range falling within that wider range, as if these narrower numerical ranges were explicitly stated herein.

[0011] When used in this document, the expression “A, B, C and / or D” includes fifteen cases: (1) A; (2) B; (3) C; (4) D; (5) A and B; (6) A and C; (7) A and D; (8) B and C; (9) B and D; (10) C and D; (11) A, B and C; (12) A, B and D; (13) A, C and D; (14) B, C and D; and (15) A, B, C and D. The meanings of similar expressions can be deduced by analogy.

[0012] Uses of compounds

[0013] This disclosure discloses the use of a compound, or a tautomer, stereoisomer, enantiomer, diastereomer, racemic mixture, solvate, isotope derivative, basic form, prodrug, acidic form, metabolite, ester, pharmaceutically acceptable salt, or solvate thereof, in the preparation of a medicament for the prevention and / or treatment of myopia, wherein the compound is a medicament for the treatment of diabetes, and the medicament for the treatment of diabetes is selected from at least one of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, insulin sensitizers, or dipeptidyl peptidase-4 inhibitors.

[0014] When used in this document, the term “treatment” means to alleviate or improve a disease or disorder (i.e., to slow or stop the development of the disease or at least one clinical symptom); or to alleviate or improve at least one physical parameter or biomarker associated with the disease or disorder.

[0015] When used in this document, the term "medication for the treatment of diabetes" means a drug that can alleviate or improve the development of at least one clinical symptom of diabetes, and / or a drug that can alleviate or improve at least one physical parameter or biomarker associated with diabetes.

[0016] When used in this paper, the term "tautomer" refers to two isomers containing heteroatoms (such as nitrogen, oxygen, or sulfur atoms) whose structural differences lie only in the migration of protons and corresponding double bonds, and which coexist in an equilibrium system and transform into each other at a fairly high rate.

[0017] When used in this article, the term "stereoisomer" refers to an isomer resulting from the different spatial arrangements of atoms in a molecule.

[0018] When used in this document, the term "enantiomer" refers to a stereoisomer that is a real object and its mirror image but cannot be superimposed.

[0019] When used in this document, the term “diastereomer” refers to a stereoisomer that has two or more chiral centers and is not a mirror image of the other molecules.

[0020] When used in this document, the term "racemate" refers to an equimolar mixture of an optically active chiral molecule and its enantiomer.

[0021] As used herein, the term "solvent" refers to the association of one or more solvent molecules with the pharmaceutically active ingredient or a salt thereof disclosed herein. Solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, ethyl acetate, or acetic acid.

[0022] As used herein, the term "isotope derivative" refers to a chemical structure having the pharmaceutical active ingredient of this disclosure, wherein one or more atoms are replaced by isotopic atoms having a selected atomic mass or mass number. Isotopes that may be incorporated into the pharmaceutical active ingredient of this disclosure include, for example, isotopes of hydrogen.

[0023] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological activity required to preserve the active pharmaceutical ingredient of this common drug and exhibits lower undesirable toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound, in its free acid or free base form, separately with a suitable base or acid.

[0024] In some embodiments of this disclosure, a pharmaceutically acceptable acid addition salt can be formed using inorganic and organic acids. The inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid. The organic acids include acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, or sulfosalicylic acid.

[0025] In some embodiments, a pharmaceutically acceptable base addition salt can be formed using an inorganic base and an organic base. The inorganic base includes, for example, ammonium salts and metals from columns I to XII of the periodic table. The organic base includes, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; basic ion exchange resins, etc. In some specific embodiments, the organic base includes isopropylamine, benzylamine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, or tromethamine, etc.

[0026] In some embodiments of this disclosure, the glucagon-like peptide-1 receptor agonist includes at least one selected from exenatide, liraglutide, abiglutide, lixisenatide, beraglutide, loxenatide, or semaglutide.

[0027] When used in this article, exenatide refers to the compound with CAS number 133514-43-9.

[0028] When used in this article, liraglutide refers to the compound with CAS number 204656-20-2.

[0029] When used in this article, abiglutide refers to the compound with CAS number 782500-75-8.

[0030] When used in this article, lixanatide refers to the compound with CAS number 320367-13-3.

[0031] When used in this article, beraglutide refers to the compound with CAS number 123475-27-4.

[0032] When used in this article, loxenatide refers to the compound with CAS number 2420483-82-3.

[0033] When used in this article, semaglutide refers to the compound with CAS number 910463-68-2.

