Use of bencycloquizium bromide, its isomers and derivatives thereof for the production of ophthalmic preparations

Abstract

The present invention relates to the field of pharmaceutical technology, particularly to the use of bencycloquidium bromide, its isomers, and derivatives for the manufacture of pharmaceuticals for the prevention or treatment of eye diseases. Furthermore, the present invention provides ophthalmic preparations containing bencycloquidium bromide, its isomers, and derivatives as active ingredients. The present invention has been found to exhibit a significant inhibitory effect on changes in axial length and refraction during the progression of myopic refractive error by administering bencycloquidium bromide, its isomers, and derivatives to the eye. Furthermore, it has been found that ophthalmic preparations containing these active ingredients are significantly advantageous in the prevention and treatment of eye diseases, particularly in the prevention of myopia and the slowing of myopia progression.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from Chinese Patent Application No. 202310050666.7, filed on February 1, 2023, entitled "Use of Bencycloquizium Bromide, Its Isomers and Derivatives Thereof for the Preparation of Ophthalmic Agents," the entire contents of which are incorporated herein by reference. [Technical Field]

[0002] The present invention relates to the field of medicine, and in particular to the use of bencycloquizium bromide, its isomers and derivatives thereof for the manufacture of medicaments for the prevention or treatment of eye diseases. [Background technology]

[0003] Myopia is a common eye disorder in which, when the eye is relaxed and accommodated, parallel light rays enter the eye and are focused in front of the retina, preventing a clear image from being formed on the retina. Myopia is typically classified as pseudomyopia, true myopia, and mixed myopia. For pseudomyopia, medications, acupuncture, ear acupuncture, physical therapy devices, or self-strengthening eye muscle training can relax the muscles, relieve fatigue, and restore vision to normal. For true myopia, treatment usually requires corrective devices, surgery, or medication.

[0004] In recent years, the incidence of myopia has been increasing in Japan, with a high incidence among children and adolescents and a tendency toward younger ages. Currently, there are few medications clinically used to prevent and treat myopia, primarily low-concentration atropine eye drops, but the mechanism of their control remains unclear. While low-concentration atropine eye drops are easy to administer, they can cause adverse reactions such as photophobia, blurred vision, and allergic conjunctivitis. Therefore, further research into the development of medications to treat or slow the progression of myopia and prevent it is crucial. In view of this situation, the present invention is presented. Summary of the Invention [Means for solving the problem]

[0005] To solve the above problems, the present invention provides the use of bencycloquizium bromide, its isomers and derivatives thereof for the manufacture of a pharmaceutical for the prevention or treatment of eye diseases. Research in the present invention has revealed that bencycloquizium bromide, its isomers and derivatives thereof have significant effects on the prevention of myopia, slowing the rate of myopia progression or mydriasis, etc.

[0006] Specifically, the technical solution of the present invention is as follows:

[0007] First, the present invention provides use of at least one of bencycloquidium bromide, its isomers, and its derivatives (which may be any one of bencycloquidium bromide, its isomers, and its derivatives, or a combination of any two or three of bencycloquidium bromide, its isomers, and its derivatives) for the manufacture of a pharmaceutical for the prevention or treatment of an eye disease.

[0008] Currently, bencycloquizium bromide, its isomers, and its derivatives are mainly used to alleviate the symptoms of allergic rhinitis, such as runny nose, stuffy nose, itchy nose, and sneezing, and are usually administered intranasally to prevent and treat allergic rhinitis. Meanwhile, the present invention has discovered for the first time that bencycloquizium bromide, its isomers, and its derivatives (nitrogen oxides, solvates, metabolites, and pharmaceutically acceptable salts thereof, such as organic or inorganic salts) can be effectively used in the manufacture of medicines for preventing or treating eye diseases, and show significant advantages.

[0009] Specifically, in the present invention, the isomer of bencycloquidium bromide is selected from the structure represented by any of Formula I, Formula II, Formula III, or Formula IV. JPEG2025529587000002.jpg13382

[0010] In the present invention, the ocular disease is selected from cycloplegia, mydriasis, amblyopia, myopic refractive error, or a combination thereof, especially myopic refractive error. The present invention can effectively prevent and delay the occurrence of myopic refractive error, protect the retina, and enhance the patient's visual fatigue resistance. Furthermore, the myopic refractive error preferably includes axial myopia or refractive myopia.

[0011] The present invention is effective in treating myopia of different degrees, such as mild myopia, moderate myopia, and high myopia, myopia of different age groups, such as myopia in children and myopia in adolescents, and myopia of different regulatory factors, such as true myopia and pseudomyopia.

[0012] The present inventors have discovered that when at least one of bencycloquidium bromide, bencycloquidium bromide isomers, and bencycloquidium bromide derivatives is applied to the eye, it has a significant inhibitory effect on changes in axial length and refractive power during the progression of myopic refractive error, and therefore can be used effectively in the prevention and treatment of eye diseases, particularly myopic refractive error.

[0013] The present invention provides use of at least one of bencycloquidium bromide, its isomers, and its derivatives (which may be any one of bencycloquidium bromide, its isomers, and its derivatives, or a combination of any two or three of bencycloquidium bromide, its isomers, and its derivatives) for the manufacture of a pharmaceutical for the prevention or treatment of eye diseases, and the pharmaceutical is preferably an ophthalmic agent.

[0014] In the present invention, the dosage form of the ophthalmic preparation is not particularly limited. That is, any ophthalmic preparation may be used as long as it is prepared using the bencycloquizium bromide, its isomers, or its derivatives as an active ingredient and a pharmaceutical-acceptable vehicle as an adjuvant. Examples of such preparations include eye drops, eye ointments, eye creams, eye gels, eye films, eye pills, intraocular inserts, and lyophilized preparations. The lyophilized preparations can be administered to the eye by dissolving them in a diluent for reconstitution.

