Use of penehyclidine in treating or preventing vision-impairing eye diseases

Abstract

The present invention provides the use of a compound of the structure represented by formula (I) or a nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof in the preparation of a medicament. JPEG2023544652000012.jpg3682

Description

[Technical field]

[0001] The present invention relates to the pharmaceutical field, specifically, the present invention relates to the use of penehyclidine in the treatment or prevention of vision-impairing eye diseases. [Background technology]

[0002] According to epidemiological reports, the incidence of amblyopia in China is 1.6-3.6%, and in some areas it is as high as 11.8%. The prevalence of myopia in the Chinese population aged 5 and above will increase to about 51%, and the disease population may reach 700 million.

[0003] At present, foreign medicines for the prevention and management of myopia and the treatment of amblyopia recommend atropine eye drops, such as 1% atropine sulfate eye drops sold in the United States and Japan, for the diagnosis or treatment of mydriasis, cycloplegia and amblyopia treatment. In recent years, low-concentration atropine sulfate eye drops (0.01%) have been approved for sale in Taiwan, China and Macau for the relief of myopia and the treatment of myopia, and clinical trials have been reported in Hong Kong, Singapore, the United States, the United Kingdom, India and other countries for the relief of myopia progression, indicating that low-concentration atropine may effectively slow the progression of myopia in children and adolescents.

[0004] The etiological hypothesis of myopia proposes that the onset of myopia is related to ciliary muscle accommodation. Sato's tone accommodation theory speculates that the long-term use of accommodation may cause ciliary muscle accommodation tone, so that the effect of myopia control in adolescence can be achieved by using atropine to relax or release the accommodation tone. Atropine blocks the mammalian ciliary muscle M receptor, thereby relaxing the accommodation tone of the ciliary muscle, and the chick ciliary muscle is striated muscle and regulated by nicotinic (N)-like receptors, so atropine cannot paralyze the chick ciliary muscle. However, McBrien et al. induced -2.8D myopia and 0.21mm axial elongation 8 days after injection of 0.01% atropine into the vitreous cavity of chick formdeprivation myopia (FDM) model eyes, while sham- and saline-injected chicks induced -18.5D and -20.9D myopia and 1.04mm and 1.00mm axial elongation, respectively, indicating that atropine can still significantly inhibit the formation and progression of myopia in chicks, indicating that atropine inhibits myopia via a nonaccommodative mechanism or that ciliary muscle accommodative paralysis is not the only target of atropine myopia control. Atropine has been shown to prevent the development of myopia in some animal models and in humans, but the mechanism of atropine's anti-myopic effect is not fully understood.

[0005] At present, the relationship between various drugs and myopia treatment has not yet been established, and since atropine is a non-selective inhibitor, it has been found that many pathways are involved in the treatment of myopia with atropine. Tropicamide is also another non-selective M receptor blocker, but through comparative studies with atropine, tropicamid does not effectively prevent or delay the onset of myopia.

[0006] In 1991, Stone et al. reported that daily subconjunctival injections of the M1 receptor blocker pirenzepine could inhibit the development of FDM, whereas the M2 receptor blocker methoctamine and the M3 receptor blocker 4-DAMP were ineffective, suggesting that the cause may be related to the M1 receptor. However, the results of trials on the treatment of myopia in relation to pirenzepine research and findings were inconsistent between research groups. Flitcroft showed that higher retinal concentrations could be achieved when another M1 receptor blocker, trihexyphenidyl, was administered topically or orally, but was not effective in preventing the development of experimental myopia.

[0007] Luft et al. studied more than 10 drugs with M cholinergic receptor blocking effects, including atropine (nonselective), pirenzepine (M1), and oxyphenonium (M2), and found that only oxyphenonium, atropine, perenzepine, and himbacine had a certain effect of preventing FDM without retinal damage, while other drugs could not prevent FDM or had different degrees of retinal damage. M receptors mediate multiple functions, and even different subtypes of M receptors in the same tissue have different pharmacological properties. In the airways, the function of M2 receptors is opposite to that of M1 and M3 receptors. Therefore, the selectivity of different subtypes of M receptors is the key to determining the prospects for the application of anticholinergic drugs. Therefore, from the reports in the research literature, the corresponding relationship between M receptors and myopia has not yet been established.

[0008] In summary, there is a need to develop new drugs for the treatment or prevention of vision disorders such as myopia and amblyopia.

[0009] So far, there have been no reports of the effectiveness of penehyclidine and its derivatives in the prevention and treatment of myopia and amblyopia. Summary of the Invention [Problem to be solved by the invention]

[0010] In the treatment of myopia and amblyopia, atropine sulfate eye drops currently being studied abroad have certain risks, atropine is prone to systemic side effects such as red face, dry mouth, increased heart rate, urinary retention, etc., which can cause poisoning and anaphylactic shock, and should be administered intravenously up to 2mg each time. If the dosage exceeds the above, it will cause poisoning, and if overdosed, it will manifest as clumsy movements, confusion, convulsions, difficulty breathing, abnormal rapid heartbeat, etc. Therefore, the safety of atropine sulfate eye drops in the use of myopia and amblyopia has been a factor limiting its large-scale promotion. At present, there is an urgent need to find safer and more effective drugs for the treatment of eye diseases on the market.

