Ophthalmic pharmaceutical composition and use thereof

Abstract

An ophthalmic pharmaceutical composition and a use thereof. The ophthalmic pharmaceutical composition comprises one or two of a choline receptor agonist, an anti-cholinesterase drug, an α-adrenergic receptor agonist or a choline receptor antagonist. The ophthalmic pharmaceutical composition has a very good curative effect on myopia, is quick to take effect, has high patient compliance, has no specific use time and occasion, and changes the conventional mode of using myopia drugs at night.

Description

An ophthalmic pharmaceutical composition and its use Technical Field

[0001] The present disclosure relates to the field of medical technology, and in particular to an ophthalmic pharmaceutical composition and uses thereof. Background Art

[0002] Myopia is a condition in which distant objects are blurred, while nearby objects are clear. When refraction is static, distant objects cannot converge on the retina, but instead form a focal point in front of it. This causes visual distortion, making distant objects blurry. Myopia is divided into two types: refractive and axial. Refractive myopia is the most severe. Refractive myopia can reach over 600 degrees, considered high myopia.

[0003] Myopia refers to a refractive condition in which, when the eye is not accommodating, parallel light rays are refracted by the eye's refractive system and focus in front of the retina. Therefore, myopia prevents distant objects from being clearly seen. As the object is gradually brought closer to the eye, the light rays disperse to a certain degree, causing the focal point to shift backward. Only when the object is brought closer to a certain point in front of the eye can it be clearly seen. The closer this point is to the eye, the more severe the myopia.

[0004] Myopia is caused by a disproportion between the axial length of the eye and its focal length, which is primarily determined by the curvature of the cornea and lens. As myopia progresses, either the axial length of the eye or the curvature of the cornea and lens increases. When the axial length is too long, the lens shape cannot change proportionally to achieve the depth of field focused on the retina. This is primarily because the ciliary muscle limits changes in lens thickness.

[0005] Atropine, a non-selective cholinergic receptor antagonist, has been clinically proven to inhibit myopia, but its mechanism of action is not fully understood. It is currently believed to work through multiple mechanisms, such as reduced axial length, scleral tissue remodeling, and inhibition of retinal γ-aminobutyric acid transfer protein expression. However, atropine can only prevent and control the development of myopia in adolescents and has no effect on adult myopia. However, atropine eye drops can cause side effects such as blurred vision, so atropine can only be used at bedtime, which makes it inconvenient to use. In addition, atropine-like drugs also have adverse reactions such as photophobia and blurred near vision, and may cause accommodative paralysis, making it difficult for children to read books and newspapers, and can also cause visual problems such as photophobia and blurred near vision.

[0006] Given the current lack of clinical drugs for the treatment of adult myopia and the side effects of atropine in the treatment of juvenile myopia, there is an urgent need to provide an ophthalmic preparation that can be used for a long time, has good stability, high patient compliance, few side effects, and is easy to use, for the treatment and improvement of distance vision in adults and adolescents.

[0007] Summary of the Invention

[0008] In response to the shortcomings of the above-mentioned myopia drugs, the present invention discloses an ophthalmic preparation for treating and improving myopia using cevimeline, providing an ophthalmic preparation for treating and improving the distance vision of adults and adolescents, achieving the goal of improving myopia, and having many functions such as long-term use, good stability, high patient compliance, few side effects, and easy use.

[0009] In order to achieve the above-mentioned purpose of the present disclosure, the specific technical solutions adopted by the present disclosure are:

[0010] In a first aspect, the present disclosure provides an ophthalmic preparation for treating and / or improving myopia, wherein the ophthalmic preparation contains cevimeline, and the concentration of cevimeline is 0.1 wt % to 10 wt % by weight.

[0011] In an optional embodiment, the ophthalmic preparation further contains at least one of other cholinergic receptor agonists, anticholinesterase drugs, α-adrenergic receptor agonists or cholinergic receptor antagonists in addition to cevimeline.

[0012] The cholinergic receptor agonists include acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, aceclidine, cevimeline, xanomeline, sabcomeline, methacholine bromide, mirameline or arecoline or derivative compounds thereof having the same function.

[0013] Among them, the anticholinesterase drug includes neostigmine, pyridostigmine, physostigmine, edrophonium chloride, ambenonium chloride, demecarium bromide, galantamine, tacrine, stigmine A or a derivative compound having the same function; optionally, it is neostigmine, and the concentration of the neostigmine is 0.0001wt% to 0.5wt% by weight.

[0014] Wherein, the α-adrenaline receptor agonist includes norepinephrine, metaraminol, phenylephrine, methoxamine, oxymetazoline, naphazoline, xylometazoline, apraclonidine, dexmedetomidine, brimonidine, dopamine, ephedrine, pseudoephedrine, mephentermine, guanfacine, apraclonidine, tetrahydrozoline, xylazine, tizanidine, moxonidine, rilmenidine or a derivative compound having the same function; optionally, it is brimonidine, and the brimonidine concentration is 0.05wt% to 1.0wt% by weight.

[0015] Wherein, the cholinergic receptor antagonist includes atropine, methylatropine bromide, ipratropium bromide, hyoscyamine, pirenzepine, mecamylamine, pancuronium bromide, propantheline, benacetizine or a derivative compound having the same function; optionally, it is atropine, and the atropine concentration is 0.01wt% to 1.0wt% by weight.

