Alpha-adrenergic receptor stimulant ophthalmic composition and application thereof

Abstract

The invention relates to an alpha-adrenergic receptor agonist ophthalmic composition and application thereof. The composition comprises an alpha-adrenergic receptor agonist and an M choline receptor agonist. The ophthalmic composition provided by the invention can meet the requirements of different patients for improving short-distance vision and long-distance vision, and has a relatively long retention time up to 10 hours. In addition, the composition provided by the invention can quickly eliminate conjunctival congestion and asthenopia, and has a good curative effect on preventing and treating eye diseases such as presbyopia, ocular hypertension, xerophthalmia, myopia, hyperopia, strabismus, astigmatism, photophobia or glaucoma.

Description

Technical Field

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

[0002] With the development of modern science and technology, people are more dependent on electronic products. Whether children, adults or the elderly, their study and life are inseparable from electronic products. The harm of electronic products to the eyes is also becoming increasingly apparent, including red bloodshot eyes, eye fatigue, blurred vision, dry and itchy eyes, fear of sunlight and decreased vision. These hazards will have a certain degree of impact on personal study and life. In the long run, they will lead to impaired vision and affect the quality of life of individuals. In addition, as the age of myopic people increases, some patients have myopia in one eye and hyperopia in the other eye.

[0003] In order to prevent microbial contamination during repeated use after opening, more than 90% of the ophthalmic preparations currently on the market and under clinical development contain preservatives. They are packaged in multiple doses and can be reused multiple times. Preservatives, also known as antibacterial agents or preservatives, are chemical drugs that can 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, etc. Therefore, single-dose ophthalmic preparations without preservatives are a new direction in the development of ophthalmic drugs.

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

[0005] M cholinergic receptor agonists bind to cholinergic receptors and produce effects similar to those of acetylcholine. The representative drug is pilocarpine, also known as pilocarpine. As early as 1959, 0.5% to 2% pilocarpine eye drops were used to treat glaucoma. It was the first FDA-approved drug for the treatment of glaucoma, but it has significant side effects, such as eye stinging and burning, conjunctival congestion, superficial keratitis, retinal detachment, headaches caused by ciliary spasms, and long-term use may cause lens opacity, so new first-line treatment drugs continue to be developed. In recent years, there have been reports of 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, and its active ingredient is 1.25% pilocarpine (WO2019209955). Eyenovia Inc delivers relatively high concentrations of pilocarpine to the eyes through the "MicroLine" technology (WO2020180793), thereby achieving the purpose of treating presbyopia. Orasis Pharmaceuticals has developed a presbyopia drug containing a low concentration (0.4%) of pilocarpine and a proprietary carrier (WO2018033792). The above presbyopia drugs that have been marketed and are under clinical research use complex formulations to improve the stability of the drugs.

[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. Summary of the invention

[0007] In order to solve the problems existing in the prior art, the purpose of the present invention is to provide an ophthalmic preparation with simple formula, long-term use, good stability, high patient compliance, few side effects, easy use and multiple functions.

[0008] In order to achieve the above objectives, the present disclosure adopts the following specific scheme:

[0009] In one aspect, the present disclosure provides an ophthalmic composition comprising an α-adrenergic receptor agonist and an M cholinergic receptor agonist.

[0010] In another aspect, the present disclosure provides the 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 an eye disease.

[0011] 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.

[0012] The present disclosure has at least the following beneficial effects:

[0013] (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.

[0014] (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 the prevention and treatment of eye diseases such as presbyopia, ocular hypertension, dry eye, myopia, hyperopia, strabismus, astigmatism, photophobia or glaucoma.

[0015] (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 the excipients, having high safety, few side effects, and being suitable for long-term use.

[0016] (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 hyperopia treatment and myopia relief is significantly better than that of a single α-adrenergic receptor agonist and a single M cholinergic receptor agonist. The synergistic therapeutic effect of the combination on myopia relief is also better than that of the combined preparation of atropine and cevimeline. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 This is a picture of the finished product of formula 11.

[0018] Figure 2 The figure is a comparison of the eye irritation of single prescription formulations 7 and 9 and formulations 10-11 before and after administration.

[0019] Figure 3 This is a comparison chart of the eye irritation of compound preparation formulas 1-3 and 5 before and after administration.

[0020] Figure 4 The figure shows the effects of formulations 4, 9 and 11 on the near vision of the subjects.