[0015] Second, the present invention provides an ophthalmic preparation containing at least one active pharmaceutical ingredient selected from the group consisting of bencycloquidium bromide, bencycloquidium bromide isomers, and bencycloquidium bromide derivatives (which may be a single active ingredient or a combination of multiple active ingredients), wherein the bencycloquidium bromide isomer is selected from the group consisting of the structures represented by Formula I, Formula II, Formula III, and Formula IV.

[0016] In some embodiments provided by the present invention, the ophthalmic agent is preferably prepared with one structure, that is, bencycloquidium bromide, its isomers, or its derivatives as the single active ingredient.

[0017] The present invention relates to the manufacture of an ophthalmic preparation using bencycloquidium bromide, its isomers, and its derivatives as an active medicinal ingredient for preventing and treating myopia. The ophthalmic preparation contributes to the rapid exertion of the active medicinal ingredient's effect in the process of preventing and treating myopia. Meanwhile, the ophthalmic preparation exerts its preventive and therapeutic effect on myopia while contributing to the corresponding reduction in adverse reactions (systemic).

[0018] Third, the present invention provides a specific ophthalmic preparation, namely, eye drops. The eye drops provided by the present invention contain an active pharmaceutical ingredient and water for injection, and the active pharmaceutical ingredient includes at least one of bencycloquidium bromide, bencycloquidium bromide isomers, and bencycloquidium bromide derivatives (which may be a single active ingredient or a combination of multiple active ingredients). Here, the bencycloquidium bromide isomer is preferably selected from the structures represented by Formula I, Formula II, Formula III, or Formula IV.

[0019] The content of the active pharmaceutical ingredient in the eye drops is, in mass percentage, 0.01% to 0.5%, preferably 0.02% to 0.1%, more preferably 0.04% to 0.06%, and even more preferably 0.05%.

[0020] In the present invention, the osmotic molar concentration of the eye drops is preferably 250 to 350 mOsmol / kg, and more preferably 280 to 320 mOsmol / kg.

[0021] In the present invention, the pH value of the eye drops is preferably 5.5 to 9.0, more preferably 5.5 to 7.5, which shows better improvement in the long-term stability of the eye drops compared to other pH ranges.

[0022] Furthermore, in some preferred embodiments provided by the present invention, when the osmolarity of the eye drops is 280 to 320 mOsmol / kg, the pH value is preferably 6.0 to 7.0. The above-mentioned osmolarity range and pH range are advantageous not only for reducing irritation to the eyes during use of the eye drops but also for the stability of the eye drops themselves.

[0023] In the prior art, bencycloquizium bromide is a non-liquid preparation or a liquid preparation that cannot be applied directly to the eye, and it causes varying degrees of irritation to the eyes. The eye drops provided by the present invention are optimized in formulation to be suitable for application to the eye, and can exert good effects on preventing myopia, slowing the progression of myopia, and reducing mydriasis.

[0024] Specifically, the present invention provides several preferred embodiments, which prepare bencycloquizium bromide ophthalmic solution by adding several specific auxiliary ingredients or by a specific preparation method, specifically including the following:

[0025] In the present invention, the eye drops may contain an osmolality adjuster, if necessary. When an osmolality adjuster is added, the osmolality adjuster is one or more selected from sodium chloride, mannitol, and sorbitol. Sodium chloride is particularly advantageous in reducing irritation to the eyes caused by the eye drops.

[0026] In particular, when the osmotic pressure adjusting agent is mannitol and / or sorbitol, the mass ratio to the active pharmaceutical ingredient is preferably 0.5-2.0:0.01-0.5, and more preferably 0.5-2.0:0.04-0.06. The content of the osmotic pressure adjusting agent in the eye drops is preferably 0.5%-2.0% by mass.

[0027] When the osmotic pressure adjusting agent is sodium chloride, the mass ratio to the active pharmaceutical ingredient is preferably 0.3-0.9:0.01-0.5, more preferably 0.3-0.9:0.04-0.5, and even more preferably 0.3-0.9:0.04-0.06. The content of the osmotic pressure adjusting agent in the eye drops is preferably 0.3%-0.9% by mass.

[0028] In the present invention, the eye drops may contain a thickener if necessary. When a thickener is added, the thickener is preferably one or more selected from glycerin, sodium hyaluronate, carbomer, polyvinyl alcohol, methyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose, and more preferably polyvinyl alcohol, which is more effective in improving the eye application of the eye drops and extending the long-term stability of the eye drops compared to other thickeners.

[0029] Furthermore, when the thickener is one or more selected from polyvinyl alcohol, sodium hyaluronate, carbomer, hydroxypropylmethylcellulose, hydroxyethylcellulose, and sodium carboxymethylcellulose, the content thereof in the eye drops is preferably 0.1% to 3.0%, and more preferably 0.1% to 1.5%, by mass.

[0030] When the thickener is polyvinyl alcohol, the content thereof in the eye drops is preferably 0.3% to 3.0%, more preferably 0.5% to 1.5%, and even more preferably 0.7% to 1.4%.

[0031] In the present invention, it is preferred to add a specific amount of a thickener to the eye drops, since this is advantageous in alleviating eye fatigue and dryness caused by overuse of the eyes.

[0032] Furthermore, in the present invention, it is preferable to control the mass ratio of the osmotic pressure adjuster to the thickener to be 0.2-2.0:0.1-3.0. More preferably, in the present invention, when sodium chloride is used as the osmotic pressure adjuster and sodium hyaluronate or carbomer is used as the thickener, the mass ratio of the osmotic pressure adjuster to the thickener is preferably 0.3-0.9:0.1-1.0, and more preferably 0.3-0.9:0.1-0.7.

