Use of galanthamine and pharmaceutically acceptable salt thereof in preparation of drug for treating eye diseases

Abstract

Provided is use of galanthamine and a pharmaceutically acceptable salt thereof in the preparation of a drug for treating eye diseases. The present invention pertains to the technical field of pharmaceuticals. In the use of galanthamine and the pharmaceutically acceptable salt thereof in the preparation of the drug for treating eye diseases, galanthamine or an enantiomer thereof, a diastereomer thereof, a racemate thereof or the pharmaceutically acceptable salt thereof, or a solvate thereof is used to prepare the drug for treating eye diseases. The drug can make the pupils contract and ameliorate age-related eye diseases and disorders, providing a new option for preventing, treating, and / or ameliorating presbyopia, cataracts, and other age-related eye diseases.

Description

Application of galantamine and its pharmaceutically acceptable salt in preparing medicines for treating eye diseases Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to the use of galanthamine or its enantiomers, diastereomers, racemates or pharmaceutically acceptable salts or solvates in the preparation of drugs for treating eye diseases. Background Art

[0002] Presbyopia is an eye disease caused by a complex degeneration of the ciliary body, vitreous humor, and lens, leading to a decrease in the eye's accommodative range. Presbyopia begins to become noticeable around age 40, and with the frequent use of electronic devices, the incidence is increasing. Symptoms of presbyopia include a tendency to hold reading materials farther away to make letters more legible, blurred vision at a normal reading distance, eye strain, and headaches after reading or doing close work. Specifically, the lens of the eye gradually thickens and loses its viscoelastic properties in older adults. This loss of lens elasticity is likely due to the cross-linking of proteins within lens fiber cells, which generates oxidized protein sulfhydryl groups and, over time, leads to a loss of the lens's accommodative ability. Currently, the main treatments for presbyopia are optical correction (reading glasses and contact lenses), surgical correction (keratitis laser surgery, refractive lens exchange, and scleral expansion), and medications (Vuity, 1.25% pilocarpine hydrochloride).

[0003] However, several factors limit the acceptance of surgical correction of presbyopia, including postoperative complications, astigmatism, and inflammation. Although reading glasses are commonly used to correct presbyopia, prolonged wear can cause adverse reactions such as dizziness, discomfort, and irreversible increases in refractive power, making them unsuitable for many patients with presbyopia. Therefore, there is a growing need for effective, easy-to-use, and non-invasive methods to treat presbyopia that do not restrict patients' daily activities. Compared to the two aforementioned methods, drug treatments are convenient, affordable, and have no postoperative complications. To date, only one potential mechanism of action for treating presbyopia has been identified: miosis. Miosis is a medical term for pupil contraction. Muscarinic receptor agonists directly stimulate cholinergic receptors, acting on a subtype of muscarinic receptor (M3) found on the iris sphincter, causing the iris sphincter to contract and produce a miotic effect. The purpose of miosis is to increase the depth of focus, thereby improving vision. To date, the only approved drug for the treatment of presbyopia is pilocarpine hydrochloride, leaving patients with limited options. Therefore, it is of great significance to develop new drugs to treat presbyopia.

[0004] Summary of the Invention

[0005] The present invention aims to address at least one of the technical problems existing in the above-mentioned prior art. To this end, the present invention provides the use of galanthamine and its pharmaceutically acceptable salts in the preparation of a medicament for treating eye diseases. Medicaments containing galanthamine and its pharmaceutically acceptable salts can treat eye diseases such as presbyopia.

[0006] The present invention provides use of galanthamine and pharmaceutically acceptable salts thereof in preparing medicines for preventing, treating or improving eye diseases.

[0007] Galantamine is a tertiary alkaloid belonging to the Compositae family. Galantamine can be isolated from many species, including Leucojums, Narcissus and Galanthus. Galantamine is an acetylcholinesterase inhibitor in the central nervous system and an allosteric enhancing ligand for neuronal cholinergic nicotinic receptors. Traditionally, galantamine has been used as an important drug for the treatment of Alzheimer's disease and diabetes, and it also has significant anti-inflammatory and antioxidant effects. Its structure is shown in formula (1). Galantamine, or its enantiomers, diastereomers, racemates or pharmaceutically acceptable salts or solvates, is an acetylcholinesterase inhibitor that can inhibit the activity of acetylcholinesterase.