[0021] Figure 5 The figure shows the effect of formulation 6 on the near vision and distance vision of the subjects. DETAILED DESCRIPTION

[0022] I. Terminology

[0023] 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.

[0024] As used herein and unless otherwise specified, 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.

[0025] In the description of this article, the term "and / or" is only a description of the association relationship of associated objects, indicating that there can be three relationships. For example, A and / or B can represent: A exists alone, A and B exist at the same time, and B exists alone. In addition, the character " / " in this article generally indicates that the associated objects before and after are in an "or" relationship.

[0026] In the description of this document, reference is made to “some embodiments”, “some implementation schemes” or “some implementation plans”, which describe a subset of all possible embodiments, but it can 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.

[0027] As used herein and unless otherwise specified, the terms "comprising", "including", "having", "containing", including grammatical equivalents thereof, should generally be understood as open and non-limiting, for example, not excluding other unlisted elements or steps.

[0028] As used herein, the articles "a" and "an" refer to one or more than one (ie, at least one) of the grammatical object to which the article refers. For example, "an element" means one element or more than one element.

[0029] "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 occur.

[0030] "Administering," "giving," and "treating" when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refers to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. "Administering," "giving," and "treating" can refer to, for example, treatment, pharmacokinetics, diagnosis, 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. "Administering," "giving," and "treating" also mean in vitro and ex vivo treatment of, for example, a cell, by an agent, a diagnosis, a combination composition, or by another cell. "Treatment," when applied to humans, veterinary medicine, or research subjects, refers to therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.

[0031] The term "consisting essentially of" or variations thereof as used throughout the specification and claims means including all recited elements or groups of elements, and optionally including other elements of similar or different properties to the recited elements, which other elements do not significantly alter the basic or novel properties of a specified dosing regimen, method, or composition.

[0032] As used herein, the term "prevent, improve, alleviate or treat" refers to the medical management of patients for the purpose of curing, improving, stabilizing or preventing diseases, pathological conditions or conditions. The term includes active therapy, i.e., treatment specifically for the purpose of improving diseases, pathological conditions or conditions, and also includes etiological treatment, i.e., treatment for the purpose of removing the cause of the relevant diseases, pathological conditions or conditions. In addition, the term also includes palliative treatment, i.e., treatment designed to relieve symptoms rather than cure diseases, pathological conditions or conditions; the term also includes preventive treatment, i.e., treatment for the purpose of minimizing or partially or completely inhibiting the development of relevant diseases, pathological conditions or conditions; and supportive treatment, i.e., treatment for supplementing another specific therapy for the purpose of improving relevant diseases, pathological conditions or conditions. In a specific embodiment of the present invention, the "prevent, improve, alleviate or treat" refers to reducing the severity of the symptoms of eye conditions that adversely affect visual acuity. Specifically, the ophthalmic preparations or ophthalmic compositions described herein can be used to improve or treat myopia or hyperopia symptoms, and patients can visually focus on objects at close distances and objects at long distances by using the preparations.

[0033] 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 for treatment. 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, cattle, cats, dogs, sheep, chickens, and goats. In some embodiments, the subject is a human, chicken, or mouse. In a preferred embodiment, 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).

[0034] As used herein, the term "effective amount" refers to an amount sufficient to obtain the desired therapeutic and / or preventive effect, such as an amount that causes prevention or alleviation of symptoms associated with ophthalmic disorders. The amount of the composition administered to the subject will depend on the type and severity of the disease and the nature of the individual, such as normal health, age, sex, weight, ethnicity, degree of myopia, rate of myopia progression, and tolerance to drugs. The amount also depends on the degree, severity, and type of the disease, as well as the treatment regimen formulated by a professional (such as a physician). Professional technicians will be able to determine the appropriate dosage based on these and other factors. The ophthalmic composition can also be administered in combination with one or more other therapeutic compound biopharmaceuticals and therapeutic molecules (such as polypeptides). In the methods described herein, α-adrenergic receptor agonists and M cholinergic receptor agonists or ophthalmic compositions containing them can be administered to subjects with one or more symptoms or signs of ophthalmic disorders. For example, a "therapeutically effective amount" refers to the average level of the physiological effects that minimize the reduction of ophthalmic disorders, preferably the average level of the physiological effects that minimize the progression of myopia.

