Ophthalmic composition of α-adrenergic receptor agonist and use thereof

Abstract

The present invention relates to an ophthalmic composition of an α-adrenergic receptor agonist and the use thereof, the ophthalmic composition comprising an α-adrenergic receptor agonist and an M choline receptor agonist. The provided ophthalmic composition can meet the requirements of different patients for improving near vision and distant vision, and has a relatively long retention time of up to 10 h. In addition, the provided composition can also quickly eliminate conjunctival congestion and eliminate asthenopia, and has good efficacy in preventing and treating eye diseases such as presbyopia, ocular hypertension, xerophthalmia, myopia, hyperopia, strabismus, astigmatism, photophobia or glaucoma.

Description

An alpha-adrenergic receptor agonist ophthalmic composition and its use Technical Field

[0001] The present disclosure belongs to the field of biomedicine technology, and specifically relates to an α-adrenergic receptor agonist ophthalmic composition and uses thereof. Background Art

[0002] With the development of modern technology, people are becoming increasingly dependent on electronic products. Children, adults, and the elderly alike are now inseparable from their studies and daily lives. The harmful effects of electronic products on the eyes are becoming increasingly apparent, including red bloodshot eyes, eye fatigue, blurred vision, dry and itchy eyes, sun sensitivity, and decreased vision. These hazards can have a certain impact on a person's studies and daily lives, and over time, they can lead to impaired vision and affect their quality of life. Furthermore, as myopic individuals age, some may experience myopia in one eye and hyperopia in the other.

[0003] To prevent microbial contamination during repeated use after opening, over 90% of ophthalmic preparations currently on the market and under clinical development contain preservatives. These preparations are packaged in multiple doses and can be reused multiple times. Preservatives, also known as antibacterial agents or preservatives, are chemicals that inhibit the growth and reproduction of microorganisms. However, preservatives themselves can cause damage to the ocular surface, and long-term use may lead to dry eyes, corneal and conjunctival epithelial damage, and other conditions. Therefore, preservative-free single-dose ophthalmic preparations are a new direction in the development of ophthalmic medications.

[0004] Adrenergic receptor agonists are a class of compounds with chemical structures and pharmacological actions similar to those of adrenaline. They bind to and stimulate adrenaline receptors, producing adrenaline-like effects. They are also known as epinephrine mimetics and are all amine compounds. Based on their selectivity for different adrenaline receptor subtypes, they are divided into three major categories: α-adrenaline receptor agonists, β-adrenaline receptor agonists, and α-β-adrenaline receptor agonists. A variety of ophthalmic preparations of α-adrenaline receptor agonists are available on the market, but most contain preservatives.

[0005] M cholinergic receptor agonists bind to cholinergic receptors and produce effects similar to acetylcholine. The representative drug is pilocarpine, also known as pilocarpine. As early as 1959, 0.5% to 2% pilocarpine eye drops have been used to treat glaucoma. It is the first FDA-approved drug for the treatment of glaucoma, but it has significant side effects, such as stinging and burning eyes, conjunctival congestion, superficial keratitis, retinal detachment, ciliary spasm causing headaches, and long-term use may cause lens opacity. Therefore, new first-line treatment drugs continue to be developed. In recent years, there have been reports on the use of M cholinergic receptor agonists in the prevention and treatment of presbyopia. In October 2021, Vuity (NDA 214028), the first FDA-approved treatment for presbyopia, improves near vision by miosis. Its active ingredient is 1.25% pilocarpine (WO2019209955). Eyenovia Inc. uses its "MicroLine" technology (WO2020180793) to deliver relatively high concentrations of pilocarpine to the eye, thereby treating presbyopia. Orasis Pharmaceuticals has developed a presbyopia drug containing a low concentration (0.4%) of pilocarpine and a proprietary carrier (WO2018033792). These presbyopia drugs, both marketed and under clinical development, employ complex formulations to enhance stability.

[0006] Therefore, the market is in urgent need of an ophthalmic preparation with a simple formula, long-term use, good stability, high patient compliance, few side effects, easy use and multiple functions.

[0007] Summary of the Invention

[0008] In order to solve the problems existing in the prior art, the purpose of the present disclosure is to provide an ophthalmic preparation with a simple formula, long-term use, good stability, high patient compliance, few side effects, easy use and multiple functions.

[0009] In order to achieve the above objectives, the present disclosure adopts the following specific solutions:

[0010] In one aspect, the present disclosure provides an ophthalmic composition comprising an α-adrenergic receptor agonist and a M cholinergic receptor agonist.

[0011] In another aspect, the present disclosure provides a use of an α-adrenergic receptor agonist and an M cholinergic receptor agonist in combination for preparing a medicament for preventing, improving, alleviating or treating eye diseases.

[0012] In another aspect, the present disclosure provides a use of the aforementioned ophthalmic composition in the preparation of a medicament for preventing, improving, alleviating or treating eye diseases.

[0013] The present disclosure has at least the following beneficial effects:

[0014] (1) The ophthalmic composition provided by the present disclosure comprises an α-adrenergic receptor agonist and an M cholinergic receptor agonist, the mixture of which synergistically increases the efficacy of the drug, can meet the needs of different patients for improving near vision and distance vision, and has a longer retention time of up to 10 hours.

[0015] (2) The ophthalmic composition provided by the present disclosure can also quickly eliminate conjunctival congestion and visual fatigue, and has a good therapeutic effect on preventing and treating eye diseases such as presbyopia, ocular hypertension, dry eye, myopia, hyperopia, strabismus, astigmatism, photophobia or glaucoma.

[0016] (3) The ophthalmic composition provided by the present disclosure does not contain other excipients such as preservatives, buffers, chelating agents and excipients, thereby reducing the irritation to the eyes caused by excipients, and has high safety, few side effects, and is suitable for long-term use.

