An ophthalmic composition based on galantamine lipoate and its application

Abstract

The present invention relates to an ophthalmic composition based on galanthamine lipoate and its application, wherein the ophthalmic composition comprises a therapeutically effective amount of a galanthamine lipoate compound, or an enantiomer, a diastereomer, a racemate of the galanthamine lipoate compound, or a pharmaceutically acceptable salt or solvate of the galanthamine lipoate compound. The ophthalmic composition of the bifunctional compound described in the present invention treats age-related eye diseases through the mechanism of pupil constriction and lens softening, producing higher efficacy and therapeutic effect.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to an ophthalmic composition based on galanthamine ester compounds or enantiomers, diastereomers, racemates or pharmaceutically acceptable salts or solvates thereof, and application of the ophthalmic composition in treating eye diseases. Background Art

[0002] Presbyopia is an eye phenomenon that occurs when the lens of the eye gradually hardens and thickens as people age, and the ability of the eye muscles to adjust also decreases, resulting in reduced zoom ability. The occurrence and development of presbyopia is directly related to age, and most of them appear after the age of 45. Its occurrence and severity are also related to other factors, such as the original refractive error, height, reading habits, lighting, and overall health. Specifically, with age, the lens of the eye gradually hardens and thickens, and due to the cross-linking of proteins in the lens fiber cells to produce oxidized protein thiol groups, the lens's ability to adjust is lost. At present, the main methods of treating presbyopia are optical correction (reading glasses), surgical correction, and drug treatment (pilocarpine hydrochloride).

[0003] The existing technology has the following defects and shortcomings: First, sequelae may occur after presbyopia surgery, such as blurred vision, dry eyes, glare, diplopia, refractive errors, etc.; second, wearing reading glasses for a long time may cause symptoms such as eye fatigue, dryness, itching, and even cause discomfort symptoms such as headaches and eye pain.

[0004] Compared with the above two methods, drug treatment is easy to use, reasonably priced, and has no postoperative complications. To date, there are two potential mechanisms of action for the treatment of presbyopia. The first mechanism of action is to reduce the pupil, also referred to as pupil contraction. Specifically, muscarinic receptor (Muscarinic Receptor: M receptor) agonists can directly stimulate cholinergic receptors, act on the muscarinic receptor (M3) subtype on the iris sphincter, cause the iris sphincter to contract and produce a miotic effect. The purpose of pupil constriction is to increase the depth of focus and thus improve vision. Currently, two M receptor agonists for the treatment of presbyopia have been approved by the FDA, namely Vuity (1.25% pilocarpine) and Qlosi (0.4% pilocarpine). The second mechanism of action is to soften the lens. As we age, the hardening of the lens is related to the increase in the content of insoluble proteins. Under environmental stimuli such as oxidative stress, more and more crystalline proteins bind to the sulfhydryl groups of glutathione and cysteine, and finally form disulfides between glutathione / cysteine ​​and crystalline proteins. The accumulation of disulfides in the intercellular space is difficult to dissolve, which can lead to reduced lens elasticity. Compounds that can reduce disulfide bonds have the potential to soften the lens. Currently, lipoic acid choline ester (UNR844) developed by Novartis has entered the clinical research stage and has shown a good lens softening effect, but the second phase of clinical trials did not reach the preset clinical endpoint, resulting in the termination of clinical development. To date, whether lens softening can treat presbyopia is still an unproven issue.

[0005] Acetylcholinesterase inhibitors can increase acetylcholine in the body, and acetylcholine can further activate M receptors to exert cholinergic pharmacological effects. The galantamine hydrobromide eye drops we studied previously can significantly reduce the pupils of rabbits and mice. The drugs prepared using them can improve age-related eye diseases and conditions, including presbyopia, glaucoma, intraocular hypertension and other eye diseases, providing a new option for the treatment of eye diseases including presbyopia. This research result has been submitted as an invention patent application CN117717558 in China.