[0008] Studies have found that galantamine can inhibit acetylcholinesterase, promote the increase of acetylcholine in the body, and acetylcholine further activates M receptors to exert cholinergic pharmacological effects. The drugs prepared using it can improve age-related eye diseases and conditions, including presbyopia, glaucoma, intraocular hypertension and other eye diseases, providing new options for the treatment of eye diseases including presbyopia.

[0009] Preferably, the eye disease includes age-related eye diseases such as presbyopia, cataract, glaucoma or intraocular hypertension.

[0010] Preferably, the pharmaceutically acceptable salt of galanthamine is at least one of its hydrochloride, hydrobromide, sulfate, nitrate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, malate, lactate, succinate, maleate, fumarate, benzoate, acetate, malonate, citrate, tartrate and lipoate. Further preferably, the pharmaceutically acceptable salt of galanthamine is galanthamine hydrobromide.

[0011] The present invention also provides a medicine for treating eye diseases.

[0012] Specifically, a drug for treating eye diseases comprises galantamine or a pharmaceutically acceptable salt thereof.

[0013] Preferably, in the drug, the concentration of galanthamine or a pharmaceutically acceptable salt thereof is 0.1% w / v-3.0% w / v; further preferably, in the drug, the concentration of galanthamine or a pharmaceutically acceptable salt thereof is 0.1% w / v-2.5% w / v.

[0014] Preferably, the drug further comprises a pharmaceutically acceptable carrier or excipient.

[0015] Preferably, the drug further comprises at least one of a buffer solution, a pH regulator, an osmotic pressure regulator, a preservative, a chelating agent, a gelling agent, a thickener or a solubilizing agent.

[0016] Preferably, the buffer solution comprises at least one of a monohydrogen phosphate / dihydrogen phosphate system solution, a citric acid / citrate system solution, an acetic acid / acetate system solution, a boric acid / chloride system solution, a tromethamine system solution, or a phthalate system solution. The monohydrogen phosphate comprises sodium monohydrogen phosphate and potassium monohydrogen phosphate; the dihydrogen phosphate comprises sodium dihydrogen phosphate and potassium dihydrogen phosphate; the citrate comprises sodium citrate and potassium citrate; the acetate comprises sodium acetate; the chloride comprises sodium chloride and potassium chloride; and the phthalate comprises sodium phthalate and potassium phthalate.

[0017] Preferably, the pH adjuster includes at least one of sodium hydroxide, potassium hydroxide, hydrochloric acid, boric acid, citric acid, tromethamine or triethanolamine.

[0018] Preferably, the osmotic pressure regulator includes at least one of mannitol, sodium chloride, glycerol, glucose or propylene glycol.

[0019] Preferably, the preservative comprises at least one of benzalkonium chloride, benzalkonium bromide, ethylparaben, phthalate or sorbic acid.

[0020] Preferably, the complexing agent comprises disodium edetate or dipotassium edetate.

[0021] Preferably, the gelling agent is at least one of gellan gum, poloxamer, carbomer and xanthan gum.

[0022] Preferably, the thickener comprises at least one of hydroxypropyl methylcellulose, sodium hyaluronate, polyvinyl alcohol, sodium carboxymethyl cellulose or sodium alginate.

[0023] Preferably, the drug is selected from a solution, a suspension, an emulsion, a gel or a sustained-release preparation; further preferably, the drug is a solution. The drug is a clear and transparent solution.

[0024] Preferably, the pH value of the drug is 4.0-9.0; further preferably, the pH value of the drug is 5.0-7.3.

[0025] Preferably, the osmotic pressure of the drug is 280-320 mOsm.

[0026] The present invention also provides a method for preparing the medicine for treating eye diseases.