[0035] 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 may take almost any physical form, including solid, liquid (e.g., solution), or gas.

[0036] As used herein, the term "pharmaceutically acceptable" means approved for use in animals, preferably humans, by regulatory authorities such as CFDA (China), EMEA (Europe) and / or FDA (US) and / or any other national regulatory authorities.

[0037] As used herein, "myopia" refers to the convergence of parallel light rays in front of the retina after passing through the eye's refractive system in a relaxed state of accommodation. According to the cause of refraction, it is divided into refractive myopia and axial myopia, and their clinical manifestations are blurred vision at a distance and good vision at a close distance. In the early stages of myopia, there is often fluctuation in long-distance vision. Since there is no or little accommodation when looking at close objects, the convergence function is correspondingly weakened, which can easily cause exotropia 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 formation of subretinal neovascularization, irregular shaped white atrophic spots, or circular black spots with pigmentation (Fuchs spots), lattice degeneration and cystic degeneration of the retina periphery, vitreous liquefaction, opacity and posterior vitreous detachment at a young age, and the risk of retinal holes and detachment is higher than that of normal people. It is often due to the long anterior-posterior diameter of the eyeball, the protruding eyeball, and the extreme expansion of the posterior part of the eyeball, forming a scleral staphyloma. People with the above clinical symptoms are called pathological myopia.

[0038] As used herein, "hyperopia" refers to a refractive state in which a parallel beam of light is refracted by the relaxed eyeball and imaged behind the retina. Hyperopia occurs when the refractive power of the eyeball is insufficient or the axial length of the eyeball is insufficient. Its optical focus is behind the retina, so the image formed on the retina is blurred.

[0039] 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 seen in Table 1.

[0040] Table 1 Eye irritation response score standard

[0041]

[0042] Eye irritation reaction Points Scattered or diffuse opacity, iris clearly visible 1 The translucent area is easy to distinguish, and the iris is blurred 2 A grayish-white translucent area appears, the details of the iris are unclear, and the size of the pupil is barely visible 3 Cornea is opaque and iris is unrecognizable 4 Iris normal 0 The wrinkles are obviously deepened, congested, and swollen, the cornea is slightly congested, and the pupil still reacts to light 1 Hemorrhage / visible necrosis / no response to light (or one of these) 2 conjunctiva Congestion (palpebral and bulbar conjunctiva) Normal blood vessels 0 Blood vessels are bright red 1 The blood vessels are dark red due to congestion and it is difficult to distinguish the blood vessels 2 Diffuse congestion purple 3

[0043] As used herein, the eye irritation evaluation criteria are shown in Table 2.

[0044] Table 2 Eye irritation evaluation criteria

[0045] Points evaluate 0～3 Non-irritating 4～8 Mild irritant 9～12 Moderate irritation 13～16 Severe irritation

[0046] II. Detailed description of specific implementation scheme

[0047] In one aspect, the present disclosure provides an ophthalmic composition comprising an α-adrenergic receptor agonist and an M cholinergic receptor agonist.

[0048] In some embodiments, the ophthalmic composition further comprises a pH adjuster, an osmotic pressure adjuster, and water.

[0049] In some embodiments, the ophthalmic composition does not contain other auxiliary materials such as preservatives, buffers, complexing agents and excipients.

[0050] In some embodiments, the alpha-adrenergic receptor agonist is selected from norepinephrine, metaraminol, phenylephrine, methoxamine, oxymetazoline, naphazoline, xylometazoline, apraclonidine, dexmedetomidine, brimonidine, dopamine, ephedrine, pseudoephedrine, mephentermine, or at least one of the derivatives of the foregoing compounds.

[0051] In some embodiments, the α-adrenaline receptor agonist is selected from at least one of oxymetazoline, naphazoline, xylometazoline, dexmedetomidine, brimonidine, or derivatives of the foregoing compounds.

[0052] In some embodiments, the α-adrenaline receptor agonist is selected from at least one of oxymetazoline, naphazoline, brimonidine, or derivatives of the foregoing compounds.

[0053] In some embodiments, the alpha-adrenergic receptor agonist is brimonidine or a derivative thereof.

[0054] In some embodiments, the alpha-adrenergic receptor agonist is brimonidine tartrate.

[0055] In some embodiments, the M cholinergic receptor agonist is selected from at least one of acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, aceclidine, cevimeline, xanomeline, and sabcomeline.