[0034] After the human body ingests food, intestinal L cells secrete glucagon-like peptide-1 (GLP-1), which, upon binding to its receptor, stimulates pancreatic β cells to secrete insulin and inhibits pancreatic α cells to secrete glucagon, thereby exerting a hypoglycemic effect. This disclosure reveals a novel use of GLP-1 receptor agonists in the preparation of drugs for the prevention and / or treatment of myopia.

[0035] In some embodiments of this disclosure, the sodium-glucose cotransporter 2 inhibitor includes at least one of empagliflozin, canagliflozin, dapagliflozin, etoragliflozin, lupugliflozin, repaggliflozin, or soragliflozin.

[0036] When used in this article, empagliflozin refers to the compound with CAS number 864070-44-0, which has the following chemical structural formula:

[0037]

[0038] When used in this article, canagliflozin refers to the compound with CAS number 842133-18-0, which has the following chemical structural formula:

[0039]

[0040] When used in this article, dapagliflozin refers to the compound with CAS number 461432-26-8, which has the following chemical structural formula:

[0041]

[0042] When used in this article, eletoggliflozin refers to the compound with CAS number 1210344-83-4, which has the following chemical structural formula:

[0043]

[0044] When used in this article, ruggliflozin refers to the compound with CAS number 898537-18-3, which has the following chemical structural formula:

[0045]

[0046] When used in this article, regorafenib refers to the compound with CAS number 442201-24-3, which has the following chemical structural formula:

[0047]

[0048] When used in this article, soragliflozin refers to the compound with CAS number 1018899-04-1, which has the following chemical structural formula:

[0049]

[0050] Sodium-glucose cotransporter 2 (SGLT2) inhibitors can lower blood glucose levels by inhibiting SGLT2. This disclosure reveals a novel use of SGLT inhibitors in the preparation of medicaments for the prevention and / or treatment of myopia.

[0051] In some embodiments of this disclosure, the insulin sensitizer includes at least one of pioglitazone or troglitazone.

[0052] When used in this article, pioglitazone refers to the compound with CAS number 146062-45-5, which has the following chemical structural formula:

[0053]

[0054] When used in this article, troglitazone refers to the compound with CAS number 97322-87-7, which has the following chemical structural formula:

[0055]

[0056] Insulin sensitizers can improve insulin sensitivity in patients with insulin resistance, enhance cellular responsiveness to insulin, and improve glucose homeostasis. This disclosure reveals a novel use of insulin sensitizers in the preparation of medicaments for the prevention and / or treatment of myopia.

[0057] In some embodiments of this disclosure, the dipeptidyl peptidase-4 inhibitor includes at least one of vildagliptin, linagliptin, sitagliptin, saxagliptin, alogliptin, giglitazone, or ticagliptin. In some embodiments of this disclosure, the dipeptidyl peptidase-4 inhibitor includes at least one of vildagliptin or linagliptin.

[0058] When used in this article, vildagliptin refers to the compound with CAS number 274901-16-5, which has the following chemical structural formula:

[0059]

[0060] When used in this article, linagliptin refers to the compound with CAS number 668270-12-0, which has the following chemical structural formula:

[0061]

[0062] When used in this article, sitagliptin refers to the compound with CAS number 486460-32-6, which has the following chemical structural formula:

[0063]

[0064] When used in this article, saxagliptin refers to the compound with CAS number 361442-04-8, which has the following chemical structural formula:

[0065]

[0066] When used in this article, alogliptin refers to the compound with CAS number 850649-61-5, which has the following chemical structural formula:

[0067]

[0068] When used in this article, gilgliptin refers to the compound with CAS number 911637-19-9, which has the following chemical structural formula:

[0069]

[0070] When used in this article, ticagliptin refers to the compound with CAS number 906093-29-6, which has the following chemical structural formula:

[0071]

[0072] Dipeptidyl peptidase-4 inhibitors increase insulin levels in the body by blocking the degradation of insulin by dipeptidyl peptidase-4, thereby controlling blood sugar. This disclosure reveals a novel use of dipeptidyl peptidase-4 inhibitors in the preparation of drugs for the prevention and / or treatment of myopia.

[0073] In some embodiments of this disclosure, the myopia is prevented and / or treated by inhibiting axial elongation.

[0074] In some embodiments of this disclosure, the myopia is prevented and / or treated by suppressing changes in refractive power.