[0017] (3) The synergistic therapeutic effect of the α-adrenergic receptor agonist and the M cholinergic receptor agonist in the ophthalmic composition provided by the present disclosure on treating hyperopia and alleviating myopia is significantly better than that of a single α-adrenergic receptor agonist and a single M cholinergic receptor agonist. The synergistic therapeutic effect of this combination on alleviating myopia is also better than that of the combination preparation of atropine and cevimeline. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is a diagram of the finished product of formulation 11.

[0019] FIG2 is a comparison of the eye irritation of single prescription formulations 7 and 9 and formulations 10-11 before and after administration.

[0020] Figure 3 is a comparison of the eye irritation of compound preparation formulas 1-3 and 5 before and after administration.

[0021] FIG4 is a graph showing the effects of formulations 4, 9, and 11 on the near vision of the subjects.

[0022] FIG5 is a graph showing the effect of formulation 6 on the near and distance vision of the subjects. DETAILED DESCRIPTION

[0023] I. Terminology

[0024] In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by those skilled in the art to which the present disclosure belongs.

[0025] As used herein and unless otherwise indicated, the term "about" or "approximately" means within plus or minus 10% of a given value or range. Where an integer is required, the term means within plus or minus 10% of a given value or range, rounded up or down to the nearest integer.

[0026] In this description, the term "and / or" simply describes a relationship between related objects, indicating that three possible relationships exist. For example, A and / or B can represent: A exists alone, A and B exist simultaneously, and B exists alone. Additionally, the character " / " in this document generally indicates that the related objects are in an "or" relationship.

[0027] In the description herein, references to “some embodiments,” “some implementation schemes,” or “some implementation plans” describe a subset of all possible embodiments, but it will be understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0028] As used herein and unless otherwise specified, the terms "comprises," "includes," "has," "contains," and their grammatical equivalents should generally be understood as open-ended and non-limiting, e.g., not excluding other unlisted elements or steps.

[0029] As used herein, the articles "a" and "an" refer to one or more than one (ie, to at least one) of the grammatical object to which the article refers. For example, "an element" means one element or more than one element.

[0030] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not.

[0031] "Administer," "give," and "treat" as applied to an animal, a human, a laboratory subject, a cell, a tissue, an organ, or a biological fluid, refers to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, a human, a subject, a cell, a tissue, an organ, or a biological fluid. "Administer," "give," and "treat" can refer to, for example, therapeutic, pharmacokinetics, diagnostics, research, and experimental procedures. Treatment of cells includes contact of an agent with a cell, and contact of an agent with a fluid, wherein the fluid is in contact with the cell. "Administer," "give," and "treat" also mean the in vitro and ex vivo treatment of, for example, a cell, by an agent, a diagnostic, a binding composition, or by another cell. "Treatment," as applied to a human, veterinary, or research subject, refers to therapeutic treatment, prophylactic or preventative measures, research, and diagnostic applications.

[0032] The term "consisting essentially of" or variations thereof as used throughout the specification and claims means that all recited elements or groups of elements are included, and optionally other elements of similar or different properties from the recited elements, which do not significantly alter the basic or novel properties of a specified dosage regimen, method, or composition.

[0033] As used herein, the term "prevent, improve, alleviate or treat" refers to the medical management of a patient for the purpose of curing, improving, stabilizing or preventing a disease, pathological state or condition. The term includes active therapy, i.e., treatment specifically for the purpose of improving a disease, pathological state or condition, and also includes etiological treatment, i.e., treatment for the purpose of removing the cause of the relevant disease, pathological state or condition. In addition, the term also includes palliative treatment, i.e., treatment designed to relieve symptoms rather than cure a disease, pathological state or condition; the term also includes preventive treatment, i.e., treatment for the purpose of minimizing or partially or completely inhibiting the development of the relevant disease, pathological state or condition; and supportive treatment, i.e., treatment that supplements another specific therapy for the purpose of improving the relevant disease, pathological state or condition. In a specific embodiment of the present invention, the "prevent, improve, alleviate or treat" refers to reducing the severity of the symptoms of an eye condition that adversely affects visual acuity. Specifically, the ophthalmic preparations or ophthalmic compositions described herein can be used to improve or treat the symptoms of myopia or hyperopia, and the patient can visually focus on objects at close range and objects at a distance by using the preparation.

[0034] As used herein, the term "subject" is used to describe an animal, human or non-human, to whom an ophthalmic formulation or ophthalmic composition or method according to the present invention is provided. Human and veterinary applications are contemplated by the present disclosure. The term includes, but is not limited to, birds, reptiles, amphibians, and mammals, such as humans, other primates, pigs, rodents, such as mice and rats, rabbits, guinea pigs, hamsters, horses, cows, cats, dogs, sheep, chickens, and goats. In some embodiments, the subject is a human, chicken, or mouse. In preferred embodiments, the subject is a human. Both pediatric and adult subjects are included. For example, a subject described herein can be an adult subject (e.g., 18 years or older, 21 years or older, 25 years or older, 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, 60 years or older, 65 years or older, 70 years or older, 75 years or older, 80 years or older, 85 years or older, 90 years or older, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 18, 20, 21, 24, 25, 27, 28, 30, 33, 35, 37, 39, 40, 42, 44, 45, 48, 50, 52, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104 or more years).

[0035] As used herein, the term "effective amount" refers to an amount sufficient to achieve the desired therapeutic and / or preventive effect, such as an amount that causes the prevention or alleviation of symptoms associated with an ophthalmic condition. The amount of the composition administered to the subject will depend on the type and severity of the disease and the characteristics of the individual, such as general health, age, sex, weight, ethnicity, degree of myopia, rate of myopia progression, and tolerance to medication. The amount also depends on the degree, severity, and type of the disease, as well as the treatment regimen formulated by a professional (e.g., a physician). A professional technician will be able to determine the appropriate dosage based on these and other factors. The ophthalmic composition may also be administered in combination with one or more other therapeutic compounds, biopharmaceuticals, and therapeutic molecules (e.g., polypeptides). In the methods described herein, α-adrenergic receptor agonists and M-cholinergic receptor agonists or ophthalmic compositions containing the same can be administered to a subject having one or more symptoms or signs of an ophthalmic condition. For example, a "therapeutically effective amount" refers to an average level of the physiological effects that minimize the alleviation of the ophthalmic condition, preferably an average level of the physiological effects that minimize the progression of myopia.

