Method for treating myopia by vinpocetine

Abstract

The invention relates to a method for treating myopia by adopting vinpocetine, which not only can effectively prevent myopia and / or control myopia progress, but also is safe and free of obvious side effects, and has a good clinical application prospect.

Description

Technical Field

[0001] This application relates to a method for treating myopia using vinpocetine, especially to a method and use for controlling the progression of myopia, and provides corresponding drugs or preparations, belonging to the field of medicine. This case is a divisional application of patent CN202210872252.8. Background Art

[0002] Myopia is one of the most common refractive errors, which refers to a refractive state in which parallel light rays are refracted through the refractive system of the eye and focus in front of the retina in a relaxed state. Myopia causes people to see distant objects blurred, which brings many inconveniences to life. Although the distance vision of myopic patients can be improved through corrective measures such as frame glasses, such technologies or methods cannot improve the social phenomenon of high incidence of myopia and increasing degree of myopia. Therefore, the number of myopic people in the world has increased year by year, especially in East Asian countries, the situation of patients with high myopia is not optimistic. However, there are many types of myopia and the pathogenesis is still unclear. At present, there is a lack of effective and safe drugs for the treatment of myopia, especially for controlling the progression of myopia. Therefore, there is an unmet clinical need for this disease.

[0003] The chemical formula of Vinpocetine is C 22 H 26 N2O2, with an average molecular weight of 350.46, is a white crystalline powder, soluble in chloroform or 96% ethanol, almost insoluble in water. It is an indole alkaloid extracted from Vinca roseus of the Apocynaceae family. Its structure is as follows:

[0004]

[0005] Vinpocetine's solubility in water is pH-dependent. It is more soluble in the gastric environment pH (1.2) and the intestinal environment pH (6.8), and has higher biological activity and less toxic side effects than vincamine. Vinpocetine has high lipid solubility. The compound can enter the blood-brain barrier, blood-eye barrier, placenta and breast milk, and has high pharmacological activity on cardiovascular and central nervous system functions.

[0006] At present, vinpocetine is mainly used for the treatment of cerebrovascular-related diseases and cognitive impairment, and the majority of the patients are elderly people. It is reported that after systemic administration, vinpocetine can selectively act on the cerebrovascular system, inhibit the activity of phosphodiesterase in the brain (i.e., as a phosphodiesterase inhibitor), relax vascular smooth muscle, and increase the blood supply to the brain. This type of drug has the characteristics of rapid metabolism in the body, short elimination half-life, and low human bioavailability of oral dosage forms. Since vinpocetine for external use in the eye can easily pass through physical barriers such as the cornea and lens, vinpocetine is also an auxiliary component of many ophthalmic drugs, and is mainly used as a microcirculation promoter to promote blood flow in the eye. Although promoting blood circulation in the eye may make the eye feel more comfortable, thereby increasing the acuity of vision in patients with refractive errors, this is not equivalent to treating myopia, and there are even reports that the use of vinpocetine may lead to myopia. Summary of the invention

[0007] The present application unexpectedly discovered a completely new use of Vinpocetine and proved through repeated experiments that Vinpocetine can treat myopia and control myopia progression. That is, Vinpocetine is not used as a supplement or auxiliary ingredient, such as a microcirculation promoter (inhibiting phosphodiesterase activity), to assist, accompany or assist other active substances for treating myopia in drugs for treating myopia to enhance (such as allowing more main ingredients of the drug to reach the effective target cells) the effect of the active substance in treating myopia; but as a direct active ingredient for treating myopia.

[0008] The present application also studies the mechanism of Vinpocetine in treating myopia. Before the present application, people used Vinpocetine as a phosphodiesterase inhibitor to enhance blood flow, but the present application found through experiments that Vinpocetine does not rely on the improvement of choroidal blood flow when treating myopia and controlling myopia progression. In other words, Vinpocetine does not treat myopia and inhibit myopia progression by dilating blood vessels or promoting blood circulation (i.e., the known functions of phosphodiesterase inhibitors), but may rely more on a new pharmacological action that is inherent but not yet known to people. Therefore, the present application actually utilizes a little-known function of Vinpocetine, and this discovery is also the key basis for forming the present application.

[0009] This application proves for the first time that vinpocetine alone can have a significant inhibitory effect on the progression of myopia, and thus it is believed that vinpocetine can effectively treat various types of myopia including simple myopia or axial myopia (such as juvenile myopia), mild or moderate myopia, etc. Compared with the use of vinpocetine to treat myopia in the elderly, or high myopia, or high myopia in the elderly, or pathological myopia, the effect of vinpocetine in treating myopia with a continuous decrease in refractive power (such as simple myopia, axial myopia, or axial simple myopia, or low and moderate myopia, or children and adolescent myopia, or progressive myopia, etc.) will be significantly better.

[0010] Vinpocetine can also be used to prevent various types of myopia. For example, using vinpocetine for drug intervention in the progression of myopia can prevent and stop the occurrence of myopia in the elderly, high myopia, high myopia in the elderly and pathological myopia.

[0011] This application further studies the concentration, ratio and formula of vinpocetine in drugs or preparations for treating myopia, as well as the frequency of administration of related drugs, combined treatment and other medication methods. Among them, local (ocular) administration is not only safe but also has a significantly better therapeutic effect than systemic administration.

[0012] The present application provides the use of vinpocetine, or its optical isomers or racemates, or solvates, or pharmaceutically acceptable salts, or prodrugs, or metabolites, or related compounds or extracts, or crystalline compounds, or combinations of these substances, wherein the use satisfies one of the following or two or more of the following simultaneously:

[0013] ①Prevention and / or treatment of myopia and its related symptoms, and / or myopia correction; or

[0014] ②Inhibit (control) the progression of myopia; or

[0015] ③ Used for myopia prevention and control or delaying the occurrence and development of myopia (eye); or

[0016] ④ Inhibit or slow down the elongation of the eye axis and / or the increase of the length (depth) of the vitreous cavity in myopic individuals or individuals with myopia tendency; or

[0017] ⑤Prevent, slow down, reduce or treat abnormal development of the eyeball associated with visual impairment; or

[0018] ⑥ Enables individuals to obtain clearer distance vision than before and / or without using these substances or methods without wearing glasses (such as frame glasses or OK lenses) or relying on vision correction methods (such as refractive surgery); or

[0019] 7. Inhibit, delay or slow down the process or speed of negative refraction in myopic individuals or individuals with myopia tendency; or

[0020] ⑧ Used for preparing a drug, preparation, composition or device, wherein the drug, preparation, composition or device is used to achieve at least one of the uses in ①-⑦ above.