[0006] Therefore, the development of a new dual-function drug for the treatment of presbyopia that can both constrict the pupil and soften the lens has great development value. While achieving pupil constriction and increasing the depth of focus, thereby improving vision in the short term, it gradually softens the lens to achieve long-term improvement in vision. Summary of the invention

[0007] In view of the background technology, the purpose of the present invention is to provide a novel drug prodrug for treating presbyopia that can simultaneously constrict the pupil and soften the lens, a preparation method of the prodrug, and its application.

[0008] To achieve the above objectives, the present invention adopts the following technical solutions:

[0009] An ophthalmic composition based on galanthamine lipoate, the composition comprising a therapeutically effective amount of a galanthamine lipoate compound, or an enantiomer, a diastereomer, a racemate of the galanthamine lipoate compound, or a pharmaceutically acceptable salt or solvate of the galanthamine lipoate compound, wherein the galanthamine lipoate compound is as shown in formula (I),

[0010]

[0011] Galantamine lipoate is a bifunctional compound, which has dual functional groups of miotic activity and disulfide bond reduction activity. After being degraded and metabolized into galantamine and lipoate under the action of intraocular enzymes, it can also realize the dual functions of miotic activity and disulfide bond reduction activity.

[0012] Furthermore, the pharmaceutically acceptable salt of the galanthamine lipoate compound 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.

[0013] The ophthalmic composition may further include at least one of a buffer solution, a pH adjuster, an osmotic pressure adjuster, a preservative, a complexing agent, a gelling agent, a thickener and a solubilizing agent.

[0014] Preferably, the buffer solution comprises at least one of a monohydrogen phosphate / dihydrogen phosphate system solution, an acetic acid / acetate system solution, a succinic acid system solution, a citric acid / citrate system solution, a boric acid / chloride system solution, a tromethamine system solution or a phthalate system solution;

[0015] Preferably, the pH adjuster comprises at least one of sodium hydroxide, potassium hydroxide, hydrochloric acid, boric acid, citric acid, tromethamine or triethanolamine, with a pH range of 4.0 to 8.0;

[0016] Preferably, the osmotic pressure regulator comprises at least one of mannitol, sodium chloride, glycerol, glucose or propylene glycol, and the preferred osmotic pressure range is 280 to 320 mOsm;

[0017] Preferably, the preservative comprises at least one of benzalkonium chloride, benzalkonium bromide, ethylparaben, phthalate or sorbic acid;

[0018] Preferably, the complexing agent includes disodium edetate or dipotassium edetate; the gelling agent is at least one of gellan gum, poloxamer, carbomer, and xanthan gum;

[0019] Preferably, the thickener comprises at least one of hydroxypropyl methylcellulose, sodium hyaluronate, polyvinyl alcohol, sodium carboxymethyl cellulose or sodium alginate.

[0020] Preferably, the solubilizing agent comprises at least one of Tween 80, polyoxyethylene (40) hydrogenated castor oil or polyoxyethylene (35) castor oil.

[0021] The therapeutically effective amount of galanthamine lipoate compound, or the enantiomer, diastereomer, racemate of the galanthamine lipoate compound, or the pharmaceutically acceptable salt or solvate of the galanthamine lipoate compound is contained in the composition in an amount ranging from 0.01% to 5.0% (weight / volume or weight / weight);

[0022] Preferably, the therapeutically effective amount of the galanthamine lipoate compound, or the enantiomer, diastereomer, racemate of the galanthamine lipoate compound, or the pharmaceutically acceptable salt or solvate of the galanthamine lipoate compound is present in the composition in a range of 0.1% to 3.0% (weight / volume or weight / weight).

[0023] The present invention also provides a use of the above ophthalmic composition in the preparation of a medicament for preventing, treating or improving an eye disease of a subject in need thereof. The eye disease includes presbyopia, cataract, glaucoma or intraocular hypertension.

[0024] The present invention also provides a method for preparing the ophthalmic composition. The method for preparing the galanthamine lipoic acid ester compound comprises the following steps: neutralizing galanthamine hydrobromide with a base to obtain galanthamine free base; and condensing the galanthamine free base with lipoic acid to obtain the ophthalmic composition.