[0075] Use of pharmaceutical compositions

[0076] This disclosure also provides the use of the pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of myopia, wherein the pharmaceutical composition comprises a compound and a pharmaceutically acceptable excipient, the compound being a medicament for the treatment of diabetes, the compound comprising at least one of a glucagon-like peptide-1 receptor agonist, a sodium-glucose cotransporter 2 inhibitor, an insulin sensitizer, or a dipeptidyl peptidase-4 inhibitor.

[0077] In some embodiments of this disclosure, the glucagon-like peptide-1 receptor agonist includes at least one of exenatide, liraglutide, abiglutide, lixisenatide, beraglutide, loxenatide, or semaglutide.

[0078] In some embodiments of this disclosure, the sodium-glucose cotransporter 2 inhibitor includes at least one of empagliflozin, canagliflozin, dapagliflozin, etoragliflozin, ruggliflozin, repaggliflozin, or soagliflozin.

[0079] In some embodiments of this disclosure, the insulin sensitizer includes at least one of pioglitazone or troglitazone.

[0080] In some embodiments of this disclosure, the dipeptidyl peptidase-4 inhibitor includes at least one of vildagliptin, linagliptin, sitagliptin, saxagliptin, alogliptin, giglitazone, or ticagliptin.

[0081] In some embodiments of this disclosure, the myopia is prevented or treated by inhibiting axial elongation and / or inhibiting changes in refractive power.

[0082] In some embodiments, the pharmaceutical composition may be any dosage form, such as a solution (e.g., eye drops), cream, lotion, ointment, emulsion, aerosol, non-aerosol spray, gel, ointment, or suspension. In some embodiments, the pharmaceutical composition may be a solution.

[0083] In some embodiments of this disclosure, the pharmaceutically acceptable excipients include at least one of pH adjusters, osmotic pressure regulators, thickeners, or surfactants.

[0084] In some embodiments of this disclosure, the pH adjuster includes at least one of hydrochloric acid, boric acid, phosphoric acid, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, borax, acetic acid, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, acetate buffer, citrate buffer, or borate buffer.

[0085] In some embodiments of this disclosure, the osmotic pressure regulator includes at least one of sodium chloride, mannitol, glycerol, laurocapram, potassium chloride, boric acid, borax, sodium sulfate, potassium sulfate, sodium nitrate, potassium nitrate, sodium acetate, propylene glycol, sorbitol, 2-(4-n-octylphenylethyl)-2-aminopropanediol hydrochloride, glucose, sucrose, fructose, or lactose.

[0086] In some embodiments of this disclosure, the thickener includes at least one of sodium hyaluronate, carbomer, polycarbofil, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, or povidone.

[0087] In some embodiments of this disclosure, the surfactant includes a nonionic surfactant. In some embodiments of this disclosure, the nonionic surfactant includes at least one selected from polysorbate, tylosap, polyoxyethylene castor oil, poloxamer, polyethylene glycol, or hydroxypropyl-β-cyclodextrin.

[0088] Adding the above-mentioned surfactants helps to improve the solubility of the compound in the solvent, which in turn helps to improve the efficacy of the drug composition.

[0089] When used in this document, the term "solubility" refers to the mass of solute that dissolves in 100g of solvent at a given temperature (e.g., 25°C) to reach saturation.

[0090] In some embodiments of this disclosure, the amount of surfactant added can be determined based on the solubility properties of the compound. In some embodiments of this disclosure, the amount of surfactant added can be expressed as a mass-volume percentage. The mass-volume percentage of the surfactant is expressed as %, referring to the mass of the surfactant contained in every 100 ml of the pharmaceutical composition, where the mass is expressed in grams.

[0091] When used herein, the unit % for mass-volume percentage can also be replaced with the unit g / 100mL, where 100mL refers to a volume of 100mL of the pharmaceutical composition.

[0092] In some embodiments of this disclosure, the mass-volume percentage of the compound satisfies the therapeutically effective dosage for the subject, wherein the mass-volume percentage of the compound is expressed in %, which refers to the mass of the compound contained in every 100 ml of the pharmaceutical composition, and the mass is expressed in g.

[0093] As used herein, the term "subject" refers to a primate (e.g., a human), a dog, a rabbit, a guinea pig, a pig, a rat, and a mouse. In some embodiments, the subject is a primate. In some specific embodiments, the subject is a human.