[0011] The present invention aims to solve at least one of the technical problems in the related art to some extent. [Means for solving the problem]

[0012] Thus, in a first aspect, the present invention provides the use of a compound of structure as shown in formula (I) or a nitrogen oxide, solvate, metabolite, pharma- ceutically acceptable salt or prodrug thereof in the preparation of a medicament, the medicament being for use in treating and / or preventing a vision-impairing eye disease. [ka]

[0013] Through extensive research, the inventors have found that the compound represented by formula (I) or its derivatives (nitrogen oxides, solvates, metabolites, pharma- ceutically acceptable salts) have good effects in treating or preventing vision-impairing eye diseases, and have significantly lower systemic toxic side effects than atropine, and have excellent application prospects.

[0014] According to an embodiment of the present invention, the above use may further include at least one of the following additional technical features:

[0015] According to an embodiment of the present invention, the salt of the compound represented by formula (I) includes an organic salt or an inorganic salt.

[0016] The compound of formula (I) is called penehyclidine. After much research, the inventors unexpectedly discovered that penehyclidine and its derivatives, such as its organic salts or inorganic salts, can effectively treat or prevent vision-impairing eye diseases such as myopia or amblyopia, and the preventive and controlling effects are better than those of atropine sulfate eye drops of the same concentration, and have the advantages of less pupil dilation, less local irritation to the eyes, high safety, and can be used for a long time.

[0017] According to an embodiment of the present invention, the salt of the compound represented by formula (I) is a hydrochloride, the structure of which is represented by formula (II).

[0018] [ka]

[0019] After repeated experiments, the inventors have found that the above-mentioned form of penehyclidine hydrochloride has good effects in treating and / or preventing diseases such as myopia, amblyopia and the like.

[0020] According to an embodiment of the present invention, the medicament is used for treating and / or preventing myopia and / or amblyopia.

[0021] According to an embodiment of the present invention, the causes of myopia and / or amblyopia include one or more of myopic shift in refractive power, myopic vitreous chamber depth increase, myopic axial length increase, morphological deprivation, refractive anisotropy, and astigmatism.

[0022] According to an embodiment of the present invention, the myopia and / or amblyopia includes one or more of the following: low myopia, moderate myopia, high myopia, axial myopia, simple myopia, pathological myopia, distance vision loss, eye fatigue, exotropia, strabismus amblyopia, fundus damage, vision blockage, visual distortion, vision ghost, color vision deficiency, light perception deficiency, reduced contrast sensitivity, and refractive amblyopia. Note that the vision-damaging eye disease described in this application does not include vision problems caused by trauma.

[0023] In a second aspect of the present invention, there is provided a pharmaceutical composition for treating and / or preventing a vision-impairing eye disease, which, according to an embodiment of the present invention, comprises a compound having a structure represented by formula (I) or a nitrogen oxide, solvate, metabolite, pharma- ceutically acceptable salt or prodrug thereof as an active ingredient.

[0024] According to an embodiment of the present invention, the above pharmaceutical composition may further include at least one of the following additional technical features:

[0025] According to an embodiment of the present invention, the pharmaceutical composition is used for treating and / or preventing myopia and / or amblyopia.

[0026] According to an embodiment of the present invention, the causes of myopia and / or amblyopia include one or more of myopic shift in refractive power, myopic vitreous chamber depth increase, myopic axial length increase, morphological deprivation, refractive anisotropy, and astigmatism.

[0027] According to an embodiment of the present invention, the myopia and / or amblyopia includes one or more of the following: low myopia, moderate myopia, high myopia, axial myopia, simple myopia, pathological myopia, distance vision loss, eye fatigue, exotropia, strabismus amblyopia, fundus damage, vision blockage, visual distortion, vision ghost, color vision deficiency, light perception deficiency, reduced contrast sensitivity, and refractive amblyopia. Note that the vision-damaging eye disease described in this application does not include vision problems caused by trauma.

[0028] According to an embodiment of the present invention, the pharmaceutical composition further comprises at least one pharma- ceutically acceptable carrier. According to the pharmaceutical composition of the embodiment of the present invention, the carrier includes, but is not limited to, aqueous carrier, aqueous miscible carrier, non-aqueous carrier, antibacterial agent or antibacterial growth preservative, stabilizer, dissolution enhancer, osmotic pressure regulator, buffer, antioxidant, local anesthetic, suspending and dispersing agent, moisturizing agent or emulsifying agent, complexing agent, polyvalent chelating agent or chelating agent, cryoprotectant, cryoprotectant, thickener, pH adjuster and inert gas. Those skilled in the art can select based on the actual needs of the formulation.

[0029] According to an embodiment of the present invention, the dosage form of the pharmaceutical composition is an ophthalmic formulation, including one or more of eye drops, ophthalmic ointments, ophthalmic creams, ophthalmic emulsions, ophthalmic gels, ophthalmic pills, eye masks, and intraocular implants.

[0030] According to an embodiment of the present invention, the mass fraction of the active ingredient in the pharmaceutical composition is 0.005%-2%.