[0036] As used herein, the terms "formulation," "ophthalmic composition," and "composition" are used interchangeably and may refer to a mixture of two or more compounds, elements, or molecules. In some aspects, the terms "formulation," "ophthalmic composition," and "composition" may be used to refer to a mixture of one or more active agents (active ingredients) with a carrier or other excipient. A composition can take virtually any physical form, including solid, liquid (e.g., solution), or gas.

[0037] As used herein, the term "pharmaceutically acceptable" means approved by regulatory authorities such as CFDA (China), EMEA (Europe) and / or FDA (US) and / or any other national regulatory authorities for use in animals, preferably humans.

[0038] As used herein, "myopia" refers to the convergence of parallel light rays through the eye's refractive system in front of the retina when accommodation is relaxed. Refractive myopia is categorized into refractive and axial myopia, both clinically manifesting as blurred vision at distance and good near vision. Early stages of myopia often include fluctuations in distance vision. Because accommodation is infrequent or infrequently used for near vision, convergence function is weakened, potentially leading to exophoria or exotropia. Myopia-related symptoms also include poor night vision, floaters, photopsia, etc., and fundus changes of varying degrees may occur, myopic arc plates, macular hemorrhage or subretinal neovascular tumors may form, irregularly shaped white atrophic spots, or circular black spots with pigmentation (Fuchs spots), lattice degeneration and cystic degeneration of the retina, vitreous liquefaction, turbidity and posterior vitreous detachment at a young age, the risk of retinal holes and detachment is higher than that of normal people, often due to the long anteroposterior diameter of the eyeball, the protruding eyeball, and the extreme expansion of the posterior eyeball, forming scleral staphyloma. People with the above clinical symptoms are called pathological myopia.

[0039] As used herein, "hyperopia" refers to a refractive condition in which a parallel beam of light is refracted by the relaxed eyeball and forms an image behind the retina. Hyperopia occurs when the eyeball has insufficient refractive power or its axial length is insufficient. The optical focus is behind the retina, resulting in a blurred image.

[0040] As used in this article, the eye irritation reaction score standard refers to the "Technical Guidelines for Drug Irritation, Allergy and Hemolysis Studies", which can be found in Table 1.

[0041] Table 1. Eye irritation response score standard

[0042] As used herein, the eye irritation evaluation criteria are shown in Table 2.

[0043] Table 2. Eye irritation evaluation criteria

[0044] II. Detailed description of specific implementation plan

[0045] In one aspect, the present disclosure provides an ophthalmic composition comprising an α-adrenergic receptor agonist and a M cholinergic receptor agonist.

[0046] In some embodiments, the ophthalmic composition further comprises a pH adjuster, an osmotic pressure adjuster, and water.

[0047] In some embodiments, the ophthalmic composition does not contain other auxiliary materials such as preservatives, buffers, complexing agents and excipients.

[0048] In some embodiments, the α-adrenergic receptor agonist is selected from at least one of norepinephrine, metaraminol, phenylephrine, methoxamine, oxymetazoline, naphazoline, xylometazoline, apraclonidine, dexmedetomidine, brimonidine, dopamine, ephedrine, pseudoephedrine, mephentermine, or derivatives of the foregoing compounds.

[0049] In some embodiments, the α-adrenergic receptor agonist is selected from at least one of oxymetazoline, naphazoline, xylometazoline, dexmedetomidine, brimonidine, or derivatives of the foregoing compounds.

[0050] In some embodiments, the α-adrenergic receptor agonist is selected from at least one of oxymetazoline, naphazoline, brimonidine, or derivatives of the foregoing compounds.

[0051] In some embodiments, the alpha-adrenergic receptor agonist is brimonidine or a derivative thereof.

[0052] In some embodiments, the alpha-adrenergic receptor agonist is brimonidine tartrate.

[0053] In some embodiments, the M cholinergic receptor agonist is at least one selected from acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, aceclidine, cevimeline, xanomeline, and sabcomeline.

[0054] In some embodiments, the M cholinergic receptor agonist is selected from at least one of carbachol, pilocarpine, aceclidine, cevimeline, or xanomeline.

[0055] In some embodiments, the M cholinergic receptor agonist is selected from at least one of pilocarpine, aceclidine, or cevimeline.

[0056] In some embodiments, the M cholinergic receptor agonist is cevimeline.

[0057] In some embodiments, the pH adjuster is selected from one or more of hydrochloric acid, boric acid, phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium bicarbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide.

[0058] In some embodiments, the pH adjuster is selected from one or more of hydrochloric acid, boric acid, citric acid, sodium hydroxide, and potassium hydroxide.

[0059] In some embodiments, the pH adjuster is selected from hydrochloric acid and / or sodium hydroxide.

[0060] In some embodiments, the α-adrenergic receptor agonist in the composition is brimonidine tartrate, and the mass ratio of the brimonidine tartrate is 0.001%-0.5% (w / w); in some embodiments, the α-adrenergic receptor agonist in the composition is brimonidine tartrate, and the mass ratio of the brimonidine tartrate is 0.001%-0.4% (w / w), for example, it can be 0.001%-0.01% (w / w), 0.01%-0.05% (w / w), 0.05%-0.2% (w / w), 0.2%-0.3% (w / w) or 0.3%- 0.4% (w / w); in some embodiments, the α-adrenergic receptor agonist in the composition is brimonidine tartrate, and the mass ratio of the brimonidine tartrate is 0.05%-0.4% (w / w); in some preferred embodiments, the α-adrenergic receptor agonist in the composition is brimonidine tartrate, and the mass ratio of the brimonidine tartrate is 0.1%-0.3% (w / w); in some preferred embodiments, the α-adrenergic receptor agonist in the composition is brimonidine tartrate, and the mass ratio of the brimonidine tartrate is 0.1%-0.2% (w / w).