[0033] In the present invention, when mannitol and / or sorbitol is used as the osmotic pressure adjuster and polyvinyl alcohol, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose is used as the thickener, the mass ratio of the osmotic pressure adjuster to the thickener is preferably 0.5-2.0:0.1-1.0, and more preferably 0.5-2.0:0.3-0.7.

[0034] In the present invention, when sodium chloride is used as the osmotic pressure adjuster and polyvinyl alcohol is used as the thickener, the mass ratio of the osmotic pressure adjuster to the thickener is preferably 0.3-0.9:0.3-3.0, and more preferably 0.3-0.9:0.5-1.5, because this is advantageous for the long-term stability of the eye drops.

[0035] The specific osmotic pressure adjuster and thickener controlled in the above ratio contribute to increasing the residence time of the eye drops in the eye, improving the moist feeling of the eyes and improving comfort, while preventing the eye from becoming too viscous and causing discomfort or irritation.

[0036] In the present invention, the eye drops may contain a bacteriostatic agent, if necessary. When a bacteriostatic agent is added, the bacteriostatic agent is preferably one or more selected from the group consisting of benzyl alcohol, phenylethanol, benzoic acid, benzoates, benzalkonium chloride, benzododecinium bromide, benzethonium chloride, phenoxyethanol, hydroxyphenyl esters, trichloro-tert-butyl alcohol, sorbic acid, and sorbates, and is preferably benzalkonium chloride, which is advantageous in reducing ocular irritation caused by the eye drops compared to other bacteriostatic agents.

[0037] Furthermore, in the present invention, when the bacteriostatic agent is benzalkonium chloride, the mass ratio of the benzalkonium chloride to the active pharmaceutical ingredient is preferably 0.01-0.05:0.01-0.5, more preferably 0.01-0.05:0.05, and even more preferably 0.02:0.05. The content of the benzalkonium chloride in the eye drops is preferably 0.01-0.05%, more preferably 0.02%, by mass percentage.

[0038] In the present invention, it is preferable to add a bacteriostatic agent component in a specific amount to the eye drop, because this can minimize irritation to the eye and avoid irritation and discomfort caused by the bacteriostatic agent while ensuring the sterility of the product.

[0039] The eye drops of the present invention may be packaged as multiple doses or as single doses. Whether packaged as multiple doses or single doses, the eye drops must be a sterile product. In another specific embodiment provided by the present invention, which is feasible but relatively expensive, the eye drops may be packaged as a single dose in a sterile manner without the use of a bacteriostatic agent, without affecting the efficacy of the product.

[0040] In the present invention, the eye drops may contain a pH adjuster, if necessary. When a pH adjuster is added, the pH adjuster is preferably one or more selected from hydrochloric acid, sodium hydroxide, phosphate buffer, citric acid-sodium citrate buffer, citric acid-disodium hydrogen phosphate buffer, and boric acid-sodium hydroxide buffer. The eye drops are used to adjust the pH range of the eye drops.

[0041] Furthermore, in order to improve the applicability of the eye drops according to the present invention to the eye, it is preferable to use a citric acid-sodium citrate buffer solution, a boric acid-sodium hydroxide buffer solution, or a phosphate buffer solution as a pH adjuster.

[0042] In the present invention, the origin of the various auxiliary materials listed above is not particularly limited, and any auxiliary material products that are generally commercially available in the field can be used as raw materials for the eye drops of the present invention to produce the product.

[0043] Fourth, the present invention provides a method for producing the eye drops, which comprises dissolving the medicinal active ingredient and the osmotic pressure adjuster in water for injection or water for injection containing a bacteriostatic agent. In this invention, the medicinal active ingredient and the osmotic pressure adjuster are simultaneously dissolved in water for injection, which allows the medicinal active ingredient to be more easily dispersed and is advantageous in reducing irritation to the eye.

[0044] Preferably, the method further comprises the step of swelling or dissolving a thickener in water for injection to obtain a thickener solution, wherein the active pharmaceutical ingredient and the osmotic pressure adjusting agent are dissolved in water for injection or water for injection containing a bacteriostatic agent, and then mixed with the thickener solution.

[0045] In the present invention, the amount of water for injection used to swell or dissolve the thickener is preferably 5% to 15% of the total mass of the eye drop. In the present invention, the thickener is swelled or dissolved in water for injection alone, and then mixed with a solution containing an active pharmaceutical ingredient and an osmotic pressure adjuster. This operation method can more uniformly disperse the thickener in the eye drop product, completely swell or dissolve the thickener, ensure appropriate viscosity of the eye drop product, and improve the quality of the eye drop product.

[0046] In one alternative specific embodiment of the present invention, the manufacturing method includes the following steps: Step 1: If the bacteriostatic agent is a hydroxyphenyl ester, dissolve the bacteriostatic agent in water for injection at 60-80°C; if the bacteriostatic agent is other than a hydroxyphenyl ester, dissolve the bacteriostatic agent in water for injection at 20-60°C to obtain solution 1. Step 2: Swelling or dissolving the thickening agent in water for injection to obtain solution 2. Step 3: Dissolve the osmolality adjuster and bencycloquidium bromide in room temperature water for injection to obtain solution 3. Step 4: Mix Solutions 1, 2, and 3 uniformly, cool to below approximately 40°C or to room temperature, adjust the pH to 5.5-9.0 with a pH adjuster, and add water for injection until the total volume is reached. Step 5: Filter through a 0.22 μm filtration membrane or filter element and bottle under aseptic conditions to obtain bencycloquidium bromide ophthalmic solution.

