Use of penehyclidine in the treatment or prevention of visual impairment eye diseases

Abstract

The application provides use of a compound shown in a structure of formula (I) or a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof in preparation of a medicine for treating and / or preventing visual impairment eye diseases, the medicine has good drug efficacy, small toxic and side effects, and raw materials are easy to obtain, and has a good application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, in particular, to the use of penehycridine in the treatment or prevention of visual impairment eye diseases. BACKGROUND

[0002] In the hypothesis of myopia pathogenesis, it is proposed that myopia development is associated with ciliary muscle accommodation. Sato's accommodation tonus theory suggests that long-term use of accommodation can cause ciliary muscle accommodation tonus, so it is speculated that the use of atropine to relax and relieve accommodation tension can achieve the effect of controlling juvenile myopia. Atropine can block the M receptors of mammalian ciliary muscles, thereby relieving the accommodation tension of the ciliary muscles. However, the ciliary muscles of chickens are striated muscles, which are dominated by nicotine (N) like receptors, so atropine cannot paralyze the ciliary muscles of chickens. However, after 8 days of intravitreal injection of atropine with a mass fraction of 0.01% into the form deprivation myopia (FDM) model eye of chickens, Mcbrien et al. induced the formation of-2.8D myopia and the elongation of the eye axis by 0.21mm. In the groups of false injection and normal saline injection, the chickens induced-18.5D myopia and-20.9D myopia, respectively, and the eye axes elongated by 1.04mm and 1.00mm, respectively. That is, atropine can still significantly inhibit the formation and progression of myopia in chickens, indicating that atropine inhibits myopia through a non-accommodation mechanism, or ciliary muscle accommodation paralysis is not the only target of atropine myopia control. Atropine has been proven to prevent the development of myopia in some animal models and humans, but the mechanism of atropine's anti-myopia effect is not completely clear.

[0003] At present, the relationship between various drugs and the treatment of myopia has not been established. Since atropine is a non-selective inhibitor, it has been found that atropine treatment of myopia is related to multiple pathways; tropicamide is another non-selective M receptor blocker, and through comparison with atropine, it is found that it cannot effectively prevent or delay the development of myopia.

[0004] Stone et al. reported in 1991 that the use of M1 receptor blocker pirenzepine for daily subconjunctival injection can inhibit the occurrence of FDM, while M2 receptor blocker methoctramine and M3 receptor blocker 4-DAMP are ineffective, suggesting that it may be related to M1 receptor. However, the study of pirenzepine found that the experimental results of different research groups in treating myopia are not consistent. Flitcroft applied another M1 receptor blocker Trihexyphenidyl topically or orally, which can achieve a high retinal concentration, but the results show that it cannot effectively prevent the development of experimental myopia.

[0005] Luft et al. studied more than ten kinds of drugs with M choline receptor blocking effect such as atropine (non-selective), pirenzepine (M1), oxyphenonium (M2), etc. It is found that only oxyphenonium, atropine, pirenzepine and himbacine have certain effects of preventing FDM without retinal damage, and other drugs either cannot prevent FDM or have different degrees of retinal damage. M receptors mediate a variety of functions, and even different subtypes of M receptors in the same tissue have different pharmacological properties. In the respiratory tract, the function of M2 receptors is completely opposite to that of M1 and M3 receptors. Therefore, the selectivity of different subtypes of M receptors is the key to determine the application prospect of anticholinergic drugs. Therefore, from the reports of the research literature, the corresponding relationship between M receptors and myopia has not been established.

[0006] In summary, new drugs for treating or preventing myopia, amblyopia and other vision impairment are urgently needed to be developed.