[0031] According to the pharmaceutical composition of the embodiment of the present invention, the mass volume fraction of the active ingredient in the pharmaceutical composition is 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%, 0.09%, 0.095%, 0.1%, 0.105%, 0.11%, 0.115%, 0.12%, 0.125%, 0.13%, 0.135%, 0.14%, 0.145%, 0.15%, 0.155%, 0.16%, 0.165%, 0.17%, 0.175%, 0.18%, 0.185%, 0.19%, 0.195%, 0.2%, 0.205%, 0.21%, 0.215%, 0.22%, 0.225%, 0.23%, 0.235%, 0.24%, 0.245%, 0.25%, 0.255%, 0 .26%, 0.265%, 0.27%, 0.275%, 0.28%, 0.285%, 0.29%, 0.295%, 0.3%, 0.305%, 0.31%, 0.315%, 0.32%, 0.325%, 0.33%, 0.335%, 0.34%, 0.345%, 0.35%, 0.35 5%, 0.36%, 0.365%, 0.37%, 0.375%, 0.38%, 0.385%, 0.39%, 0.395%, 0.4%, 0.405%, 0.41%, 0.415%, 0.42%, 0.425%, 0.43%, 0.435%, 0.44%, 0.445%, 0.45% ,0.455%,0.46%,0.465%,0.47%,0.475%,0.48%,0.485%,0.49%,0.495%,0.5%,0.505%,0.510%,0.515%,0.520%,0.525%,0.530%,0.535%,0.540%,0.54 5%, 0.550%, 0.555%, 0.560%, 0.565%, 0.570%, 0.575%, 0.580%, 0.585%, 0.590%, 0.595%, 0.600%, 0.605%, 0.610%, 0.615%, 0.620%, 0.625%, 0.630%, 0.6 35%, 0.640%, 0.645%, 0.650%, 0.655%, 0.660%, 0.665%, 0.670%, 0.675%, 0.680%, 0.685%, 0.690%, 0.695%, 0.700%, 0.705%, 0.710%, 0.715%, 0.720%, 0.725%、0.730%、0.735%、0.740%、0.745%、0.750%、0.755%、0.760%、0.765%、0.770%、0.775%、0.780%、0.785%、0.790%、0.795%、0.800%、0.805%、0.810%、0.815%、0.820%、0.825%、0.830%、0.835%、0.840%、0.845%、0.850%、0.855%、0.860%、0.865%、0.870%、0.875%、0.880%、0.885%、0.890%、0.895%、0.900%、0.905%、0.910%、0.915%、0.920%、0.925%、0.930%、0.935%、0.940%、0.945%、0.950%、0.955%、0.960%、0.965%、0.970%、0.975%、0.980%、0.985%、0.990%、0.995%、1.000%、1.005%、1.010%、1.015%、1.020%、1.025%、1.030%、1.035%、1.040%、1.045%、1.050%、1.055%、1.060%、1.065%、1.070%、1.075%、1.080%、1.085%、1.090%、1.095%、1.100%、1.105%、1.110%、1.115%、1.120%、1.125%、1.130%、1.135%、1.140%、1.145%、1.150%、1.155%、1.160%、1.165%、1.170%、1.175%、1.180%、1.185%、1.190%、1.195%、1.200%、1.205%、1.210%、1.215%、1.220%、1.225%、1.230%、1.235%、1.240%、1.245%、1.250%、1.255%、1.260%、1.265%、1.270%、1.275%、1.280%、1.285%、1.290%、1.295%、1.300%、1.305%、1.310%、1.315%、1.320%、1.325%、1.330%、1.335%、1.340%、1.345%、1.350%、1.355%、1.360%、1.365%、1.370%、1.375%、1.380%、1.385%、1.390%、1.395%、1.400%、1.405%、1.410%、1.415%、1.420%、1.425%、1.430%、1.435%、1.440%, 1.445%, 1.450%, 1.455%, 1.460%, 1.465%, 1.470%, 1.475%, 1.480%, 1.485%, 1.490%, 1.495%, 1.500%, 1.505%, 1.510%, 1.515%, 1.520%, 1.525%, 1.530%, 1.535%, 1.540%, 1.545%, 1.550%, 1.555%, 1.560%, 1.565%, 1.570%, 1.575%, 1.58 0%, 1.585%, 1.590%, 1.595%, 1.600%, 1.605%, 1.610%, 1.615%, 1.620%, 1.625%, 1.630%, 1.635%, 1.640%, 1.645%, 1.650%, 1.655%, 1.660%, 1.665%, 1.670%, 1.675%, 1.680%, 1.685%, 1.690%, 1.695%, 1.700%, 1.705%, 1.710%, 1.715%, 1.720% ,1.725%,1.730%,1.735%,1.740%,1.745%,1.750%,1.755%,1.760%,1.765%,1.770%,1.775%,1.780%,1.785%,1.790%,1.795%,1.800%,1.805%,1.810%,1.815%,1.820%,1.825%,1.830%,1.835%,1.840%,1.845%,1.850%,1.855%,1.860%,1. .865%, 1.870%, 1.875%, 1.880%, 1.885%, 1.890%, 1.895%, 1.900%, 1.905%, 1.910%, 1.915%, 1.920%, 1.925%, 1.930%, 1.935%, 1.940%, 1.945%, 1.950%, 1.955%, 1.960%, 1.965%, 1.970%, 1.975%, 1.980%, 1.985%, 1.990%, 1.995%, 2.000%.

[0032] According to a specific embodiment of the present invention, the dosage of the pharmaceutical composition depends on the type and weight of the subject to be treated, the nature and severity of the disease, the type of formulation and the mode of administration of the drug, and the administration period or time interval.

[0033] In the third aspect of the present invention, the present invention provides an ophthalmic preparation for treating and / or preventing visual impairment eye diseases. According to an embodiment of the present invention, the mass fraction of the active ingredient in the ophthalmic preparation is 0.005%-2%, and the active ingredient is a compound of the structure shown in formula (I) or its nitrogen oxide, solvate, metabolite, pharma-ceutically acceptable salt or prodrug. Through a number of tests, the inventors have found that the ophthalmic preparation has a clear dose-related relaxing effect on the ciliary muscle, has the effect of significantly slowing down the elongation of the eye axis, slows down the progression of myopia, achieves the treatment of myopia, gradually recovers the tendency of amblyopia in animal amblyopic models, gradually shortens the latency period, and after a certain period of administration, amblyopia basically returns to normal levels.