[0056] In some embodiments, the M cholinergic receptor agonist is selected from at least one of carbachol, pilocarpine, aceclidine, cevimeline, or xanomeline.

[0057] In some embodiments, the M cholinergic receptor agonist is selected from at least one of pilocarpine, aceclidine, or cevimeline.

[0058] In some embodiments, the M cholinergic receptor agonist is cevimeline.

[0059] 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.

[0060] In some embodiments, the pH adjuster is selected from one or more of hydrochloric acid, boric acid, citric acid, sodium hydroxide, and potassium hydroxide.

[0061] In some embodiments, the pH adjuster is selected from hydrochloric acid and / or sodium hydroxide.

[0062] 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).

[0063] 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).

[0064] 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).

[0065] 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).

[0066] In another aspect, the present disclosure provides a method for preparing the aforementioned ophthalmic composition, comprising the following steps:

[0067] 1. Dissolution of main drug

[0068] (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;

[0069] (2) Dissolution of the M cholinergic receptor agonist: Add the prescribed amount of the M cholinergic receptor agonist to the injection water while stirring, stir until completely dissolved, and set aside;

[0070] 2. Preparation

[0071] Add water for injection into the liquid preparation tank, add the prescribed amount of sodium chloride into the liquid preparation 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;

[0072] 3. Adjust pH

[0073] 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 to 7.0, and the pH value of the drug solution is preferably 6.6;

[0074] 4. Set the volume

[0075] Use water for injection to make up to the prescribed amount;

[0076] 5. Filter

[0077] The ophthalmic composition preparation was obtained by filtering and sterilizing through a microporous filter membrane (one 0.45 μm hydrophilic PES filter membrane and two 0.22 μm hydrophilic PES filter membranes).

[0078] 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.

[0079] In some embodiments, when the dosage form of the ophthalmic composition is eye drops, the preparation method is: the α-adrenergic receptor agonist and a small amount of water for injection are mixed and stirred to dissolve for standby use, and the M cholinergic receptor agonist and a small amount of water for injection are mixed and stirred to dissolve for standby use. Add an appropriate amount of water for injection to the liquid preparation tank, add the osmotic pressure regulator to the liquid preparation tank in the required amount and stir to dissolve, then add the α-adrenergic receptor agonist solution and the M cholinergic receptor agonist solution to the liquid preparation tank, mix well, take samples to detect the pH of the liquid, and according to the pH value of the liquid, continuously add the pH regulator to adjust the internal control standard of the liquid pH; then use water for injection to make up to the prescribed amount, stir, and then filter and sterilize through a microporous filter membrane to obtain α-adrenergic receptor agonist eye drops.

[0080] In some embodiments, the preparation method further comprises filtering and sterilizing through a microporous filter membrane, and aseptically filling the finished product by Blow / Fill / Seal under the sterile protection of a Class A air shower.

[0081] In another aspect, the present disclosure provides the 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 an eye disease.

[0082] 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.

[0083] In some embodiments, the ophthalmic composition further comprises a pharmaceutically acceptable carrier and / or excipient. These substances are used to help the stability of the formulation or to help improve the activity or its biological effectiveness, or in the case of an eye drop experiment, to efficiently transport the drug to the posterior segment of the eye. The preparation that can be used in such an ophthalmic composition can be in the form of its original compound itself, or optionally in the form of its pharmaceutically acceptable salt. The ophthalmic composition thus formulated can select any appropriate method known to those skilled in the art to administer the drug as needed.

[0084] In some embodiments, the suitable dosage of the ophthalmic composition can be prescribed in a variety of ways according to factors such as the formulation method, administration mode, patient's age, weight, sex, morbidity, diet, administration time, administration route, excretion rate and reaction sensitivity. A skilled doctor 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 certain subject (such as a mammal: a human) may 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, etc. In addition, those skilled in the art know that the administration mode, 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 mode, dosage form and dosage of the ophthalmic preparation or ophthalmic composition described in the present invention are not limited to the administration mode, dosage form and dosage described in the embodiments of the present invention.