[0007] So far, there is no report on the effect of penehyclidine and its derivatives in preventing and treating myopia and amblyopia. SUMMARY

[0008] In the treatment of myopia and amblyopia, the atropine sulfate eye drops currently under research abroad have certain risks. Atropine can easily cause systemic side effects such as facial flushing and dry mouth, increased heart rate, urinary retention, and even cause poisoning and anaphylactic shock. Intravenous maximum dose is 2 mg each time. Exceeding the above dosage will cause poisoning. Overdose shows clumsy and unstable movement, unconsciousness, convulsions, difficulty breathing, and abnormal rapid heartbeat. Therefore, the safety problem of atropine sulfate eye drops in the use of myopia and amblyopia has been a factor limiting its large-scale promotion. It is urgent to find more safe and effective drugs for the treatment of eye diseases on the market.

[0009] The present application aims to at least solve one of the problems in the related art.

[0010] To this end, in a first aspect of the present application, the present application provides a use of a compound represented by the structure of formula (I) or its nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug in the preparation of a medicament for treating and / or preventing vision impairment eye diseases,

[0011]

[0012] The inventors found through a large number of studies that the compound represented by the structure of formula (I) or its derivative (nitroxide, solvate, metabolite, pharmaceutically acceptable salt) has good effect in treating or preventing vision impairment eye diseases, and the systemic toxic side effects are significantly lower than atropine, which has good application prospect.

[0013] According to embodiments of the present invention, the above-described uses may further include at least one of the following additional technical features:

[0014] According to embodiments of the present invention, the salt of the compound represented by formula (I) includes an organic salt or an inorganic salt.

[0015] The compound shown in formula (I) is called pentoxyverine. The inventors made an unexpected and delightful discovery through extensive research that pentoxyverine and its derivatives, such as its organic or inorganic salts, can effectively treat or prevent visual impairment eye diseases such as myopia or amblyopia. The preventive and control effects are better than those of atropine sulfate eye drops of the same concentration. In addition, it has the advantages of less mydriatic effect, less local irritation to the eye and better safety, and can be used for a long time.

[0016] According to an embodiment of the present invention, the salt of the compound shown in formula (I) is a hydrochloride salt, and the structure of the hydrochloride salt is shown in formula (II).

[0017]

[0018] Through repeated experiments, the inventors discovered that the above-mentioned form of pentoxyverine hydrochloride has good effects in treating and / or preventing diseases such as myopia and amblyopia.

[0019] According to embodiments of the present invention, the drug is used to treat and / or prevent myopia and / or amblyopia.

[0020] According to embodiments of the present invention, the causes of the myopia and / or amblyopia include one or more of the following: myopic refractive error, myopic vitreous cavity depth elongation, myopic axial length elongation, form deprivation, anisometropia, and astigmatism.

[0021] According to embodiments of the present invention, the myopia and / or amblyopia includes one or more of the following: mild myopia, moderate myopia, high myopia, axial myopia, simple myopia, pathological myopia, decreased distance vision, eye strain, exotropia, strabismic amblyopia, fundus injury, visual occlusion, visual distortion, double vision, color vision abnormalities, light vision abnormalities, decreased contrast sensitivity, and refractive amblyopia. It should be noted that the visual impairment eye diseases described in this application do not include visual problems caused by trauma.

[0022] In a second aspect, the present invention provides a pharmaceutical composition for treating and / or preventing myopia and / or amblyopia. According to embodiments of the invention, a compound containing the structure shown in formula (I) or its nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug is used as the active ingredient.

[0023] According to embodiments of the present invention, the above-described pharmaceutical composition may further include at least one of the following additional technical features:

[0024] According to embodiments of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier. The carrier in the pharmaceutical composition according to embodiments of the present invention includes, but is not limited to, aqueous carriers, water-miscible carriers, non-aqueous carriers, antimicrobial agents or preservatives that inhibit microbial growth, stabilizers, solubilizers, osmotic pressure regulators, buffers, antioxidants, local anesthetics, suspending agents and dispersants, wetting agents or emulsifiers, complexing agents, multivalent chelating agents or chelating agents, antifreeze agents, cryoprotectants, thickeners, pH adjusters, and inert gases, which can be selected by those skilled in the art according to the actual needs of the formulation.