[0016] In an alternative embodiment, the ophthalmic preparation is used to improve, alleviate, inhibit and / or reduce pupillary photophobia, near vision blur and / or accommodative eye fatigue in adolescents and adults.

[0017] In another alternative embodiment, the ophthalmic preparation can also be used to improve and enhance the distance vision of adolescents and adults.

[0018] In an optional embodiment, the ophthalmic preparation further contains a pharmaceutically acceptable carrier and / or excipient, including but not limited to one or more of a pH regulator, an osmotic pressure regulator or a buffer.

[0019] In an optional embodiment, the dosage form of the ophthalmic preparation includes eye drops, eye gels, eye ointments, eye patches, eye masks, eye washes or intraocular injections.

[0020] In a second aspect, the present disclosure provides the use of cevimeline or a derivative thereof in the preparation of a medicament for treating or preventing myopia. The uses include (a) improving, alleviating, inhibiting, and / or alleviating pupillary photophobia, near vision blur, and / or accommodative eye fatigue in adolescents and adults, and / or (b) improving or enhancing distance vision in adolescents and adults.

[0021] In a third aspect, the present disclosure provides use of the ophthalmic preparation described in the first aspect in preparing a drug having the above-mentioned function.

[0022] In a fourth aspect, the present disclosure provides a method for preparing the ophthalmic preparation according to the first aspect, the preparation method comprising adding cevimeline or a derivative thereof to a solvent to a fixed volume to obtain the ophthalmic preparation.

[0023] In a fifth aspect, the present disclosure provides a method for treating or preventing myopia, the method comprising administering a therapeutically effective amount of the ophthalmic preparation or drug of the present disclosure to a subject.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The present disclosure discloses the preparation of a drug for treating and preventing myopia using cevimeline, which can be used alone or in combination with other medicinal components for treating eye diseases to effectively improve the performance of myopia patients. Furthermore, by adjusting the dosage of cevimeline with different other medicinal components and at different concentrations, the drug can achieve the technical effect of rapidly and persistently improving distance vision.

[0026] This disclosure also demonstrates that the combined use of cevimeline and atropine can significantly alleviate atropine's side effects and increase the upper limit of atropine's safe dosage, thereby further enhancing the therapeutic or preventive effects of myopia using higher concentrations of atropine. The elimination of side effects improves patient compliance, enabling safe long-term use.

[0027] In addition, it has been verified that the ophthalmic preparation provided by the present disclosure breaks the limitation that atropine is only effective for adolescents, and also achieves significant improvement effects on adults. Moreover, after testing the improvement of refractive power and axial length, the present disclosure confirms that the combined use of cevimeline and atropine has a synergistic effect in reducing refractive power and reducing axial length. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present disclosure are further clearly described. The described embodiments are only a part of the present disclosure and are used to explain the present disclosure, but not to limit the present disclosure. Therefore, other embodiments obtained by other technical personnel in the field without creative work all fall within the scope of protection of the present disclosure.

[0029] (I) Terms and Definitions

[0030] Unless otherwise specified in this disclosure, the term "cholinoceptor agonists" refers to drugs that can directly bind to and stimulate acetylcholine (ACh) M receptors (M-like receptors, muscarinic receptors) and / or acetylcholine (ACh) N receptors (nicotinic receptors), including direct-acting cholinomimetic drugs that act directly on cholinergic receptors, which belong to direct-acting parasympathomimetics. According to the different receptors they bind to, they can be divided into the following three specific types:

[0031] (1) Choline esters: drug components that can act on both M receptors and N receptors simultaneously, including multiple drug components with high consistency in structure and function with acetylcholine, such as methacholine and carbachol.

[0032] (2) Alkaloids: drug components that selectively act on M receptors, including artificially synthesized substances that can stimulate acetylcholine receptors, such as pilocarpine, arecoline, etc.

[0033] (3) Nicotine: It is a drug component that selectively stimulates N receptors. However, the effects of nicotine are complex and bidirectional: when nicotine is first used, it has an stimulatory effect on N receptors, but over time, it has an inhibitory effect on N receptors, which continues.

[0034] Unless otherwise specified in this disclosure, the term "anticholinesterase drug" refers to a class of drug molecules that can bind to cholinesterase (AChE), inhibiting cholinesterase activity, leading to acetylcholine accumulation, and producing a cholinergic effect. Anticholinesterase drugs can be divided into reversible and irreversible anticholinesterase drugs based on the degree of binding to cholinesterase.

[0035] Unless otherwise specified in the present disclosure, the term "α-adrenergic receptor agonist" refers to a class of drug molecules that can activate adrenergic α1 receptors and α2 receptors. Generally, this class of drug molecules has a weak agonist effect on β1 receptors and almost no effect on β2 receptors.

[0036] Unless otherwise specified in this disclosure, the term "cholinergic receptor antagonist," also known as cholinergic receptor blocking drugs, refers to a class of drug molecules that can bind to cholinergic receptors, hindering the binding of ACh or cholinergic receptor agonists to cholinergic receptors, thereby antagonizing the mimetic effects of cholinergics. Depending on the receptors blocked, they can be divided into M receptor antagonists, such as atropine and its similar alkaloids (such as anisodamine), or atropine substitutes (such as propantheline and benacetin), which can bind to cholinergic receptors and competitively prevent ACh from binding to the receptors, preventing ACh from causing depolarization of ganglion cells, thereby blocking the transmission of nerve impulses in the ganglion.