[0025] Furthermore, a therapeutically effective amount of galanthamine lipoate compound, or the enantiomer, diastereomer, racemate of the galanthamine lipoate compound, or a pharmaceutically acceptable salt or solvate of the galanthamine lipoate compound, and a pharmaceutically acceptable carrier or excipient are dissolved in a buffer solution, and the filtrate is obtained by filtration and sterilization to obtain the ophthalmic composition.

[0026] Compared with the prior art, the present invention has the following advantages:

[0027] The present invention significantly overcomes the uncertainty or unpredictability of clinical efficacy associated with the separate use of a miotic agent and a disulfide bond reducing agent by bonding the two physical chemical moieties of galantamine free base and lipoic acid through appropriate chemical bonds. This produces a single, novel, and effective bifunctional compound that can be used to treat age-related eye diseases through the mechanism of pupil constriction and lens softening. The combined action of this bifunctional compound produces higher efficacy and therapeutic effect than the two component compounds used alone or separately.

[0028] The present invention will be further described in detail below in conjunction with specific embodiments, but no limitation is imposed on the claims of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Photo of a rabbit's pupil constricted for Vuity eye drops;

[0030] Figure 2 Photograph of constricted rabbit pupils for 0.5% galantamine lipoate hydrochloride;

[0031] Figure 3 Graph showing constriction of rabbit pupils for Vuity and 0.5% galantamine lipoate hydrochloride;

[0032] Figure 4 OCT (Optical Coherence Tomography) image recording of mouse pupil constriction by Vuity eye drops;

[0033] Figure 5 OCT image recording of constricted mouse pupils for 1.0% galantamine lipoate hydrochloride;

[0034] Figure 6 Data for the effects of Vuity and 1.0% galantamine lipoate hydrochloride on mouse lens elasticity. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0036] 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.

[0037] Example 1: Preparation of galanthamine free base

[0038]

[0039] Weigh 5.0 g of galanthamine hydrobromide and stir and dissolve it in 30 mL of ethyl acetate. After complete dissolution, add 30 mL of saturated sodium bicarbonate solution to the solution and stir at room temperature for 30 minutes; separate the two phases, wash the ethyl acetate phase with 15 mL of saturated brine, dry the ethyl acetate phase with anhydrous sodium sulfate, filter and concentrate in vacuo to obtain 2.9 g of galanthamine free base, with a yield of 74.33%.

[0040] Embodiment 2 Preparation method of galanthamine lipoate

[0041]

[0042] 0.66 g of galanthamine free base, 0.52 g of thioctic acid and 0.14 g of 4-dimethylaminopyridine were weighed respectively, dissolved in 15 mL of dichloromethane under stirring at 0° C. 0.53 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was weighed and added to the solution, and the solution was stirred overnight at room temperature; 15 mL of water was added and stirred for 10 minutes, and extracted with dichloromethane (3*10 mL); the organic phases were combined, anhydrous sodium sulfate was added to the organic phases, dried, filtered, and concentrated in vacuo, and the residue was separated and purified by silica gel chromatography (dichloromethane / methanol, 100:0-10:1) to obtain 0.73 g of galanthamine thioctic acid ester solid, with a yield of 66.82%.

[0043] Example 3 Preparation method of galantamine lipoate hydrochloride

[0044]

[0045] Weigh 0.50 g of galanthamine lipoate, dissolve it in 10 mL of acetonitrile, add an appropriate amount of 4N hydrochloric acid / dioxane, stir at room temperature for 30 minutes, and then concentrate in vacuo to obtain 0.40 g of galanthamine lipoate hydrochloride, with a yield of 74.30%.