[0061] In some embodiments, the M cholinergic receptor agonist in the composition is cevimeline, and the mass ratio of the M cholinergic receptor agonist is 0.1%-10% (w / w), for example, it can be 0.1%-0.5% (w / w), 0.5%-1% (w / w), 1%-2% (w / w), 2%-4% (w / w), 4%-8% (w / w) or 8%-10% (w / w); in some preferred embodiments, the M cholinergic receptor agonist in the composition is cevimeline, and the mass ratio of the M cholinergic receptor agonist is 1%-4.5% (w / w); in some preferred embodiments, the M cholinergic receptor agonist in the composition is cevimeline, and the mass ratio of the M cholinergic receptor agonist is 1.25%-4.5% (w / w); in some preferred embodiments, the M cholinergic receptor agonist in the composition is cevimeline, and the mass ratio of the M cholinergic receptor agonist is 1.25%-4% (w / w).

[0062] In some embodiments, the pH regulator in the composition is hydrochloric acid and / or sodium hydroxide, and the mass ratio of the hydrochloric acid and / or sodium hydroxide is 0.001%-0.5% (w / w), for example, 0.001%-0.002% (w / w), 0.002%-0.001% (w / w), 0.001%-0.1% (w / w), 0.1%-0.2% (w / w), 0.2%-0.4% (w / w) or 0.2%-0.5% (w / w); in some preferred embodiments, the combination In some preferred embodiments, the pH regulator in the composition is hydrochloric acid and / or sodium hydroxide, and the mass ratio of the hydrochloric acid and / or sodium hydroxide is 0.001%-0.2% (w / w); in some preferred embodiments, the pH regulator in the composition is hydrochloric acid and / or sodium hydroxide, and the mass ratio of the hydrochloric acid and / or sodium hydroxide is 0.001%-0.1% (w / w); in some preferred embodiments, the pH regulator in the composition is hydrochloric acid and / or sodium hydroxide, and the mass ratio of the hydrochloric acid and / or sodium hydroxide is 0.002%-0.05% (w / w).

[0063] In some embodiments, the osmotic pressure regulator in the composition is sodium chloride, and the mass ratio of the sodium chloride is 0-0.9% (w / w), for example, it can be: 0%-0.001% (w / w), 0.001%-0.01% (w / w), 0.01%-0.1% (w / w), 0.1%-0.3% (w / w), 0.3%-0.5% (w / w) or 0.5%-0.9% (w / w); in some preferred embodiments, the mass ratio of the osmotic pressure regulator in the composition is 0%-0.8% (w / w); in some preferred embodiments, the mass ratio of the osmotic pressure regulator in the composition is 0%-0.7% (w / w); in some preferred embodiments, the mass ratio of the osmotic pressure regulator in the composition is 0%-0.6% (w / w).

[0064] In another aspect, the present disclosure provides a method for preparing the aforementioned ophthalmic composition, comprising the following steps:

[0065] 1. Dissolution of the main drug

[0066] (1) Dissolution of α-adrenergic receptor agonist: Add the prescribed amount of α-adrenergic receptor agonist to the water for injection while stirring, stir until completely dissolved, and set aside;

[0067] (2) Dissolution of the M cholinergic receptor agonist: Add the prescribed amount of the M cholinergic receptor agonist to the water for injection while stirring, stir until completely dissolved, and set aside;

[0068] 2. Preparation

[0069] Add water for injection to the mixing tank, add the prescribed amount of sodium chloride to the mixing tank and stir to dissolve, add the prescribed amount of α-adrenergic receptor agonist solution and the prescribed amount of M cholinergic receptor agonist solution respectively, and stir to mix;

[0070] 3. Adjust pH

[0071] Before adjusting the pH, measure the pH value first, then add 0.5 mol / L NaOH solution or 0.1 mol / L HCl solution to adjust the pH value to the internal control standard of 6.0-7.0, and the pH of the solution is preferably 6.6;

[0072] 4. Set the volume

[0073] Use water for injection to make up to the prescribed amount;

[0074] 5. Filter

[0075] The ophthalmic composition preparation was obtained by filtration through a microporous filter membrane (one 0.45 μm hydrophilic PES filter membrane and two 0.22 μm hydrophilic PES filter membranes) for sterilization.

[0076] In some embodiments, the ophthalmic composition can be prepared into any dosage form of ophthalmic preparations, including eye drops, eye gels, eye ointments, eye patches, eye masks, eye washes, or intraocular injections.

[0077] In some embodiments, when the ophthalmic composition is in the form of eye drops, the preparation method is as follows: the α-adrenergic receptor agonist and a small amount of water for injection are mixed and stirred to dissolve for later use; the M cholinergic receptor agonist and a small amount of water for injection are mixed and stirred to dissolve for later use. An appropriate amount of water for injection is added to the liquid preparation tank, the osmotic pressure regulator is added to the liquid preparation tank in the required amount and stirred to dissolve, and then the α-adrenergic receptor agonist solution and the M cholinergic receptor agonist solution are added to the liquid preparation tank. After mixing, samples are taken to detect the pH value of the liquid. According to the pH value of the liquid, the pH regulator is continuously added to adjust the internal control standard of the liquid pH; then, the volume is made up to the prescribed amount with water for injection, and stirred, and then sterilized by filtration through a microporous filter membrane to obtain the α-adrenergic receptor agonist eye drops.

[0078] In some embodiments, the preparation method further comprises filtering and sterilizing through a microporous membrane, and aseptically filling the finished product by blow / fill / seal under the sterile protection of a Class A air shower.

[0079] In another aspect, the present disclosure provides a use of an α-adrenergic receptor agonist and an M cholinergic receptor agonist in combination for preparing a medicament for preventing, improving, alleviating or treating eye diseases.

[0080] In another aspect, the present disclosure provides a use of the aforementioned ophthalmic composition in the preparation of a medicament for preventing, improving, alleviating or treating eye diseases.