[0027] Specifically, the method for preparing the above-mentioned drug for treating eye diseases comprises the following steps:

[0028] The galanthamine or its pharmaceutically acceptable salt and other components are dissolved in a buffer solution, and the filtrate is obtained by filtration and sterilization to prepare the medicine.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The present invention proposes the use of galantamine and its pharmaceutically acceptable salts in the preparation of a medicament for treating ocular diseases. Galantamine and its pharmaceutically acceptable salts are used to prepare a medicament for treating ocular diseases. The medicament can constrict the pupil and improve age-related ocular diseases and conditions, providing a new option for treating ocular diseases such as presbyopia, glaucoma, and intraocular hypertension. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 shows a picture of Vuity eye drops constricting the pupils of a rabbit;

[0032] FIG2 is a graph showing the constriction of rabbit pupils by the drug (0.5%) for treating eye diseases provided in Example 11;

[0033] FIG3 is a graph showing the constriction of rabbit pupils by the drug (1.0%) for treating eye diseases provided in Example 10;

[0034] FIG4 is a graph showing the constriction of rabbit pupils by the drug (2.0%) for treating eye diseases provided in Example 4;

[0035] FIG5 is a graph showing the effect of different treatment groups on the contraction of rabbit pupils;

[0036] FIG6 is an OCT image recording of Vuity eye drops constricting the pupil of a mouse;

[0037] FIG7 is an OCT image recording of the pupil constriction of mice by the drug for treating eye diseases (1.0%) provided in Example 10. DETAILED DESCRIPTION

[0038] In order to make the technical solution of the present invention more clearly understood by those skilled in the art, the following examples are given for illustration. It should be noted that the following examples do not limit the scope of protection claimed by the present invention.

[0039] Unless otherwise specified, the raw materials, reagents, or devices used in the following examples can be obtained from conventional commercial sources or by existing known methods.

[0040] Example 1

[0041] A drug for treating eye diseases (galanthamine hydrobromide eye drops) contains 3.0% galanthamine hydrobromide, 0.5% mannitol, and 0.01% benzalkonium chloride. The specific raw materials and auxiliary materials are shown in Table 1:

[0042] Table 1

[0043] The preparation method is as follows:

[0044] Weigh 6.80 g of potassium dihydrogen phosphate, add 291.0 mL of 0.1 M NaOH solution, add 600 mL of deionized water, and sonicate until completely dissolved. Adjust the pH to 7.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution, and dilute to 1000 mL with deionized water to prepare a pH 7.0 phosphate buffer solution.

[0045] Measure 60 mL of the phosphate buffer solution, add 0.0075 g of benzalkonium chloride, and dissolve completely; remove 12 mL, add 0.450 g of galanthamine hydrobromide, and stir to dissolve; adjust the pH to 4.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution; add 0.075 g of mannitol, and adjust the volume to 15 mL with phosphate buffer solution; filter using a 0.22 μm PES filter; and obtain a drug with an osmotic pressure of 280-320 mOsm and a clear solution.

[0046] Example 2

[0047] A drug for treating eye diseases (galanthamine hydrobromide eye drops) contains 2.0% galanthamine hydrobromide, 1.13% mannitol, and 0.01% benzalkonium chloride. The specific raw materials and auxiliary materials are shown in Table 2:

[0048] Table 2

[0049] The preparation method is as follows:

[0050] Measure 60 mL of the phosphate buffer solution prepared in Example 1, add 0.0075 g of benzalkonium chloride, and dissolve completely; remove 12 mL, add 0.300 g of galanthamine hydrobromide, and stir to dissolve; adjust the pH to 7.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution; add 0.170 g of mannitol, and make up to 15 mL with phosphate buffer solution; filter using a 0.22 μm PES filter; and obtain a drug having an osmotic pressure of 280-320 mOsm and a clear and transparent solution.

[0051] Example 3

[0052] A drug for treating eye diseases (galanthamine hydrobromide eye drops) contains 0.1% galanthamine hydrobromide, 3.0% mannitol, and 0.01% benzalkonium chloride. The specific raw materials and auxiliary materials are shown in Table 3:

[0053] Table 3

[0054] The preparation method is as follows:

[0055] Measure 60 mL of the phosphate buffer solution prepared in Example 1, add 0.0075 g of benzalkonium chloride, and dissolve completely; remove 12 mL, add 0.015 g of galanthamine hydrobromide, and stir to dissolve; adjust the pH to 9.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution; add 0.450 g of mannitol and make up to 15 mL with phosphate buffer solution; filter using a 0.22 μm PES filter; and obtain a drug having an osmotic pressure of 280-320 mOsm and a clear and transparent solution.