[0094] As used herein, the term "therapeutic effective dose" refers to an amount that results in benefit or treatment of a disease in a corresponding subject who did not receive that amount, but is sufficiently low within the range of reasonable medical judgment to avoid serious side effects. The therapeutic effective dose of a water-soluble composition will vary depending on the specific compound chosen (e.g., taking into account the compound's potency, efficacy, and half-life); the chosen route of administration; the disease being treated; the severity of the disease being treated; the age, body type, weight, and physical condition of the patient being treated; the patient's medical history; the duration of treatment; the nature of concurrent treatments; the desired therapeutic effect, etc., but can still be determined by those skilled in the art in a conventional manner.

[0095] In some embodiments of this disclosure, the mass-volume percentage of the compound is 0.5%-2%. In some embodiments of this disclosure, the mass-volume percentage of the compound is 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, or a range of any two of the above mass-volume percentages, or a value within such a range.

[0096] In some embodiments of this disclosure, the pH value of the pharmaceutical composition is 6.5-8.0. In some embodiments of this disclosure, the pH value of the pharmaceutical composition is 6.8-7.8.

[0097] In some embodiments of this disclosure, the pH value of the pharmaceutical composition can be any value in the range of 6.5-8.0, such as 6.5, 6.55, 6.6, 6.65, 6.7, 6.75, 6.8, 6.85, 6.9, 6.95, 7, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, 7.4, 7.45, 7.5, 7.55, 7.6, 7.65, 7.7, 7.75, 7.8, 7.85, 7.9, 7.95, 8.0, or other unlisted values ​​in the range of 6.5-8.0.

[0098] In some embodiments of this disclosure, the osmotic pressure of the pharmaceutical composition is 260-320 mOsmol / kg. In some embodiments of this disclosure, the osmotic pressure of the pharmaceutical composition is 270 mOsmol / kg-310 mOsmol / kg.

[0099] In some embodiments of this disclosure, the osmotic pressure of the water-soluble composition can be any value in the range of 260-320 mOsmol / kg, such as 260 mOsmol / kg, 265 mOsmol / kg, 270 mOsmol / kg, 275 mOsmol / kg, 280 mOsmol / kg, 285 mOsmol / kg, 290 mOsmol / kg, 295 mOsmol / kg, 300 mOsmol / kg, 305 mOsmol / kg, 310 mOsmol / kg, 315 mOsmol / kg, 320 mOsmol / kg, or other unlisted values ​​in the range of 260-320 mOsmol / kg.

[0100] In some embodiments of this disclosure, the pharmaceutical composition includes a second pharmaceutically active ingredient.

[0101] In some embodiments of this disclosure, the second active pharmaceutical ingredient may be a compound in any embodiment of this disclosure, or may be other active pharmaceutical ingredients for the prevention and / or treatment of myopia not disclosed in this disclosure.

[0102] The various embodiments and preferences described above regarding the use of the compounds and pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of myopia can be combined with each other (provided they are not inherently contradictory) and are equally applicable to this disclosure. All embodiments formed by such combinations are considered part of this disclosure.

[0103] The technical solutions of this disclosure will be illustrated more clearly and explicitly below with reference to embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of protection of this disclosure. The scope of protection of this disclosure is defined only by the claims.

[0104] Example

[0105] The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0106] Materials and methods

[0107] The exenatide and liraglutide used in the examples were purchased from Maclean's, abiglutide, lixisenatide and atropine sulfate were purchased from Mycolin, empagliflozin, canagliflozin and dapagliflozin were purchased from MedChemexpress, pioglitazone, vildagliptin and linagliptin were purchased from Bidex Pharmaceuticals, and phosphate-buffered saline (PBS) was purchased from Thermo Fisher Scientific.

[0108] The magnetic stirrer used in this embodiment is model IKA, the pH meter is model Mettler FE28, the electronic balance is model Ohaus AR2140, the osmometer is model OM-819.C, the strip retinoscope is model YZ24, and the anterior section-OCT is model CASIA2.

[0109] Examples 1-10

[0110] Myopia model drug efficacy experiment:

[0111] A form deprivation myopia model was established using 14-day-old tricolor guinea pigs. Unmodeled guinea pigs served as a blank control group. After successful modeling, the modeling guinea pigs were divided into a blank solvent group (PBS), an experimental group (containing exenatide, liraglutide, abiglutide, lisglutide, empagliflozin, canagliflozin, dapagliflozin, pioglitazone, vildagliptin, and linagliptin diluted in PBS to a volume percentage of 1%), and a positive control group (containing atropine sulfate diluted in PBS to a volume percentage of 1%). Each group consisted of 30 modeling guinea pigs (half male and half female). Specifically, the blank control group consisted of... Animals without a form deprivation myopia model received no eye drops. Animals with a form deprivation myopia model, including the blank solvent group, experimental group, and positive control group, underwent eye drop trials at a dose of 15 μL / eye / day for 21 days. After modeling, the refractive error and axial length of the guinea pigs were measured before and 21 days after administration, according to the instrument's operating instructions. The refractive error was measured using a strip retinoscope, and the axial length was measured using an anterior segment-OCT. The test results are shown in Table 1.