[0021] In some embodiments, systemic administration (such as oral administration, intravenous infusion), and / or local administration (eye drops, eye injections, eye implants, skin cream / cream periocular application or eye ointment application), and / or parenteral administration (such as through mucosal administration, transdermal administration, microneedle administration), and / or non-invasive administration (such as administration using eye spray) are adopted.

[0022] In some embodiments, the drug, preparation or composition can be an injection, tablet, lyophilized powder injection, capsule, effervescent tablet, chewable tablet, buccal tablet, granule, ointment, syrup, oral solution, aerosol, nasal drops, external preparation, oral preparation, etc.; preferably an ophthalmic dosage form, including but not limited to eye drops (eye drops), eye ointment, eye spray, implant, eye gel, eye patch, eye microsphere, eye sustained-release preparation, periocular injection, intraocular injection; it can also be a free solution, oil-water mixture, suspension (agent), ointment, lotion, cream, drops, granules, spray, ointment, patch, paste, pill, suppository, emulsion, containing cellulose (such as methylcellulose), polyhydroxy alcohol, cyclodextrin (such as hydroxypropyl-β-cyclodextrin), acidic cosolvent (such as citric acid), dendritic polymer, nanomaterial, sustained-release material, liposome or a combination thereof.

[0023] In some embodiments, the myopic individual or the individual with myopia tendency is a child and / or an adolescent, preferably a person aged 3 to 26, more preferably a person aged 6 to 18; or a minor, preferably a person whose eyes (eyeballs) are still in the growth and development stage; or a school-age person, preferably a person in grades 1 to 12; or a person whose parents are highly myopic; or a person with insufficient hyperopia reserve.

[0024] In some embodiments, myopia is refractive myopia or axial myopia; congenital myopia (myopia from birth or before school age), early myopia (under 14 years old), delayed myopia (16-18 years old), late myopia (after adulthood); low myopia (mild myopia), moderate myopia, high myopia (severe myopia); pseudomyopia, true myopia; myopia in children and / or adolescents (preferably the age of the population is 3-26 years old, more preferably the age of the population is 6-18 years old), myopia in minors, myopia in adults, myopia in the elderly; simple myopia, pathological myopia; axial simple myopia, simple axial myopia; axial myopia in children and / or adolescents (preferably the age of the population is 3-26 years old, more preferably the age of the population is 6-18 years old); axial myopia in school-age and preschool populations; primary myopia, secondary myopia; primary myopia in children and / or adolescents (preferably the age of the population is 3-26 years old, more preferably the age of the population is 6 -18 years old); or progressive myopia in children and / or adolescents (preferably aged 3-26 years old, more preferably aged 6-18 years old); curvature myopia, index myopia, astigmatism myopia, positional myopia, bending myopia; axial myopia with continuously negative refractive power; myopia caused by long-term close-range eye use, myopia and pseudomyopia caused by visual fatigue, negative refractive power caused by adverse drug reactions, myopia, myopia caused by reading, myopia caused by using mobile phones and other electronic products, myopia caused by mismatch of refractive media (components), refractive myopia, myopia caused by abnormal refractive development, myopia caused by excessive eye growth, myopia caused by unhygienic eye use, myopia caused by various reasons where the imaging focus of distant objects falls in front of the retina, myopia with poor or ineffective treatment with atropine, myopia caused by insufficient outdoor exercise, accommodative tension myopia, children's myopia, infant myopia, hereditary myopia, and myopia dominated by environmental factors.

[0025] In some embodiments, myopia-related symptoms include complications caused by myopia, such as complications of high myopia, such as floaters, glaucoma, posterior scleral staphyloma, retinal detachment, retinal tear, amblyopia, macular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or macular lesions, visual field loss, progressive or sudden decrease in vision (especially near vision), eye soreness and / or pain, night blindness, astigmatism, anisometropia, blindness, vitreous liquefaction, vitreous opacity, strabismus, frequent blinking, frequent rubbing of eyes, anisometropia, blurred vision when looking at distant objects, needing to squint or partially close the eyelids to see distant objects clearly, headaches caused by eyestrain, inattention caused by myopia, difficulty with vision when driving, especially at night (night myopia), retinal atrophy and degeneration (hemorrhage and holes), subretinal neovascularization, or eyeball atrophy.

[0026] In some embodiments, the drug, preparation, composition or device further comprises other drugs or ophthalmic preparations, including but not limited to myopia treatment drugs (such as pirenzepine, muscarinic antagonists, ampicillin, anthocyanin, timolol maleate, epinephrine, pirenzepine, pyrazine, pyropenem, pyropenem, pyrenzepine, methylamine, chloranol, acetylcholinesterase inhibitors, dopamine agonists, γ-aminobutyric acid, naloxone, glucagon, retinoic acid, salidroside, formononetin, etc.), M receptor blockers (such as blockers or antagonists or inhibitors for M2 or M3 receptors), benzalkonium chloride and its various salt forms (bendalidine), atropine, dimethoate, polyunsaturated fatty acids (such as DHA, EPA), prazosin, homatropine, scopolamine (racemic), tropicamide, 7-methylxanthine, niacin, piracetam (Piracetam ), salvia miltiorrhiza extract, safflower extract, fish oil, bear bile extract, vitamins, adenosine triphosphate (ATP), smooth muscle relaxants, drugs to prevent vasospasm, non-selective adenylate antagonists, vasodilators, mydriatic components, hyperemia removal components, eye muscle (such as ciliary muscle) regulation components, anti-(anti-)inflammatory components, astringent components, antihistamine components, anti-allergic components, collagen degradation inhibition components, liver protection (avoid or reduce liver toxicity) components, blood-retinal barrier enhancement components (making it more difficult for compounds to penetrate through the physiological barrier), amino acids, antibacterial components, antioxidant components, sugars, polymers or their derivatives, cellulose or its derivatives, local anesthetic components, amblyopia treatment components, glaucoma treatment components, cataract treatment components, type I phosphodiesterase inhibitors (specific or non-specific), miRNA and its modifications, therapeutic components for ophthalmic diseases, excipients, etc.