[0034] According to an embodiment of the present invention, the ophthalmic preparation may further comprise at least one of the following additional technical features: According to an embodiment of the invention, the active ingredient is a salt of a compound of formula (I), said salt being the hydrochloride salt.

[0035] According to an embodiment of the invention, the ophthalmic preparation is used for treating and / or preventing myopia and / or amblyopia.

[0036] According to an embodiment of the present invention, the causes of myopia and / or amblyopia include one or more of myopic shift in refractive power, myopic vitreous chamber depth increase, myopic axial length increase, morphological deprivation, refractive anisotropy, and astigmatism.

[0037] According to an embodiment of the present invention, the myopia and / or amblyopia includes one or more of the following: low myopia, moderate myopia, high myopia, axial myopia, simple myopia, pathological myopia, distance vision loss, eye fatigue, exotropia, strabismus amblyopia, fundus damage, vision blockage, visual distortion, vision ghost, color vision deficiency, light perception deficiency, reduced contrast sensitivity, and refractive amblyopia. Note that the vision-damaging eye disease described in this application does not include vision problems caused by trauma.

[0038] In a fourth aspect of the present invention, the present invention provides a method for treating or preventing myopia and / or amblyopia. According to an embodiment of the present invention, the method comprises administering the above composition or the above ophthalmic preparation to the ocular surface of a subject. The inventors have found through multiple tests that the use of the above composition or ophthalmic preparation can slow the progression of the subject's myopia, achieve treatment of myopia, and also restore the subject's amblyopia to an essentially normal level.

[0039] According to an embodiment of the invention, the method is used for treating or preventing myopia and / or amblyopia.

[0040] According to an embodiment of the present invention, the causes of the myopia and / or amblyopia are one or more selected from the group consisting of myopic shift of refractive power, myopic vitreous chamber depth increase, myopic axial length increase, morphological deprivation, refractive anisotropy, and astigmatism.

[0041] According to an embodiment of the present invention, the myopia and / or amblyopia includes one or more of the following: mild myopia, moderate myopia, severe myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, distance vision loss, eyestrain, exotropia, strabismic amblyopia, axial elongation, fundus damage, vision occlusion, visual distortion, vision ghost, color vision deficiency, light perception abnormality, reduced contrast sensitivity, refractive anisotropy amblyopia, refractive ametropia amblyopia, unilateral form deprivation amblyopia, and bilateral form deprivation amblyopia.

[0042] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. [Brief description of the drawings]

[0043] [Figure 1] This shows the relative change in lens thickness in each group before and after drug administration (Mean±SD, n=6 eyes / group). [Diagram 2] This shows the relative change in pupil diameter in each group before and after drug administration (Mean±SD, n=6 eyes / group). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] The following describes the examples of the present invention in detail, and the examples described below are illustrative and are intended to illustrate the present invention, and the limitations of the present invention cannot be understood. If no specific techniques or conditions are shown in the examples, they shall be carried out according to the techniques or conditions described in the literature of the relevant technical field or according to the product specifications. The reagents or instruments used are conventional products available on the market when the manufacturer is not specified.

[0045] It should be noted that the terms "first", "second" and the like are for explanatory purposes only and cannot be considered to indicate or imply relative importance or to imply the number of technical features. Thus, a feature defined as "first" or "second" may expressly or imply that it includes one or more of the feature, and in the description of the invention, unless otherwise expressly and specifically limited, the concept of "plurality" is at least two, e.g., two or three.

[0046] Pharmaceutical Use The use of the compound of the structure represented by formula (I) or a nitrogen oxide, solvate, metabolite, pharma- ceutically acceptable salt or prodrug thereof according to the present invention in the preparation of a medicament may be to prepare a medicinal product for the treatment, prevention, amelioration, control or alleviation of visual impairment diseases in mammals, particularly humans, or to produce other medicinal products which antagonize M receptors and have reduced toxic side effects.

[0047] The term "solvate" as used herein means that a solvent is present on the surface, in the crystal lattice, or on the surface and in the crystal lattice. A specific example of a solvate is a hydrate, in which the solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice is water. A hydrate may or may not have a solvent other than water on the surface, in the crystal lattice, or in the surface and in the crystal lattice of a substance.

[0048] The "metabolite" of the present invention means a product obtained by metabolism in the body of the compound of the structure represented by formula (I) or a salt thereof. The metabolite of a compound can be identified by techniques known in the art, and its activity can be expressed by a test method as in the present invention. The "pharmaceutical acceptable salt" used in the present invention refers to organic and inorganic salts of the compound of the present invention.

[0049] The term "prodrug" as used herein refers to a compound that is converted in the body to a compound of formula (I), where the prodrug is subject to hydrolysis in the blood or enzymatic conversion to the parent structure in the blood or tissues.

[0050] Drug Composition The term "composition" as used in the present invention refers to a product containing the specified amounts of the specified ingredients, and any product that is produced directly or indirectly by the combination of the specified amounts of the specified ingredients. The meaning of this term in relation to a pharmaceutical composition includes a product containing the active ingredient(s) and the inactive ingredient(s) that constitute the carrier, and any product that results directly or indirectly from the mixing, combination or aggregation of any two or more ingredients, or the decomposition of one or more ingredients, or any other type of reaction or interaction of one or more ingredients. Thus, a pharmaceutical composition of the present invention includes any composition prepared by mixing a compound of the present invention with a pharmaceutically acceptable carrier.

[0051] The pharmaceutical composition according to the present invention comprises at least one pharmaceutically acceptable carrier.Exemplary, the pharmaceutical composition is in the form of an ophthalmic preparation.For example, eye drops, ophthalmic ointments, ophthalmic creams, ophthalmic emulsions, ophthalmic gels, ophthalmic pills, eye masks, intraocular implants.

