Ophthalmic pharmaceutical composition and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to an ophthalmic pharmaceutical composition and application thereof. The ophthalmic pharmaceutical composition comprises one or two of a choline receptor stimulant, an anti-cholinesterase drug, an alpha-adrenergic receptor stimulant or a choline receptor antagonist. The ophthalmic pharmaceutical composition disclosed by the invention has a very good curative effect on myopia, takes effect quickly, is high in patient compliance, has no specific use time and occasion, and changes the conventional mode of using myopia drugs at night.

Description

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 symptom in which the eyes cannot see distant objects clearly, but can see nearby objects clearly. Under the premise of static refraction, distant objects cannot converge on the retina, but form a focus in front of the retina, thus causing visual distortion and making distant objects blurry. Myopia is divided into two types: refractive and axial. Among them, refractive myopia is the most serious. Refractive myopia can reach more than 600 degrees, which is called high myopia.

[0003] Myopia refers to a refractive state in which parallel light rays are refracted by the eye's refractive system and focus in front of the retina when the eye is not adjusting. Therefore, myopia cannot see distant targets clearly. If the target is gradually moved closer to the eye, the emitted light will be dispersed to a certain extent, and the focus will move backward. The target object can only be seen clearly when it is moved closer to a certain point in front of the eye. The closer this point is to the eye, the more serious the myopia.

[0004] Myopia is caused by the disproportion between the axial length of the eye and the focal length, which is mainly determined by the curvature of the cornea and lens. In the development of myopia, the axial length of the eye increases or the curvature of the cornea and lens increases. When the axial length of the eye is too long, the shape of the lens cannot change in proportion to form the depth of field focused on the retina, mainly because the function of the ciliary muscle limits the change in the thickness of the lens.

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

[0006] In view of 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. Summary of the invention

[0007] In view of the shortcomings of the above-mentioned myopia drugs, the present invention discloses the preparation of an ophthalmic preparation for treating and improving myopia using Cevimeline, and provides an ophthalmic preparation for treating and improving the distance vision of adults and adolescents, thereby achieving the improvement of myopia, and having many functions such as long-term use, good stability, high patient compliance, few side effects, and easy use.

[0008] In order to achieve the above-mentioned purpose of the present disclosure, the specific technical solution adopted by the present disclosure is:

[0009] 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.

[0010] 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 other than cevimeline.

[0011] The cholinergic receptor agonist includes acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, aceclidine, cevimeline, xanomeline, sabcomeline, methacholine bromide, mirameline or arecoline or derivative compounds having the same function.

[0012] Wherein, the anticholinesterase drug includes neostigmine, pyridostigmine, physostigmine, edrophonium chloride, ambenonium chloride, demecarium bromide, galantamine, tacrine, styraxine A or derivative compounds having the same function; optionally, it is neostigmine, and the concentration of the neostigmine is 0.0001wt% to 0.5wt% by weight.

[0013] 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 thereof; optionally, it is brimonidine, and the concentration of the brimonidine is 0.05wt% to 1.0wt% by weight.

[0014] Wherein, the cholinergic receptor antagonist includes atropine, methylatropine bromide, ipratropium bromide, scopolamine, pirenzepine, mecamylamine, pancuronium bromide, propantheline, benatizine or derivative compounds having the same function; optionally, it is atropine, and the atropine concentration is 0.01wt% to 1.0wt% by weight.

[0015] 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.

[0016] In another alternative embodiment, the ophthalmic preparation can also be used to improve and enhance the distance vision of teenagers and adults.

[0017] 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.

[0018] 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.

[0019] In a second aspect, the present disclosure provides the use of Cevimeline or its derivatives 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 and enhancing the distance vision of adolescents and adults.

[0020] 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.

[0021] In a fourth aspect, the present disclosure provides a method for preparing the ophthalmic preparation of 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.

[0022] In a fifth aspect, the present disclosure provides a method for treating or preventing myopia, the method comprising administering the ophthalmic preparation or drug described in the present disclosure to a subject.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The present invention discloses the preparation of a drug for treating and preventing myopia by using Cevimeline alone or in combination with other medicinal components related to the treatment of eye diseases, which can effectively improve the condition of myopic patients. Moreover, by adjusting with different other medicinal components and different concentrations, the technical effect of quickly and permanently adjusting the distance vision can be achieved.