[0037] Unless otherwise specified in the present disclosure, the term "effective amount" or "effective dose" refers to the amount of a drug that can produce a therapeutic effect on humans and / or animals and can be accepted by humans and / or animals. For example, a therapeutically or pharmaceutically effective amount refers to the amount of a drug required to produce the desired therapeutic effect, and the therapeutic effect can be reflected by the results of clinical trials, model animal studies and / or in vitro studies. The pharmaceutically effective amount depends on several factors, including (but not limited to): characteristic factors of the subject to be treated (such as the height, weight, gender, age and medication history of the subject to be treated), and the severity of the disease. In a specific embodiment of the present disclosure, the "effective amount" refers to an amount sufficient to inhibit, slow down or prevent the development of myopia in the subject.

[0038] In the absence of special instructions in this disclosure, the term "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, that is, treatment specifically for the purpose of improving a disease, pathological state or condition, and also includes etiological treatment, that is, treatment for the purpose of removing the cause of the relevant disease, pathological state or condition. In addition, the term also includes palliative treatment, that is, treatment designed to relieve symptoms rather than cure a disease, pathological state or condition; the term also includes preventive treatment, that is, treatment for the purpose of minimizing or partially or completely inhibiting the development of the relevant disease, pathological state or condition; and supportive treatment, that is, 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 disclosure, the "improve, alleviate or treat" refers to reducing the severity of the symptoms of an eye condition that adversely affects visual acuity. Specifically, the ophthalmic preparation or pharmaceutical composition described herein can be used to improve or treat myopia symptoms, and the patient can visually focus on objects at a distance by using the preparation.

[0039] (II) Specific implementation methods

[0040] In some aspects, the present disclosure provides an ophthalmic preparation for treating and / or improving myopia, wherein the ophthalmic preparation contains cevimeline.

[0041] In some embodiments of the present disclosure, the ophthalmic preparation may further contain one or more other cholinergic receptor agonists in addition to cevimeline, or the ophthalmic preparation may further contain one or more anticholinesterase drugs, or the ophthalmic preparation may further contain one or more α-adrenergic receptor agonists, or the ophthalmic preparation may further contain one or more cholinergic receptor antagonists.

[0042] In an alternative embodiment, the ophthalmic formulation contains cevimeline and another cholinergic receptor agonist, such as cevimeline and acetylcholine.

[0043] In an alternative embodiment, the ophthalmic preparation contains cevimeline and at least two or more cholinergic receptor agonists.

[0044] In an alternative embodiment, the ophthalmic formulation contains cevimeline and at least one anticholinesterase, such as cevimeline and neostigmine.

[0045] In an alternative embodiment, the ophthalmic preparation contains cevimeline and at least two or more other anticholinesterase drugs.

[0046] In an alternative embodiment, the ophthalmic formulation contains cevimeline and at least one alpha adrenergic receptor agonist, such as cevimeline and brimonidine.

[0047] In an alternative embodiment, the ophthalmic preparation contains cevimeline and at least two or more α-adrenoceptor agonists.

[0048] In an alternative embodiment, the ophthalmic formulation contains cevimeline and at least one cholinergic receptor antagonist, such as cevimeline and atropine.

[0049] In an alternative embodiment, the ophthalmic preparation contains cevimeline and at least two or more cholinergic receptor antagonists.

[0050] In some embodiments of the present disclosure, the ophthalmic preparation further contains at least two of other cholinergic receptor agonists, anticholinesterase drugs, or α-adrenergic receptor agonists. For example, a combination of cevimeline, one or more other cholinergic receptor agonists, and one or more anticholinesterase drugs; a combination of cevimeline, one or more other cholinergic receptor agonists, and one or more anticholinesterase drugs; a combination of cevimeline, one or more cholinergic receptor antagonists, and one or more anticholinesterase drugs; and other inexhaustible combinations.

[0051] In some embodiments of the present disclosure, the cholinergic receptor agonist includes acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, aceclidine, cevimeline, xanomeline, sabcomeline, methacholine bromide, mirameline or arecoline, or a derivative compound having the same function thereof.

[0052] In some embodiments of the present disclosure, the anticholinesterase drug includes neostigmine, pyridostigmine, physostigmine, edrophonium chloride, ambenonium chloride, demecarium bromide, galantamine, tacrine, schizolinone A, or derivative compounds having the same function.

[0053] In some embodiments of the present disclosure, the α-adrenaline receptor agonist includes norepinephrine, metaraminol, phenylephrine, methoxamine, oxymetazoline, naphazoline, xylometazoline, apraclonidine, dexmedetomidine, brimonidine, dopamine, ephedrine, pseudoephedrine, mephentermine, guanfacine, apraclonidine, tetrahydrozoline, xylazine, tizanidine, moxonidine, rilmenidine or a derivative compound having the same function thereof.

[0054] In some embodiments of the present disclosure, the cholinergic receptor antagonist includes atropine, methylatropine bromide, ipratropium bromide, scopolamine, pirenzepine, mecamylamine, pancuronium bromide, propantheline, benacetizine, or a derivative compound having the same function.

[0055] In some embodiments of the present disclosure, the derivative compound includes a cross-linked compound, stereoisomer, organic solution or pharmaceutically acceptable organic salt containing the cholinergic receptor agonist, anticholinesterase drug, α-adrenergic receptor agonist or cholinergic receptor antagonist.