[0025] According to embodiments of the present invention, 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, ophthalmic films, and intraocular implants.

[0026] According to embodiments of the present invention, the active ingredient in the pharmaceutical composition has a mass fraction of 0.005%-2%. According to embodiments of the present invention, the active ingredient in the pharmaceutical composition has a mass-volume fraction of 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%, etc. 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%, 0.355%, 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%, 0.545%, 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%, 0.635%, 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%, 1.580%, 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 0.710%, 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%, 1.85 5%, 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%.

[0027] According to specific embodiments of the present invention, the dosage of the pharmaceutical composition depends on the type and weight of the patient, the nature and severity of the disease, the type of formulation and the route of administration, as well as the dosing cycle or time interval.

[0028] In a third aspect, the present invention provides an ophthalmic preparation for treating or preventing myopia or amblyopia. According to embodiments of the present invention, the active ingredient in the ophthalmic preparation has a mass fraction of 0.005%-2%, and the active ingredient is a compound of formula (I) or its nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs; preferably, the active ingredient is a salt of the compound of formula (I) in the form of a hydrochloride. Through extensive experiments, the inventors have discovered that this ophthalmic preparation has a clear dose-related relaxing effect on the ciliary muscle and a significant effect in delaying axial elongation, thus delaying the progression of myopia and achieving a therapeutic effect on myopia. Furthermore, it can gradually restore the amblyopia trend in animal amblyopia models, gradually shortening the latency period, and after a certain period of administration, the amblyopia essentially recovers to a normal level.

[0029] 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. Attached Figure Description

[0030] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0031] Figure 1 The relative changes in lens thickness before and after drug administration (Mean±SD, n=6 eyes / group);

[0032] Figure 2 The relative pupil diameter changes before and after drug administration were calculated (Mean±SD, n=6 eyes / group). Detailed Implementation

[0033] Embodiments of the present invention are described in detail below, examples of which are illustrated in the accompanying drawings, wherein the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention.

[0034] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one of that feature. In the description of this invention, "a plurality of" means at least two, such as two, three, etc., unless otherwise explicitly specified.

[0035] Pharmaceutical uses

[0036] The use of compounds with the structure shown in formula (I) of the present invention, or their nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, in the preparation of pharmaceuticals is as follows: to prepare pharmaceuticals for the treatment, prevention, improvement, control or relief of visual impairment diseases in mammals, especially humans, and can also be used to prepare other pharmaceuticals for antagonizing M receptors, with minimal toxic side effects.

[0037] The term "solvent" in this invention refers to a solvent present on a surface, in a crystal lattice, or both on a surface and in a crystal lattice. A specific example of a solvate is a hydrate, wherein the solvent present on a surface, in a crystal lattice, or both on a surface and in a crystal lattice is water. A hydrate may or may not have other solvents besides water on a surface, in a crystal lattice, or both on a surface and in a crystal lattice.

[0038] In this invention, "metabolite" refers to the product obtained in vivo by the metabolism of a compound with the structure shown in formula (I) or its salt. A metabolite of a compound can be identified using techniques known in the art, and its activity can be characterized by experimental methods as described in this invention. "Pharmaceutically acceptable salt" as used in this invention refers to both organic and inorganic salts of the compounds of this invention.

[0039] As used in this invention, the term "prodrug" refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues.

[0040] Pharmaceutical Composition

[0041] As used in this invention, the term "composition" refers to a product comprising a specified amount of a specified ingredient, or any product directly or indirectly produced by a combination of specified amounts of a specified ingredient. In the context of pharmaceutical compositions, this term includes products comprising an active ingredient (single or multiple) and an inert ingredient (single or multiple) constituting a carrier, as well as any product directly or indirectly produced by mixing, compounding, or aggregating any two or more ingredients, or by decomposing one or more ingredients, or by other types of reactions or interactions of one or more ingredients. Therefore, pharmaceutical compositions of this invention include any compositions prepared by mixing compounds of this invention with a pharmaceutically acceptable carrier.