[0025] The present disclosure also confirms that the combined use of Cevimeline and atropine can significantly improve the side effects of atropine and increase the upper limit of the safe dose of atropine, thereby further improving the treatment or prevention effect of myopia by using atropine at a higher concentration. The elimination of side effects improves patient compliance and enables patients to use the drug safely for a long time.

[0026] 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 axial length. DETAILED DESCRIPTION

[0027] 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 technicians in the field without creative work all belong to the protection scope of the present disclosure.

[0028] (I) Terms and Definitions

[0029] Unless otherwise specified in the present disclosure, the term "cholinoceptor agonists" refers to drugs that can directly bind to and excite acetylcholine (ACh) M receptors (M-like receptors, muscarinicreceptor) and / or acetylcholine (ACh) N receptors (nicotinic receptors, nicotinic receptors), including direct-acting cholinomimetic drugs that directly act on cholinergic receptors, which belong to direct-acting parasympathomimetics. According to the different binding receptors, they can be divided into the following three specific types:

[0030] (1) Choline esters: drug components that can act on both M receptors and N receptors at the same time, including multiple drug components with high consistency in structure and function with acetylcholine, such as methacholine and carbachol.

[0031] (2) Alkaloids: drug components that selectively act on M receptors, including artificially synthesized substances that can stimulate acetylcholine receptors, such as pilocarpine, arecoline, etc.

[0032] (3) Nicotine: It is a drug component that selectively stimulates N receptors. However, the effects of nicotine are more complex and bidirectional: when nicotine is first used, it has an stimulatory effect on N receptors, but as time goes by, it has an inhibitory effect on N receptors and continues to do so.

[0033] Unless otherwise specified in the present disclosure, the term "anticholinesterase drug" refers to a class of drug molecules that can bind to cholinesterase (AChE) to inhibit cholinesterase activity, leading to acetylcholine accumulation and producing a mimetic cholinergic effect. According to the degree of binding to cholinesterase, anticholinesterase drugs can be divided into reversible anticholinesterase drugs and irreversible anticholinesterase drugs.

[0034] Unless otherwise specified in the present disclosure, the term "α-adrenaline receptor agonist" refers to a class of drug molecules that can activate adrenaline α1 receptors and α2 receptors. Generally, this class of drug molecules has a weaker agonist effect on β1 receptors and almost no effect on β2 receptors.

[0035] Unless otherwise specified in the present 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, hinder the binding of Ach or cholinergic receptor agonists to cholinergic receptors, and thus antagonize the mimetic cholinergic effect. According to the different blocking receptors, they can be divided into M receptor antagonists, such as atropine and its similar alkaloids (scopolamine, etc.), or atropine substitutes (propantheline, benatirizine, etc.), which can bind to cholinergic receptors, competitively prevent ACh from binding to receptors, so that ACh cannot cause depolarization of ganglion cells, thereby blocking the transmission of nerve impulses in ganglia.

[0036] 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 (such as the height, weight, gender, age and medication history of the subject), 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.

[0037] In the absence of special instructions in the present disclosure, the term "improvement, alleviation or treatment" 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, that is, treatment specifically for the purpose of improving diseases, pathological conditions or conditions, and also includes etiological treatment, that is, treatment for the purpose of removing the cause of the relevant diseases, pathological conditions or conditions. In addition, the term also includes palliative treatment, that is, treatment designed to relieve symptoms rather than cure diseases, pathological conditions or conditions; the term also includes preventive treatment, that is, treatment for the purpose of minimizing or partially or completely inhibiting the development of relevant diseases, pathological conditions or conditions; and supportive treatment, that is, treatment for supplementing another specific therapy for the purpose of improving relevant diseases, pathological conditions or conditions. In a specific embodiment of the present disclosure, the "improvement, alleviation or treatment" refers to reducing the severity of the symptoms of eye conditions that adversely affect visual acuity. Specifically, the ophthalmic preparations or pharmaceutical compositions described herein can be used to improve or treat myopia symptoms, and patients can visually focus on objects at a distance by using the preparations.

[0038] (II) Specific implementation methods

[0039] In some aspects, the present disclosure provides an ophthalmic preparation for treating and / or improving myopia, wherein the ophthalmic preparation contains cevimeline.