[0056] The organic salt can be a salt formed by a cholinergic receptor agonist, an anticholinesterase drug, an α-adrenergic receptor agonist or a cholinergic receptor antagonist and a cation, for example, an ammonium salt, an alkali metal salt (including a sodium salt, a lithium salt and a potassium salt), an alkaline earth metal salt (including a calcium salt and a magnesium salt). It can also be a salt formed by a cholinergic receptor agonist, an anticholinesterase drug, an α-adrenergic receptor agonist or a cholinergic receptor antagonist and an organic base, for example, an organic amine, benzathines, dicyclohexylamine, hydrabamines formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine. It can also be a salt formed with an amino acid, for example, an arginine salt, a lysine salt, an aspartate salt. Salts formed with organic acids are also possible, for example, acetate, adipate, alginate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthylethanesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, sulfonate, tartrate, thiocyanate, toluenesulfonate or undecanoate.

[0057] In some embodiments of the present disclosure, the concentration of cevimeline in the ophthalmic preparation is 0.1 wt% to 10 wt%, including but not limited to 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 7.5 wt%, 8.0 wt%, 8.5 wt%, 9.0 wt%, 9.5 wt% or 10 wt%, preferably 0.5 wt% to 8 wt%, more preferably 1 wt% to 5 wt%, more preferably 2 wt% to 3 wt%, and more preferably 2.25 wt%.

[0058] In some embodiments of the present disclosure, the anticholinesterase drug is neostigmine, and the concentration of the neostigmine is 0.0001wt% to 0.5wt% by weight, including but not limited to 0.0001wt%, 0.0002wt%, 0.0003wt%, 0.0004wt%, 0.0005wt%, 0.0006wt%, 0.0007wt%, 0.0008wt%, 0.0009wt%, 0.0010wt%, 0.0 015wt%, 0.0020wt%, 0.0025wt%, 0.0030wt%, 0.0035wt%, 0.0040wt%, 0.0045wt%, 0.0050wt%, 0.0055wt %, 0.0060wt%, 0.0065wt%, 0.0070wt%, 0.0075wt%, 0.0080wt%, 0.0085wt%, 0.0090wt%, 0.0095wt%, 0.0 10wt%, 0.015wt%, 0.020wt%, 0.025wt%, 0.030wt%, 0.035wt%, 0.040wt%, 0.045wt%, 0.050wt%, 0.055wt %, 0.060wt%, 0.065wt%, 0.070wt%, 0.075wt%, 0.080wt%, 0.085wt%, 0.090wt%, 0.095wt%, 0.10wt%, 0.1 5wt%, 0.20wt%, 0.25wt%, 0.30wt%, 0.35wt%, 0.40wt%, 0.45wt% or 0.50wt%, preferably 0.0001wt% to 0.1wt%, more preferably 0.0001wt% to 0.05wt%, more preferably 0.0001wt% to 0.01wt%, more preferably 0.0001wt% to 0.001wt%, more preferably 0.0001wt% to 0.001wt%, more preferably 0.0001wt%.

[0059] In some embodiments of the present disclosure, the α-adrenergic receptor agonist is brimonidine, and the concentration of brimonidine is 0.05wt% to 1.0wt%, including but not limited to 0.05wt%, 0.06wt%, 0.07wt%, 0.08wt%, 0.09wt%, 0.10wt%, 0.15wt%, 0.20wt%, 0.25wt%, 0.30wt%, 0.35wt%, 0.40wt%, 0. .45wt%, 0.50wt%, 0.55wt%, 0.60wt%, 0.65wt%, 0.70wt%, 0.75wt%, 0.80wt%, 0.85wt%, 0.90wt%, 0.95wt% or 1.0wt%, preferably 0.05wt% to 0.5wt%, more preferably 0.05wt% to 0.2wt%, more preferably 0.1wt% to 0.2wt%, more preferably 0.15wt%.

[0060] In some embodiments of the present disclosure, the cholinergic receptor antagonist is atropine, and the atropine concentration is 0.01 wt% to 1.0 wt% by weight, including but not limited to 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.10 wt%, 0.15 wt%, 0.20 wt%, 0.25 wt%, 0.30 wt%, 0. 35wt%, 0.40wt%, 0.45wt%, 0.50wt%, 0.55wt%, 0.60wt%, 0.65wt%, 0.70wt%, 0.75wt%, 0.80wt%, 0.85wt%, 0.90wt%, 0.95wt% or 1.0wt%, preferably 0.01wt% to 0.5wt%, preferably 0.01wt% to 0.1wt%, preferably 0.03wt% to 0.07wt%, and further preferably 0.05wt%.

[0061] In some embodiments of the present disclosure, the ophthalmic preparations provided herein are used to improve, alleviate, inhibit and / or reduce pupillary photophobia, near vision blur and / or accommodative eye fatigue in adolescents and adults. In other embodiments of the present disclosure, the ophthalmic preparations provided herein can also be used to improve and enhance distance vision in adolescents and adults.