[0046] 1H NMR(400MHz,Chloroform-d)δ6.69(d,J=8.2Hz,1H),6.61(d,J=8.2Hz,1H),6.24(d,J=10.3Hz,1H),5.94(dd,J=10.3,5.0Hz,1H),5.3 3(t,J=5.2Hz,1H),4.58(d,J=3.7Hz,1H),4.26(d,J=15.2Hz,1H),3.86(s,3H),3.81(d,J=15.3Hz,1H),3.54–3.41(m,2H),3.18–3.04( m,3H),2.92(d,J=29.0Hz,1H),2.68(ddt,J=16.2,3.0,1.5Hz,1H),2.46(s,3H),2.40(ddd,J=13.0,6.4,5.4Hz,1H),2.30(t,J=7.5Hz ,2H),2.17(t,J=13.6Hz,1H),2.08(ddd,J=16.3,5.5,3.3Hz,1H),1.83(dq,J=12.8,6.9Hz,1H),1.67–1.58(m,4H),1.49–1.34(m,2H). ESI-MS(M+H + )m / z:476.

[0047] Example 4: Preparation of a pharmaceutical composition and preparation method using galantamine lipoate hydrochloride as an active ingredient

[0048] The specific ingredients are shown in Table 1:

[0049] Table 1

[0050]

[0051] The preparation method is as follows:

[0052] Weigh 0.37 g of sodium dihydrogen phosphate and 0.52 g of anhydrous disodium hydrogen phosphate, add to about 95 mL of ultrapure water, stir to dissolve, adjust the pH to 7.0 with hydrochloric acid, add water to make up to 100 mL, and prepare a pH 7.0 buffer solution.

[0053] Weigh 0.001 g of benzalkonium chloride, 0.05 g of galantamine lipoate hydrochloride, and 0.333 g of mannitol, add the above buffer solution, adjust the pH to 7.0 with tromethamine, and make the volume to 10.0 mL with the above pH 7.0 buffer solution; filter with a 0.22 μm PTFE filter; and obtain a pharmaceutical composition with an osmotic pressure of 280-320 mOsm.

[0054] Example 5 Preparation of a pharmaceutical composition using galantamine lipoate hydrochloride as an active ingredient

[0055] The specific auxiliary materials are shown in Table 2:

[0056] Table 2

[0057]

[0058] The preparation method is as follows:

[0059] Weigh 0.68 g of potassium dihydrogen phosphate, add it to about 80 mL of ultrapure water, stir to dissolve it, adjust the pH to 4.5 with hydrochloric acid, add water to make up to 100 mL, and prepare a pH 4.5 buffer solution.

[0060] Weigh 0.001 g of benzalkonium chloride, 0.10 g of galantamine lipoate hydrochloride, and 0.333 g of mannitol, add the above buffer solution, adjust the pH to 4.5 with tromethamine, and make the volume to 10.0 mL with the above pH 4.5 buffer solution; filter with a 0.22 μm PTFE filter; and obtain a pharmaceutical composition with an osmotic pressure of 280-320 mOsm.

[0061] Example 6 Preparation of a pharmaceutical composition using galantamine lipoate hydrochloride as an active ingredient

[0062] The specific auxiliary materials are shown in Table 3:

[0063] Table 3

[0064]

[0065]

[0066] The preparation method is as follows:

[0067] Weigh 6.3 g of anhydrous sodium acetate, add it to about 80 mL of ultrapure water, stir to dissolve it, adjust the pH to 4.0 with acetic acid, add water to make up to 100 mL, and prepare a pH 4.0 buffer solution;

[0068] Weigh 0.001 g of benzalkonium chloride, 0.30 g of galantamine lipoate hydrochloride, and 0.333 g of mannitol, add the above buffer solution, adjust the pH to 4.0 with tromethamine, and make the volume to 10.0 mL with the above pH 4.0 buffer solution; filter with a 0.22 μm PTFE filter; and obtain a pharmaceutical composition with an osmotic pressure of 280-320 mOsm.