[0027] In some embodiments, vinpocetine, or its optical isomers or racemates, or solvates, or pharmaceutically acceptable salts, or prodrugs, or metabolites, or related compounds or extracts, or crystalline compounds, or a combination of these substances and one or more myopia prevention and control drugs and / or myopia treatment drugs are formulated or designed to be administered continuously, or simultaneously, or sequentially, or alternately, or intermittently, or separately.

[0028] In some embodiments, the vinpocetine-related compound or extract is selected from one or more substances in vinpocetine metabolites (such as apovincaminic acid, hydroxyvinpocetine, hydroxyl-apovincaminic acid and dihydroxy-vinpocetine-glycinate), vinca alkaloids, apovincamine, periwinkle extract, vincamine, voacanga africana extract, apocynaceae plant extract, vincristine, tabersonine, vinblastine, vindoline, apovincaminic acid hydrochloride, catharanthine, ethyl vincaminate, methoxyvinpocetine, and dihydrovinpocetine.

[0029] In some embodiments, the preparation is an oral product such as a health product, food, dietary supplement, nutrient, beverage, or cosmetic. The cosmetic can be a free solution, oil-water mixture, suspension (agent), liniment, lotion, spray, cream, drop, granule, ointment, paste, pill, suppository, emulsion, patch, or a combination of several thereof.

[0030] In some embodiments, the device is an instrument, equipment, consumables, system, medical device, health care product, or product that changes the appearance of the eye that can release drugs or has drug delivery function or potential drug delivery capability, such as corneal contact lenses, glasses, artificial lenses, sutures, OK lens cleaning (maintenance) systems, eye patches, eye patches, cosmetic contact lenses, microneedles, eye spray systems, eye massagers, eye fumigators, ocular surface drug delivery devices, intraocular drug delivery devices, fundus drug delivery devices, implanted pumps, wearable devices, acupoint massagers, eye relaxation devices, myopia treatment devices, or drug-device combinations for myopia prevention and control.

[0031] In some embodiments, vinpocetine, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or a combination of these substances, is used as the sole active ingredient, the main active ingredient, or the direct active ingredient; or the content or efficacy of vinpocetine, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or a combination of these substances accounts for 1% or less, or more than 1%, more than 10%, more than 20%, more than 30%, more than 40%, or more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or 100% of all active ingredients of the use, and the percentage (%) can be a mass ratio, a molar ratio, or a potency ratio.

[0032] In some embodiments, the concentration of vinpocetine, or its optical isomers or racemates, or solvates, or pharmaceutically acceptable salts, or prodrugs, or metabolites, or related compounds or extracts, or crystalline compounds, or a combination of these substances in the drug, preparation, composition or device is 0.001 μM to 10 mM, preferably 0.01 μM to 1000 μM, preferably 0.05 μM to 100 μM, more preferably 0.1 μM to 25 μM, more preferably 0.1 μM to 15 μM; or the concentration or proportion of these substances or their combination in the drug, preparation, composition or device is less than 25%, preferably less than 5%, preferably less than 1%, more preferably less than 0.01%, more preferably less than 0.001%, and the percentage (%) can be mass / volume concentration (grams per 100 ml) or mass percentage or molar (number) ratio.

[0033] The present application provides a drug, preparation, composition or device for ocular administration, wherein the concentration of vinpocetine, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or a combination of these substances in the drug, preparation, composition or device is 0.001 μM to 10 mM, preferably 0.01 μM to 1000 μM, preferably 0.05 μM to 100 μM, more preferably 0.1 μM to 25 μM, more preferably 0.1 μM to 15 μM; or the concentration or proportion of these substances or their combination in the drug, preparation, composition or device is less than 25%, preferably less than 5%, preferably less than 1%, more preferably less than 0.01%, more preferably less than 0.001%, and the percentage (%) may be mass / volume concentration (grams per 100 milliliters) or mass percentage or molar (number) ratio.

[0034] The present application also provides a pharmaceutical composition or compound preparation containing at least two active substances, including vinpocetine, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or a combination of these substances and other active substances for treating myopia. Preferably, the amount, concentration and / or efficacy of vinpocetine, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or a combination of these substances is not lower than any other active substance for treating myopia, and the efficacy is for treating myopia or controlling myopia progression.

[0035] The present application also provides a pharmaceutical composition or compound preparation, comprising vinpocetine, or its optical isomers or racemates, or solvates, or pharmaceutically acceptable salts, or prodrugs, or metabolites, or related compounds or extracts, or crystalline compounds, or combinations of these substances and other active substances for treating myopia, wherein the other active substances for treating myopia do not contain long-acting beta-adrenergic receptor agonists, long-acting muscarinic antagonists and / or muscarinic antagonists.

[0036] The present application further provides an ocular preparation or medicine, in which vinpocetine, or its optical isomers or racemates, or solvates, or pharmaceutically acceptable salts, or prodrugs, or metabolites, or related compounds or extracts, or crystalline compounds, or a combination of these substances is used as the direct, sole, or main active ingredient.

[0037] In some embodiments, the preparation or drug includes but is not limited to eye drops, eye ointments, eye sprays, implants, eye gels, eye patches, eye microspheres, eye sustained-release preparations, periocular injections, or intraocular injections.

[0038] In some embodiments, the concentration of vinpocetine, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or a combination of these substances is 0.001 μM to 10 mM, preferably 0.01 μM to 1000 μM, preferably 0.05 μM to 100 μM, more preferably 0.1 μM to 25 μM, more preferably 0.1 μM to 15 μM; or the concentration or proportion of vinpocetine is less than 25%, preferably less than 5%, preferably less than 1%, more preferably less than 0.01%, more preferably less than 0.001%, and the percentage (%) can be mass / volume concentration (grams per 100 ml) or mass percentage or molar (number) ratio.