[0047] In another more preferred specific embodiment of the present invention, the manufacturing method comprises the following steps: Step 1: If the bacteriostatic agent is a hydroxyphenyl ester, dissolve the bacteriostatic agent in water for injection at 60-80°C; if the bacteriostatic agent is other than a hydroxyphenyl ester, dissolve the bacteriostatic agent in water for injection at 20-60°C to obtain solution 1. Step 2: Dissolve the osmolality adjuster and bencycloquidium bromide in solution 1 to obtain solution 2. Step 3: Swelling or dissolving the thickening agent in water for injection to obtain solution 3. Step 4: Mix Solution 2 and Solution 3 uniformly, cool to below approximately 40°C or to room temperature, adjust the pH to 5.5-9.0 with a pH adjuster, and add water for injection until the total volume is reached. Step 5: Filter through a 0.22 μm filtration membrane or filter element and bottle under aseptic conditions to obtain bencycloquidium bromide ophthalmic solution.

[0048] In the above two specific embodiments, it is preferable to control the pH value of the eye drops to be 5.5 to 7.5.

[0049] Fifth, the present invention further provides use of at least one of bencycloquidium bromide, its isomers, and its derivatives, the ophthalmic preparation, the eye drops, or the eye drops produced by the production method, for preventing myopia, slowing the rate of myopia progression, or reducing mydriasis. [Effects of the Invention]

[0050] The present invention provides use of at least one of bencycloquidium bromide, its isomers, and derivatives thereof in the manufacture of a pharmaceutical for preventing or treating eye diseases, specifically, an eye drop containing at least one of bencycloquidium bromide, its isomers, and derivatives thereof as an active ingredient. The eye drop can be effectively used to treat eye diseases, has significant advantages in preventing myopia and slowing the rate of myopia progression, and has shown good stability in both long-term and accelerated tests. A 12-month long-term stability test and a 6-month accelerated test showed that the eye drop maintained its initial medicinal activity and safety, caused no obvious irritation or dryness to the eye, and was of stable quality, showing excellent prospects for widespread application. [Brief explanation of the drawings]

[0051] In order to more clearly explain the technical solutions in the present invention or the prior art, the following describes the drawings necessary for explaining the embodiments or the prior art. [Figure 1] FIG. 1 is a graph showing the change in refractive power over time over a 4-week period when the bencycloquidium bromide ophthalmic solution prepared in Experimental Example 1 of the present invention was used in a form-deprived myopic animal model experiment. [Figure 2] FIG. 1 is a graph comparing the change in refractive power at the fourth week of an experiment in which the bencycloquidium bromide ophthalmic solution prepared in Experimental Example 1 of the present invention was used in an animal model experiment on form deprivation myopia. [Figure 3] FIG. 1 is a graph showing the change in axial length over a 4-week period when the bencycloquidium bromide ophthalmic solution prepared in Experimental Example 1 of the present invention was used in a form-deprived myopic animal model experiment. [Figure 4] FIG. 1 is a graph comparing the change in axial length at the fourth week of an experiment in which the bencycloquidium bromide ophthalmic solution prepared in Experimental Example 1 of the present invention was used in an animal model experiment on form-deprived myopia. DETAILED DESCRIPTION OF THE INVENTION

[0052] The technical solutions provided by the present invention will be described in detail below with reference to examples, which are not intended to limit the scope of protection of the present invention. Unless otherwise specified, the experimental methods used in the examples are conventional methods, and the materials, reagents, etc. used are all commercially available.

[0053] Example 1 This example provides an eye drop solution containing bencycloquidium bromide as an active ingredient, and the specific formulation is as follows. Active ingredient: Bencycloquizium bromide 0.05%; Osmolality adjusters: sodium chloride, used to adjust the osmolarity of eye drops to 300-320 mOsmol / kg; Thickener: Polyvinyl alcohol 1.0%; Bacteriostatic agent: benzalkonium chloride 0.02%; pH adjusters: phosphate buffer (NaH2PO4-Na2HPO4), used to adjust the pH value of eye drops to 6.8; Water for injection: until full volume.

[0054] In addition, this example provides a method for producing the above eye drops, and the specific production steps are as follows: (1) The bacteriostatic agent was dissolved in water for injection at 30°C so as to obtain the above-mentioned blending ratio, thereby obtaining Solution 1. (2) The osmolality adjuster and bencycloquizium bromide were dissolved in solution 1 to obtain solution 2 in the above-mentioned proportions. (3) The thickener was added to 10% water for injection (temperature 25°C) so as to achieve the above blend ratio, and stirred until completely dissolved, to obtain solution 3. (4) Solutions 2 and 3 were stirred uniformly, cooled to room temperature, the pH was adjusted with a pH adjuster, and water for injection was added to bring the total volume to 100%. (5) The solution was filtered through a 0.22 μm filter membrane or filter element and bottled under aseptic conditions to obtain bencycloquidium bromide ophthalmic solution.

[0055] Example 2 This example provides an eye drop solution containing bencycloquidium bromide as an active ingredient, and the specific formulation is as follows. Active ingredient: Bencycloquizium bromide 0.05%; Osmolarity adjusters: sodium chloride, used to adjust the osmolarity of eye drops to 280-300 mOsmol / kg; Thickener: Polyvinyl alcohol 1.4%; Bacteriostatic agent: benzalkonium chloride 0.02%; pH adjusters: phosphate buffer (NaH2PO4-Na2HPO4), used to adjust the pH value of eye drops to 6.5; Water for injection: until full volume.

[0056] In addition, this example provides a method for producing the above eye drops, and the specific production steps are as follows: (1) The bacteriostatic agent was dissolved in water for injection at 30°C so as to obtain the above-mentioned blending ratio, thereby obtaining Solution 1. (2) The osmolality adjuster and bencycloquizium bromide were dissolved in solution 1 to obtain solution 2 in the above-mentioned proportions. (3) The thickener was dissolved in water for injection to obtain the above-mentioned blend ratio, thereby obtaining Solution 3. (4) Solutions 2 and 3 were stirred uniformly, cooled to room temperature, the pH was adjusted with a pH adjuster, and water for injection was added to bring the total volume to 100%. The solution was filtered through a 0.22 μm filter membrane or filter element and bottled under sterile conditions to obtain bencycloquidium bromide ophthalmic solution.