[0069] Example 7 Preparation of a pharmaceutical composition using galantamine lipoate hydrochloride as an active ingredient

[0070] The specific auxiliary materials are shown in Table 4:

[0071] Table 4

[0072]

[0073] The preparation method is as follows:

[0074] Weigh 1.18 g of succinic acid, add to about 60 mL of ultrapure water, stir to dissolve, adjust the pH to 4.5 with 1 M sodium hydroxide, add water to make up to 100 mL, and prepare a pH 4.5 buffer solution;

[0075] Weigh 0.001 g of benzalkonium chloride, 0.05 g of galantamine lipoate hydrochloride, 0.01 g of disodium edetate, and 0.300 g of mannitol, add the above buffer solution, adjust the pH to 4.5 with sodium hydroxide, and make the volume to 10.0 mL with the above pH 4.5 buffer solution; filter with a 0.22 μm PTFE filter; and obtain a pharmaceutical composition with an osmotic pressure of 280-320 mOsm.

[0076] Example 8: Preparation of a pharmaceutical composition and preparation method using galantamine lipoate hydrochloride as an active ingredient

[0077] The specific ingredients are shown in Table 5:

[0078] Table 5

[0079]

[0080] The preparation method is as follows:

[0081] Weigh 2.0 g of potassium dihydrogen phosphate, add it to about 90 mL of ultrapure water, stir to dissolve it, adjust the pH to 8.0 with hydrochloric acid, add water to make up to 100 mL, and prepare a pH 8.0 buffer solution;

[0082] Weigh 0.001 g of benzalkonium chloride, 0.05 g of galantamine lipoate hydrochloride, and 0.03 g of sodium chloride, add the above-mentioned buffer solution, adjust the pH to 8.0 with hydrochloric acid and sodium hydroxide, and make the volume to 10.0 mL with the above-mentioned pH 8.0 buffer solution; filter with a 0.22 μm PTFE filter; and obtain a pharmaceutical composition with an osmotic pressure of 280-320 mOsm.

[0083] Example 9: Preparation of a pharmaceutical composition and preparation method using galantamine lipoate hydrochloride as an active ingredient

[0084] The specific ingredients are shown in Table 6:

[0085] Table 6

[0086]

[0087] The preparation method is as follows:

[0088] Weigh 0.001 g of benzalkonium bromide, 0.05 g of galantamine lipoate hydrochloride, 0.025 g of gellan gum, 0.02 g of sodium chloride, and 0.25 g of mannitol, add the buffer prepared in Example 5, adjust the pH to 4.5 with tromethamine, and make the volume to 10.0 mL with the above pH 4.5 buffer solution; filter with a 0.22 μm PTFE filter; and obtain a pharmaceutical composition with an osmotic pressure of 280-320 mOsm.

[0089] Example 10: Preparation of a pharmaceutical composition and preparation method using galanthamine lipoate hydrochloride as an active ingredient

[0090] The specific ingredients are shown in Table 7:

[0091] Table 7

[0092]

[0093]

[0094] The preparation method is as follows:

[0095] Weigh 0.001 g of benzalkonium bromide, 0.05 g of galantamine lipoate hydrochloride, 0.025 g of hydroxypropyl methylcellulose, and 0.30 g of mannitol, add the buffer prepared in Example 5, adjust the pH to 4.5 with tromethamine, and make the volume to 10.0 mL with the above pH 4.5 buffer solution; filter with a 0.22 μm PTFE filter; and obtain a pharmaceutical composition with an osmotic pressure of 280-320 mOsm.

[0096] Example 11: Preparation of a pharmaceutical composition and preparation method using galantamine lipoate hydrochloride as an active ingredient

[0097] The specific ingredients are shown in Table 8:

[0098] Table 8

[0099]

[0100] The preparation method is as follows:

[0101] 0.001 g of benzalkonium bromide, 0.06 g of galantamine lipoate hydrochloride, 0.40 g of Tween 80, and 0.25 g of mannitol were weighed and added to the buffer prepared in Example 5, the pH was adjusted to 4.5 with tromethamine, and the volume was made up to 10.0 mL with the above pH 4.5 buffer solution; filtered using a 0.22 μm PTFE filter; and a pharmaceutical composition with an osmotic pressure of 280-320 mOsm was obtained.