[0081] In some embodiments, the ophthalmic composition further comprises a pharmaceutically acceptable carrier and / or excipient. These substances are used to help stabilize the formulation, improve its activity or bioavailability, or efficiently deliver the drug to the posterior segment of the eye in the case of an eye drop experiment. The formulation that can be used in such an ophthalmic composition can be in the form of the original compound itself, or optionally in the form of a pharmaceutically acceptable salt thereof. The ophthalmic composition thus formulated can be administered by any appropriate method known to those skilled in the art, as needed.

[0082] In some embodiments, the suitable dosage of the ophthalmic composition can be prescribed in a variety of ways depending on factors such as the formulation method, administration method, patient age, weight, sex, morbidity, diet, administration time, administration route, excretion rate and reaction sensitivity. A skilled physician can usually easily determine the prescription and the dosage that is effective for the desired treatment or prevention. The therapeutically effective amount and specific treatment regimen for a subject (e.g., mammal: human) can be affected by many factors, including the pharmacodynamic activity of the drug used, the age, weight, general condition, sex, diet, administration time, disease susceptibility, disease progression and the judgment of the treating physician. In addition, it is clear to those skilled in the art that the administration method, dosage form and dosage of the drug are affected by many factors such as the patient's age, weight, sex, morbidity, diet, administration time, excretion rate and reaction sensitivity. Therefore, the administration method, dosage form and dosage of the ophthalmic preparation or ophthalmic composition described in the present invention are not limited to the administration method, dosage form and dosage described in the embodiments of the present invention.

[0083] In some embodiments, the eye diseases include conjunctival congestion caused by environmental irritation, infection, or inflammation; visual fatigue caused by prolonged close-up use; presbyopia, ocular hypertension, dry eye, myopia, hyperopia, strabismus, astigmatism, photophobia, or glaucoma. Environmental irritants include irritating smog, sandstorms, ultraviolet radiation, and long-term topical medication use. Visual fatigue can include dry eyes, soreness, swelling, and pain, blurred vision, and even symptoms such as decreased vision and dizziness.

[0084] In another aspect, the present disclosure provides a method for preventing, improving, alleviating or treating an eye disease, comprising administering an effective amount of the aforementioned ophthalmic drug to an affected eye of a subject.

[0085] In some embodiments, the subject refers to any animal, including humans and non-human animals. Non-human animals include all vertebrates, for example, mammals, such as non-human primates (particularly higher primates), sheep, dogs, rodents (e.g., mice or rats), guinea pigs, goats, pigs, cats, rabbits, cows, and any livestock or pets; as well as non-mammals, such as chickens, amphibians, reptiles, etc. In a specific embodiment of the present invention, the subject is preferably a human.

[0086] In some embodiments, the ophthalmic preparation provided by the present disclosure is applied to one or both eyes of a patient showing symptoms of an eye disease to improve the symptoms of the eye disease. In some embodiments, independent of other treatment methods, the application of the ophthalmic preparation provided by the present invention can fully improve the patient's near visual acuity. For example, administering the ophthalmic preparation provided by the present invention can enable the patient to focus on objects at a distance around the normal reading distance without using corrective lenses or corrective eye surgery. For patients in the early stages of presbyopia, administering the ophthalmic preparation provided by the present invention can alleviate presbyopia-related symptoms, including making near visual acuity possible without using corrective lenses or glasses. In some embodiments, independent of other treatment methods, the application of the ophthalmic preparation provided by the present invention can fully improve the patient's distance visual acuity. For example, administering the ophthalmic preparation provided by the present invention can enable the patient to focus on objects at a distance around the normal reading distance without using corrective lenses or corrective eye surgery. For patients in the early stages of myopia, administering the ophthalmic preparation provided by the present invention can alleviate myopia-related symptoms, including making distance visual acuity possible without using corrective lenses or glasses.

[0087] In some embodiments, ophthalmic compositions provided herein are administered to a patient to improve the patient's ability to focus on near and distant objects after the patient has undergone corrective surgery to treat an eye condition (e.g., including corrective eye surgery to treat cataracts).

[0088] In one aspect, the present disclosure provides the aforementioned composition, which is used to treat a patient's hyperopia while also alleviating the patient's myopia symptoms.

[0089] In some embodiments, alleviating the patient's myopia symptoms is improving the patient's distance vision.

[0090] In one aspect, the present disclosure provides a method for preventing, improving, alleviating or treating an eye disease, comprising administering an effective amount of an α-adrenergic receptor agonist and an M cholinergic receptor agonist, or the aforementioned ophthalmic composition to a subject in need thereof.

[0091] In some embodiments, the eye disease is selected from one or more of conjunctival congestion, asthenopia, presbyopia, ocular hypertension, dry eye, myopia, hyperopia, strabismus, astigmatism, photophobia, or glaucoma.

[0092] In one aspect, the present disclosure provides an ophthalmic composition comprising a combination of an α-adrenergic receptor agonist and an M cholinergic receptor agonist or the foregoing, for use in preventing, improving, alleviating or treating eye diseases;

[0093] In some embodiments, the eye disease is selected from one or more of conjunctival congestion, asthenopia, presbyopia, ocular hypertension, dry eye, myopia, hyperopia, strabismus, astigmatism, photophobia, or glaucoma.

[0094] Example

[0095] A further understanding of the present disclosure may be obtained by reference to some of the specific examples provided herein, which are intended to illustrate the present disclosure only and are not intended to limit the scope of the present disclosure in any way. Obviously, various modifications and variations may be made to the present disclosure without departing from the essence of the present disclosure, and therefore, such modifications and variations are also within the scope of protection claimed in this application.