[0039] In some embodiments, the type I phosphodiesterase inhibitor is PDE1-IN-2, LY1 (Sherif Khedr et al., Selective Phosphodiesterase 1 Inhibitor LY1 Reduces Blood Pressure in Spontaneously Hypertensive and Dahl Salt Sensitive Rats, The FASEB Journal, 2020 April 1, Volume 34, Issue S1, Pages 1-1.), Lu AF41228, Lu AF58027 (Morten Laursen et al., Novel selective PDE type 1 inhibitors cause vasodilatation and lower blood pressure in rats, Br J Pharmacol, 2017 Aug; 174(15):2563-2575.), BTTQ (Asim B Dey et al., elective Phosphodiesterase 1 Inhibitor BTTQ Reduces Blood Pressure in Spontaneously Hypertensive and Dahl Salt Sensitive Rats: Role of Peripheral Vasodilation, Front Physiol, 2020 Sep 8; 11:543727.), Nimodipine, Zaprinast, Caffeine, Deprenyl, Amantadine (Alexandre E Medina, Therapeutic utility of phosphodiesterase type I inhibitors in neurological conditions, Front Neurosci,. 2011 Feb 18; 5:21.), KS505a, bepril, flunarizine, amiodarone, zaprinast, 8-methoxymethyl IPMX, SCH 51866, Nimodipine, IC224 (Claire Lugnier, Cyclicnucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents, Pharmacol Ther, 2006 Mar; 109 (3): 366-98.), ITI-214 (Peng Li et al., Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases, J Med Chem, 2016 Feb 11; 59 (3): 1149-64.), etc. Since Vinpocetine is a type I phosphodiesterase inhibitor (PDE1 inhibitor), perhaps other type I phosphodiesterase inhibitors known before the application (whether specific or not) have the same unknown activity or efficacy as Vinpocetine, such as being able to prevent and / or treat myopia and control myopia progression.

[0040] In some embodiments, the miRNA and its modifications are MicroRNA-328 or MicroRNA-328 reverse strand compositions.

[0041] In some embodiments, a combination of two or more substances of vinpocetine, or its optical isomers or racemates, or its solvates, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites, or its related compounds or extracts, or its crystalline compounds is administered concurrently, such as simultaneous or sequential administration, administration on the same day, administration in the same week, administration in the same month, or administration in the same year in a specific medication (treatment) process; or administration is alternately administered at intervals, such as alternating administration at intervals of 4 hours, alternating administration at intervals of 12 hours, alternating administration every other day, alternating administration every other week, alternating administration every other month, or alternating administration every other year; or:

[0042] Vinpocetine, or its optical isomers or racemates, or solvates, or pharmaceutically acceptable salts, or prodrugs, or metabolites, or related compounds or extracts, or crystalline compounds, or a combination of these substances, is administered concurrently with one or more other drugs, such as simultaneous or sequential administration, administration on the same day, administration in the same week, administration in the same month, or administration in the same year in a specific medication (treatment) process; or administration is alternately administered at intervals, such as alternating administration at intervals of 4 hours, alternating administration at intervals of 12 hours, alternating administration every other day, alternating administration every other week, alternating administration every other month, or alternating administration every other year; or:

[0043] Vinpocetine, or its optical isomers or racemates, or its solvates, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites, or its related compounds or extracts, or its crystalline compounds, or a combination of these substances is used in combination with a device (such as a corneal contact lens) and / or surgery (such as refractive surgery, myopic keratitis laser surgery, lens surgery).

[0044] In some embodiments, the one or more other drugs are myopia prevention and control and / or myopia treatment drugs (such as benzydrylamine, atropine, dimethoate, polyunsaturated fatty acids, DHA, fish oil, prazosin, M receptor blockers, niacin, pirenzepine, muscarinic antagonists, 7-methylxanthine (7MX), pirenzepine, ampicillin, anandamide, timolol maleate, epinephrine, pyrazine, pyridine, pyridine, pyridine, methylamine, chlorpromazine, acetylcholinesterase inhibitors, dopamine agonists, γ-aminobutyric acid, succinate ... -aminobutyric acid, naloxone, glucagon, retinoic acid, salidroside, formononetin, etc.), vasodilators, smooth muscle relaxants, drugs to prevent vasospasm, drugs to regulate collagen metabolism, piracetam, antiallergic drugs, liver protection drugs, vinpocetine, or its optical isomers or racemates, or solvates, or pharmaceutically acceptable salts, or prodrugs, or metabolites, or related compounds or extracts, or crystalline compounds, or combinations thereof.

[0045] In some embodiments, the device is various glasses that delay the progression of myopia, OK glasses, frame glasses, eye patches, (myopia) acupoint massagers, eye relaxation equipment, myopia treatment devices, and other instruments, equipment, consumables, medical devices or health care products that have the function of protecting vision or treating (correcting) myopia.

[0046] In some embodiments, the drug, one or more other drugs, myopia prevention and control drugs, myopia treatment drugs, or ophthalmic preparations may not be long-acting β-adrenoceptor agonists (LABA), long-acting muscarinic antagonists (LAMA) and / or muscarinic antagonists, for example, not salmeterol and / or tiotropium bromide.

[0047] In some embodiments, in the process of achieving the use, a systemic dosage form (such as an oral tablet) and a local dosage form (such as eye drops) are used simultaneously, or used in combination, or used alternately, or used at intervals, or used separately.

[0048] In some embodiments, the abnormal development of the eyeball is mainly induced by environmental factors, or is mainly caused by human factors, which is a refractive developmental abnormality (such as long-term close reading, frequent use of electronic screens, continuous near vision without the opportunity for hyperopia, improper use of refractive correction glasses, side effects of drugs, obesity, trauma, poor lighting in the learning environment, and lack of outdoor exercise), and is unrelated to genetic factors, or genetic factors are a secondary factor, a concomitant factor, or a synergistic factor. The abnormal development is, for example, abnormal development of the size of the eyeball in children and adolescents (such as 3-26 years old).