[0052] The pharmaceutical compositions according to the present invention may further comprise carriers such as suitable antibacterial agents or preservatives, suitable isotonicity agents, suitable antioxidants, suitable local anesthetic agents, suitable suspending and dispersing agents, suitable emulsifying agents, suitable polyvalent chelating agents or chelating agents, suitable pH adjusting agents, etc.

[0053] The pharmaceutical composition of the present invention is useful for treating vision-impairing eye diseases in humans, and can also be used in veterinary treatment of pets, breeding animals, and farm animals in mammals. Examples of other animals include horses, dogs, cats, etc. Here, the compounds of the present invention include pharmaceutically acceptable derivatives. EXAMPLES

[0054] The present invention will be described below with reference to specific examples. However, these examples are merely illustrative and do not limit the present invention in any way.

[0055] All data results in the following examples were statistically calculated using Mean±SD.

[0056] Example: Preparation of penehyclidine hydrochloride solution samples Mix penehyclidine hydrochloride with saline and stir until completely dissolved to prepare 0.01%, 0.1%, 0.5%, 1% and 2% penehyclidine hydrochloride solutions as test samples.

[0057] Example of effect Efficacy Example 1: Effects of penehyclidine hydrochloride on the lens and pupil of monkeys Healthy cynomolgus monkeys that passed quarantine were selected, aged 2.5-3.5 years, weighing 2.0-4.0 kg, and of either sex. They were randomly divided into six groups, with three monkeys in each group, for a total of 18 monkeys. Groups 1, 2, and 3 were administered 1%, 0.1%, and 0.01% atropine sulfate eye drops (commercially available 1% atropine sulfate eye drops were used, diluted to different concentrations with PBS), and groups 4, 5, and 6 were administered 1%, 0.1%, and 0.01% penehyclidine hydrochloride solutions, respectively, administered once to both eyes, 30 μL per eye. The lens thickness and pupil diameter of both eyes were examined using amplitude-modulated ultrasound before administration, and 1 h, 2 h, 4 h, 6 h, 24 h after administration, and on D3, D5, D7, D13, and D15. Relative lens thickness and pupil diameter (Mean ± SD, n = 6 eyes / group) were calculated based on the values ​​before administration. The results are shown in Figures 1 and 2.

[0058] As shown in Figure 1, the results of lens thickness showed that each administration group had the lowest lens thickness 6 hours after administration, and the higher the concentration, the stronger the effect of reducing lens thickness. The order of the strength of the effect of reducing lens thickness 6 hours after administration was 1% test substance > 0.1% test substance ~ 1% atropine > 0.01% test substance > 0.1% atropine > 0.01% atropine. Each dosage group gradually recovered from D1, and the lower the concentration, the faster the recovery. The 0.01% ~ 0.1% test substance and atropine groups were fully recovered 3-5 days after administration, and the 1% test substance and 1% atropine groups did not fully recover even 14 days after administration. Penehyclidine hydrochloride showed a clear dose-related relaxing effect on the ciliary muscles throughout the body, slowing the progression of myopia and achieving a myopia treatment effect, and its action strength was stronger than atropine.

[0059] As shown in Figure 2, the pupil diameter results showed no pupil dilation in the 0.01% test group, while the pupil diameter in the other groups showed an increase in correlation with the dose, reaching a maximum 6 hours after administration, and the order of pupil dilation effect was 1% atropine > 0.1% atropine > 1% test product > 0.01% atropine > 0.1% test product. After 6 hours, the pupil dilation gradually recovered, and the 0.1%-1% test product group and the 0.01% atropine group returned to normal 2-4 days (D3-D5) after administration, while the 0.1%-1% atropine group had not yet fully recovered 14 days (D15) after administration. Compared with the atropine group, the pupil dilation side effect of the 0.1%-1% test product group was obviously weaker, and the recovery time was shorter, which could significantly reduce side effects such as photophobia and blurred vision caused by pupil dilation.

[0060] Efficacy Example 2: Study on the treatment of myopia in visually deprived guinea pigs with penehyclidine hydrochloride Select 2-week-old weaned healthy short-haired tricolor guinea pigs, regardless of sex. After passing the quarantine, select a total of 48 guinea pigs with monocular refraction ≥ +1.00D and binocular refraction difference ≤ 1.50D, and randomly divide them into 6 groups. Each group includes test item groups (high, medium, and low doses), negative control groups, and positive control groups (atropine groups), with 8 animals in each group. For all animals, the left eye was modeled, and the right eye was not treated. The modeling method was isoflurane inhalation anesthesia. Cyanoacrylate adhesive was used to glue the bottom of the hook-and-loop fastener of the homemade styrene plastic diffuser and the skin around the eye, and the adhesion was confirmed to be firm. The diffuser can be freely removed and attached, and there is no light leakage except for the diffuser, and the disinfection and surgery process is controlled within 3 to 5 minutes. The animals wake up after 5 to 10 minutes. On the day of model preparation, 0.01%, 0.1%, 0.5%, and 1% penehyclidine hydrochloride solution, 1% atropine sulfate eye drops, and phosphate buffered saline (PBS) were administered into the conjunctival sac of the model eye, once a day, 20 μL / eye / time, for 6 consecutive weeks. During the test period, the animal condition and the diffuser attachment condition were observed once a day. The refraction and axial length of the animals in each group were measured using a retinoscope and amplitude-modulated ultrasound before the test (D-1), 2 weeks after the test (D14), 4 weeks after the test (D28), and 6 weeks after the test (D42), respectively, and the results are shown in Tables 1 and 2.