[0042] The pharmaceutical compositions provided by this invention include at least one pharmaceutically acceptable carrier. Exemplarily, the dosage form of the pharmaceutical composition is an ophthalmic preparation. Examples include eye drops, ophthalmic ointments, ophthalmic creams, ophthalmic emulsions, ophthalmic gels, ophthalmic pills, ophthalmic films, and intraocular implants.

[0043] The pharmaceutical composition provided by the present invention may further include: a suitable antimicrobial agent or preservative, a suitable isotonic agent, a suitable antioxidant, a suitable local anesthetic, a suitable suspending agent and dispersant, a suitable emulsifier, a suitable multivalent chelating agent or chelating agent, a suitable pH adjuster, and other carriers.

[0044] In addition to being beneficial for human visual impairment eye diseases, the pharmaceutical compositions of the present invention can also be used in veterinary treatment of mammals in pets, introduced breeds, and farm animals. Other examples of animals include horses, dogs, and cats. Herein, the compounds of the present invention include their pharmaceutically acceptable derivatives.

[0045] The present invention will now be described with reference to specific embodiments. It should be noted that these embodiments are merely descriptive and do not limit the present invention in any way.

[0046] It should be noted that the data results in the following examples are all statistically expressed as Mean ± SD.

[0047] Example: Preparation of pentoxyverine hydrochloride solution as a test sample

[0048] Pentyl quinoline hydrochloride and physiological saline were mixed and stirred until completely dissolved to prepare 0.01%, 0.1%, 0.5%, 1% and 2% pentyl quinoline hydrochloride solutions as test samples.

[0049] Effect Example

[0050] Example 1: Effects of pentoxyverine hydrochloride on the lens and pupil of a monkey

[0051] Healthy cynomolgus macaques, aged 2.5–3.5 years and weighing 2.0–4.0 kg, of any sex, were selected and randomly divided into 6 groups of 3 macaques each, for a total of 18 macaques. Groups 1, 2, and 3 were administered 1%, 0.1%, and 0.01% atropine sulfate eye drops, respectively (commercially available 1% atropine sulfate eye drops diluted with PBS to different concentrations). Groups 4, 5, and 6 were administered 1%, 0.1%, and 0.01% pentoxyverine hydrochloride solution, respectively. A single administration to both eyes, 30 μL / eye, was performed. Lens thickness and pupil diameter were examined bilaterally using A-scan ultrasound before administration and at 1 h, 2 h, 4 h, 6 h, 24 h, D3, D5, D7, D13, and D15. Relative lens thickness and pupil diameter (Mean ± SD, n = 6 eyes / group) were calculated based on the pre-administration baseline. Results are shown below. Figure 1 and Figure 2 As shown.

[0052] The results of lens thickness are as follows Figure 1As shown, the lens thickness of each treatment group decreased to its lowest point 6 hours after administration, with higher concentrations resulting in a stronger effect on reducing lens thickness. The order of lens thickness reduction at 6 hours after administration was: 1% test sample > 0.1% test sample ≈ 1% atropine > 0.01% test sample > 0.1% atropine > 0.01% atropine. Recovery in each dosage group began gradually from day 1, with lower concentrations leading to faster recovery. The 0.01%–0.1% test sample and atropine groups recovered completely within 3–5 days after administration, while the 1% test sample and 1% atropine groups did not fully recover even after 14 days. This indicates that pentoxyverine hydrochloride has a clear dose-related relaxing effect on the ciliary muscle in vivo, which can delay the progression of myopia and achieve a therapeutic effect, with a stronger effect than atropine.