[0049] In some embodiments, abnormal development or developmental abnormality includes excessive axial length or a mismatch between the rate of axial lengthening and the refractive system, resulting in the focus of parallel light rays passing through the normal or abnormal refractive system of the eye being located in front of the retina. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 :The effects of high, medium and low concentrations of vinpocetine on refraction, vitreous cavity depth and axial length in the FDM group. A is the difference in refraction between the experimental eye and the fellow eye; B is the difference in vitreous cavity depth between the experimental eye and the fellow eye; C is the difference in axial length between the experimental eye and the fellow eye.

[0051] Figure 2 :The effects of high, medium and low concentrations of vinpocetine on refraction, vitreous cavity depth and axial length in the LIM group. A is the difference in refraction between the experimental eye and the fellow eye; B is the difference in vitreous cavity depth between the experimental eye and the fellow eye; C is the difference in axial length between the experimental eye and the fellow eye.

[0052] Figure 3:The effects of high, medium and low concentrations of vinpocetine on choroidal thickness and blood flow in the FDM group. A is the effect of vinpocetine on choroidal thickness ChT; B is the effect of vinpocetine on choroidal blood flow ChBP.

[0053] Figure 4 :The effects of high, medium and low concentrations of vinpocetine on choroidal thickness and blood flow in the LIM group. A is the effect of vinpocetine on choroidal thickness ChT; B is the effect of vinpocetine on choroidal blood flow ChBP.

[0054] Note: * represents p<0.05, ** represents p<0.01, *** represents p<0.001.

[0055] The results of the assay are shown in 5 bar graphs at each different time period (LIM group: before administration, 3 days of administration, and 7 days of administration or FDM group: before administration, 1 week of administration, and 2 weeks of administration). Figure 1 , Figure 3 In the figure, every five consecutive bar graphs from left to right are FDM+Vehicle, FDM+Atropine (0.1%), FDM+VPN (0.01μM), FDM+VPN (0.1μM), and FDM+VPN (1μM). Figure 2 , Figure 4 In the figure, each of the five consecutive bar graphs from left to right is LIM+Vehicle, LIM+Atropine (0.1%), LIM+VPN (0.01 μM), LIM+VPN (0.1 μM), LIM+VPN (1 μM). VPN=vinpocetine.

[0056] Figure 5 : Changes of refraction and axial length parameters in myopic individuals with different doses of systemic administration of vinpocetine. The differences in refraction (A), vitreous cavity depth (B), and axial length (C) between the two eyes of the subjects were compared before the experiment, 1 week after the experiment, and 2 weeks after the experiment. VPN: vinpocetine; Vehicle: vehicle; Week: week; Refraction: refraction; VCD: vitreous cavity depth; AL: axial length; N: sample size. Repeated measures analysis of variance (AC).

[0057] Figure 6: Salmeterol and tiotropium in the treatment of myopia. The effects of different drug groups on the difference in refraction (A), vitreous cavity depth (B), axial length (C), anterior chamber depth (D), lens thickness (E), and corneal curvature (F) between the two eyes of myopic individuals were compared before and after the experiment. VPN = V: vinpocetine; T: tiotropium; S: salmeterol; Vehicle: vehicle; Week: week; Refraction: refraction; VCD: vitreous cavity depth; AL: axial length; ACD: anterior chamber depth; LT: lens thickness; RCC: corneal curvature; N: sample size. *P<0.05, **P<0.01, ***P<0.001. Repeated measures analysis of variance (AF).

[0058] Figure 7 : The intervention effect of vinpocetine eye drops on the refraction, vitreous cavity depth and axial length of myopic individuals. The differences in refraction (A), vitreous cavity depth (B), axial length (C), anterior chamber depth (D), lens thickness (E) and corneal curvature (F) between the eyes of the same subject were compared before and 2 weeks after the different drug administration groups. VPN: vinpocetine; Vehicle: vehicle; Refraction: refraction; VCD: vitreous cavity depth; AL: axial length; ACD: anterior chamber depth; LT: lens thickness; RCC: corneal curvature; N: sample size. *P<0.05, **P<0.01, ***P<0.001. Repeated measures analysis of variance (AF).

[0059] Figure 8 : The intervention effect of vinpocetine metabolite AVA on the refraction, vitreous cavity depth and axial length of myopic individuals. The differences in refraction (A), vitreous cavity depth (B) and axial length (C) between the two eyes of the subjects were compared before and after 1 week of experimental administration. AVA: apovincaminic acid, a metabolite of vinpocetine; Vehicle: solvent; Week: week; Refraction: refraction; VCD: vitreous cavity depth; AL: axial length; N: sample size. *P<0.05, **P<0.01, ***P<0.001. Repeated measures analysis of variance (AC). DETAILED DESCRIPTION

[0060] The following will exemplarily show the embodiments of the present application. Although the present application has been described in conjunction with these specific embodiments, it should be understood that the present application is not intended to be limited to such specific embodiments. On the contrary, the present application is intended to cover such alternatives, modifications, substitutions, variations and equivalents that may be included in the spirit and scope of the present application as defined by the appended claims.

[0061] The present application provides a method for preventing and treating myopia, which involves topically administering vinpocetine or its related compounds to the eye.

[0062] The present application further provides a drug for the treatment of myopia and the control of myopia progression, which is topically applied to the eye and uses vinpocetine as the only or main active ingredient. In the prior art, vinpocetine is mainly tablets and injections, and is administered systemically. When vinpocetine is used to treat myopia, if systemic administration is performed, it will be affected by the first-pass effect of the drug, the blood-retinal barrier (BRB), etc., and a large dose of the drug needs to be given to ensure that the vinpocetine or its metabolites entering the eye reach the therapeutic concentration threshold. Such a treatment strategy has a potential risk of systemic adverse reactions, especially for young people and requires long-term continuous administration. At the same time, systemic administration is affected by more individual differences, which increases the uncertainty of the efficacy of vinpocetine in preventing and controlling myopia. Therefore, the present application has developed a vinpocetine drug with better effectiveness and safety, which is topically applied to the eye. This drug development strategy targets the use of vinpocetine and its related compounds (such as fluorinated compounds) in the prevention and control of myopia in children and adolescents. Its advantages are that it is convenient for patients to use the medicine and has a high degree of compliance. It can be given for a long time (such as one month, half a year, one year, three years, five years, or ten years), the growth and development of young individuals are less affected, and the ophthalmic dosage form is safe and reliable.