[0061] [Table 1]

[0062] As for the refraction results, as shown in Table 1, there is a statistical difference between the refraction values ​​of each group of model eyes at different time periods compared to D-1. After 2 weeks of administration, the model eyes of the animals in the PBS eye drop group induced a relative myopia of -2.69±3.21D, and the refraction of each administration group shifted to myopia, but relative myopia was not induced. As time extended, the relative myopia of the model eyes in the PBS group increased, and the relative myopia of the other groups increased slightly. After 6 weeks of treatment, the model eyes of the animals in the PBS eye drop group induced a relative myopia of -5.06±1.04D, while the model eyes of the 1% atropine eye drop group, 1%, 0.5%, 0.1%, and 0.01% penehyclidine hydrochloride solution test sample groups induced a relative myopia of -1.18±2.52D, -0.28±1.79D, -0.35±1.56D, -0.48±1.49D, and -1.06±2.48D, respectively, and the refractive index values ​​of each treatment group were significantly lower than those of the PBS group (P<0.05%). Each treatment group had obvious myopia treatment effect, and the relative myopia degree was lower after treatment in the test sample groups of different concentrations, indicating that the myopia treatment effect was stronger than that of the 1% atropine group.

[0063] [Table 2]

[0064] In this example, the axial length of the guinea pigs at D-1 was 8.2-8.3 mm, and there was no significant difference in the amount of axial elongation between the left and right eyes of each group (P>0.05%), nor between the groups (P>0.05%). The results of axial elongation are shown in Table 2. Two weeks after the model was created and drug administration, the amount of axial elongation of the model eyes was significantly greater than that of the OD eyes (P<0.05%). This shows that in addition to normal growth of the eye axis, the axial length was significantly increased by creating the model.

[0065] Four weeks after the model was created and the drug was administered, the axial elongation of the OS in the PBS and 1% atropine groups was still significantly greater than that of the OD eyes in the same period (P<0.05%), the axial elongation of the 0.01%-1% test sample groups was not significantly different from that of the OD eyes in the same period (P>0.05%), and the axial elongation of the OS in the 1.0%, 0.5% and 0.1% test sample groups was significantly lower than that of the OS eyes in the PBS group (P<0.05%). This showed that the test sample groups at each concentration had the effect of significantly slowing the axial elongation earlier than the atropine group.

[0066] Six weeks after the drug administration, the axial elongation of the OS in the PBS group was still significantly greater than that of the OD eyes in the same period (P<0.05%), and the axial elongation of the OS in each administration group was not significantly different from that of the OD eyes in the same period (P>0.05%). The axial elongation of the OS in the 1.0%, 0.5% and 0.1% test sample groups was significantly lower than that of the OS eyes in the PBS group (P<0.05%), and the axial elongation of the OS in the 0.01% test sample and 1% atropine groups was not significantly different from that of the OS eyes in the PBS group (P>0.05%). Each administration group had the effect of delaying the elongation of the axial length, and the axial elongation of the 0.1%~1% test sample groups was smaller, showing that the myopia treatment effect was stronger than that of 1% atropine.

[0067] As described above, the 0.01% to 1% penehyclidine hydrochloride solution according to the embodiment of the present invention can effectively treat the progression of myopia, and has a better effect than 1% atropine sulfate ophthalmic solution.

[0068] Efficacy Example 3: Study on the treatment of strabismus and amblyopia in cats with penehyclidine hydrochloride A total of 24 normal 4-week-old domestic cats were selected and randomly divided into PBS group, 1% and 2% penehyclidine hydrochloride solution test group, and 1% atropine control group, with 6 cats in each group. Each group underwent right lateral rectus muscle resection at 4 weeks of age, and after 4 weeks of surgery, the formation of amblyopia was confirmed by graphic visual evoked potential (P-VEP) test. Phosphate buffer solution (PBS), 1% and 2% test group, and 1% atropine sulfate eye drops were administered into the conjunctival sac, respectively, once a day, 20μL / eye / time, for 12 consecutive weeks, and P-VEP was recorded every 4 weeks. The results are shown in Table 3.

[0069] [Table 3]

[0070] As shown in Table 3, before the model was made, the latency and amplitude (nv) of P-wave in each group were basically the same. After 4 weeks of model making, the latency of P-VEP in each group was significantly prolonged and the amplitude was significantly decreased, and the difference from before the model was made was statistically significant. After right ocular lateral rectus muscle resection, each group demonstrated successful creation of an animal amblyopia model after 4 weeks. During 4-12 weeks of continuous administration, the latency of P-VEP in the PBS group continued to prolong and the amplitude continued to decrease. The tendency of P-VEP in each treatment group gradually recovered, the latency gradually shortened and the amplitude gradually increased. By 12 weeks after administration, the 1% and 2% test sample groups had almost recovered to the state before the model was made, and the 1% and 2% test sample groups had a higher amblyopia recovery effect than the 1% atropine group. A 1% to 2% solution of penehyclidine hydrochloride has been shown to have amblyopic treatment effect, and its effect is stronger than that of atropine.