[0040] In some embodiments of the present disclosure, the ophthalmic preparation may also contain one or more other cholinergic receptor agonists in addition to Cevimeline, or the ophthalmic preparation may also contain one or more anticholinesterase drugs, or the ophthalmic preparation may also contain one or more α-adrenaline receptor agonists, or the ophthalmic preparation may also contain one or more cholinergic receptor antagonists.

[0041] In alternative embodiments, the ophthalmic formulation contains cevimeline and another cholinergic receptor agonist, such as cevimeline and acetylcholine.

[0042] In an alternative embodiment, the ophthalmic preparation contains cevimeline and at least two or more additional cholinergic receptor agonists.

[0043] In an alternative embodiment, the ophthalmic formulation contains cevimeline and at least one anticholinesterase, such as cevimeline and neostigmine.

[0044] In an alternative embodiment, the ophthalmic preparation contains cevimeline and at least two or more other anticholinesterase drugs.

[0045] In alternative embodiments, the ophthalmic formulation contains cevimeline and at least one alpha adrenergic receptor agonist, such as cevimeline and brimonidine.

[0046] In an alternative embodiment, the ophthalmic preparation contains cevimeline and at least two or more additional alpha adrenergic receptor agonists.

[0047] In an alternative embodiment, the ophthalmic formulation contains cevimeline and at least one cholinergic receptor antagonist, such as cevimeline and atropine.

[0048] In an alternative embodiment, the ophthalmic preparation contains cevimeline and at least two or more additional cholinergic receptor antagonists.

[0049] In some embodiments of the present disclosure, the ophthalmic preparation further contains at least two of other choline receptor agonists, anticholinesterase drugs or alpha adrenergic receptor agonists. For example, a combination of Cevimeline, one or more other choline receptor agonists and one or more anticholinesterase drugs; a combination of Cevimeline, one or more other choline receptor agonists and one or more anticholinesterase drugs; a combination of Cevimeline, one or more choline receptor antagonists and one or more anticholinesterase drugs; and other combinations that cannot be exhaustively listed.

[0050] 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.

[0051] In some embodiments of the present disclosure, the anticholinesterase drug includes neostigmine, pyridostigmine, physostigmine, edrophonium, ambenonium, demecarium bromide, galantamine, tacrine, styraxine A or a derivative compound having the same function.

[0052] 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.

[0053] 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.

[0054] In some embodiments of the present disclosure, the derivative compound includes a cross-linked compound, a stereoisomer, an organic solution or a pharmaceutically acceptable organic salt containing the cholinergic receptor agonist, anticholinesterase drug, α-adrenergic receptor agonist or cholinergic receptor antagonist.

[0055] The organic salt can be a salt formed by a choline receptor agonist, an anticholinesterase drug, an α-adrenergic receptor agonist or a choline 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 choline receptor agonist, an anticholinesterase drug, an α-adrenergic receptor agonist or a choline receptor antagonist and an organic base, for example, an organic amine, benzathines, dicyclohexylamine, hydrabamines formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, 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 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-naphthalenemethylsulfonate, 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.

[0056] In some embodiments of the present disclosure, the concentration of Cevimeline in the ophthalmic preparation is 0.1wt% to 10wt%, including but not limited to 0.1wt%, 0.2wt%, 0.3wt%, 0.4wt%, 0.5wt%, 0.6wt%, 0.7wt%, 0.8wt%, 0.9wt%, 1.0wt%, 1.5wt%, 2.0wt%, 2.5wt%, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt%, 5.0wt%, 5.5wt%, 6.0wt%, 6.5wt%, 7.0wt%, 7.5wt%, 8.0wt%, 8.5wt%, 9.0wt%, 9.5wt% or 10wt%, preferably 0.5wt% to 8wt%, more preferably 1wt% to 5wt%, more preferably 2wt% to 3wt%, and more preferably 2.25wt%.

[0057] 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% to 0.001wt%, more preferably 0.0001wt%.

[0058] 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% by weight, 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%, 0.50wt%, 0.60wt%, 0.70wt%, 0.80wt%, 0.90wt%, 0.10wt%, 0.15wt%, 0.20wt%, 0.25wt%, 0.30wt%, 0.35wt%, 0.40wt%, 0.50wt%, 0.60wt%, 0.80wt%, 0.90wt%, 0.10wt%, 0.15wt%, 0.20wt%, 0.25wt%, 0.30wt%, 0.35wt%, 0.40wt%, 0.50wt%, 0.80wt%, 0.90wt%, 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%.