[0062] In some embodiments, the ophthalmic preparation provided by the present disclosure is applied to one or both eyes of a patient showing symptoms of myopia to improve the patient's ability to focus on an object at a distance (including an object at normal reading distance surroundings). In some embodiments, independent of other treatment methods, administering the ophthalmic preparation provided by the present disclosure can fully improve the patient's hyperopia. For example, administering the ophthalmic preparation provided by the present disclosure can enable the patient to focus on an object at a distance around the normal reading distance without the use of corrective lenses or corrective eye surgery. For adolescents and adults suffering from myopia, administering the ophthalmic preparation provided by the present disclosure can alleviate the related symptoms of myopia, including making it possible to achieve long-distance visual sensitivity without the use of corrective lenses or glasses, and alleviating the symptoms of photophobia or blurred vision caused by the myopia symptoms themselves, or the administration of other drugs.

[0063] In some embodiments, the ophthalmic formulations provided herein are administered to patients with myopia to improve near visual acuity so that the patient can read without relying on corrective treatments such as bifocal / multifocal lenses or monovision contact lenses.

[0064] In some embodiments, an ophthalmic formulation provided herein is administered to one or both eyes of a patient to provide treatment for myopia as an alternative to corrective eye surgery. For example, an ophthalmic formulation provided herein can be administered to a patient with symptoms of myopia when the patient is unable to undergo corrective eye surgery to treat myopia. Alternatively, an ophthalmic formulation provided herein can be administered to a patient who continues to have symptoms of myopia after the patient has undergone corrective eye surgery for myopia.

[0065] In some embodiments, following corrective eye surgery for distance vision at a younger age, an ophthalmic formulation provided by the present disclosure is administered to one or both eyes of a patient to reduce the decrease in distance vision sensitivity.

[0066] In some embodiments, administration of an ophthalmic formulation provided herein is beneficial for improving myopia symptoms in patients who have reversed previous corrective eye surgery for myopia. For example, administration of an ophthalmic formulation can enable restoration of binocular vision in a patient after reversal or resolution of previous monocular laser surgery for myopia.

[0067] In some embodiments, an ophthalmic formulation provided herein is administered to a patient to improve the patient's ability to focus on distant objects after the patient has undergone corrective eye surgery to treat an eye condition other than myopia (e.g., including corrective eye surgery to treat cataracts).

[0068] In other embodiments of the present disclosure, the ophthalmic preparation further contains a pharmaceutically acceptable carrier and / or excipient. The pharmaceutically acceptable carrier and / or excipient refers to a pharmaceutically acceptable material, composition or excipient that is recognized in the art and includes, for example, a liquid or solid filler, pH regulator, osmotic pressure regulator, diluent, solvent or encapsulating material that is involved in carrying or transporting any subject composition from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the main formulation and not harmful to the patient.

[0069] In some embodiments, the ophthalmic preparations described herein contain a preservative, such as benzalkonium chloride, sorbic acid, oxychloride complex, citric acid, chlorobutanol, thimerosal, phenylmercuric acetate, disodium edetate, phenylmercuric nitrate, perborate, or benzyl alcohol.

[0070] In some embodiments, the ophthalmic formulations described herein do not contain any preservatives.

[0071] In some embodiments, the pH adjuster contained in the ophthalmic preparations of the present disclosure is selected from one or more of hydrochloric acid, boric acid, phosphoric acid, citric acid, sodium hydroxide, potassium hydroxide, acetate buffer, citrate buffer, phosphate buffer or borate buffer.

[0072] In some embodiments, the osmotic pressure regulator contained in the ophthalmic preparation of the present disclosure is selected from one or more of sodium chloride, sodium sulfate, potassium chloride, magnesium chloride, mannitol, mannose or dextrose.

[0073] In some embodiments, the ophthalmic preparations described herein contain a buffer, wherein the buffer comprises one or more of carbonates, phosphates, citrates, acetates, borates, barbiturates, and 3-(N-morpholino)propanesulfonate.

[0074] In some embodiments of the present disclosure, the dosage form of the ophthalmic preparation provided by the present disclosure includes eye drops, eye gels, eye ointments, eye patches, eye films, eye washes or intraocular injections. The dosage form of the ophthalmic preparation is matched with different modes of administration and dosages, and is specifically affected by factors such as the age, weight, sex, morbidity, diet, excretion rate and reaction sensitivity of the subject or patient, and a variety of prescriptions can be applied. A skilled doctor can usually easily determine the prescription dosage form, and the prescription is effective for the desired treatment or prevention of dosage and mode of administration. In addition, it is clear to those skilled in the art that the mode of administration, dosage form and dosage of the drug are affected by many factors such as the age, weight, sex, morbidity, diet, administration time, excretion rate and reaction sensitivity of the patient. Therefore, the mode of administration, dosage form and dosage of the ophthalmic preparation or pharmaceutical composition described in the present disclosure are not limited to the mode of administration, dosage form and dosage described in the embodiments of the present disclosure.

[0075] Furthermore, 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; as well as non-mammals, such as chickens, amphibians, reptiles, etc. In a specific embodiment of the present disclosure, the subject is preferably a human.

[0076] In another aspect, the present disclosure provides the use of the aforementioned cevimeline or its derivatives in the preparation of a medicament for treating or preventing myopia, wherein the use includes (a) improving, alleviating, inhibiting and / or reducing pupillary photophobia, near vision blur and / or accommodative eye fatigue in adolescents and adults, and / or (b) improving and enhancing the distance vision of adolescents and adults.

[0077] In some embodiments, the cevimeline or its derivatives are used alone to prepare a medicament for treating or preventing myopia.