[0071] Efficacy Example 4: Repeated eye drop toxicity study in rabbits with penehyclidine hydrochloride Thirty healthy Dutch rabbits that passed quarantine were selected, both male and female, and randomly divided into five groups, with six rabbits in each group. The groups included a solvent control group, a 1% atropine control group, and 0.01%, 1%, and 2% penehyclidine hydrochloride solution test groups, which were administered once daily by instillation into the conjunctival sac of both eyes, 30 μL per eye per administration, for 12 weeks. During all animal testing periods, the animals were observed at least once a day for death, illness, respiration, secretions, feces, and eating and drinking, drinking, etc. Each animal was observed with the naked eye for pupil light reflex before each administration, and for eye irritation within one minute after each administration. Irritation observations included, but were not limited to, squinting, blinking, head shaking, etc. If any of the above abnormalities were observed in the animals, the frequency of occurrence (number of times per minute) and / or duration (recorded as less than 60 seconds or more than 60 seconds) were recorded. All animals underwent ocular local observations prior to dosing at D1, 4 weeks, 8 weeks, and 12 weeks, including but not limited to redness, swelling, conjunctival hyperemia, and discharge. The anterior segment and fundus were examined using a handheld slit lamp and direct ophthalmoscope, and the results are shown in Tables 4-6.

[0072] [Table 4]

[0073] As a result of eye irritation, as shown in Table 4, the 1% atropine group showed moderate irritation and the pupillary reflex to light disappeared, while in the test sample group, the 2% high dose group showed slight irritation and the pupillary reflex to light weakened, while the 1% and 0.01% test sample groups showed no irritation and, like the solvent control group, the pupillary reflex to light was normal. It was shown that penehyclidine hydrochloride has good safety when administered to the eye and has little effect on the pupil.

[0074] [Table 5] [Table 6]

[0075] As a result of local observation of the eye, different concentrations of test products were repeatedly administered by eye drop for 12 weeks, but no corneal opacity or conjunctival edema occurred, and the intraocular pressure was similar to that of the solvent control group, as shown in Table 6. In contrast, after 4 weeks of repeated administration to the atropine group, mild corneal opacity and slight conjunctival edema appeared, indicating that the safety of repeated administration of penehyclidine hydrochloride is clearly superior to that of atropine at the same concentration.

[0076] In the description of this specification, a description including terms such as "one embodiment", "several embodiments", "examples", "specific examples" or "several examples" is intended to mean that the specific features, structures, materials or advantages described using the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, exemplary expressions related to the above terms do not necessarily refer to the same embodiment or example. It should be noted that the specific features, structures, materials or advantages described can be combined in any one or more embodiments or examples in an appropriate manner. Furthermore, unless mutually inconsistent, a person skilled in the art can blend or combine different embodiments or examples described in this specification and features of different embodiments or examples.

[0077] Although the embodiments of the present invention have been shown and described above, the above embodiments are merely illustrative and do not limit the present invention. Those skilled in the art can change, modify, substitute, and modify the above embodiments within the scope of the present invention. The present disclosure also includes the following aspects. <1> 2. Use of a compound of the structure represented by formula (I) or a nitrogen oxide, solvate, metabolite, pharma- ceutically acceptable salt or prodrug thereof in the preparation of a medicament for treating and / or preventing a vision-impairing eye disease. [ka] <2> The salt of the compound represented by formula (I) is selected from organic salts and inorganic salts. <1> The use described in. <3> The salt of the compound represented by formula (I) is a hydrochloride, and preferably, the structure of the hydrochloride is represented by formula (II). <1> The use described in. [ka] <4> The drug is characterized in that it is used for treating and / or preventing myopia and / or amblyopia. <1> The use described in. <5> The cause of myopia and / or amblyopia is one or more selected from the group consisting of myopic shift in refractive power, myopic vitreous cavity depth increase, myopic axial length increase, morphological deprivation, refractive anisocoria, and astigmatism. <4> The use described in. <6> The drug is used for treating and / or preventing myopia and / or amblyopia, and the myopia and / or amblyopia includes one or more of low myopia, moderate myopia, high myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, distance vision loss, eye fatigue, exotropia, strabismus amblyopia, axial elongation, fundus damage, vision obstruction, visual distortion, vision ghost, color vision abnormality, light perception abnormality, reduced contrast sensitivity, refractive anisotropy amblyopia, refractive ametropia amblyopia, unilateral form deprivation amblyopia, and bilateral form deprivation amblyopia. <1> The use described in. <7> A pharmaceutical composition for treating and / or preventing a vision-impairing eye disease, the pharmaceutical composition comprising: <1> A pharmaceutical composition comprising a compound having the structure represented by formula (I) or a nitrogen oxide, solvate, metabolite, pharma- ceutically acceptable salt or prodrug thereof as an active ingredient. <8> The pharmaceutical composition further comprises at least one pharma- ceutically acceptable carrier. <7> The pharmaceutical composition according to claim 1, <9> The dosage form of the pharmaceutical composition is an ophthalmic preparation, which includes one or more of eye drops, ophthalmic ointments, ophthalmic creams, ophthalmic emulsions, ophthalmic gels, ophthalmic pills, eye masks, and intraocular implants. <7> The pharmaceutical composition according to claim 1, <10> The mass fraction of the active ingredient in the pharmaceutical composition is 0.005% to 2% by weight. <7> The pharmaceutical composition according to claim 1, <11> The pharmaceutical composition is characterized in that it is used for treating or preventing myopia and / or amblyopia. <7> ~ <10> 13. The pharmaceutical composition according to claim 12, <12> The cause of myopia and / or amblyopia is one or more selected from the group consisting of myopic shift in refractive power, myopic vitreous cavity depth increase, myopic axial length increase, morphological deprivation, refractive anisocoria, and astigmatism. <11> The pharmaceutical composition according to claim 1, <13> The myopia and / or amblyopia includes one or more of the following: low myopia, moderate myopia, high myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, distance vision loss, eye fatigue, exotropia, strabismus amblyopia, axial elongation, fundus damage, vision occlusion, visual distortion, vision ghost, color vision abnormality, light perception abnormality, reduced contrast sensitivity, refractive anisotropy amblyopia, refractive ametropia amblyopia, unilateral form deprivation amblyopia, and bilateral form deprivation amblyopia. <11> The pharmaceutical composition according to claim 1, <14> An ophthalmic preparation for treating and / or preventing a visually-impairing eye disease, the mass fraction of an active ingredient in the ophthalmic preparation being 0.005% to 2%, the active ingredient being <1> 1. An ophthalmic preparation comprising a compound having a structure represented by formula (I) or a nitrogen oxide, solvate, metabolite, pharma- ceutically acceptable salt or prodrug thereof. <15> The active ingredient is a salt of a compound represented by formula (I), and the salt is a hydrochloride. <14> 13. An ophthalmic preparation according to claim 12. <16> The ophthalmic preparation is characterized in that it is used for treating or preventing myopia and / or amblyopia. <14> ~ <15> 13. The ophthalmic preparation according to claim 12, <17> The cause of myopia and / or amblyopia is one or more selected from the group consisting of myopic shift in refractive power, myopic vitreous cavity depth increase, myopic axial length increase, morphological deprivation, refractive anisocoria, and astigmatism. <16> 13. An ophthalmic preparation according to claim 12. <18> The myopia and / or amblyopia includes one or more of the following: low myopia, moderate myopia, high myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, distance vision loss, eye fatigue, exotropia, strabismus amblyopia, axial elongation, fundus damage, vision occlusion, visual distortion, vision ghost, color vision abnormality, light perception abnormality, reduced contrast sensitivity, refractive anisotropy amblyopia, refractive ametropia amblyopia, unilateral form deprivation amblyopia, and bilateral form deprivation amblyopia. <16> 13. An ophthalmic preparation according to claim 12. <19> On the subject's eye surface <7> ~ <13> or <14> ~ <18> 2. A method for treating and / or preventing a vision-impairing eye disease, comprising administering an ophthalmic formulation according to any one of claims 1 to 11. <20> The method is characterized in that it is used to treat or prevent myopia and / or amblyopia. <19> The method according to <21> The cause of myopia and / or amblyopia is one or more selected from the group consisting of myopic shift in refractive power, myopic vitreous cavity depth increase, myopic axial length increase, morphological deprivation, refractive anisocoria, and astigmatism. <20> The method according to <22> The myopia and / or amblyopia includes one or more of the following: low myopia, moderate myopia, high myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, distance vision loss, eye fatigue, exotropia, strabismus amblyopia, axial elongation, fundus damage, vision occlusion, visual distortion, vision ghost, color vision abnormality, light perception abnormality, reduced contrast sensitivity, refractive anisotropy amblyopia, refractive ametropia amblyopia, unilateral form deprivation amblyopia, and bilateral form deprivation amblyopia. <20> The method according to