[0057] Example 3 This example provides an eye drop solution containing bencycloquidium bromide as an active ingredient, and the specific formulation is as follows. Active ingredient: Bencycloquizium bromide 0.05%; Osmolarity adjusters: mannitol, used to adjust the osmolarity of eye drops to 300-310 mOsmol / kg; Thickener: Polyvinyl alcohol 0.7%; Bacteriostatic agent: hydroxyphenylethyl ester 0.08%; pH adjuster: phosphate buffer solution (NaH2PO4-Na2HPO4), used to adjust the pH value of eye drops to 6.0-6.5; Water for injection: until full volume.

[0058] In addition, this example provides a method for producing the above eye drops, and the specific production steps are as follows: (1) The bacteriostatic agent was dissolved in water for injection at 60°C so as to obtain the above-mentioned blending ratio, thereby obtaining Solution 1. (2) The osmolality adjuster and bencycloquizium bromide were dissolved in solution 1 to obtain solution 2 in the above-mentioned proportions. (3) The thickener was dissolved in water for injection to obtain the above-mentioned blend ratio, thereby obtaining Solution 3. (4) Solutions 2 and 3 were stirred uniformly, cooled to room temperature, the pH was adjusted with a pH adjuster, and water for injection was added to bring the total volume to 100%. (5) The solution was filtered through a 0.22 μm filter membrane or filter element and bottled under aseptic conditions to obtain bencycloquidium bromide ophthalmic solution.

[0059] Example 4 This example provides an eye drop solution containing bencycloquidium bromide as an active ingredient, and the specific formulation is as follows. Active ingredient: Bencycloquizium bromide 0.05%; Osmolality adjusters: sodium chloride, used to adjust the osmolarity of eye drops to 300-310 mOsmol / kg; Thickener: Carbomer 0.1%; Bacteriostatic agent: benzalkonium chloride 0.025%; pH adjuster: boric acid-sodium hydroxide buffer solution, used to adjust the pH value of eye drops to 7.0-7.5; Water for injection: until full volume.

[0060] In addition, this example provides a method for producing the above eye drops, and the specific production steps are as follows: (1) The bacteriostatic agent was dissolved in water for injection at 35°C so as to obtain the above-mentioned blending ratio, thereby obtaining Solution 1. (2) The osmolality adjuster and bencycloquizium bromide were dissolved in solution 1 to obtain solution 2 in the above-mentioned proportions. (3) The thickener was dissolved in water for injection to obtain the above-mentioned blend ratio, thereby obtaining Solution 3. (4) Solutions 2 and 3 were stirred uniformly, cooled to room temperature, the pH was adjusted with a pH adjuster, and water for injection was added to bring the total volume to 100%. (5) The solution was filtered through a 0.22 μm filter membrane or filter element and bottled under aseptic conditions to obtain bencycloquidium bromide ophthalmic solution.

[0061] Example 5 This example provides an eye drop solution containing bencycloquidium bromide as an active ingredient, and the specific formulation is as follows. Active ingredient: Bencycloquizium bromide 0.01%; Osmolarity adjusters: sorbitol, used to adjust the osmolarity of eye drops to 290-300 mOsmol / kg; Thickener: Sodium carboxymethylcellulose 0.3%; Bacteriostatic agent: phenylethanol 0.3%; pH adjusters: citric acid - sodium citrate, used to adjust the pH value of eye drops to 6.5-7.0; Water for injection: until full volume.

[0062] In addition, this example provides a method for producing the above eye drops, and the specific production steps are as follows: (1) The bacteriostatic agent was dissolved in water for injection at 35°C so as to obtain the above-mentioned blending ratio, thereby obtaining Solution 1. (2) The osmolality adjuster and bencycloquizium bromide were dissolved in solution 1 to obtain solution 2 in the above-mentioned proportions. (3) The thickener was swelled in water for injection so as to achieve the above-mentioned blending ratio, to obtain Solution 3. (4) Solutions 2 and 3 were stirred uniformly, cooled to room temperature, the pH was adjusted with a pH adjuster, and water for injection was added to bring the total volume to 100%. (5) The solution was filtered through a 0.22 μm filter membrane or filter element and bottled under aseptic conditions to obtain bencycloquidium bromide ophthalmic solution.

[0063] Example 6 This example provides an eye drop solution containing bencycloquidium bromide as an active ingredient, and the specific formulation is as follows. Active ingredient: Bencycloquizium bromide 0.1%; Osmolality adjusters: sodium chloride, used to adjust the osmolarity of eye drops to 290-300 mOsmol / kg; Bacteriostatic agent: benzalkonium chloride 0.05%; pH adjuster: hydrochloric acid; Water for injection: until full volume.

[0064] In addition, this example provides a method for producing the above eye drops, and the specific production steps are as follows: (1) The bacteriostatic agent was dissolved in water for injection at 45°C so as to obtain the above-mentioned blending ratio, thereby obtaining Solution 1. (2) The osmolality adjuster and bencycloquizium bromide were dissolved in solution 1 to obtain solution 2 in the above-mentioned proportions. (3) Solution 2 was cooled to about 40°C or less, the pH was adjusted to 6.0 with a pH adjuster, and water for injection was added to bring the total volume to 100%. (4) The solution was filtered through a 0.22 μm filter membrane or filter element and bottled under aseptic conditions to obtain bencycloquidium bromide ophthalmic solution.

[0065] Example 7 This example provides an eye drop solution containing a bencycloquizium bromide isomer as an active ingredient, and the specific formulation is as follows. Active ingredient: Bencycloquidium bromide isomer (structure represented by formula IV) 0.05%; Osmolality adjusters: sodium chloride, used to adjust the osmolarity of eye drops to 290-300 mOsmol / kg; pH adjuster: phosphate buffer solution (NaH2PO4-Na2HPO4), used to adjust the pH value of eye drops to 6.5-7.0; Water for injection: until full volume.