[0112] Table 1

[0113]

[0114] Note: / indicates that the substance was added or that the test was not performed.

[0115] According to the table above, the comparison between the blank control group and the blank solvent group shows that the form deprivation myopia model was successfully established. The comparison between Examples 1-10 and the blank solvent group shows that glucagon-like peptide-1 receptor agonists (e.g., exenatide, liraglutide, abiglutide, lisglutide), sodium-glucose cotransporter 2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin), insulin sensitizers (e.g., pioglitazone), and dipeptidyl peptidase-4 inhibitors (e.g., vildagliptin, linagliptin) can effectively inhibit axial elongation and refractive changes, thus exhibiting good preventative and / or therapeutic effects on myopia.

[0116] As can be seen from the comparison between Examples 1-10 and the positive control group, exenatide, abiglutide, and dapagliflozin have an inhibitory effect on axial elongation and refractive changes comparable to atropine sulfate in the positive control group.

[0117] Examples 11-20

[0118] Preparation method of Example 11:

[0119] Add PBS and polysorbate 80 to a beaker, then add the compound exenatide, and mix the solution thoroughly using a magnetic stirrer. The exenatide has a mass-volume percentage of 1%, and the polysorbate 80 has a mass-volume percentage of 4%.

[0120] The preparation method for 12-20 is the same as that in Example 11, except that the types of compounds added are different, as shown in Table 2 below.

[0121] Myopia model drug efficacy experiment:

[0122] A form deprivation myopia model was established using 14-day-old tricolor guinea pigs. Unmodeled guinea pigs served as a blank control group. After successful modeling, the modeling guinea pigs were divided into a blank solvent group (PBS + polysorbate 80), an experimental group (Examples 11-20), and a positive control group (atropine sulfate diluted with PBS to 1% by volume; the positive control group also included 4% polysorbate 80 by volume), with 30 modeling guinea pigs (half male and half female) in each group. Specifically, the blank control group consisted of animals without a form deprivation myopia model and received no eye drops. The blank solvent group, experimental group, and positive control group received eye drops at a dose of 15 μL / eye / day for 21 days. After modeling, the refractive error and axial length of the guinea pigs were measured before and 21 days after administration, according to the instrument's operating instructions. The instrument used for refractive error measurement was a strip retinoscope, and the instrument used for axial length measurement was anterior segment-OCT. The test results are shown in Table 2.

[0123] Table 2

[0124]

[0125]

[0126] Note: / indicates that the substance was added or that the test was not performed.

[0127] According to the table above, the comparison between the blank control group and the blank solvent group shows that the form deprivation myopia model was successfully established. According to Tables 1 and 2, the comparison between Examples 2 and 12, Examples 4 and 14, Examples 5 and 15, Examples 6 and 16, Examples 8 and 18, Examples 9 and 19, and Examples 10 and 20 shows that after adding the solubilizer polysorbate 80, the state of the water-poorly soluble active pharmaceutical ingredient changed from a suspension to an emulsion. The use of a solubilizer facilitates the dissolution of the water-poorly soluble active pharmaceutical ingredient, thereby further enhancing its inhibitory effect on axial elongation and refractive changes, and thus further improving its preventive and / or therapeutic effects on myopia. As demonstrated in Examples 11-20 and the positive control group, the use of solubilizing glucagon-like peptide-1 receptor agonists (e.g., exenatide, liraglutide, abiglutide, lisglutide), sodium-glucose cotransporter 2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin), insulin sensitizers (e.g., pioglitazone), and dipeptidyl peptidase-4 inhibitors (e.g., vildagliptin, linagliptin) all achieved similar efficacy to atropine sulfate in the positive control group.

[0128] This article uses specific examples to illustrate the principles and implementation methods of this disclosure. The description of the above embodiments is only for the purpose of helping to understand the technical solutions and core ideas of this disclosure. Those skilled in the art should understand that they can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. These modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this disclosure.