[0096] Example 1. Preparation method of ophthalmic composition preparation

[0097] 1. Dissolution of the main drug

[0098] (1) Dissolution of α-adrenergic receptor agonist: Add the prescribed amount of α-adrenergic receptor agonist to the water for injection while stirring, stir until completely dissolved, and set aside;

[0099] (2) Dissolution of the M cholinergic receptor agonist: Add the prescribed amount of the M cholinergic receptor agonist to the water for injection while stirring, stir until completely dissolved, and set aside;

[0100] 2. Preparation

[0101] Add water for injection to the mixing tank, add the prescribed amount of sodium chloride to the mixing tank and stir to dissolve, add the prescribed amount of α-adrenergic receptor agonist solution and the prescribed amount of M cholinergic receptor agonist solution respectively, and stir to mix;

[0102] 3. Adjust pH

[0103] Before adjusting the pH, measure the pH value first, then add 0.5 mol / L NaOH solution or 0.1 mol / L HCl solution to adjust the pH value to the internal control standard of 6.0-7.0, and the pH of the solution is preferably 6.6;

[0104] 4. Set the volume

[0105] Use water for injection to make up to the prescribed amount;

[0106] 5. Filter

[0107] The ophthalmic composition was sterilized by filtration through a microporous filter membrane (one 0.45 μm hydrophilic PES filter and two 0.22 μm hydrophilic PES filters). The concentrations of the components in the prepared formulations are shown in Table 3.

[0108] Table 3. Component concentrations of various formulations *Note: All ophthalmic preparations given to the subjects were prepared and used immediately.

[0109] Formulations 1-11 were observed to form stable, homogeneous solutions. The finished product of Formulation 11 is shown in Figure 1. The properties of the other formulations were similar to those of Formulation 11, all being clear, transparent solutions. Formulations 4, 5, 6, and 11 showed no significant changes in pH, osmolarity, purity, or content after being stored at 40°C for one month. The stability results are shown in Table 4.

[0110] Table 4. Stability results of formulations 4, 5, 6, and 11

[0111] Example 2. Eye irritation test of different formulations

[0112] Subject Information: The subjects were a male, approximately 60 years old, with mild presbyopia, and a female, approximately 45 years old, with myopia. Both subjects were in good health, able to comply with all requirements during the trial, undergo all examinations as specified in the trial protocol, and report subjective symptoms. The subjects volunteered to participate in the trial after understanding the purpose of the trial, the nature of the investigational drug, the potential risks of the trial, and their own rights. When different formulations were administered to the same subject, at least two days elapsed between the first and second formulations.

[0113] Take one drop of each of the single-prescription formulations 7-11 and drip it into the subject's inferior conjunctival fornix. Remind the subject to slightly lift the lower eyelid outward, close the eye, and then press the inner canthus while rotating the eyeball. Keep doing this for one minute, and record the eye irritation before and 5 minutes after administration. Calculate the score according to the "Technical Guidelines for Drug Irritation, Allergy, and Hemolytic Studies" (i.e., Table 1), and determine the degree of irritation according to Table 2. Specific test results are shown in Table 5. The eye conditions of the subjects after the corresponding experiments with some formulations are shown in Figure 2. There was no eye irritation in the subjects after the experiment with formulation 8. The eye conditions of the subjects can refer to the experimental photos of formulation 7.

[0114] Table 5. Eye irritation scores of single prescription preparations

[0115] From the experimental results in Table 5 and Figure 2, it can be seen that before and after the use of single-prescription formulation 7 (0.002% naphazoline eye drops), formulation 8 (0.025% oxymetazoline hydrochloride eye drops), and formulation 9 (0.2% brimonidine tartrate eye drops), there was no obvious increase or decrease in conjunctival congestion in the eyes of the subjects. According to actual observations and the subjects' descriptions, there was basically no irritation or discomfort during the entire process. After the subjects used single-prescription formulation 10 (1.25% pilocarpine nitrate eye drops) and formulation 11 (2.25% cevimeline eye drops), the eyes showed slight conjunctival congestion, among which the symptoms of formulation 11 were milder than those of formulation 10. Continuing to observe, the subjects' eye symptoms were basically able to return to normal after 10 minutes, and there was basically no irritation or discomfort during the entire process. Separately, one drop of each of the compound preparations, Formulas 1-5, was instilled into the subject's inferior conjunctival fornix. The subject was then instructed to slightly lift the lower eyelid outward, close the eye, and then press the inner canthus while rotating the eyeball. This was maintained for one minute. The eye irritation was recorded before and 5 minutes after administration. The score was calculated according to Table 1, and the degree of irritation was determined according to Table 2. Specific test results are shown in Table 6. The eye conditions of the subjects after the corresponding experiments with some of the formulas are shown in Figure 3. The subject's eye showed no irritation after the experiment with Formula 4. The subject's eye condition can be referred to the experimental photos of Formula 3.

[0116] Table 6. Eye irritation score of compound preparations

[0117] From the experimental results in Table 6 and Figure 3, it can be seen that the subjects had mild conjunctival congestion symptoms before using the compound ophthalmic preparation formula 1 (compound eye drops of 0.002% naphazoline and 2.25% cevimeline). After using the compound ophthalmic preparation formula 1, the conjunctival congestion symptoms disappeared quickly; after using the preparation formula 2 (compound eye drops of 0.025% oxymetazoline hydrochloride and 1.25% pilocarpine nitrate), preparation formula 3 (compound eye drops of 0.1% brimonidine tartrate and 2% cevimeline), preparation formula 4 (compound eye drops of 0.1% brimonidine tartrate and 4% cevimeline), preparation formula 5 (compound eye drops of 0.15% brimonidine tartrate and 4% cevimeline) and preparation formula 6 (compound eye drops of 0.2% brimonidine tartrate and 4% cevimeline), the subjects' eyes did not experience conjunctival congestion symptoms. Before using Formulation 3, some subjects experienced scattered or diffuse corneal opacities, but after using Formulation 3, the corneas became clear. Based on actual observations and subject descriptions, the combination formulation provided superior comfort compared to the single-formulation formulations. Throughout the entire process, there was no irritation, itching, redness, swelling, dryness, or other discomfort, such as increased eye discharge. The combination formulation improved eye comfort, alleviated eye fatigue, and enhanced visual clarity.