[0066] In addition, this example provides a method for producing the above eye drops, and the specific production steps are as follows: (1) The osmolality adjuster and bencycloquizium bromide isomer were dissolved in water for injection so as to obtain the above-mentioned blend ratio, and the mixture was stirred uniformly to obtain Solution 1. (2) Solution 1 was cooled to room temperature, the pH was adjusted with phosphate buffer (NaH2PO4-Na2HPO4), and water for injection was added to bring the total volume to the final volume. (3) The solution was filtered through a 0.22 μm filter membrane or filter element and bottled under aseptic conditions to obtain bencycloquidium bromide isomer ophthalmic solution.

[0067] Example 8 This example provides an eye drop solution containing bencycloquidium bromide as an active ingredient, and the specific formulation is as follows. Active ingredient: Bencycloquizium bromide 0.05%; Osmolality adjusters: sodium chloride, used to adjust the osmolarity of eye drops to 300-320 mOsmol / kg; Bacteriostatic agent: benzalkonium chloride 0.02%; pH adjusters: phosphate buffer (NaH2PO4-Na2HPO4), used to adjust the pH value of eye drops to 6.8; Water for injection: until full volume.

[0068] In addition, this example provides a method for producing the above eye drops, and the specific production steps are as follows: (1) The bacteriostatic agent was dissolved in water for injection at 30°C so as to obtain the above-mentioned blending ratio, thereby obtaining Solution 1. (2) The osmolality adjuster and bencycloquizium bromide were dissolved in Solution 1 to achieve the above-mentioned composition ratio, cooled to room temperature, the pH was adjusted with a pH adjuster, and water for injection was added to make up the total volume. (3) The solution was filtered through a 0.22 μm filter membrane or filter element and bottled under aseptic conditions to obtain bencycloquidium bromide ophthalmic solution.

[0069] Example 9 This example provides an eye drop solution containing bencycloquidium bromide as an active ingredient, and the specific formulation is as follows. Active ingredient: Bencycloquizium bromide 0.05%; Osmolality adjusters: sodium chloride, used to adjust the osmolarity of eye drops to 300-320 mOsmol / kg; Thickener: Hydroxyethylcellulose 0.7%; Bacteriostatic agent: benzalkonium chloride 0.02%; pH adjusters: phosphate buffer (NaH2PO4-Na2HPO4), used to adjust the pH value of eye drops to 6.8; Water for injection: until full volume.

[0070] In addition, this example provides a method for producing the above eye drops, and the specific production steps are as follows: (1) The bacteriostatic agent was dissolved in water for injection at 30°C so as to obtain the above-mentioned blending ratio, thereby obtaining Solution 1. (2) The osmolality adjuster and bencycloquizium bromide were dissolved in solution 1 to obtain solution 2 in the above-mentioned proportions. (3) A 10% thickener was added to 25°C water for injection so as to achieve the above blend ratio, and the mixture was stirred. Stirring was continued for 60 minutes to obtain Solution 3. (4) Solutions 2 and 3 were stirred uniformly, cooled to room temperature, the pH was adjusted with a pH adjuster, and water for injection was added to bring the total volume to 100%. (5) The solution was filtered through a 0.22 μm filter membrane or filter element and bottled under aseptic conditions to obtain bencycloquidium bromide ophthalmic solution.

[0071] Example 10 This example provides an eye drop solution containing bencycloquidium bromide as an active ingredient, and the specific formulation is as follows. Active ingredient: Bencycloquizium bromide 0.05%; Osmolality adjusters: sodium chloride, used to adjust the osmolarity of eye drops to 300-320 mOsmol / kg; Thickener: Polyvinyl alcohol 1.0%; Bacteriostatic agent: benzalkonium chloride 0.02%; pH adjuster: phosphate buffer (NaH2PO4-Na2HPO4), used to adjust the pH value of eye drops to 8.0; Water for injection: until full volume.

[0072] In addition, this example provides a method for producing the above eye drops, and the specific production steps are as follows: (1) The bacteriostatic agent was dissolved in water for injection at 30°C so as to obtain the above-mentioned blending ratio, thereby obtaining Solution 1. (2) The osmolality adjuster and bencycloquizium bromide were dissolved in solution 1 to obtain solution 2 in the above-mentioned proportions. (3) The thickener was added to 10% water for injection (temperature 25°C) so as to achieve the above blend ratio, and stirred until completely dissolved, to obtain solution 3. (4) Solutions 2 and 3 were stirred uniformly, cooled to room temperature, the pH was adjusted with a pH adjuster, and water for injection was added to bring the total volume to 100%. (5) The solution was filtered through a 0.22 μm filter membrane or filter element and bottled under aseptic conditions to obtain bencycloquidium bromide ophthalmic solution.

[0073] Experimental Example 1 In this experimental example, a myopia model experiment was carried out on pigmented guinea pigs using the bencycloquidium bromide ophthalmic solution prepared in Example 1. Specifically, the experiment was carried out as follows.

[0074] An animal model of form deprived myopia (FDM) was created by the monocular deprived (MD) method, that is, by covering one eye with a non-transparent eye mask to deprive it of form.

[0075] Eighteen healthy guinea pigs that met the experimental requirements were randomly divided into three groups: a model control group, a positive control group, and a benzalkonium bromide group. Models were constructed in each group, and treatment began on day 1 of model construction. Blank vehicle, 0.05% atropine, and 0.05% benzalkonium bromide were instilled into the conjunctival sac once daily at 20 μL per eye for a total of 4 weeks in the model control (FDM), positive control (FDM + atropine), and benzalkonium bromide (FDM + benzalkonium bromide) groups, respectively. The blank vehicle consisted of water for injection, and the 0.05% atropine consisted of 0.05% atropine, 1.0% polyvinyl alcohol, and 0.02% benzalkonium chloride in water for injection. Sodium chloride was used as an osmolality adjuster to adjust the osmolality of the eye drops to 300-320 mOsmol / kg, and phosphate buffer (NaH2PO4-Na2HPO4) was used as a pH adjuster to adjust the pH value of the eye drops to 6.8.