[0102] Example 12: Preparation of a pharmaceutical composition and preparation method using galantamine lipoate hydrochloride as an active ingredient

[0103] The specific components are shown in Table 9:

[0104] Table 9

[0105]

[0106] The preparation method is as follows:

[0107] Weigh 0.001 g of benzalkonium bromide, 0.06 g of galantamine thioctic acid ester hydrochloride, 0.10 g of polyoxyethylene (40) hydrogenated castor oil, and 0.30 g of mannitol, add them to the buffer solution prepared in Example 5, adjust the pH to 4.5 with tromethamine, and make up the volume to 10.0 mL with the above pH 4.5 buffer solution; filter with a 0.22 μm PTFE filter head; prepare a pharmaceutical composition with an osmotic pressure of 280 - 320 mOsm.

[0108] Example 13: Study on the effect of the pharmaceutical composition (0.5% galantamine thioctic acid ester hydrochloride) on the pupil diameter of rabbits

[0109] 13.1 Drug

[0110] The pharmaceutical composition (0.5% galantamine thioctic acid ester hydrochloride) provided in Example 4, and the positive control is Vuity eye drops (1.25% pilocarpine hydrochloride).

[0111] 13.2 Experimental animals

[0112] 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.

[0113] 13.3 Experimental method

[0114] 13.3.1 Measurement of pupil

[0115] Fix the rabbit in a rabbit box, and measure the pupil diameter (mm) before drug administration with a pupil gauge and take a photo for record before the experiment.

[0116] 13.3.2 Drug administration method

[0117] Six New Zealand rabbits were randomly divided into two groups, with three rabbits in each group. Under a constant light source (light intensity 40Lux), the test rabbits did not need anesthesia, and the rabbits were fixed in the rabbit box. Before the experiment, the pupil diameter (mm) before drug administration was measured with a pupillometer and photographed and recorded. The rabbit eyelids were gently opened, and the drug was sucked by a pipette and dropped on the surface of the rabbit cornea (20μL / eye, binocular administration), so that the drug was retained in the rabbit eyelid conjunctival sac for 1min, and the nasolacrimal duct was pressed for 1min. The administration time was recorded, and the pupil diameter was measured with a pupillometer at 5min, 10min, 15min, 30min, 45min, 1h, 2h, 3h, 4h, and 5h after administration, and photographed and recorded with a SLR camera (CanonEOS M6Mark II). Each eye was photographed 3 times at each time point. The average of the three times was taken as the pupil diameter at each time point.

[0118] 13.4 Statistical Analysis

[0119] Data were expressed as mean ± 95% confidence interval, and one-way ANOVA and LSD-t test were used for multiple comparison statistical analysis in SPSS software to compare the differences between groups at different time points.

[0120]

[0121]

[0122] Table 11

[0123]

[0124]

[0125] Example 14 Study on the effect of the pharmaceutical composition (1.0% galanthamine lipoate hydrochloride) on pupil diameter and lens elasticity in mice

[0126] 14.1 Drugs

[0127] Example 5 pharmaceutical composition (1.0% galanthamine lipoate hydrochloride), positive control is Vuity eye drops (1.25% pilocarpine hydrochloride).

[0128] 14.2 Experimental Animals

[0129] Six aged C57BL / 6J male mice (>8 months old) were divided into two groups according to their age (and weight) using Provantis, with 3 mice in each group. They were provided by Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd., license number SCXK(Zhe)2019-0001.

[0130] 14.3 Experimental Methods

[0131] 14.3.1 Administration

[0132] Use a micropipette to draw 5 μL of the test substance, drop it on the animal's eye surface, and restrain it for at least 20 seconds (restraint must be recorded). All animals complete OCT photography of the pupil before and 25±5 minutes after administration. The brightness and darkness of the room should be kept consistent during each OCT examination.