Claims

1. A therapeutic agent for preventing and / or treating myopia and / or amblyopia, comprising a compound of the structure represented by formula (I) or a nitrogen oxide, solvate, or pharma- ceutically acceptable salt thereof. 【Chemistry 1】

2. The therapeutic agent according to claim 1, characterized in that the salt of the compound represented by formula (I) is selected from organic salts and inorganic salts.

3. The therapeutic agent of claim 1 , wherein the salt of the compound represented by formula (I) has the structure represented by formula (II): 【Chemistry 2】

4. The therapeutic drug according to claim 1, characterized in that the myopia and / or amblyopia includes one or more of the following: weak myopia, moderate myopia, strong myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, strabismic amblyopia, anisometropic amblyopia, ametropic amblyopia, unilateral form deprivation amblyopia, and bilateral form deprivation amblyopia.

5. A pharmaceutical composition for treating and / or preventing myopia and / or amblyopia, comprising a compound having a structure represented by formula (I) as set forth in claim 1 or a nitrogen oxide, solvate, or pharma- ceutically acceptable salt thereof as an active ingredient.

6. The pharmaceutical composition of claim 5, further comprising at least one pharma- ceutically acceptable carrier.

7. The pharmaceutical composition according to claim 5, characterized in that the dosage form of the pharmaceutical composition is an ophthalmic preparation, including one or more of eye drops, ophthalmic ointments, ophthalmic creams, ophthalmic emulsions, ophthalmic gels, ophthalmic pills, eye masks, and intraocular implants.

8. The pharmaceutical composition according to claim 5, characterized in that the mass fraction of the active ingredient in the pharmaceutical composition is 0.005% to 2% by weight.

9. The pharmaceutical composition according to claim 5, characterized in that the myopia and / or amblyopia includes one or more of the following: low myopia, moderate myopia, high myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, strabismic amblyopia, refractive anisotropic amblyopia, refractive ametropia amblyopia, unilateral form deprivation amblyopia, and bilateral form deprivation amblyopia.

10. An ophthalmic formulation for treating and / or preventing myopia and / or amblyopia, wherein the mass fraction of an active ingredient in the ophthalmic formulation is 0.005% to 2%, and the active ingredient is a compound having a structure represented by formula (I) according to claim 1 or a nitrogen oxide, solvate, or pharma- ceutically acceptable salt thereof.

11. 11. The ophthalmic formulation of claim 10, wherein the active ingredient is a salt of a compound of formula (I), the salt being the hydrochloride salt.

12. The ophthalmic preparation according to claim 10, characterized in that the myopia and / or amblyopia includes one or more of the following: weak myopia, moderate myopia, strong myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, strabismic amblyopia, anisotropic amblyopia, ametropic amblyopia, unilateral form deprivation amblyopia, and bilateral form deprivation amblyopia.

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