[0076] The detection indicators were as follows: (1) General clinical observations of the animals were performed once a day. (2) Animal weights were measured on the day of arrival, the 7th day of quarantine, and the 14th day of quarantine, and twice a week after model construction. (3) The anterior chamber depth, lens thickness, vitreous cavity length, and axial length were measured once a week before model construction and after administration. (4) Refractive index was examined once a week before model construction and after administration.

[0077] Before constructing the model, there was no significant difference in the refractive power and axial length of the eyes of the animals in each group. After 4 weeks of the experiment, the measurement results of the animals in each group were as follows:

[0078] There was no significant difference in the body weight of the animals in each group during the test period. Compared with the model control group, the positive control group and the bencycloquizium bromide group showed a significant decrease in the change in axial length after four weeks of administration. The change in axial length showed that bencycloquizium bromide can suppress the increase in axial length of the guinea pig myopia model. The experimental results of the refractive power and axial length of the eye are shown in FIGS.

[0079] The experimental results showed that by depriving the eyes for 4 weeks to create a guinea pig FDM myopia model, there was a clear tendency for the refractive power to decrease and the change in axial length to increase significantly, resulting in a clear tendency for the model to become a myopic model.By administering 20μL of 0.05% bencycloquidium bromide daily during model construction, the tendency for the decrease in refractive power and the change in axial length in the FDM model guinea pigs was significantly suppressed, indicating that bencycloquidium bromide has a significant preventive effect on the guinea pig FDM myopia model.

[0080] When the eye drops obtained in the other Examples were used in repeated myopia model experiments, the same conclusions were basically reached, with all of them showing a significant myopia prevention effect.

[0081] Experimental Example 2 In this experimental example, rabbit experiments were carried out using the bencycloquidium bromide ophthalmic solutions prepared in Examples 1, 3, 5, 8 and 9. The specific procedures were as follows.

[0082] Twenty-five New Zealand rabbits (both sexes, weighing 2-2.5 kg) were randomly divided into five groups and administered the test product to the left eye and an equal volume of blank to the right eye in a self-administered, bilateral comparison. Experimental group 1 received Test Product 1 (the eye drops provided in Example 8), experimental group 2 received Test Product 2 (the eye drops provided in Example 9), experimental group 3 received Test Product 3 (the eye drops provided in Example 1), experimental group 4 received Test Product 4 (the eye drops provided in Example 3), experimental group 5 received Test Product 5 (the eye drops provided in Example 5), and the blank was water for injection. The test product was administered twice daily (once in the morning and once in the afternoon) at 20 μL per eye for 14 consecutive days. The eyes were observed for irritation of ocular tissues, such as the cornea, iris, and conjunctiva, using a slit lamp before and 1, 2, 4, 24, 48, and 72 hours after administration.

[0083] According to the experiment, during the experimental period, in experimental group 1, the conjunctiva of the left eye of two rabbits became congested and bright red, and slight edema was observed, in experimental group 2, the conjunctiva of one rabbit became congested and bright red, in experimental group 3, no obvious irritation reaction was observed, in experimental group 4, slight edema was observed in the left eye of one rabbit, and in experimental group 5, slight congestion and slight edema were observed in the conjunctiva of one rabbit's left eye. In a study of irritation to rabbit ocular tissue, the eye drops containing polyvinyl alcohol as a thickener caused the least irritation, and the eye drops without added thickener (Example 8) caused strong irritation to rabbit ocular tissue.

[0084] Experimental Example 3 In this experimental example, long-term stability experiments and accelerated stability experiments were conducted using the bencycloquidium bromide ophthalmic solutions prepared in Examples 1, 8, 9, and 10. Here, Sample A was derived from the ophthalmic solution provided in Example 9, Sample B was derived from the ophthalmic solution provided in Example 1, Sample C was derived from the ophthalmic solution provided in Example 8, and Sample D was derived from the ophthalmic solution provided in Example 10. The long-term stability experiment was conducted under conditions of 25°C and 60% RH, and the accelerated stability experiment was conducted under conditions of 40°C and 75% RH. The results of the long-term stability experiments are shown in Table 1.

[0085] [Table 1]

[0086] The results of the accelerated stability experiments are shown in Table 2.

[0087] [Table 2]

[0088] The results of a 12-month long-term stability study and a 6-month accelerated stability study showed that: Sample B, which used polyvinyl alcohol as a thickener, showed the best stability with no obvious changes in either the content or related substances. In sample C, which did not contain any thickener, the content decreased significantly and the related substances increased significantly. Sample A showed a slight decrease in content and a slight increase in related substances.

[0089] Furthermore, there was a difference in stability between Samples B and D, which used the same thickener but were controlled to different pH levels. In Sample B at pH 6.8, there was no obvious change in either the content or related substances, while in Sample D at pH 8.0, the content clearly decreased and the related substances clearly increased. Compared to pH 8.0, the samples were more stable at pH 6.8.

[0090] Experimental Example 4 In this experiment, rabbit experiments were carried out using the bencycloquidium bromide ophthalmic solutions of Examples 1, 8, 9, and 10, which had been subjected to a 12-month long-term stability experiment in Experimental Example 3. The specific results were as follows.