Claims

1. Use of a compound, or a tautomer, stereoisomer, enantiomer, diastereomer, racemate, solvate, isotopic derivative, base form, prodrug, acid form, metabolite, ester, pharmaceutically acceptable salt, or solvate thereof, in the manufacture of a medicament for the prevention and / or treatment of myopia, wherein, The compound is a drug for treating diabetes, and the drug for treating diabetes is selected from at least one of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, insulin sensitizers, or dipeptidyl peptidase-4 inhibitors.

2. Use according to claim 1, characterized in that, The glucagon-like peptide-1 receptor agonist includes at least one of exenatide, liraglutide, abiglutide, lixisenatide, beraglutide, loxenatide, or semaglutide; and / or, The sodium-glucose cotransporter 2 inhibitor includes at least one of empagliflozin, canagliflozin, dapagliflozin, eltoggliflozin, ruggliflozin, repaggliflozin, or soragliflozin; and / or, The insulin sensitizer includes at least one of pioglitazone or troglitazone; and / or, The dipeptidyl peptidase-4 inhibitors include at least one of vildagliptin, linagliptin, sitagliptin, saxagliptin, alogliptin, giglitazone, or ticagliptin.

3. Use according to claim 1 or 2, characterized in that, The myopia is prevented and / or treated by inhibiting axial elongation and / or inhibiting changes in refractive power.

4. Use of a pharmaceutical composition for the manufacture of a medicament for the prevention and / or treatment of myopia, wherein, The pharmaceutical composition comprises a compound and a pharmaceutically acceptable excipient, wherein the compound is a drug for treating diabetes, and the drug for treating diabetes comprises at least one of a glucagon-like peptide-1 receptor agonist, a sodium-glucose cotransporter 2 inhibitor, an insulin sensitizer, or a dipeptidyl peptidase-4 inhibitor.

5. Use according to claim 4, characterized in that, The glucagon-like peptide-1 receptor agonist includes at least one of exenatide, liraglutide, abiglutide, lixisenatide, beraglutide, loxenatide, or semaglutide; and / or, The sodium-glucose cotransporter 2 inhibitor includes at least one of empagliflozin, canagliflozin, dapagliflozin, eltoggliflozin, ruggliflozin, repaggliflozin, or soragliflozin; and / or, The insulin sensitizer includes at least one of pioglitazone or troglitazone; and / or, The dipeptidyl peptidase-4 inhibitors include at least one of vildagliptin, linagliptin, sitagliptin, saxagliptin, alogliptin, giglitazone, or ticagliptin.

6. Use according to claim 4 or 5, characterized in that, The myopia is prevented and / or treated by inhibiting axial elongation and / or inhibiting changes in refractive power.

7. Use according to any one of claims 4-6, characterized in that, The pharmaceutically acceptable excipients include at least one of pH adjusters, osmotic pressure regulators, thickeners, or surfactants.

8. Use according to any one of claims 4-7, characterized in that, The pH adjuster includes at least one of hydrochloric acid, boric acid, phosphoric acid, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, borax, acetic acid, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, acetate buffer, citrate buffer, or borate buffer. Optionally, the osmotic pressure regulator includes at least one of sodium chloride, mannitol, glycerol, laurocapram, potassium chloride, boric acid, borax, sodium sulfate, potassium sulfate, sodium nitrate, potassium nitrate, sodium acetate, propylene glycol, sorbitol, 2-(4-n-octylphenylethyl)-2-aminopropanediol hydrochloride, glucose, sucrose, fructose, or lactose. Optionally, the thickener includes at least one of sodium hyaluronate, carbomer, polycarbofil, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, or povidone. Optionally, the surfactant includes a nonionic surfactant; more preferably, the nonionic surfactant includes at least one of polysorbate, tylosap, polyoxyethylene castor oil, poloxamer, polyethylene glycol, or hydroxypropyl-β-cyclodextrin.

9. Use according to any one of claims 4-8, characterized in that, The pH value of the pharmaceutical composition is 6.5-8.0, and optionally, the pH value of the pharmaceutical composition is 6.8-7.8; Optionally, the osmotic pressure of the pharmaceutical composition is 260-320 mOsmol / kg, and more preferably, the osmotic pressure of the pharmaceutical composition is 270-310 mOsmol / kg.

10. Use according to any one of claims 4-9, characterized in that, The pharmaceutical composition includes a second active pharmaceutical ingredient.

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