[0063] The present application also provides a method, which comprises administering an effective dose of vinpocetine or a related compound thereof to a suitable subject, for treating myopia and / or inhibiting the elongation of the axial length thereof.

[0064] The method or pharmaceutical composition of the present application can significantly inhibit myopia, especially inhibit myopia in children and / or adolescents (preferably the age of the population is 3-26 years old, more preferably the age of the population is 6-18 years old), or early or middle myopia, or mild or moderate myopia, or non-pathological myopia, or axial simple myopia, or axial myopia in children and / or adolescents (preferably the age of the population is 3-26 years old, more preferably the age of the population is 6-18 years old), or progressive myopia in children and / or adolescents (preferably the age of the population is 3-26 years old, more preferably the age of the population is 6-18 years old), or primary myopia, or non-senile myopia, or myopia in minors, or progressive myopia, or non-refractive myopia.

[0065] The method or pharmaceutical composition of the present application can significantly inhibit or slow down the elongation of the eye axis and / or the increase of the vitreous cavity length in myopic individuals (including individuals who are not yet myopic but are about to develop myopia). Preferably, the method or pharmaceutical composition of the present application is applicable to a population including those suffering from children and / or adolescent myopia (preferably a population aged 3-26 years old, more preferably a population aged 6-18 years old), or early or mid-term myopia, or mild or moderate myopia, or non-pathological myopia, or axial simple myopia, or children and / or adolescent axial myopia (preferably a population aged 3-26 years old, more preferably a population aged 6-18 years old), or children and / or adolescent progressive myopia (preferably a population aged 3-26 years old, more preferably a population aged 6-18 years old), or primary myopia, or non-senile myopia, or juvenile myopia, or progressive myopia, or non-refractive myopia. The axial length elongation and / or increase in vitreous cavity length of these myopic individuals (including individuals who are not yet myopic but are about to develop myopia) are inhibited or even stopped by the method or pharmaceutical composition of the present application.

[0066] The present application provides a method for treating, preventing or alleviating myopia and related symptoms in a subject, comprising administering to the subject a therapeutically effective amount of vinpocetine or a therapeutically acceptable salt thereof or a related compound thereof. Preferably, the vinpocetine is administered alone, preferably, the vinpocetine is administered simultaneously, sequentially, intermittently or alternately with other drugs, preferably, the vinpocetine is administered in the form of a pharmaceutical composition, preferably, the pharmaceutical composition is prepared into an ophthalmic preparation, preferably, the ophthalmic preparation further comprises a pharmaceutically acceptable carrier, preferably, the carrier is an ophthalmologically acceptable carrier.

[0067] The present application also provides a pharmaceutical composition for treating, preventing or alleviating myopia and its related symptoms, the pharmaceutical composition comprising vinpocetine or its therapeutically acceptable salt or its related compound. Preferably, the pharmaceutical composition is prepared as an ophthalmic preparation, preferably, the ophthalmic preparation further comprises a pharmaceutically acceptable carrier, preferably, the carrier is an ophthalmologically acceptable carrier.

[0068] The present application also provides the use of a compound or its therapeutically acceptable salt and derivatives thereof in the preparation of a pharmaceutical composition for treating, preventing or alleviating myopia and its related symptoms. The compound may be a metabolite of vinpocetine (such as apovincaminic acid), vinca alkaloid, apovincamine, periwinkle extract, vincamine, voacanga africana extract, apocynaceae plant extract, vincristine, tabersonine, vinblastine, vindoline, apovincaminic acid hydrochloride, catharanthine, ethylvincaminate, etc.; preferably, the compound is vinpocetine or its therapeutically acceptable salt and derivatives thereof. Preferably, the pharmaceutical composition is prepared as an ophthalmic preparation. Preferably, the ophthalmic preparation further comprises a pharmaceutically acceptable carrier. Preferably, the carrier is an ophthalmologically acceptable carrier.

[0069] The myopia-related symptoms include, but are not limited to, floaters, glaucoma, posterior scleral staphyloma, retinal detachment, amblyopia, macular hemorrhage, visual field loss, progressive or sudden decrease in vision (especially near vision), eye soreness and / or pain, and night blindness.

[0070] According to one aspect of the present application, the myopia is refractive myopia. According to another aspect of the present application, the myopia is axial myopia.

[0071] The present application also provides a myopia treatment (inhibiting myopia progression) scheme in which vinpocetine or its salt form is used in combination with, or intermittently or alternately with, other myopia prevention and control drugs (such as atropine) or optical prevention and control means (such as OK lenses) in the prevention, alleviation and treatment of myopia.

[0072] The present application also provides a myopia treatment (inhibiting myopia progression and / or axial lengthening) regimen of vinpocetine or its salt form, which is a combination or alternating use of systemic administration dosage forms (such as oral tablets) and local administration dosage forms (such as eye drops) in the prevention, alleviation and treatment of myopia.

[0073] Terms and Definitions

[0074] "Myopia" refers to the situation in which parallel light rays converge in front of the retina after passing through the eye's refractive system in a relaxed state of accommodation. Myopia is usually manifested by lower than normal distance vision and normal near vision. The clinical concept of a myopic individual is: a person with a static refraction of ≥-0.25D. The clinical manifestations are blurred vision at a distance and good vision at a close distance. In the early stages of myopia, there are often fluctuations in distance vision. Since no or little accommodation is used when looking at close objects, the convergence function is correspondingly weakened, which can easily cause exotropia or exotropia. In some paragraphs of this article, there is no difference between the concepts represented by the words "myopia" and "myopia", and the two can be interchangeable. Researchers in this field should correctly understand the meaning of "myopia" or "myopia" in this patent through the context in which they are located.