[0091] Twenty New Zealand rabbits (both males and females, weighing 2-2.5 kg) were randomly divided into four groups and administered the test product to the left eye and an equal volume of blank to the right eye in a self-administered, bilateral comparison. Experimental group 1 received Test Product 1 (the eye drops provided in Example 8), experimental group 2 received Test Product 2 (the eye drops provided in Example 9), experimental group 3 received Test Product 3 (the eye drops provided in Example 1), experimental group 4 received Test Product 4 (the eye drops provided in Example 10), and the blank was water for injection. The eye was administered at 20 μL per eye twice daily (once in the morning and once in the afternoon) for 14 consecutive days. The eyes were observed for irritation of ocular tissues, such as the cornea, iris, and conjunctiva, using a slit lamp before and 1, 2, 4, 24, 48, and 72 hours after administration.

[0092] According to the experiment, during the experimental period, in experimental group 1, the conjunctiva of the left eyes of four rabbits became congested and bright red, and slight edema was observed; in experimental group 2, the conjunctiva of the left eye of one rabbit became congested and bright red, and slight edema was observed, and the conjunctiva of the left eye of two rabbits became slightly congested; in experimental group 3, no obvious irritation reaction was observed; and in experimental group 4, the conjunctiva of the left eyes of two rabbits became congested and bright red, and the conjunctiva of the left eye of one rabbit became slightly congested and slight edema was observed.

[0093] The above examples are intended to illustrate some embodiments of the present invention, and are provided for the purpose of providing a concrete and detailed understanding of the technical solutions of the present invention, but are not intended to limit the scope of the claims of the present invention. However, any modifications and improvements within the inventive concept of the present invention are intended to be included in the protection scope of the present invention. [Industrial Applicability]

[0094] The present invention provides use of bencycloquidium bromide, its isomers, and derivatives for the manufacture of a pharmaceutical for the prevention or treatment of eye diseases. The present invention also provides an ophthalmic preparation containing bencycloquidium bromide, its isomers, and derivatives as an active ingredient. It has been discovered that the use of bencycloquidium bromide, its isomers, and derivatives in the eye exhibits a significant inhibitory effect on changes in axial length and refraction during the progression of myopic refractive error. It has also been discovered that ophthalmic preparations containing these active ingredients have significant advantages in the prevention and treatment of eye diseases, particularly in the prevention of myopia and slowing the rate of myopia progression, and have good economic value and prospects for application.

Claims

1. Use of bencycloquizium bromide, its isomers and derivatives thereof for the manufacture of a medicament for the prevention or treatment of eye diseases.

2. The use according to claim 1, characterized in that the isomer of bencycloquidium bromide is selected from the structure represented by any one of formulas I, II, III, or IV.

3. 3. The use according to claim 1 or 2, wherein the eye disease comprises myopic refractive error.

4. the pharmaceutical agent is an ophthalmic agent, The use according to any one of claims 1 to 3, characterized in that the ophthalmic preparation is preferably an eye drop, an eye ointment, an eye cream, an eye gel, an eye film, an eye pill or an intraocular insert.

5. An ophthalmic preparation, characterized in that the active pharmaceutical ingredient contains at least one of bencycloquidium bromide, bencycloquidium bromide isomers, and bencycloquidium bromide derivatives.

6. An eye drop comprising an active pharmaceutical ingredient and water for injection, The active pharmaceutical ingredient comprises at least one of bencycloquizium bromide, bencycloquizium bromide isomers, and bencycloquizium bromide derivatives; The content of the active pharmaceutical ingredient in the eye drops is 0.01% to 0.5% by mass, Preferably, the ophthalmic solution has an osmotic molar concentration of 250 to 350 mOsmol / kg and / or a pH value of 5.5 to 9.

0.

7. Contains at least one of an osmolality adjuster and a viscosity enhancer, Preferably, the osmotic pressure adjusting agent is one or more selected from sodium chloride, mannitol, and sorbitol, and the thickener is one or more selected from glycerin, sodium hyaluronate, carbomer, polyvinyl alcohol, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and sodium carboxymethylcellulose; 7. The eye drop preparation according to claim 6, wherein the mass ratio of the osmotic pressure adjusting agent to the thickener is preferably 0.2 to 2:0.1 to 5.

0.

8. the osmolality adjusting agent is sodium chloride; The thickener is polyvinyl alcohol, 8. The eye drop preparation according to claim 7, wherein the mass ratio of the sodium chloride to the polyvinyl alcohol is 0.3 to 0.9:0.3 to 3.

0.

9. Contains a bacteriostatic agent, Preferably, the bacteriostatic agent is one or more selected from the group consisting of benzyl alcohol, phenylethanol, benzoic acid, benzoates, benzalkonium chloride, benzododecinium bromide, benzethonium chloride, phenoxyethanol, hydroxyphenyl esters, trichloro-tert-butyl alcohol, sorbic acid, and sorbates; More preferably, the eye drop according to any one of claims 6 to 8, wherein the bacteriostatic agent is benzalkonium chloride, and the mass ratio of the benzalkonium chloride to the active medicinal ingredient is 0.01-0.05:0.01-0.

5.

10. A method for producing the eye drop according to any one of claims 6 to 9, comprising the steps of: A method for producing an eye drop, comprising the step of dissolving an active pharmaceutical ingredient and an osmotic pressure adjusting agent in water for injection or water for injection containing a bacteriostatic agent.

11. The method further comprises the step of swelling or dissolving a thickening agent in water for injection to obtain a thickening agent solution; The method according to claim 10, characterized in that the medicinal active ingredient and the osmotic pressure adjusting agent are preferably dissolved in water for injection or water for injection containing a bacteriostatic agent, and then mixed with the thickener solution.

12. Use of bencycloquidium bromide, its isomers and derivatives thereof, the ophthalmic preparation according to claim 5, the eye drops according to any one of claims 6 to 9, or the eye drops produced by the production method according to claim 10 or 11, for the prevention of myopia, slowing the rate of progression of myopia, or slowing mydriasis.

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