[0085] In some embodiments, the eye diseases include conjunctival congestion caused by environmental factors, infection or inflammation, visual fatigue caused by long-term close-up use of the eyes, and presbyopia, ocular hypertension, dry eye, myopia, hyperopia, strabismus, astigmatism, photophobia or glaucoma. Among them, the environmental stimuli include irritating smoke, wind and sand, ultraviolet radiation and long-term topical medication. Visual fatigue includes dry eyes, soreness and pain, blurred vision, and even symptoms such as decreased vision and dizziness.

[0086] 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.

[0087] 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, cattle, and any livestock or pets; and non-mammals, such as chickens, amphibians, reptiles, etc. In a specific embodiment of the present invention, the subject is preferably a human.

[0088] 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 ocular disease to improve the symptoms of the ocular 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 long-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 long-distance visual acuity possible without using corrective lenses or glasses.

[0089] In some embodiments, an ophthalmic composition provided by the present disclosure is 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).

[0090] 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.

[0091] In some embodiments, the relieving the patient's myopia symptoms is improving the patient's distance vision.

[0092] Example

[0093] A further understanding of the present disclosure can be obtained by referring to some specific embodiments given herein, which are only used to illustrate the present disclosure and are not intended to limit the scope of the present disclosure. Obviously, various modifications and changes can be made to the present disclosure without departing from the essence of the present disclosure, and therefore, these modifications and changes are also within the scope of the protection required by the present application.

[0094] Example 1 Preparation method of ophthalmic composition preparation

[0095] 1. Dissolution of main drug

[0096] (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;

[0097] (2) Dissolution of the M cholinergic receptor agonist: Add the prescribed amount of the M cholinergic receptor agonist to the injection water while stirring, stir until completely dissolved, and set aside;

[0098] 2. Preparation

[0099] Add water for injection into the liquid preparation tank, add the prescribed amount of sodium chloride into the liquid preparation 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;

[0100] 3. Adjust pH

[0101] 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 to 7.0, and the pH value of the drug solution is preferably 6.6;

[0102] 4. Set the volume

[0103] Use water for injection to make up to the prescribed amount;

[0104] 5. Filter

[0105] The ophthalmic composition preparation was obtained by filtering and sterilizing through a microporous filter membrane (one 0.45 μm hydrophilic PES filter membrane and two 0.22 μm hydrophilic PES filter membranes). The component concentrations in the prepared formulations are shown in Table 3.

[0106] Table 3 Component concentrations of various formulations

[0107]

[0108]

[0109] *Note: All ophthalmic preparations given to the subjects were prepared and used immediately.

[0110] It was observed that formulas 1-11 can form stable and uniform solutions. Figure 1 The properties of other formulations are similar to those of formulation 11, all of which are clear and transparent solutions. Formulations 4, 5, 6 and 11 were placed at high temperature of 40°C for 1 month, and their pH, osmotic pressure molar concentration, purity or content did not change significantly. The stability results are shown in Table 4.

[0111] Table 4 Stability results of formulations 4, 5, 6 and 11

[0112]

[0113] Example 2 Eye irritation test of different formulations

[0114] Subject information: The subjects are a male, about 60 years old, with mild presbyopia, and a female, about 45 years old, with myopia. Both subjects are in good health, can comply with the requirements during the trial, can undergo various examinations as specified in the trial protocol, and can report subjective symptoms. The subjects understand the purpose of the trial, the nature of the trial drugs, the possible risks of the trial, and their own rights and interests and voluntarily participate in this trial. When the same subject undergoes different groups of formulations, there is at least a two-day interval between the first group of formulations and the second group of formulations.

[0115] Take one drop of each solution of single prescription preparation formula 7-11, drip it into the lower conjunctival fornix of the subject, remind the subject to slightly lift the lower eyelid outward, close the eyes, and then press the inner canthus, while rotating the eyeball, keep it 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 Hemolysis Research" (i.e. Table 1), and judge the degree of irritation according to Table 2. The specific test results are shown in Table 5, and the eye conditions of the subjects after the corresponding part of the formula experiment are shown in Figure 2 After the test of Formulation 8, there was no irritation to the eyes of the subjects. The eye conditions of the subjects can be referred to the experimental photos of Formulation 7.