[0059] In some embodiments of the present disclosure, the cholinergic receptor antagonist is atropine, and the atropine concentration is 0.01wt% to 1.0wt% by weight, including but not limited to 0.01wt%, 0.02wt%, 0.03wt%, 0.04wt%, 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 0.01wt% to 0.5wt%, preferably 0.01wt% to 0.1wt%, preferably 0.03wt% to 0.07wt%, and more preferably 0.05wt%.

[0060] In some embodiments of the present disclosure, the ophthalmic preparations provided by the present disclosure 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 by the present disclosure can also be used to improve and enhance the distance vision of adolescents and adults.

[0061] 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 objects at a distance (including objects around the normal reading distance). In some embodiments, independent of other treatment methods, the use of the ophthalmic preparation provided by the present disclosure can fully improve the patient's long-sightedness. For example, administering the ophthalmic preparation provided by the present disclosure 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 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 make long-distance visual sensitivity without using corrective lenses or glasses, and alleviating the symptoms of photophobia or blurred vision caused by the symptoms of myopia itself, or administering other drugs.

[0062] In some embodiments, an ophthalmic formulation provided by the present disclosure is administered to a patient with myopia to facilitate near visual acuity so that the patient can read without relying on corrective treatments such as bifocal / multifocal lenses or monovision contact lenses.

[0063] In some embodiments, the ophthalmic preparation provided by the present disclosure is administered to one or both eyes of the patient to provide treatment for myopia as an alternative to corrective eye surgery. For example, when the patient cannot undergo corrective eye surgery to treat myopia, the ophthalmic preparation provided by the present disclosure can be administered to a patient with symptoms of myopia. Alternatively, after the patient has undergone corrective eye surgery for myopia, the ophthalmic preparation provided by the present disclosure can be administered to a patient who continues to have symptoms of myopia.

[0064] In some embodiments, following corrective eye surgery for distance vision at a younger age, an ophthalmic formulation provided by the present disclosure is applied to one or both eyes of a patient to reduce the decrease in distance vision sensitivity.

[0065] In some embodiments, administration of an ophthalmic formulation provided by the present disclosure is beneficial for improving myopia symptoms in patients who have reversed corrective eye surgery previously performed for myopia. For example, administration of an ophthalmic formulation may enable restoration of binocular vision for a patient after reversal or regression of monocular laser surgery previously performed to treat myopia.

[0066] In some embodiments, an ophthalmic formulation provided by the present disclosure is administered to a patient to improve the patient's ability to focus on distant objects after the patient has undergone corrective surgery to treat an eye condition other than myopia (e.g., including corrective eye surgery to treat cataracts).

[0067] In other embodiments of the present disclosure, the ophthalmic preparation also 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 encapsulation 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 preparation and harmless to the patient.

[0068] In some embodiments, the ophthalmic preparations described in the present disclosure 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.

[0069] In some embodiments, the ophthalmic formulations described herein do not contain any preservatives.

[0070] In some embodiments, the pH adjuster contained in the ophthalmic preparation described in 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.

[0071] In some embodiments, the osmotic pressure regulator contained in the ophthalmic preparation described in the present disclosure is selected from one or more of sodium chloride, sodium sulfate, potassium chloride, magnesium chloride, mannitol, mannose or dextrose.

[0072] In some embodiments, the ophthalmic preparations described in the present disclosure contain a buffer, and the buffer includes one or more of carbonates, phosphates, citrates, acetates, borates, barbiturates and 3-(N-morpholino)propanesulfonates.

[0073] 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, and a skilled doctor can usually easily determine the prescription dosage form, and the prescription is effective for the desired treatment or prevention of the 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, and 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.

[0074] Further, 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 disclosure, the subject is preferably a human.

[0075] 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, the uses comprising (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.

[0076] In some embodiments, the Cevimeline or its derivatives are used alone to prepare a medicament for treating or preventing myopia.

[0077] 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 for preparing a drug for treating or preventing myopia.

[0078] 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.

[0079] In another aspect, the present disclosure provides the use of the aforementioned ophthalmic preparations in the preparation of a medicament for treating or preventing myopia, the uses comprising (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.