[0078] In other embodiments, the cevimeline or its derivative is combined with at least one of other cholinergic receptor agonists, anticholinesterase drugs, α-adrenergic receptor agonists or cholinergic receptor antagonists other than cevimeline to prepare a drug for treating or preventing myopia.

[0079] In some embodiments, the drug for treating or preventing myopia with cevimeline as the main active ingredient further contains a pharmaceutically acceptable carrier and / or excipient, for example, at least one of a pH regulator, an osmotic pressure regulator, or a buffer.

[0080] In another aspect, the present disclosure provides a use of the aforementioned ophthalmic preparation in the preparation of a medicament for treating or preventing myopia, said use comprising (a) improving, alleviating, inhibiting and / or reducing pupillary photophobia, near vision blur and / or accommodative eye fatigue in adolescents and adults, and / or, (b) improving and enhancing the distance vision of adolescents and adults.

[0081] In another aspect, the present disclosure provides a method for preparing the ophthalmic preparation of the present disclosure, comprising adding cevimeline or a derivative thereof to a solvent and settling the volume to obtain the ophthalmic preparation. When cevimeline or a derivative thereof is used in combination with other active ingredients, such as at least one of other cholinergic receptor agonists, anticholinesterase drugs, α-adrenergic receptor agonists, or cholinergic receptor antagonists, the other active ingredients need to be added before settling the volume.

[0082] Preferably, a pharmaceutically acceptable carrier and / or excipient, such as at least one of a pH regulator, an osmotic pressure regulator or a buffer, needs to be added before adjusting the volume.

[0083] In another aspect, the present disclosure further provides a method for treating or preventing myopia, comprising administering to a subject a therapeutically effective amount of an ophthalmic preparation or drug according to the present disclosure. The dosage form of the ophthalmic preparation is compatible with different administration routes and dosages, specifically influenced by factors such as the subject's or patient's age, weight, sex, condition, diet, excretion rate, and reaction sensitivity. A variety of prescriptions can be used, and a skilled physician can generally easily determine a prescription dosage form, a dosage, and an administration route that are effective for the desired treatment or prevention.

[0084] On the other hand, the present disclosure also provides a drug for treating or preventing myopia, comprising cevimeline or a derivative thereof.

[0085] In some embodiments, the medicament is used to (a) improve, alleviate, inhibit and / or reduce pupillary photophobia, near vision blur and / or accommodative eye fatigue in adolescents and adults, and / or (b) improve and enhance distance vision in adolescents and adults.

[0086] On the other hand, the present disclosure also provides a drug for treating or preventing myopia, which comprises the aforementioned ophthalmic preparation.

[0087] In some embodiments, the drug is used to (a) improve, alleviate, inhibit and / or reduce pupillary photophobia, near vision blur and / or accommodative eye fatigue in adolescents and adults, and / or (b) improve and enhance distance vision in adolescents and adults. The active ingredients of the ophthalmic preparations described in the present disclosure and their corresponding CAS numbers or scientific names or molecular structural formulas are as follows:

[0088] Example 1: Preparation of a single-component ophthalmic preparation

[0089] An effective dose of the medicinal component and a small amount of water for injection are mixed and stirred to dissolve to obtain a medicinal component solution for use; an appropriate amount of water for injection is added to the preparation tank; an osmotic pressure regulator is added to the preparation tank in the required amount and stirred to dissolve; then the medicinal component solution is added to the preparation tank, mixed and sampled to detect the pH value of the drug solution; according to the pH value of the drug solution, the pH regulator is continuously added to adjust the internal control standard of the pH of the drug solution to 6.0-7.0; then, water for injection is used to make up the volume to the prescribed amount, and stirred to obtain a single-component ophthalmic preparation.

[0090] Example 1-1 and Example 1-2 respectively adopt the preparation method of Example 1 to prepare eye drops containing different concentrations of cevimeline. The specific parameters of the eye drops are as follows:

[0091] Example 2: Preparation of multi-component ophthalmic preparation

[0092] Preparation of ophthalmic formulation formula 3 (compound eye drops of 0.05% atropine and 2.25% cevimeline)

[0093] Mix an appropriate amount of medicinal component A with a small amount of water for injection and stir to dissolve to obtain solution A for use. Mix an appropriate amount of medicinal component B with a small amount of water for injection and stir to dissolve to obtain solution B for use. Add an appropriate amount of water for injection to the preparation tank, add the required amount of sodium chloride to the preparation tank and stir to dissolve, then add solution A and solution B to the preparation tank. After mixing, take samples to test the pH of the solution. Based on the pH value of the solution, continuously add pH regulator to adjust the pH of the solution to the internal control standard of 5.0 to 7.0. Then, use water for injection to make up to the prescribed volume and stir to obtain the A+B two-component compound eye drops.

[0094] Examples 2-1, 2-2, and 2-3 respectively adopt the preparation method of Example 2 to prepare eye drops containing different medicinal components or concentrations. The specific parameters of the eye drops are as follows:

[0095] Comparative Example 1

[0096] In this comparative example, the preparation method provided in Example 1 was used to prepare a plurality of atropine single-component ophthalmic preparations with different concentrations. The specific compositions are as follows:

[0097] Comparative Example 2

[0098] This comparative example adopts the preparation method provided in Example 2 to prepare ophthalmic preparations containing multiple different pharmaceutical components. The specific compositions are as follows:

[0099] Effect test

[0100] Test Example 1: Investigating the long-distance vision effects of the ophthalmic preparations provided in Examples 1 and 2

[0101] Subject information: The subjects are a male, approximately 60 years old, who is both presbyopic and myopic, and a female, approximately 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.