[0116] Table 5 Eye irritation rating of single prescription preparations

[0117]

[0118]

[0119] From Table 5 and Figure 2 The experimental results show 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 descriptions of the subjects, there was basically no irritation or discomfort during the whole 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 lighter than those of formulation 10. Continuing to observe, the eye symptoms of the subjects were basically able to return to normal after 10 minutes, and there was basically no irritation or discomfort during the whole process. Take one drop of each of the solutions of compound preparation formulas 1-5 and drip it into the lower conjunctival fornix of the subject. Remind the subject to slightly lift the lower eyelid outward, close the eye, and then press the inner canthus while rotating the eyeball for one minute. Record the eye irritation before and 5 minutes after administration. Calculate the score according to Table 1, and judge the irritation degree according to Table 2. The specific test results are shown in Table 6, and the eye conditions of the subjects after the corresponding part of the formula experiment are shown in Figure 3 After the test of Formulation 4, there was no irritation to the eyes of the subjects. The eye conditions of the subjects can be referred to the experimental photos of Formulation 3.

[0120] Table 6 Eye irritation score of compound preparations

[0121]

[0122]

[0123] From Table 6 and Figure 3 The experimental results show 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), and the conjunctival congestion symptoms disappeared quickly after using the compound ophthalmic preparation formula 1; 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 show conjunctival congestion symptoms. Before using formulation 3, the subjects had scattered or diffuse corneal opacity, while the cornea was clear after using formulation 3. According to actual observations and subject descriptions, the compound preparation is more comfortable than the single prescription preparation. There is no irritation, itching, redness, swelling, dryness, increased eye secretions or other discomfort during the whole process. The compound preparation can improve eye comfort, eliminate eye fatigue, and improve the clarity of vision.

[0124] Example 3 Effects of different formulations on myopia patients

[0125] Information on the subjects of formulations 4, 9 and 11: The subject is a female, about 45 years old, myopic, in good health, able to comply with all requirements during the trial, able to undergo various examinations as specified in the trial protocol, and able to report subjective symptoms; the subject understands the purpose of the trial, the nature of the trial drugs, the possible risks of the trial, and her own rights and interests and voluntarily participates in this trial. When the same subject undergoes different groups of formulations, there shall be at least two days between the first group of formulation trials and the second group of formulation trials.

[0126] Take one drop of each of the solutions of formulations 4, 9 and 11, drip it into the subject's inferior conjunctival fornix, then slightly lift the lower eyelid outward, close the eye, and then press the inner canthus. At the same time, you can rotate the eyeball. Keep doing this for one minute, observe the eye irritation before and after administration, and record the near vision 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. Among them, the near vision of the subject is checked by using the national standard near vision test chart, with a distance of 30 cm as the standard, and the test is carried out in sufficient light. The best visual acuity is 0.8. During the test, the tester uses a vision test rod to point to the sight mark on the vision chart, and requires the subject to say or use gestures to indicate the direction of the gap in the sight mark while tightly covering one of the left and right eyes. Test line by line to find the best recognition line for the subject, thereby testing the specific vision of the left and right eyes respectively. See the test results. Figure 4 .

[0127] Depend on Figure 4 It can be seen that the use of single prescription formulation 9 (0.2% brimonidine tartrate eye drops) did not improve the near vision ability of the subjects; 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 did not feel irritation, itching, redness, swelling, dryness, increased eye secretions and other discomfort during the test, and could eliminate eye fatigue, improve the clarity of vision, and improve the near vision by 0.3 in a short time, and then continue to maintain the near vision until the end of observation (8h); compound formulation 4 can improve the near vision by 0.3 within 15min, which is better than single prescription formulation 11. From the analysis of the results, it can be concluded that the mixture of brimonidine tartrate and cevimeline synergistically increases the efficacy of the drug and prolongs the duration of action.

[0128] Example 4 Effect of Formulation 6 on Myopia and Hyperopia in Patients

[0129] Subject information: The subject is a male, about 60 years old, with both presbyopia and myopia, in good health, able to comply with all requirements during the trial, able to undergo various examinations as specified in the trial protocol, and able to report subjective symptoms; the subject understands the purpose of the trial, the nature of the trial drugs, the possible risks of the trial, and his own rights and interests and voluntarily participates in this trial. Before using the compound preparation formula 6, the subject had symptoms of eye fatigue and mild congestion of the conjunctiva.