[0056] Example 4

[0057] A drug for treating eye diseases (galanthamine hydrobromide eye drops) contains 2.0% galanthamine hydrobromide, 1.33% mannitol, and 0.01% benzalkonium chloride. The specific raw materials and auxiliary materials are shown in Table 4:

[0058] Table 4

[0059] The preparation method is as follows:

[0060] Measure 90 mL of deionized water and add it to a beaker. Weigh 0.10 g of anhydrous sodium dihydrogen phosphate and 0.17 g of anhydrous disodium hydrogen phosphate, add them to the beaker, stir to dissolve completely, adjust the pH to 7.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution, make up to 100 mL, stir evenly, and prepare pH 7.0 phosphate buffer solution.

[0061] Measure 60 mL of the phosphate buffer solution, add 0.0075 g of benzalkonium chloride, and dissolve completely; remove 12 mL, add 0.300 g of galanthamine hydrobromide, and stir to dissolve; adjust the pH to 7.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution; add 0.200 g of mannitol, and make up to 15 mL with phosphate buffer solution; filter using a 0.22 μm PES filter; and obtain a drug having an osmotic pressure of 280-320 mOsm and a clear solution.

[0062] Example 5

[0063] A drug for treating eye diseases (galanthamine hydrobromide eye drops) contains 2.0% galanthamine hydrobromide, 2.0% mannitol, and 0.01% benzalkonium chloride. The specific raw materials and auxiliary materials are shown in Table 5:

[0064] Table 5

[0065] The preparation method is as follows:

[0066] Measure 90 mL of deionized water and add it to a beaker. Weigh 0.008 g of citric acid monohydrate and 0.576 g of sodium citrate dihydrate, add them to the beaker, and stir to dissolve completely. Adjust the pH to 7.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution, make up to 100 mL, and stir evenly to prepare a pH 7.0 citrate buffer solution.

[0067] 60 mL of the citrate buffer solution was measured, 0.0075 g of benzalkonium chloride was added, and the solution was completely dissolved; 12 mL was removed, 0.300 g of galanthamine hydrobromide was added, and the solution was stirred to dissolve; the pH was adjusted to 7.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution; 0.300 g of mannitol was added, and the volume was adjusted to 15 mL with phosphate buffer solution; and the solution was filtered using a 0.22 μm PES filter to obtain a clear and transparent drug with an osmotic pressure of 280-320 mOsm.

[0068] Example 6

[0069] A drug for treating eye diseases (galanthamine hydrobromide eye drops) contains 2.0% galanthamine hydrobromide, 1.13% mannitol, and 0.01% benzalkonium chloride. The specific raw materials and auxiliary materials are shown in Table 6:

[0070] Table 6

[0071] The preparation method is as follows:

[0072] Measure 90 mL of deionized water and add it to a beaker. Weigh 1.0 g of boric acid (H3BO3) and add it to the beaker. Stir to dissolve completely. Adjust the pH to 7.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution. Make up to 100 mL and stir evenly to prepare a pH 7.0 boric acid buffer solution.

[0073] 60 mL of the boric acid buffer solution was measured, 0.0075 g of benzalkonium chloride was added, and the solution was completely dissolved; 12 mL was removed, 0.300 g of galanthamine hydrobromide was added, and the solution was stirred to dissolve; the pH was adjusted to 7.0 with boric acid and tromethamine solution; 0.170 g of mannitol was added, and the volume was adjusted to 15 mL with phosphate buffer solution; and the solution was filtered using a 0.22 μm PES filter to obtain a clear and transparent drug solution with an osmotic pressure of 280-320 mOsm.

[0074] Example 7

[0075] A drug for treating eye diseases (galanthamine hydrobromide eye drops) contains 2.0% galanthamine hydrobromide, 2.0% mannitol, and 0.01% benzalkonium chloride. The specific raw materials and auxiliary materials are shown in Table 7:

[0076] Table 7

[0077] The preparation method is as follows:

[0078] Measure 90 mL of deionized water and add it to a beaker. Weigh 0.05 g of anhydrous sodium dihydrogen phosphate and 0.085 g of anhydrous disodium hydrogen phosphate, add them to the beaker, stir to dissolve completely, adjust the pH to 7.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution, make up to 100 mL, stir evenly, and prepare pH 7.0 phosphate buffer solution.