[0102] 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.

[0103] One drop of each of the ophthalmic preparations provided in Example 1 and Example 2 was instilled into the lower conjunctival fornix of the subject. The lower eyelid was 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, 20 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 5 hours, 7 hours, 8 hours, and 10 hours after administration. The results are shown in the table below:

[0104] Results analysis: As can be seen from the above table, all ophthalmic preparations provided in Example 1 and Example 2 can improve distance vision. Among them, ophthalmic preparation 1-1 and ophthalmic preparation 2-2 can improve distance vision by 0.3 at 15 minutes, ophthalmic preparation 1-2 and ophthalmic preparation 2-3 can improve distance vision by 0.3 at 20 minutes, and ophthalmic preparation 2-1 improves distance vision more slowly, and distance vision can reach 0.3 after 30 minutes. Afterwards, ophthalmic preparations 2-1 and 2-2 continue to maintain distance vision until the end of observation (10 hours). From this result analysis, it is concluded that cevimeline eye drops can improve distance vision, and the onset time is fast and the duration is long; the compound eye drops of atropine and cevimeline are slightly slower than the cevimeline eye drops of the same concentration, but have a longer duration; the compound eye drops of brimonidine tartrate and cevimeline not only have a fast onset, but also have a longer duration.

[0105] Test Example 2 Comparative Example 1 provides an ophthalmic preparation for improving long-distance vision

[0106] Subject information: The subjects are a male, 14 years old, myopic, and a female, approximately 45 years old, 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.

[0107] One drop of each of the multiple ophthalmic preparations provided in Comparative Example 1 was instilled into the subject's inferior conjunctival fornix. The subject then slightly lifted the lower eyelid outward, closed the eye, and then pressed the inner canthus while rotating the eyeball for 1 minute. The distance vision was recorded before administration and 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, and 1 hour after administration. The results are shown in the following table:

[0108] Results Within 1 hour, the control subject reported blurred vision and was unable to focus on the distance vision chart, so further observation of the subject's distance vision was not conducted.

[0109] Test Example 3 Comparison of the Effects of Different Embodiments of the Ophthalmic Preparations on the Adjustment of Ocular Refractive Power and Axis

[0110] To establish a form-deprivation myopia model, the right eye of the experimental group chickens was covered, and the left eye served as a control eye. Both eyes of the normal control group and the control eye of the experimental group were left untreated. The chickens were reared for four weeks, and the cover was regularly checked for displacement or obstruction of the control eye. At the end of the fourth week, the refractive index and axial length of the eyes were measured.

[0111] Dosage regimen: The mice were divided into 5 groups. Group 1 was the model group. Group 2 was the model group plus the eye drops of comparative examples 1-3. Group 3 was the model group plus the eye drops of examples 1-2. Group 4 was the model group plus the eye drops of example 2-1. Group 5 was the model group plus the eye drops of example 2-2. After 4 weeks of feeding, the refractive error (D) and axial elongation (mm) of both eyes were measured to evaluate the regulatory effect of different preparations on myopia. The results are shown in the following table: Compared with the model group, * indicates p < 0.05. There was no significant difference between Group 2 and Group 4.

[0112] As shown in the table above, compared with the model group, Comparative Examples 1-3 (0.05wt% atropine) and Example 2-1 (2.25wt% cevimeline + 0.05wt% atropine) can effectively improve the refractive power and inhibit the growth of the eye axis. However, Example 1-2 (2.25wt% cevimeline) and Example 2-2 (2.25wt% cevimeline and 0.15wt% brimonidine tartrate) were not able to improve the refractive power or inhibit the growth of the eye axis. Moreover, as shown in the results of Comprehensive Test Example 2, atropine eye drops will produce side effects such as blurred vision and photophobia, but the addition of cevimeline can avoid the above side effects, and the use is not restricted by time and occasion, the compliance is high, and the use is more convenient. Therefore, long-term and effective prevention and control of the occurrence and development of juvenile myopia requires the use of the combination preparation of atropine and cevimeline provided in Example 2-1.

[0113] The above detailed description is a specific description of one feasible embodiment of the present disclosure. The embodiment is not intended to limit the patent scope of the present disclosure. Any equivalent implementation or modification that does not depart from the present disclosure should be included in the scope of the technical solution of the present disclosure.

Claims

1. An ophthalmic preparation for treating and / or improving myopia, wherein: The ophthalmic preparation contains Cevimeline.

2. The ophthalmic preparation according to claim 1, wherein The ophthalmic preparation further contains at least one of other choline receptor agonists, anticholinesterase drugs, α-adrenergic receptor agonists or choline receptor antagonists.

3. The ophthalmic preparation according to claim 2, wherein The cholinergic receptor agonist includes acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, aceclidine, cevimeline, xanomeline, sabcomeline, methacholine bromide, milameline or arecoline or derivative compounds having the same function.

4. The ophthalmic preparation according to claim 2 or 3, wherein The anticholinesterase drugs include neostigmine, pyridostigmine, physostigmine, edrophonium chloride, ambenonium chloride, demecarium bromide, galantamine, tacrine, schizothrine A or derivative compounds having the same functions; optionally, neostigmine.