[0080] On the other hand, the present disclosure provides a method for preparing the ophthalmic preparation of the present disclosure, the preparation method comprising adding Cevimeline or its derivatives to a solvent to obtain an ophthalmic preparation. When Cevimeline or its derivatives are used in combination with other effective components, such as at least one of other cholinergic receptor agonists, anticholinesterase drugs, α-adrenergic receptor agonists or cholinergic receptor antagonists, other effective components need to be added before the volume is fixed.

[0081] 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.

[0082] In another aspect, the present disclosure also provides a method for treating or preventing myopia, the method comprising administering the ophthalmic preparation or drug of the present disclosure to a subject. The dosage form of the ophthalmic preparation is matched with different administration methods and dosages, which are 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 administered. A skilled doctor can usually easily determine the prescription dosage form, and the dosage and administration method that are effective for the desired treatment or prevention.

[0083] The active ingredients of the ophthalmic preparations disclosed herein and their corresponding CAS numbers or scientific names or molecular structural formulas are as follows:

[0084]

[0085]

[0086] Example 1: Preparation of a single-component ophthalmic preparation

[0087] 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 liquid preparation tank, an osmotic pressure regulator is added to the liquid preparation tank in a required amount and stirred to dissolve, and then the medicinal component solution is added to the liquid preparation tank, and after mixing, a sample is taken to detect the pH value of the liquid. According to the pH value of the liquid, the pH regulator is continuously added to adjust the internal control standard of the pH of the liquid to 6.0-7.0; then, water for injection is used to make up the volume to the prescribed amount, and the single-component ophthalmic preparation is obtained by stirring.

[0088] 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:

[0089] Example Cevimeline concentration pH (adjusting reagent) Osmotic pressure (adjusting reagent) 1-1 4wt% 6.7(0.5mol / L NaOH) 287mOsmol / kg(NaCl) 1-2 2.25wt% 6.7(0.5mol / L NaOH) 281mOsmol / kg(NaCl)

[0090] Example 2: Preparation of multi-component ophthalmic preparation

[0091] Preparation of ophthalmic formulation formula 3 (compound eye drops of 0.05% atropine and 2.25% cevimeline)

[0092] An appropriate amount of medicinal component A and a small amount of water for injection are mixed and stirred to dissolve to obtain solution A for standby use, and an appropriate amount of medicinal component B and a small amount of water for injection are mixed and stirred to dissolve to obtain solution B for standby use. An appropriate amount of water for injection is added to the liquid preparation tank, sodium chloride is added to the liquid preparation tank in the required amount and stirred to dissolve, and then solution A and solution B are added to the liquid preparation tank, mixed and sampled to detect the pH value of the liquid, and pH regulators are continuously added according to the pH value of the liquid to adjust the internal control standard of the pH of the liquid to 5.0-7.0; then water for injection is used to make up the volume to the prescribed amount, and stirred to obtain A+B two-component compound eye drops.

[0093] 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:

[0094] Example Component A Component B pH (adjusting reagent) Osmotic pressure 2-1 0.05wt% Atropine 2.25wt% Cevimeline 5.5(0.5mol / L NaOH) 293mOsmol / kg(NaCl) 2-2 0.15wt% Brimonidine tartrate 2.25wt% Cevimeline 6.6(0.5mol / L NaOH) 291mOsmol / kg(NaCl) 2-3 0.0001wt% Neostigmine 2.25wt% Cevimeline 6.5(0.5mol / L NaOH) 288mOsmol / kg(NaCl)

[0095] Comparative Example 1

[0096] This comparative example adopts the preparation method provided in Example 1 to prepare a plurality of atropine single-component ophthalmic preparations with different concentrations, and the specific compositions are as follows:

[0097] Comparative Example atropine pH (adjusting reagent) Osmotic pressure (adjusting reagent) 1-1 0.01wt% 5.6(0.5mol / L NaOH) 288mOsmol / kg(NaCl) 1-2 0.03wt% 5.3 (0.5 mol / L NaOH) 290mOsmol / kg(NaCl) 1-3 0.05wt% 5.5(0.5mol / L NaOH) 293mOsmol / kg(NaCl) 1-4 0.1wt% 5.5(0.5mol / L NaOH) 290mOsmol / kg(NaCl) 1-5 1wt% 5.5(0.5mol / L NaOH) 290mOsmol / kg(NaCl)

[0098] Comparative Example 2

[0099] This comparative example adopts the preparation method provided in Example 2 to prepare ophthalmic preparations with multiple different pharmaceutical components, and the specific composition is as follows:

[0100] Comparative Example Component A Component B pH (adjusting reagent) Osmotic pressure (adjusting reagent) 2-1 0.05wt% Atropine 0.15wt% Brimonidine tartrate 5.5(0.5mol / L NaOH) 290mOsmol / kg(NaCl) 2-2 0.05wt% Atropine 0.0001wt% Neostigmine 5.5(0.5mol / L NaOH) 292mOsmol / kg(NaCl)

[0101] Effect test

[0102] Test Example 1: Investigating the long-distance vision effects of the ophthalmic preparations provided in Example 1 and Example 2

[0103] Subject information: The subjects are a male, about 60 years old, with both presbyopia and myopia, and a female, about 45 years old, with myopia. They are in good health, can comply with various 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.

[0104] 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.

[0105] Take one drop of each of the ophthalmic preparations provided in Example 1 and Example 2, and drip it into the lower conjunctival fornix of the test 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, 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 following table:

[0106]

[0107] Result analysis: As can be seen from the above table, all ophthalmic preparations provided in Example 1 and Example 2 can improve long-distance vision. Among them, ophthalmic preparation 1-1 and ophthalmic preparation 2-2 can improve long-distance vision by 0.3 at 15min, ophthalmic preparation 1-2 and ophthalmic preparation 2-3 can improve long-distance vision by 0.3 at 20min, and ophthalmic preparation 2-1 improves long-distance vision slowly, and long-distance vision can be 0.3 after 30min. After that, ophthalmic preparations 2-1 and 2-2 continue to maintain long-distance power until the end of observation (10h). From this result analysis, it is concluded that Cevimeline eye drops can improve long-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; Brimonidine tartrate and Cevimeline compound eye drops not only have a fast onset, but also have a longer duration.

[0108] Test Example 2 Comparative Example 1 Provides an eye preparation for improving long-distance vision

[0109] Subject information: The subjects are a male, 14 years old, myopic patient and a female, about 45 years old, myopic patient. 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.

[0110] Take one drop of each of the multiple groups of ophthalmic preparations provided in Comparative Example 1, drop it into the lower conjunctival fornix of the subject, slightly lift the lower eyelid outward, close the eye, and then press the inner canthus, while rotating the eyeball, keep it for 1 minute, and record the distance vision 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:

[0111] Implementation 1 hour of distance vision Is it blurred? Whether afraid of light Comparative Example 1-1 Not improved yes no Comparative Example 1-2 Not improved yes no Comparative Examples 1-3 Not improved yes yes Comparative Examples 1-4 Not improved yes yes Comparative Examples 1-5 Not improved yes yes Example 2-1 Improved by 0.3 no no

[0112] Results Within 1 hour, the control subjects reported blurred vision and were unable to focus on the distance vision chart, so the distance vision of the subjects was not further observed.

[0113] Test Example 3 Comparison of the adjustment of ophthalmic preparations provided in different embodiments on ocular refraction and eye axis

[0114] Form deprivation myopia model was established: The right eye of the experimental group chickens was covered, and the left eye was used as the control eye. No treatment was done on both eyes of the normal control group and the control eye of the experimental group. The chickens were raised for 4 weeks, and the cover was regularly checked to see if it was displaced or covered the control eye. The refractive state and axial length of the chickens' eyes were measured at the end of the 4th week.

[0115] Dosage scheme: divided into 5 groups, group 1 is the model group, group 2 is the model group + comparative example 1-3 eye drops, group 3 is the model group + example 1-2, group 4 is the model group + example 2-1 eye drops, group 5 is the model group + example 2-2 eye drops. After 4 weeks of feeding, the refractive error (Refractive error, D) and axial length (Axial elongation, mm) of both eyes were detected to evaluate the regulatory effect of different preparations on myopia. The results are shown in the following table:

[0116]

[0117] Compared with the model group, * indicates p < 0.05. There was no significant difference between Group 2 and Group 4.

[0118] 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 diopter 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) failed to improve the diopter and did not 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 limited by time and occasion, with high compliance and more convenient use. Therefore, long-term and effective prevention and control of the occurrence and development of juvenile myopia requires the use of atropine and Cevimeline provided in Example 2-1. Combination preparation.

[0119] The above detailed description is a specific description of one of the feasible embodiments 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 deviate 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, suppressing 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.

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