[0053] Pupil diameter results as follows Figure 2 As shown, the 0.01% test sample group did not produce a mydriatic effect. In all other groups, the pupil diameter increased in a dose-related manner, reaching its maximum at 6 hours post-administration. The order of mydriatic effect strength was 1% atropine > 0.1% atropine > 1% test sample > 0.01% atropine > 0.1% test sample. The mydriatic effect gradually recovered after 6 hours. The 0.1%–1% test sample group and the 0.01% atropine group returned to normal within 2–4 days (D3–D5), while the 0.1%–1% atropine group was not fully recovered even at 14 days (D15). Compared to the atropine group, the 0.1%–1% test sample group showed significantly reduced mydriatic side effects and a shorter recovery time, significantly reducing side effects such as photophobia and blurred vision caused by pupil dilation.

[0054] Example 2: Study on the treatment of form deprivation myopia in guinea pigs with pentoxyverine hydrochloride

[0055] Two-week-old weaned, healthy, short-haired tricolor guinea pigs (male and female) were selected. After quarantine, 48 guinea pigs with a monocular refractive error ≥ +1.00D and a binocular anisometropia ≤ 1.50D were screened and randomly divided into 6 groups: test sample group (high, medium, and low doses), negative control group, and positive control group (atropine group), with 8 animals in each group. The left eye of all animals was used for modeling, while the right eye remained untreated. The modeling method involved isoflurane inhalation anesthesia. A self-made styrene plastic diffuser was glued to the skin around the eye using cyanoacrylate adhesive, ensuring a firm bond and allowing for easy removal and installation of the diffuser. No light leakage was observed except for the diffuser itself. The disinfection and surgical procedures were completed within 3–5 minutes, and the animals awoke after 5–10 minutes. On the day of modeling, 0.01%, 0.1%, 0.5%, and 1% pentoxyverine hydrochloride solution, 1% atropine sulfate eye drops, and phosphate-buffered saline (PBS) were administered intraconjunctivally to the modeling eye, 20 μL / eye / time, once daily for 6 weeks. Animal condition and diffuse body adhesion were observed daily during the experiment. Refractive error and axial length were measured using retinoscopy and A-scan ultrasound at pre-experiment (D-1), two weeks (D14), four weeks (D28), and six weeks (D42) for each group of animals. The results are shown in Tables 1 and 2.

[0056] Table 1: Refractive power results

[0057]

[0058] Note: a indicates p ≤ 0.05% compared to D-1; b indicates p ≤ 0.05% compared to the PBS group at the same time point.

[0059] The refractive error results are shown in Table 1. At different time points, the refractive error values ​​of the model eyes in each group showed statistically significant differences compared to D-1. Two weeks after administration, the model eyes in the PBS eye drop group induced a relative myopia of -2.69±3.21D. The refractive errors in all other treatment groups shifted towards myopia, but no relative myopia was induced. With prolonged time, the relative myopia in the PBS group increased, while the relative myopia in the other groups increased slightly. Six weeks after administration, the model eyes of animals in the PBS eye drop group induced a relative myopia of -5.06±1.04D. The model eyes of animals in the 1% atropine eye drop group, and the test sample groups (1%, 0.5%, 0.1%, and 0.01% pentoxyverine hydrochloride solution) induced relative myopias of -1.18±2.52D, -0.28±1.79D, -0.35±1.56D, -0.48±1.49D, and -1.06±2.48D, respectively. The refractive power values ​​of each treatment group were significantly lower than those of the PBS group (P<0.05%). This indicates that all treatment groups had significant therapeutic effects on myopia, with lower relative myopia after treatment in different concentrations of the test sample groups, and the therapeutic effect was stronger than that of the 1% atropine group.

[0060] Table 2: Results of Axial Growth

[0061]

[0062] Note: a indicates p < 0.05% compared to the same period OD; b indicates p < 0.05% compared to PBS.

[0063] In this embodiment, the axial length of the eyes of the D-1 guinea pigs was between 8.2 and 8.3 mm. There was no significant difference in the axial growth between the left and right eyes in each group (P > 0.05%), and there was also no significant difference between the groups (P > 0.05%). The results of axial growth are shown in Table 2. Two weeks after the model was established and the drug was administered, the axial growth of the modeled eye was significantly higher than that of the OD eye (P < 0.05%), indicating that in addition to normal growth, the modeling caused a significant increase in axial length.