[0079] Measure 60 mL of the phosphate buffer solution, add 0.0075 g of benzalkonium chloride, and dissolve completely; remove 12 mL, add 0.300 g of galanthamine hydrobromide, and stir to dissolve; adjust the pH to 7.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution; add 0.300 g of mannitol, and make up to 15 mL with phosphate buffer solution; filter using a 0.22 μm PES filter; and obtain a drug having an osmotic pressure of 280-320 mOsm and a clear solution.

[0080] Example 8

[0081] A drug for treating eye diseases (galanthamine hydrobromide eye drops) contains 2.0% galanthamine hydrobromide, 1.13% mannitol, and 0.01% benzalkonium chloride. The specific raw materials and auxiliary materials are shown in Table 8:

[0082] Table 8

[0083] The preparation method is as follows:

[0084] Measure 90 mL of deionized water and add it to a beaker. Weigh 0.20 g of anhydrous sodium dihydrogen phosphate and 0.34 g of anhydrous disodium hydrogen phosphate, add them to the beaker, stir to dissolve completely, adjust the pH to 7.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution, make up to 100 mL, stir evenly, and prepare pH 7.0 phosphate buffer solution.

[0085] Measure 60 mL of the phosphate buffer solution, add 0.0075 g of benzalkonium chloride, and dissolve completely; remove 12 mL, add 0.300 g of galanthamine hydrobromide, and stir to dissolve; adjust the pH to 7.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution; add 0.170 g of mannitol, and adjust the volume to 15 mL with phosphate buffer solution; filter using a 0.22 μm PES filter; and obtain a drug with an osmotic pressure of 280-320 mOsm and a clear solution.

[0086] Example 9

[0087] A drug for treating eye diseases (galanthamine hydrobromide eye drops) contains 2.0% galanthamine hydrobromide, 0.36% sodium chloride, and 0.01% benzalkonium chloride. The specific raw materials and auxiliary materials are shown in Table 9:

[0088] Table 9

[0089] The preparation method is as follows:

[0090] Measure 60 mL of the phosphate buffer solution prepared in Example 4, add 0.0075 g of benzalkonium chloride, and dissolve completely; remove 12 mL, add 0.300 g of galanthamine hydrobromide, and stir to dissolve; adjust the pH to 7.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution; add 0.054 g of sodium chloride and make up to 15 mL with phosphate buffer solution; filter using a 0.22 μm PES filter; and obtain a drug having an osmotic pressure of 280-320 mOsm and a clear and transparent solution.

[0091] Example 10

[0092] A drug for treating eye diseases (galanthamine hydrobromide eye drops) comprising 1.0% galanthamine hydrobromide, 3.0% mannitol, and 0.01% benzalkonium chloride. The specific raw and auxiliary materials are shown in Table 10:

[0093] Table 10

[0094] The preparation method is as follows:

[0095] Measure 60 mL of the phosphate buffer solution prepared in Example 4, add 0.0075 g of benzalkonium chloride, and dissolve completely; remove 12 mL, add 0.150 g of galanthamine hydrobromide, and stir to dissolve; adjust the pH to 7.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution; add 0.450 g of mannitol and make up to 15 mL with phosphate buffer solution; filter using a 0.22 μm PES filter; and obtain a drug with an osmotic pressure of 280-320 mOsm and a clear and transparent solution.

[0096] Example 11

[0097] A drug for treating eye diseases (galanthamine hydrobromide eye drops) contains 0.5% galanthamine hydrobromide, 3.4% mannitol, and 0.01% benzalkonium chloride. The specific raw materials and auxiliary materials are shown in Table 11:

[0098] Table 11

[0099] The preparation method is as follows:

[0100] Measure 60 mL of the phosphate buffer solution prepared in Example 4, add 0.0075 g of benzalkonium chloride, and dissolve completely; remove 12 mL, add 0.075 g of galanthamine hydrobromide, and stir to dissolve; adjust the pH to 7.0 with 1.0 mol / L hydrochloric acid and 1.0 mol / L sodium hydroxide solution; add 0.510 g of mannitol and make up to 15 mL with phosphate buffer solution; filter using a 0.22 μm PES filter; and obtain a drug with an osmotic pressure of 280-320 mOsm and a clear and transparent solution.