[0133] 14.3.2 Determination of pupil

[0134] The OCT anterior segment mode was used to collect anterior segment photos of both eyes of the animal to measure the pupil diameter of the mouse.

[0135] 14.3.3 Lens elasticity test

[0136] On the 31st day of administration, all experimental animals were euthanized by bleeding after CO2 anesthesia, and the eyeballs of both eyes were collected, the lenses were separated, and immediately placed in a container containing Hanks' balanced salt solution (HBSS). There was no obvious damage or scratches on the lens. A pressure rod was slowly approached to the lens until it just touched, which was recorded as the origin. The pressure rod then compressed the lens at 25μm / step, and the elastic force of the lens was recorded after each compression. The interval between each step of the pressure rod was at least 10 seconds. After the experiment, the remaining eyeball tissue and lens were directly discarded.

[0137] 14.4 Statistical Analysis

[0138] The pupil diameter was measured by analysis of variance between groups using the LSD-t test method.

[0139] For the determination of lens elasticity, all numerical data were calculated using Microsoft Excel software for group mean and standard deviation calculation.

[0140] 14.5 Experimental Results

[0141] 14.5.1 Determination of pupil diameter

[0142] The data of mouse pupil constriction ratio are shown in Table 12. As can be seen from the data in Table 12, both Vuity and galantamine lipoate hydrochloride can constrict mouse pupils.

[0143] Table 12

[0144]

[0145] Note: *Continuous administration for 15 days, 25±5 minutes after administration

[0146] OCT images of Vuity eye drops and the pharmaceutical composition of Example 5 (1.0% galanthamine lipoate hydrochloride) on mouse pupils were recorded as follows: Figure 4 and Figure 5 shown. Figure 4 A in the middle represents the OCT image before Vuity administration. Figure 4 Middle B represents the OCT image 25 ± 5 min after Vuity administration; Figure 5 A in the middle represents the OCT image before administration of galantamine lipoate hydrochloride. Figure 5 B in the figure represents the OCT image at 25±5 min after administration of galantamine lipoate hydrochloride. Figure 4 and Figure 5 It can be seen that both Vuity eye drops and 1.0% galanthamine lipoic acid ester hydrochloride can contract the pupillary sphincter of C57BL / 6J mice, causing pupil constriction, and the 1.0% galanthamine lipoic acid ester hydrochloride of the present invention causes a higher pupil constriction ratio. The pharmaceutical composition (1.0% galanthamine lipoic acid ester hydrochloride) provided by the present invention can effectively contract the pupil, thereby playing the effect of treating eye diseases such as presbyopia, glaucoma, and intraocular hypertension.

[0147] 14.5.2 Determination of lens elasticity

[0148] The mouse lens elasticity data are shown in Tables 13, 14 and 15. From the data in Tables 13, 14 and 15, it can be seen that Vuity has no lens softening effect, and galantamine lipoic acid ester hydrochloride has a certain degree of lens softening tendency in the range of 200-450 μm.

[0149] Table 13

[0150]

[0151] Table 14

[0152]

[0153] Table 15

[0154]

[0155] Mouse lens elasticity data curve Figure 6 As shown, Figure 6 The results showed that the elastic force of the 1.0% galantamine lipoate hydrochloride group was slightly less than that of the Vuity group in the range of 200-450 μm, indicating that 1.0% galantamine lipoate hydrochloride may have a certain effect on softening the mouse lens.

[0156] Based on the above data, the present invention provides a bifunctional compound, preferably galanthamine lipoate hydrochloride eye drops, which has both mydriasis and lens softening effects. Compared with the use of mydriasis and lens softeners alone or separately, the combined action of this bifunctional compound will produce higher efficacy and therapeutic effect.

[0157] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. An ophthalmic composition based on galantamine lipoate, characterized in that, The composition comprises a therapeutically effective amount of a galanthamine lipoate compound, or an enantiomer, a diastereomer, a racemate of the galanthamine lipoate compound, or a pharmaceutically acceptable salt or solvate of the galanthamine lipoate compound, wherein the galanthamine lipoate compound is as shown in formula (I), 2. The ophthalmic composition according to claim 1, characterized in that The pharmaceutically acceptable salt of the galanthamine lipoate compound 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.