[0118] Example 3. Effects of different formulations on myopia patients

[0119] Information on the subjects for formulations 4, 9, and 11: The subject was a female, approximately 45 years old, myopic, in good health, able to comply with all requirements during the trial, undergo all examinations as specified in the trial protocol, and report subjective symptoms. The subject understood the purpose of the trial, the properties of the investigational drug, the potential risks of the trial, and her rights and interests, and voluntarily participated in the trial. When the same subject was tested on different formulations, at least two days elapsed between the first and second formulations.

[0120] One drop of each of Formulations 4, 9, and 11 was instilled into the subject's inferior conjunctival fornix. The subject was then instructed to slightly lift the lower eyelid outward, close the eye, and apply pressure to the inner canthus while rotating the eyeball. This was performed for one minute. Ocular irritation was observed before and after administration, and near vision was recorded before and 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 5 hours, 7 hours, and 8 hours after administration. Near vision was assessed using a national standard near vision chart, conducted at a distance of 30 cm in ample light, with an optimal visual acuity of 0.8. During the test, the examiner pointed to the chart's sight mark with a rod. While tightly covering one eye, the subject was instructed to indicate the direction of the sight mark's notch by name or gesture. The test was performed row by row, identifying the row that best discerned the sight mark. This tested the visual acuity of each eye. The results are shown in Figure 4.

[0121] As shown in Figure 4, the use of single prescription formulation 9 (0.2% brimonidine tartrate eye drops) did not improve the subjects' near vision ability. After using single prescription formulation 11 (2.25% cevimeline eye drops) and compound formulation 4 (0.1% brimonidine tartrate and 4% cevimeline compound eye drops), the subjects experienced no irritation, itching, redness, swelling, dryness, increased eye secretions, or other discomfort during the test. In addition, eye fatigue was eliminated, visual clarity was improved, and near vision was improved by 0.3 in a short period of time. After that, near vision was maintained until the end of the observation (8 hours). Compound formulation 4 improved near vision by 0.3 within 15 minutes, which was better than single prescription formulation 11. From this result analysis, it can be concluded that the combination of brimonidine tartrate and cevimeline synergistically increased the efficacy of the drug and prolonged its duration of action.

[0122] Example 4. Effect of Formulation 6 on Myopia and Hyperopia in Patients

[0123] Subject Information: The subject was a male, approximately 60 years of age, with both presbyopia and myopia. He was in good health, able to comply with all requirements during the trial, undergo all examinations as specified in the trial protocol, and report subjective symptoms. The subject volunteered to participate in the trial after understanding the purpose of the trial, the properties of the trial drug, the potential risks of the trial, and his or her rights. Prior to using Compound Preparation Formula 6, the subject experienced eye fatigue and mild conjunctival hyperemia.

[0124] Take the solution of formulation 6, drop one drop in the lower conjunctival fornix of the subject, remind the subject to slightly lift the lower eyelid outward, close the eyes, then press the inner canthus, and at the same time, rotate the eyeball, keep it for one minute, observe the eye irritation before and after administration, and record the near and far vision conditions before and after administration 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 5 hours, 7 hours, 8 hours, 10 hours. The method for measuring myopia is the same as in Example 3. The method for testing hyperopia is tested by using the national standard logarithmic visual acuity test chart, with a distance of 5m as the standard, and tested in the case of sufficient light. The best visual acuity is 1.0. During the test, the tester uses a benchmark for testing vision to point to the sight mark of the vision chart, and requires the subject to say or use gestures to indicate the direction of the notch of the sight mark under the premise of strictly covering one of the left and right eyes, and detect line by line to find the best recognition line for the testee, thereby testing the specific vision of the left and right eyes respectively. The test results are shown in Figure 5.

[0125] As shown in Figure 5 and the actual observation results, after using Compound Preparation Formula 6 (0.2% brimonidine tartrate and 4% cevimeline compound eye drops), the subjects were able to quickly eliminate conjunctival congestion symptoms. The entire process was free of irritation, itching, redness, swelling, dryness, increased eye discharge, and other discomforts. It also eliminated eye fatigue and improved visual clarity. The subjects' short-term (10 minutes) near vision improved by 0.1 (on a 1.0 scale), and 15 minutes of near vision improved by 0.3, and then continued to maintain near vision until the end of observation (10 hours). Distance vision also improved, with a 20-minute distance vision improvement of 0.2, and then continued to maintain distance vision until the end of observation (10 hours).

[0126] In summary, the compound eye drops of brimonidine tartrate and cevimeline can improve not only near vision but also distance vision. Furthermore, it can be shown that the ophthalmic composition of the present invention can improve the clarity of vision for patients with refractive error, has a long duration of action, and is safe.

[0127] Comparative Example 1

[0128] Subject Information: The subjects were a male, approximately 60 years old, with both presbyopia and myopia, and a female, approximately 45 years old, with myopia. They were in good health, able to comply with all requirements during the trial, undergo all examinations as specified in the trial protocol, and report subjective symptoms. The subjects understood the purpose of the trial, the nature of the investigational drug, the potential risks of the trial, and their own rights and interests and voluntarily participated in the trial. When the same subject received different formulations, at least two days elapsed between the first and second formulations.

[0129] Distance vision is primarily assessed using a national standard logarithmic visual acuity chart, with the test performed in well-lit conditions at a distance of 5 meters. The optimal visual acuity is 1.0. During the test, the examiner points to the chart's sight mark with a sight mark marker. The examinee is instructed to indicate the direction of the notch in the sight mark, while tightly covering one eye. The test is conducted line by line to identify the line that best identifies the examinee, thereby testing the specific vision of each eye.

[0130] In order to further verify the synergistic effect of the combination preparation of brimonidine tartrate and cevimeline, the applicant further prepared a formula 12 ophthalmic composition containing 0.05wt% atropine + 2.25wt% cevimeline, and a formula 13 ophthalmic composition containing 0.15wt% brimonidine tartrate + 2.25wt% cevimeline. The specific preparation process can be referred to Example 1.