[0101] Example 12

[0102] A drug for treating eye diseases (galanthamine hydrobromide eye drops) comprises 1.0% galanthamine hydrobromide, 0.25% gellan gum, 0.20% boric acid, 0.50% tromethamine, 0.20% sodium chloride, 3.00% mannitol, and 0.01% benzalkonium bromide. The specific raw and auxiliary materials are shown in Table 12:

[0103] Table 12

[0104] The preparation method is as follows:

[0105] Solution 1: Measure 200g of deionized water and add it to a 250mL beaker. While stirring, weigh 0.8313g of gellan gum and add it. Stir at room temperature for 10 minutes. Place the above beakers in a 70℃ water bath and stir for 10 minutes. After dissolving, cool it and add water to the previous weight. Filter the above solution while it is hot and set aside. PTFE 25mm×0.22μm, place the beakers at room temperature and stir and cool. Weigh 12.01g of the filtrate and set aside.

[0106] Solution 2: Weigh 0.1014 g of benzalkonium bromide into a 100 mL beaker. Weigh 50.10 g of deionized water into the beaker, stir to dissolve, and set aside. Weigh 1.1904 g of the above benzalkonium bromide solution, 0.7205 g of mannitol, 0.0484 g of NaCl, 0.0483 g of boric acid, and 0.2404 g of galanthamine hydrobromide into a beaker, add water to the volume to 8.0 g, and stir to mix. The solution has a pH of 2.79. Adjust the pH to 6.53 with tromethamine, consuming a total of 0.1167 g of tromethamine. Adjust the volume to 8.4 g with water. Filter the above solution, and weigh 7.0 g of the filtrate through a 25 mm × 0.22 μm PES tube.

[0107] Solution 1 and solution 2 were mixed, the pH was measured to be 7.0 using a pH meter, and the volume was adjusted to 20 g with filtered deionized water.

[0108] Example 13

[0109] A drug for treating eye diseases (galanthamine hydrobromide eye drops) comprising 1.0% galanthamine hydrobromide, 0.60% gellan gum, 0.55% tromethamine, 4.00% mannitol, and 0.01% benzalkonium bromide. Specific raw materials and auxiliary materials are shown in Table 13:

[0110] Table 13

[0111] The preparation method is as follows:

[0112] Solution 1: Measure 200g of deionized water and add it to a 250mL beaker. While stirring, weigh 2.0123g of gellan gum and add it. Stir at room temperature for 10 minutes. Place the above beakers in a 70℃ water bath and stir for 10 minutes. After dissolving, cool it and add water to the previous weight. Filter the above solution while it is hot and set aside. PTFE 25mm×0.22μm, place the beaker at room temperature and stir and cool it. Weigh 30.00g of the filtrate and set aside.

[0113] Solution 2: Take a 50 mL beaker, weigh 11.0123 g of deionized water and add it to the beaker. Weigh 0.1006 g of benzalkonium bromide and add it to 50 g of water, stir in a 100 mL beaker to obtain 0.2% benzalkonium bromide. Weigh 2.4101 g of the above benzalkonium bromide solution, 1.9236 g of mannitol, and 0.4817 g of galantamine hydrobromide and add them to the above beaker, add water to make the weight up to 16.0 g, stir and mix evenly, adjust the pH to 7.00 with tromethamine, and make the volume up to 16.4 g with water. Filter the above solution, PES 25 mm×0.22 μm.

[0114] Weigh 14.0127 g of the filtrate of Solution 2, and at the same time weigh 24.0609 g of the filtrate of Solution 1. Slowly drip the filtrate of Solution 1 into the filtrate of Solution 2, measure the pH to be 7.07, and add deionized water to make the weight up to 40.0 g.

[0115] Animal miosis pharmacodynamic evaluation

[0116] 1. Study the effect of the drug for treating eye diseases (galantamine hydrobromide eye drops) provided in the research example on the pupil diameter of New Zealand rabbits.

[0117] 1.1 Drug

[0118] The drugs for treating eye diseases (galantamine hydrobromide eye drops) provided in Examples 4, 10 and 11, the positive control is Vuity eye drops (1.25% pilocarpine hydrochloride), and the negative control is the blank prescription solution of Examples 4, 10 and 11.