3. The ophthalmic composition according to claim 1 or 2, characterized in that It may also include at least one of a buffer solution, a pH regulator, an osmotic pressure regulator, a preservative, a complexing agent, a gelling agent, a thickener and a solubilizing agent.

4. The ophthalmic composition according to claim 3, characterized in that The buffer solution includes at least one of a monohydrogen phosphate / dihydrogen phosphate system solution, an acetic acid / acetate system solution, a succinic acid system solution, a citric acid / citrate system solution, a boric acid / chloride system solution, a tromethamine system solution or a phthalate system solution.

5. The ophthalmic composition according to claim 3, characterized in that The pH regulator includes at least one of sodium hydroxide, potassium hydroxide, hydrochloric acid, boric acid, citric acid, tromethamine or triethanolamine, preferably, the pH range is 4.0 to 8.

0. 。 6. The ophthalmic composition according to claim 3, characterized in that The osmotic pressure regulator includes at least one of mannitol, sodium chloride, glycerol, glucose or propylene glycol. Preferably, the osmotic pressure ranges from 280 to 320 mOsm.

7. The ophthalmic composition according to claim 3, characterized in that The preservative includes at least one of benzalkonium chloride, benzalkonium bromide, ethylparaben, phthalate or sorbic acid.

8. The ophthalmic composition according to claim 3, characterized in that The complexing agent includes disodium edetate or dipotassium edetate.

9. The ophthalmic composition according to claim 3, characterized in that The gelling agent is at least one of gellan gum, poloxamer, carbomer and xanthan gum.

10. The ophthalmic composition according to claim 3, characterized in that The thickener includes at least one of hydroxypropyl methylcellulose, sodium hyaluronate, polyvinyl alcohol, sodium carboxymethyl cellulose or sodium alginate.

11. The ophthalmic composition according to claim 3, characterized in that The solubilizing agent includes at least one of Tween 80, polyoxyethylene (40) hydrogenated castor oil or polyoxyethylene (35) castor oil.

12. The ophthalmic composition according to any one of claims 1 to 11, characterized in that: The therapeutically effective amount of the galanthamine lipoate compound, or the enantiomer, diastereomer, racemate of the galanthamine lipoate compound, or the pharmaceutically acceptable salt or solvate of the galanthamine lipoate compound in the composition is in a range of 0.01% to 5.0% (weight / volume or weight / weight); preferably, the therapeutically effective amount of the galanthamine lipoate compound, or the enantiomer, diastereomer, racemate of the galanthamine lipoate compound, or the pharmaceutically acceptable salt or solvate of the galanthamine lipoate compound in the composition is in a range of 0.1% to 3.0% (weight / volume or weight / weight).

13. Use of the ophthalmic composition according to any one of claims 1 to 12 in the preparation of a medicament for preventing, treating or ameliorating an eye disease in a subject in need thereof.

14. The use according to claim 13, characterized in that The eye disease includes presbyopia, cataract, glaucoma or intraocular hypertension.

15. A method for preparing the ophthalmic composition according to claim 1, characterized in that: The preparation method of the galanthamine lipoic acid ester compound comprises the following steps: neutralizing galanthamine hydrobromide with a base to obtain galanthamine free base; and condensing the galanthamine free base with lipoic acid to obtain the galanthamine lipoic acid ester compound.

16. The method for preparing the ophthalmic composition according to claim 15, characterized in that: The ophthalmic composition is prepared by dissolving a therapeutically effective amount of a galanthamine lipoate compound, or an enantiomer, a diastereomer, a racemate of the galanthamine lipoate compound, or a pharmaceutically acceptable salt or solvate of the galanthamine lipoate compound, and a pharmaceutically acceptable carrier or excipient in a buffer solution, and filtering and sterilizing to obtain a filtrate.

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