[0064] Four weeks after modeling and drug administration, the axial length increase of the eyes in the PBS group and the 1% atropine group was still significantly higher than that in the eyes in the OD group at the same time point (P < 0.05%), while the axial length increase of the eyes in the 0.01%–1% test drug groups was not significantly different from that in the eyes in the OD group at the same time point (P > 0.05%). The axial length increase of the eyes in the 1.0%, 0.5%, and 0.1% test drug groups was significantly lower than that in the PBS group (P < 0.05%), indicating that the test drug groups at each concentration produced a significant delay in axial length increase earlier than the atropine group.

[0065] Six weeks after modeling and drug administration, the axial length increase in the PBS group was still significantly higher than that in the OD group at the same time point (P < 0.05%), while there was no significant difference in axial length increase between the OS and OD groups in any of the drug administration groups (P > 0.05%). The axial length increase in the OS of the 1.0%, 0.5%, and 0.1% test drug groups was significantly lower than that of the PBS group (P < 0.05%), while there was no significant difference in axial length increase between the 0.01% test drug and 1% atropine groups and the PBS group (P > 0.05%). This indicates that all drug administration groups produced an effect of delaying axial length increase, and the axial length increase in the 0.1%–1% test drug groups was smaller, indicating that the therapeutic effect on myopia was stronger than that of 1% atropine.

[0066] In summary, the 0.01% to 1% pentoxyverine hydrochloride solution provided in the embodiments of the present invention can effectively treat the progression of myopia, and is more effective than 1% atropine sulfate eye drops.

[0067] Example 3: Study on the treatment of strabismic amblyopia in cats with pentoxyverine hydrochloride

[0068] Twenty-four ordinary 4-week-old domestic cats were randomly divided into three groups: a PBS group, a 1% or 2% pentoxyverine hydrochloride test sample group, and a 1% atropine control group, with six cats in each group. At 4 weeks of age, each group underwent right lateral rectus muscle resection. Four weeks postoperatively, amblyopia was confirmed by pattern visual evoked potential (P-VEP) testing. The cats were then treated with phosphate-buffered saline (PBS), 1% or 2% test sample group, and 1% atropine sulfate eye drops, administered intraconjunctivally once daily at a dose of 20 μL per eye for 12 consecutive weeks. P-VEP was recorded every 4 weeks. The results are shown in Table 3.

[0069] Table 3: P-VEP Results

[0070]

[0071] As shown in Table 3, before modeling, the latency and amplitude (nv) of P waves in each group were basically the same. Four weeks after modeling, the latency of P-VEP in each group was significantly prolonged and the amplitude was significantly reduced, with statistically significant differences compared to before modeling. This indicates that after right lateral rectus muscle resection, animal amblyopia models were successfully established in each group after 4 weeks. During continuous administration for 4-12 weeks, the latency of P-VEP in the PBS group continued to prolong and the amplitude continued to decrease; the P-VEP trend in each treatment group gradually recovered, the latency gradually shortened, and the amplitude gradually increased. By the 12-week administration period, the 1% and 2% test product groups were close to recovering to pre-modeling levels, and the amblyopia recovery effect of 1% and 2% test products was higher than that of 1% atropine. This indicates that 1%–2% pentoxyverine hydrochloride solution has a therapeutic effect on amblyopia, and its effect is stronger than that of atropine.