[0075] There are four common types of myopia: (1) Based on the size of the refractive power, it can be divided into mild (300 degrees and below), moderate (300 degrees to 600 degrees) and severe (600 degrees or above -6D); (2) Based on whether the refractive component is abnormal, it can be divided into refractive myopia and axial myopia; (3) Based on whether pathological changes occur, it can be divided into pathological myopia and simple myopia; (4) Based on the cause, it can be divided into primary myopia and concurrent / secondary myopia.

[0076] For "mild or moderate myopia", the patient has no other symptoms except blurred vision of distant objects, that is, the main symptoms are a gradual decrease in distance vision, blurred distant objects, and normal near vision. Usually, there are no special changes in the eyes except for the length of the axial length.

[0077] For "high myopia" (such as -6D), the patient's anterior chamber is deep, the pupil is large, and the eyeball appears slightly protruding due to the excessive length of the anterior-posterior axis. White or grayish white crescent-shaped spots can be seen on the temporal side of the optic disc, called myopic half-moon spots. This is because the sclera stretches backwards, the retinal pigment epithelium and choroid are detached from the temporal edge of the optic disc, and the sclera or part of the choroid and sclera are exposed. The posterior sclera continues to expand backwards, and genu fissure-like stripes and subretinal neovascularization may appear in the macula, and plaque-like atrophy and degeneration of the nearby retina and choroid may occur, leading to posterior scleral staphyloma. There is often pigment hyperplasia and even bleeding in the macula, forming an atrophic spot (Forster-Fuchs spot). Such patients are often accompanied by vitreous liquefaction and turbidity, and a few may also develop retinal detachment and concurrent cataracts. In addition, high myopia often has poor vision at both far and near due to turbidity of the refractive medium and degeneration of the retina and choroid, and is sometimes accompanied by floating black shadows in front of the eyes. If such a lesion occurs, this type of myopia is no longer simple myopia.

[0078] "Refractive myopia" is mainly caused by excessive curvature of the cornea or lens, which causes the refractive power to exceed the normal range, while the axial length of the eye is within the normal range.

[0079] "Axial myopia" means that the axial length of the eye exceeds the normal range, while the curvature of the cornea and lens is basically within the normal range. Axial myopia is the main type of myopia in children and adolescents.

[0080] "Pathological myopia", also known as degenerative myopia, is a degenerative lesion of the fundus. Patients usually have a high degree of myopia (such as greater than 600 degrees), and their visual function is significantly impaired, with worse distance vision. In addition, there are also many abnormalities in visual field, light perception, and contrast perception, often accompanied by poor night vision (night blindness), floaters, floating objects, and flashes of light. The fundus of patients can be seen to be thinning of the retinal pigment epithelium and choroid, often accompanied by symptoms such as retinal pigment epithelium atrophy, choroidal neovascularization, retinal detachment, and macular degeneration. In addition, pathological changes in the fundus continue to develop after development stops. This type of myopia can be severe and can cause blindness.

[0081] "Simple myopia" refers to myopia that develops during the growth period of the eyeball. When the growth stops, the myopia tends to stabilize. For example, it often occurs during school age, the myopia degree is below 600 degrees, and there is generally no obvious pathological change in the fundus. This is also called acquired myopia (eye). This type of myopia develops progressively, and the axial length of the eye also gradually increases. Appropriate lenses can be used to correct vision to normal, and other visual function indicators are mostly normal. On the contrary, it is non-simple myopia. Examples of non-simple myopia include pathological myopia, high myopia, and myopia in the elderly.

[0082] "Primary myopia" is the main type of myopia. "Primary" refers to a type of myopia with unknown causes, such as the cause and mechanism of occurrence that cannot be determined using existing diagnostic technology. During its occurrence and development, it manifests pathological or physiological functional-structural changes specific to myopia, including congenital myopia and acquired simple myopia.

[0083] "Concurrent / secondary myopia" refers to temporary myopia caused by eye adjustment dysfunction or abnormal refractive index due to internal and external factors (such as toxic myopia, drug-induced myopia, traumatic myopia, diabetic myopia and initial cataract myopia). This type of myopia is characterized by clear inducing factors and repeated fluctuations in vision. This type of myopia is often prevalent among the elderly.

[0084] "Axial simple myopia" is sometimes also called simple axial myopia. It belongs to simple myopia, which is characterized by simple myopia in which the imaging focus is located in front of the retina due to elongation of the eye axis and / or increased depth of the vitreous cavity. This myopia has basically normal refractive tissues (such as the lens) in the eye. It is the most common type of myopia in children and adolescents, and is more common in people aged 3 to 26, especially those aged 6-18 (Paul N Baird, Nat Rev Dis Primers. 2020 Dec 17; 6(1): 99. and A J Adams, Am J Optom Physiol Opt. 1987 Feb; 64(2): 150-2 and Seang-Mei Saw, Ophthalmic Physiol Opt. 2005 Sep; 25(5): 381-91.).

[0085] "Curvature myopia" is myopia caused simply by an increase in the curvature of the cornea or lens.

[0086] "Index myopia" is myopia caused mainly by the increase in refractive power due to the increase in the refractive index of aqueous humor and lens, which belongs to refractive myopia.

[0087] "Progressive myopia" refers to a type of myopia in which the refractive power continues to decrease over time or as the individual ages. If this type of myopia is not intervened, it will generally eventually develop into high myopia.

[0088] "Children and adolescents' myopia" is a simple myopia caused by long-term close-range eye use. Most of these myopia patients have not developed pathological myopia. The eyeballs of children or adolescents are in the growth and development stage, with strong accommodation ability and relatively large sclera stretchability. When reading, writing and other close-range work, the eyeballs are in a defocused state. Over time, the anterior-posterior axis of the eyeball will become longer, which is easy to form axial myopia in children and adolescents. If the eye habits are not changed or medical intervention is not taken for myopia, the degree of myopia in children and adolescents will gradually increase, and the corresponding axial length will further increase. Therefore, with the growth and development and learning rhythm of children or adolescents, the axial length of this type of myopia has been in a dynamic state, and the refractive power has continued to become negative, that is, it is a progressive myopia, rather than a static state like myopia in adults or the elderly. Therefore, the clinical evaluation of the efficacy of this type of myopia treatment drugs is based on controlling the progression of myopia and inhibiting the elongation of the axial length as the main indicators.