[0119] 1.2 Experimental animals

[0120] New Zealand white rabbits, 19 - 20 weeks old, male, 2.5 kg, provided by the Experimental Animal Center of South China Agricultural University, license number SYSK (Guangdong) 2022 - 0136.

[0121] 1.3 Experimental methods

[0122] 1.3.1 Measurement of pupil

[0123] Fix the rabbit in the rabbit box. Before the experiment, measure the pupil diameter (mm) before drug administration with a pupil gauge and take a photo for record.

[0124] 1.3. The drug administration method

[0125] Fifteen New Zealand rabbits were randomly divided into five groups, with three rabbits in each group. Under a constant light source (light intensity 40 Lux), the rabbits were fixed in a rabbit box without anesthesia. Before the experiment, the pupil diameter (mm) was measured with a pupillometer and photographed. The rabbit eyelids were gently opened, and the drug was pipetted onto the corneal surface of the rabbit (20 μL / eye, binocular administration). The drug was allowed to remain in the conjunctival sac of the rabbit's eyelid for 1 minute, while the nasolacrimal duct was pressed for 1 minute. The administration time was recorded. Pupil diameter was measured with a pupillometer at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, and 5 hours after administration. Each eye was photographed three times at each time point. The average of the three measurements was used as the pupil diameter at each time point.

[0126] 1.4 Statistical analysis

[0127] The data were expressed as mean ± 95% confidence interval. One-way ANOVA and LSD-t test were used for multiple comparison statistical analysis in SPSS software to compare the differences between the groups at different time points. Compared with the control group, a P value of < 0.05 was statistically significant.

[0128] 1.5 Experimental Results

[0129] The rabbit pupil miosis ratio data are shown in Tables 14 and 15. As shown in Tables 14 and 15, the drugs (eye drops) containing 0.5%, 1.0%, and 2.0% galanthamine hydrobromide all constricted the pupillary sphincter of New Zealand rabbits, causing pupil constriction, with significant differences compared to the placebo group (P < 0.05). Figures 1-4 show the constriction of rabbit pupils using Vuity eye drops and the drugs for treating ocular diseases provided in Examples 11, 10, and 4. In Figures 1-4, 0 min represents pre-dose, Figures 1-4 A represent the miosis of the right eye at different exposure times, and Figures 1-4 B represent the miosis of the left eye at different exposure times. Figure 5 shows the pupil constriction curves of rabbits treated with drugs in different groups. As shown in Figure 5, the mydriasis effect of the drugs for treating eye diseases (galanthamine hydrobromide eye drops) provided in Example 10 (1.0%) and Example 4 (2.0%) is better than that of the positive drug Vuity, and there is a significant difference, P < 0.05.

[0130] Table 14

[0131] Table 15

[0132] 2. Study the effect of the drug for treating eye diseases (galanthamine hydrobromide eye drops) provided in the examples on the pupil diameter of mice.

[0133] 2.1 Drugs

[0134] The drug for treating eye diseases provided in Example 10 (galanthamine hydrobromide eye drops) and the positive control were Vuity eye drops (1.25% pilocarpine hydrochloride).

[0135] 2.2 Experimental animals

[0136] Six elderly male C57BL / 6J mice (>8 months old) were divided into two groups of 3 mice each according to their age (and weight) using Provantis. They were provided by Zhejiang Weitonglihua Laboratory Animal Technology Co., Ltd., license number SCXK(Zhe)2019-0001.

[0137] 2.3 Experimental methods

[0138] 2.3.1 Pupil measurement

[0139] OCT anterior segment mode was used to capture images of the anterior segments of both eyes of the animal for measuring the pupil diameter of the mouse.

[0140] 2.3.2 Method of administration

[0141] Use a micropipette to aspirate 5 μL of the test article and place it on the animal's eye. Restrain the eye for at least 20 seconds (recording is required for the duration of the restraint). All animals should have their pupils imaged by optical coherence tomography (OCT) before and 25 ± 5 minutes after administration. The room's light and dark levels should remain consistent throughout each OCT examination.

[0142] 2.3.3 Statistical analysis

[0143] The LSD-t test method was used for analysis of variance between groups.