[0072] Example 4: Repeated ophthalmic toxicity study of pentoxyverine hydrochloride in rabbits

[0073] Thirty healthy Dutch rabbits, of any sex, that passed quarantine were randomly divided into five groups of six each. These groups included a solvent control group, a 1% atropine control group, and groups treated with 0.01%, 1%, and 2% pentoxyverine hydrochloride solution. Each animal received 30 μL of the solution as eye drops once daily for 12 weeks. All animals were observed for mortality, disease onset, respiration, secretions, feces, and dietary and water intake at least once daily throughout the experiment. Before each administration, the pupillary light reflex was visually observed in each animal. Eye irritation was observed within one minute after each administration, including but not limited to squinting, blinking, and head shaking. If any of these abnormalities were observed, the frequency (number of times per minute) and / or duration (less than or more than 60 seconds) were recorded. All animals underwent local ocular observation at D1, 4 weeks, 8 weeks, and 12 weeks prior to drug administration. Local ocular observation included, but was not limited to, redness, swelling, conjunctival hyperemia, and discharge. The anterior segment and fundus were examined using a handheld slit lamp and a direct ophthalmoscope. The results are shown in Tables 4-6.

[0074] Table 4: Results of eye irritation

[0075]

[0076] Note: Frequency means the number of times per minute, S means the duration is less than 60 seconds, L means the duration is greater than 60 seconds, and √ means no abnormality.

[0077] The results of ocular irritation are shown in Table 4. The 1% atropine group showed moderate irritation with loss of pupillary light reflex. Except for the 2% high-dose group which showed mild irritation and weakened pupillary light reflex, the 1% and 0.01% test sample groups showed no irritation. Similar to the solvent control group, the pupillary light reflex was normal, indicating that pentoxyverine hydrochloride has good ocular safety and minimal impact on the pupil.

[0078] Table 5: Results of Ophthalmological Examinations

[0079]

[0080] Table 6: Results of Local Observation of the Eye

[0081]

[0082] The results of local ocular observation are shown in Table 6. After repeated eye drops of different concentrations of the test product for 12 weeks, no corneal opacity or conjunctival edema was observed. The intraocular pressure was similar to that of the solvent control group. However, mild corneal opacity and slight conjunctival edema appeared in the atropine group starting 4 weeks after repeated administration. This indicates that the safety of repeated administration of pentoxyverine hydrochloride is significantly better than that of atropine at the same concentration.

[0083] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0084] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prevention of myopia and / or amblyopia, wherein, The causes of the aforementioned myopia and / or amblyopia are selected from one or more of the following: myopic deviation of refractive power, myopic elongation of vitreous cavity depth, myopic elongation of axial length, form deprivation, anisometropia, and astigmatism. Formula (I).

2. The use according to claim 1, characterized in that, The myopia and / or amblyopia include one or more of the following: mild myopia, moderate myopia, high myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, decreased distance vision, eye strain, exotropia, strabismic amblyopia, elongation of the axial length, fundus injury, visual obstruction, visual distortion, double vision, color vision abnormalities, light vision abnormalities, decreased contrast sensitivity, anisometropic amblyopia, refractive amblyopia, unilateral form deprivation amblyopia, and bilateral form deprivation amblyopia.

3. The use according to claim 1, characterized in that, The drug further includes at least one pharmaceutically acceptable carrier.

4. The use according to claim 1, characterized in that, The dosage form of the drug is an ophthalmic preparation, including one or more of the following: eye drops, ophthalmic ointments, ophthalmic creams, ophthalmic emulsions, ophthalmic gels, ophthalmic pills, ophthalmic films, and intraocular implants.

5. The use according to claim 1, characterized in that, The drug, by weight, contains a compound of the structure shown in formula (I) or a pharmaceutically acceptable salt thereof in a mass fraction of 0.005%-2%.

6. The use according to claim 1, characterized in that, The dosage form of the drug is an ophthalmic preparation used to treat or prevent myopia and / or amblyopia. The mass fraction of the active ingredient in the ophthalmic preparation is 0.005%-2%, and the active ingredient is a compound with the structure shown in formula (I) or a pharmaceutically acceptable salt thereof.

7. The use according to claim 6, characterized in that, The pharmaceutically acceptable salt is a hydrochloride salt.

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