[0131] One drop of each of the ophthalmic preparations of Formulation 12 and Formulation 13 was instilled into the inferior conjunctival fornix of the subject. The lower eyelid was then slightly lifted outward, the eye was closed, and the inner canthus was pressed while the eyeball was rotated. This was maintained for 1 minute. The distance vision was recorded before administration and 5 minutes, 10 minutes, 15 minutes, and 20 minutes after administration. The results are shown in Table 7 below.

[0132] Table 7. Distance vision test results

[0133] As shown in Table 7, both formulations 12 and 13 can improve distance vision. The ophthalmic composition of formulation 13 improved distance vision by 0.3 at 20 minutes, while the ophthalmic composition of formulation 12, which contains atropine, only improved distance vision by 0.1 at this time. These results indicate that the combination of brimonidine tartrate and cevimeline can improve distance vision with a rapid onset of action, resulting in a significant improvement in distance vision. The compound eye drops of atropine and cevimeline have a slightly slower onset of action than cevimeline eye drops of the same concentration, resulting in a lesser improvement in distance vision.

[0134] In summary, the synergistic effect of the ophthalmic composition of brimonidine tartrate and cevimeline was further verified.

[0135] The above description is only an embodiment of the present invention and does not limit the present invention in any form or substance. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention. Any equivalent changes, modifications and evolutions made by technicians familiar with this profession without departing from the spirit and scope of the present invention by using the technical content disclosed above are all equivalent embodiments of the present invention; at the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. An ophthalmic composition comprising an α-adrenergic receptor agonist and an M cholinergic receptor agonist.

2. The ophthalmic composition according to claim 1, characterized in that The ophthalmic composition further comprises a pH adjuster, an osmotic pressure adjuster and water.

3. The ophthalmic composition according to claim 1, characterized in that The α-adrenaline receptor agonist is selected from at least one of norepinephrine, metaraminol, phenylephrine, methoxamine, oxymetazoline, naphazoline, xylometazoline, apraclonidine, dexmedetomidine, brimonidine, dopamine, ephedrine, pseudoephedrine, mephentermine or derivatives of the aforementioned compounds; Preferably, the α-adrenaline receptor agonist is brimonidine; Preferably, the α-adrenaline receptor agonist is brimonidine tartrate.

4. The ophthalmic composition according to claim 1, characterized in that The M cholinergic receptor agonist is at least one selected from acetylcholine, methacholine, carbachol, bethanechol chloride, pilocarpine, aceclidine, cevimeline, xanomeline, and sabcomeline; Preferably, the M cholinergic receptor agonist is cevimeline.

5. The ophthalmic composition according to claim 2, characterized in that The pH regulator is selected from one or more of hydrochloric acid, boric acid, phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium bicarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide; Preferably, the pH adjuster is hydrochloric acid and / or sodium hydroxide.

6. The ophthalmic composition according to any one of claims 1 to 5, characterized in that The α-adrenergic receptor agonist is brimonidine tartrate, and the mass ratio of the brimonidine tartrate is 0.001%-0.5% (w / w), preferably 0.001%-0.4% (w / w), more preferably 0.1%-0.3% (w / w), and more preferably 0.1%-0.2% (w / w).

7. The ophthalmic composition according to any one of claims 1 to 6, characterized in that The M cholinergic receptor agonist is cevimeline, and the mass ratio of the M cholinergic receptor agonist is 0.1%-10% (w / w), more preferably 1%-4.5% (w / w), more preferably 1.25%-4.5% (w / w), and more preferably 1.25%-4% (w / w).

8. The ophthalmic composition according to any one of claims 1 to 7, characterized in that The pH adjuster is hydrochloric acid and / or sodium hydroxide, and the mass ratio of the hydrochloric acid and / or sodium hydroxide is 0.001%-0.5% (w / w), more preferably 0.001%-0.2% (w / w), more preferably 0.001%-0.1% (w / w), and more preferably 0.002%-0.05% (w / w).

9. The ophthalmic composition according to any one of claims 1 to 8, characterized in that The osmotic pressure regulator is sodium chloride, and the mass ratio of the sodium chloride is 0-0.9% (w / w), more preferably 0%-0.8% (w / w), more preferably 0%-0.7% (w / w), and more preferably 0%-0.6% (w / w).

10. Use of an α-adrenergic receptor agonist and an M cholinergic receptor agonist in combination in the preparation of a drug for preventing, improving, alleviating or treating eye diseases.

11. Use of the ophthalmic composition according to any one of claims 1 to 9 in the preparation of a medicament for preventing, improving, alleviating or treating eye diseases; Preferably, the drug further comprises a pharmaceutically acceptable carrier and / or excipient.

12. The use according to claim 10 or 11, wherein the eye disease is selected from one or more of conjunctival congestion, visual fatigue, presbyopia, ocular hypertension, dry eye, myopia, hyperopia, strabismus, astigmatism, photophobia or glaucoma.

13. The ophthalmic composition according to any one of claims 1 to 9, which is used to treat hyperopia in patients and relieve myopia symptoms in patients; Preferably, the relieving of the patient's myopia symptoms is to improve the patient's distance vision.

14. A method for preventing, improving, alleviating or treating an eye disease, comprising administering an effective amount of an α-adrenaline receptor agonist and an M cholinergic receptor agonist, or the ophthalmic composition according to any one of claims 1 to 9 to a subject in need thereof; Preferably, the eye disease is selected from one or more of conjunctival congestion, visual fatigue, presbyopia, ocular hypertension, dry eye, myopia, hyperopia, strabismus, astigmatism, photophobia or glaucoma.

15. An ophthalmic composition comprising a combination of an α-adrenergic receptor agonist and an M cholinergic receptor agonist or any one of claims 1 to 9, for preventing, improving, alleviating or treating ocular diseases; Preferably, the eye disease is selected from one or more of conjunctival congestion, visual fatigue, presbyopia, ocular hypertension, dry eye, myopia, hyperopia, strabismus, astigmatism, photophobia or glaucoma.

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