[0144] 2.3.4 Experimental results

[0145] The mouse pupil miosis ratio data are shown in Table 16.

[0146] Table 16 Note: *25±5 minutes after administration

[0147] The OCT images of the mouse pupils of the Vuity eye drops and the medicine for treating eye diseases provided in Example 10 (galanthamine hydrobromide eye drops) are recorded as shown in Figures 6 and 7. In Figure 6, A represents the OCT image before administration, and in Figure 6, B represents the OCT image 25±5 minutes after administration; in Figure 7, A represents the OCT image before administration, and in Figure 7, B represents the OCT image 25±5 minutes after administration. As shown in Table 14 and Figures 6 and 7, the medicine for treating eye diseases provided in Example 10 (galanthamine hydrobromide eye drops) and Vuity eye drops can both contract the pupillary sphincter of C57BL / 6J mice, causing pupil constriction, and the medicine provided in Example 10 of the present invention causes a higher pupil constriction ratio. The medicine for treating eye diseases provided by the present invention (galanthamine hydrobromide eye drops) can effectively constrict the pupil, thereby playing the effect of treating eye diseases such as presbyopia, glaucoma, and intraocular hypertension, and its effect is better than that of Vuity eye drops.

[0148] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. Use of galantamine or its enantiomers, diastereomers, racemates or pharmaceutically acceptable salts or solvates in the preparation of drugs for preventing, treating or improving eye diseases.

2. The use according to claim 1, characterized in that: The eye disease includes presbyopia, cataract, glaucoma or intraocular hypertension.

3. The use according to claim 1 or 2, characterized in that: The pharmaceutically acceptable salt of galanthamine is at least one of its hydrochloride, hydrobromide, sulfate, nitrate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, malate, lactate, succinate, maleate, fumarate, benzoate, acetate, malonate, citrate, tartrate and lipoic acid salt.

4. A pharmaceutical composition for treating eye diseases, characterized in that: It includes galantamine or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt or solvate.

5. The pharmaceutical composition according to claim 4, characterized in that The concentration of galantamine or a pharmaceutically acceptable salt thereof is 0.1% w / v-3.0% w / v.

6. The pharmaceutical composition according to claim 4 or 5, characterized in that The pharmaceutical composition also includes a pharmaceutically acceptable carrier or excipient.

7. The pharmaceutical composition according to claim 4 or 5, characterized in that The pharmaceutical composition further comprises at least one of a buffer solution, a pH regulator, an osmotic pressure regulator, a preservative, a complexing agent, a gelling agent, a thickener or a solubilizing agent.

8. The pharmaceutical composition according to claim 7, characterized in that The buffer solution includes at least one of a monohydrogen phosphate / dihydrogen phosphate system solution, a citric acid / citrate system solution, an acetic acid / acetate system solution, a boric acid / chloride system solution, a tromethamine system solution or a phthalate system solution; the pH regulator includes at least one of sodium hydroxide, potassium hydroxide, hydrochloric acid, boric acid, citric acid, tromethamine or triethanolamine; the osmotic pressure regulator includes at least one of mannitol, sodium chloride, glycerol, glucose or propylene glycol; the preservative includes at least one of benzalkonium chloride, benzalkonium bromide, ethylparaben, phthalate or sorbic acid; the chelating agent includes disodium edetate or dipotassium edetate; the gelling agent is at least one of gellan gum, poloxamer, carbomer and xanthan gum; the thickener includes at least one of hydroxypropyl methylcellulose, sodium hyaluronate, polyvinyl alcohol, sodium carboxymethyl cellulose or sodium alginate.

9. The pharmaceutical composition according to any one of claims 4, 5 or 8, characterized in that The pharmaceutical composition is selected from one of a solution, a suspension, an emulsion, a gel or a sustained-release preparation; and / or the pH value of the drug is 4.0-9.0, and the osmotic pressure is 280-320 mOsm.

10. The method for preparing the pharmaceutical composition for treating eye diseases according to claim 8, characterized in that: The following steps are involved: The pharmaceutical composition is prepared by dissolving galanthamine or its enantiomer, diastereomer, racemate or its pharmaceutically acceptable salt, solvate and other components in a buffer solution, filtering and sterilizing to obtain a filtrate.

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