5. The ophthalmic preparation according to any one of claims 2 to 4, wherein The α-adrenaline receptor agonist includes norepinephrine, metaraminol, phenylephrine, methoxamine, oxymetazoline, naphazoline, xylometazoline, apraclonidine, dexmedetomidine, brimonidine, dopamine, ephedrine, pseudoephedrine, mephentermine, guanfacine, apraclonidine, tetrahydrozoline, xylazine, tizanidine, moxonidine, rilmenidine or a derivative compound having the same function; optionally, brimonidine.

6. The ophthalmic preparation according to any one of claims 2 to 5, wherein The cholinergic receptor antagonists include atropine, methylatropine bromide, ipratropium bromide, scopolamine, pirenzepine, mecamylamine, pancuronium bromide, propantheline, benatizine or derivative compounds having the same function; optionally, atropine.

7. The ophthalmic preparation according to any one of claims 1 to 6, wherein The concentration of Cevimeline is 0.1wt% to 10wt%, preferably 0.5wt% to 8wt%, more preferably 1wt% to 5wt%, and more preferably 2wt% to 3wt%.

8. The ophthalmic preparation according to any one of claims 1 to 7, wherein The anticholinesterase drug is neostigmine. Calculated by weight percentage, the concentration of the neostigmine is 0.0001wt% to 0.5wt%, preferably 0.0001wt% to 0.1wt%, more preferably 0.0001wt% to 0.05wt%, more preferably 0.0001wt% to 0.01wt%, more preferably 0.0001wt% to 0.001wt%.

9. The ophthalmic preparation according to any one of claims 1 to 8, wherein The α-adrenergic receptor agonist is brimonidine. In terms of weight percentage, the concentration of brimonidine is 0.05wt% to 1.0wt%, preferably 0.05wt% to 0.5wt%, more preferably 0.05wt% to 0.2wt%, and more preferably 0.1wt% to 0.2wt%.

10. The ophthalmic preparation according to any one of claims 1 to 9, wherein The cholinergic receptor antagonist is atropine. Calculated by weight percentage, the concentration of atropine is 0.01wt% to 1.0wt%, preferably 0.01wt% to 0.5wt%, preferably 0.01wt% to 0.1wt%, and preferably 0.03wt% to 0.07wt%.

11. The ophthalmic preparation according to any one of claims 1 to 10, wherein The ophthalmic preparation is used for improving, alleviating, inhibiting and / or alleviating pupil photophobia, near vision blur and / or accommodative eye fatigue in adolescents and adults.

12. The ophthalmic preparation according to any one of claims 1 to 10, wherein The ophthalmic preparation is used for improving and enhancing the distance vision of teenagers and adults.

13. The ophthalmic preparation according to any one of claims 1 to 12, wherein The ophthalmic preparation further contains a pharmaceutically acceptable carrier and / or excipient; Preferably, the auxiliary material comprises at least one of a pH regulator, an osmotic pressure regulator or a buffer.

14. The ophthalmic preparation according to any one of claims 1 to 13, wherein The dosage forms of the ophthalmic preparation include eye drops, eye gels, eye ointments, eye patches, eye masks, eye washes or intraocular injections.

15. Use of Cevimeline or its derivatives in the preparation of a medicament for treating or preventing myopia.

16. The use according to claim 15, wherein The uses include (a) improving, alleviating, inhibiting and / or alleviating pupillary photophobia, near vision blur and / or accommodative eye fatigue in adolescents and adults, and / or (b) improving and enhancing the distance vision of adolescents and adults.

17. Use of the ophthalmic preparation according to any one of claims 1 to 14 in the preparation of a medicament for treating or preventing myopia.

18. The use according to claim 17, wherein The uses include (a) improving, alleviating, inhibiting and / or alleviating pupillary photophobia, near vision blur and / or accommodative eye fatigue in adolescents and adults, and / or (b) improving and enhancing the distance vision of adolescents and adults.

19. The method for preparing an ophthalmic preparation according to any one of claims 1 to 14, wherein: The preparation method comprises adding cevimeline or its derivatives into a solvent to obtain an ophthalmic preparation; Preferably, at least one of other cholinergic receptor agonists, anticholinesterase drugs, α-adrenergic receptor agonists or cholinergic receptor antagonists is added before the volume is fixed; Preferably, a pharmaceutically acceptable carrier and / or excipient is added before adjusting the volume.

20. A drug for treating or preventing myopia, comprising cevimeline or a derivative thereof.

21. The drug according to claim 20, wherein The drug is used for (a) improving, alleviating, inhibiting and / or alleviating pupillary photophobia, near vision blur and / or accommodative eye fatigue in adolescents and adults, and / or (b) improving and enhancing the distance vision of adolescents and adults.

22. A medicament for treating or preventing myopia, comprising the ophthalmic preparation according to any one of claims 1 to 14.

23. The drug according to claim 22, wherein The drug is used for (a) improving, alleviating, inhibiting and / or alleviating pupillary photophobia, near vision blur and / or accommodative eye fatigue in adolescents and adults, and / or (b) improving and enhancing the distance vision of adolescents and adults.

24. A method for treating or preventing myopia, the method comprising administering a therapeutically effective amount of the ophthalmic preparation according to any one of claims 1 to 14 to a subject.

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