[0130] Take the solution of formulation 6, drop one drop on the lower conjunctival fornix of the subject, remind the subject to slightly lift the lower eyelid outward, close the eyes, and then press the inner canthus. At the same time, the eyeball can be rotated for one minute. Observe the eye irritation before and after administration, and record the near and far vision 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 determining myopia is the same as that in Example 3. The method for testing hyperopia is to use the national standard logarithmic visual acuity examination chart for detection, with a distance of 5m as the standard, and to test in 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 on the vision chart, and requires the subject to say or use gestures to indicate the direction of the gap in the sight mark while tightly covering one of the left and right eyes. Test line by line to find the best recognition line for the subject, thereby testing the specific vision of the left and right eyes respectively. See the test results in Figure 5 .

[0131] Depend on Figure 5 According to the actual observation results, after using the compound preparation formula 6 (0.2% brimonidine tartrate and 4% cevimeline compound eye drops), the subjects can quickly eliminate the symptoms of conjunctival congestion, and there is no irritation, itching, redness, swelling, dryness, increased eye secretions and other discomforts during the whole process, and it can eliminate eye fatigue and improve the clarity of vision. The subjects' short-term (10min) near vision can be improved by 0.1 (scored as 1.0), and the near vision can be improved by 0.3 for 15min, and then the near vision is maintained until the end of observation (10h); the distance vision is also improved, and the distance vision can be improved by 0.2 for 20min, and then the distance vision is maintained until the end of observation (10h).

[0132] In summary, the compound eye drops of brimonidine tartrate and cevimeline can not only improve near vision, but also improve long-distance vision. On the other hand, it can be shown that the ophthalmic composition of the present invention can improve the clarity of vision of patients with refractive errors, and has a long action time and good safety.

[0133] Comparative Example 1

[0134] Subject information: The subjects are a male, about 60 years old, who is both presbyopic and myopic, and a female, about 45 years old, who is myopic. They are in good health, can comply with all requirements during the trial, can undergo various examinations as specified in the trial protocol, and can report subjective symptoms. The subjects understand the purpose of the trial, the nature of the trial drugs, the possible risks of the trial, and their own rights and interests and voluntarily participate in this trial. When the same subject undergoes different groups of formulations, there will be at least two days between the first group of formulations and the second group of formulations.

[0135] Determination of long-distance vision: It is mainly tested by using the national standard logarithmic vision test chart to check the patient's long-distance vision, with a distance of 5m as the standard and the test performed in sufficient light. The best visual acuity is 1.0. During the test, the tester points to the sight mark on the vision chart with a vision test pole, and requires the subject to say or use gestures to indicate the direction of the gap in the sight mark while tightly covering one of the left or right eyes. The test is carried out line by line to find the best recognition line for the testee, so as to test the specific vision of the left and right eyes respectively.

[0136] 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 refer to Example 1.

[0137] Take one drop of each of the ophthalmic preparations of Formulation 12 and Formulation 13, drip it into the lower conjunctival fornix of the subject, then slightly lift the lower eyelid outward, close the eye, and then press the inner canthus while rotating the eyeball for 1 minute. Record the distance vision before administration and 5 minutes, 10 minutes, 15 minutes, and 20 minutes after administration. The results are shown in Table 7 below.

[0138] Table 7 Distance vision test results

[0139]

[0140] As can be seen from Table 7, the ophthalmic compositions of formulas 12 and 13 can both improve long-distance vision. The ophthalmic composition of formula 13 can improve long-distance vision by 0.3 at 20 minutes, while the ophthalmic composition of formula 12 containing atropine can only improve long-distance vision by 0.1. From the analysis of the results, it can be concluded that the combination of brimonidine tartrate and cevimeline can improve long-distance vision, and the onset time is fast, and the long-distance vision is improved more; the compound eye drops of atropine and cevimeline have a slightly slower onset than the same concentration of cevimeline eye drops, and the long-distance vision is improved less.

[0141] In summary, the synergistic effect of the ophthalmic composition of brimonidine tartrate and cevimeline was further verified.

[0142] The above is only an embodiment of the present invention, and is not any formal or substantial limitation of the present invention. 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, and these improvements and supplements should also be regarded as the protection scope of the present invention. Any technician familiar with this profession, without departing from the spirit and scope of the present invention, can make some changes, modifications and equivalent changes made by using the technical content disclosed above, which are equivalent embodiments of the present invention; at the same time, any changes, modifications and evolutions of any equivalent changes 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.

12. The use according to claim 11, wherein the medicine further comprises a pharmaceutically acceptable carrier and / or excipient.

13. The use according to claim 11 or 12, 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.

14. 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.

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