[0089] "Myopia in the elderly" is usually more complicated, easily affected by the aging of body organs and underlying diseases, often accompanied by symptoms such as blood sugar changes, vascular sclerosis, insufficient blood supply, ocular microcirculation disorders, and mostly high myopia. A notable feature of adults or elderly myopia patients is that the degree of myopia generally does not increase with age, and the main reason is that the eye growth and development of this type of individual basically stops, and the axial length no longer changes due to long-term close-up viewing. Therefore, myopia in the elderly (including adults) and myopia in children and adolescents (minors) are two completely different types of diseases, and these two indications need to be clearly distinguished in myopia treatment methods. Although the medicine or method of the present application is suitable for treating various myopia types, it is preferred that simple myopia excludes non-simple myopia such as myopia in the elderly, high myopia, and pathological myopia, because these myopia patients The clinical intervention strategy is no longer to inhibit the extension of the axial length, but more to prevent blindness caused by severe eye lesions, such as blindness caused by retinal detachment.

[0090] "Myopia-related symptoms" include complications caused by myopia, such as complications of high myopia, floaters, glaucoma, posterior scleral staphyloma, retinal detachment, retinal tear, amblyopia, macular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or macular lesions, visual field loss, progressive or sudden decrease in vision (especially near vision), eye soreness and / or pain, poor night vision (such as night blindness), astigmatism, anisometropia, blindness, vitreous liquefaction, vitreous opacities, strabismus, frequent blinking, flashes of light, frequent rubbing of the eyes, anisometropia, blurred vision when looking at distant objects, the need to squint or partially close the eyelids to see distant objects clearly, and headaches caused by eyestrain. Pain, difficulty seeing while driving, especially at night (night myopia), retinal atrophy and degeneration (hemorrhage and holes), subretinal neovascularization, and eyeball atrophy; varying degrees of fundus changes may also occur, myopic arcuate plates, macular hemorrhage or formation of subretinal neovascular tumors, irregularly shaped white atrophic spots, or circular black spots with pigmentation (Fuchs spots), lattice degeneration and cystic degeneration of the retina periphery, vitreous liquefaction, opacity and posterior vitreous detachment at a young age, the risk of retinal holes and detachment is higher than that of normal people, often due to the long anterior-posterior diameter of the eyeball, the eyeball is more prominent, the posterior part of the eyeball is extremely dilated, and a scleral staphyloma is formed.

[0091] "Accommodative tension myopia" is myopia caused by excessive near vision load on the eyeball and excessive adjustment of the ciliary muscle, resulting in accommodation tension or accommodation spasm.

[0092] "Astigmatic myopia" is a type of myopia in which the external light is scattered in all directions and cannot form a focus on the retina due to damage to the cornea or varying degrees of curvature.

[0093] In some embodiments, the myopia of the present invention may include or exclude pathological myopia, high myopia, senile myopia, astigmatic myopia, and these myopias can be corrected by the function of vinpocetine to improve blood flow, and the progression of myopia can also be prevented, treated or slowed down (controlled) by unknown mechanisms of vinpocetine.

[0094] Intervention measures for myopia can be divided into myopia correction and myopia treatment, among which myopia treatment has the main feature and purpose of inhibiting (controlling) the progression of myopia.

[0095] "Myopia correction" is to correct or reduce the degree of myopia through optical methods. Commonly used correction methods include wearing frame glasses, transparent lens phacoemulsification, intraocular lens implantation, corneal laser surgery, etc. However, this method only corrects the individual's refractive power and cannot delay the progression of myopia or reverse the excessive length of the eye axis. In other words, this type of myopia intervention method will not stop or slow down the process of continuous negative refractive power and cannot inhibit the progression of myopia. Therefore, myopia correction methods such as corneal laser surgery will compensate for the patient's refractive error and restore their distance vision. It is suitable for improving vision in people with pathological myopia, high myopia or elderly myopia, but it is not suitable for treating axial myopia or simple myopia, such as children or adolescents with myopia, primary myopia, or mild or moderate myopia. In fact, although the distance vision of individuals with axial myopia is temporarily restored after wearing frame glasses, this correction method will not inhibit the further elongation of their eye axis or control the speed of their myopia development. In the absence of other drug treatments, the result is that the degree of myopia will further increase, and patients will need to replace frame glasses with higher degrees every once in a while to continue to correct their vision.

[0096] "Inhibiting (controlling) myopia progression" refers to the use of various methods or drugs to delay (slow down) the continuous deepening of myopia, slow down the speed of negative refraction, control the development of myopia and inhibit (control) the continuous elongation of the axial length. It is an etiological treatment, and most of the patients are minors who are still in the stage of eye development. For the treatment of myopia in children or adolescents, slowing down, controlling or even stopping the continuous negative refraction and inhibiting the corresponding increase in axial length are the primary goals of the development of myopia treatment drugs. That is, the treatment of myopia for children or adolescents, axial myopia, simple myopia and other types of myopia should achieve the effect of controlling or inhibiting the development of myopia, rather than simply reversing or correcting this refractive error.

[0097] Unless otherwise specified, the "treatment (myopia)" of the present application refers to the inhibition (control) of myopia progression, rather than the correction of myopia. The terms "treatment", "slowdown", "delay", "inhibition", "control", or "prevention and control" used herein refer to treatment measures and preventive or preventive measures, the purpose of which is to prevent or slow down (mitigate) or terminate the target disease or disorder. For example, after receiving a therapeutic amount of a vinpocetine compound or a pharmaceutical composition containing it according to the method described herein, the subject shows observable and / or measured inhibition, delay, reduction and disappearance of one or more symptoms and symptoms of an ophthalmic disorder, or a slowdown and delay in the progression of the disease, then the ophthalmic disorder of the subject is successfully treated. It should also be understood that the various modes of treatment or prevention of medical disorders described herein are intended to represent "significant", which include complete treatment or prevention and less than complete treatment or prevention, wherein a certain biologically relevant or medically relevant result is achieved. In some embodiments, "treatment" does not require 100% elimination of myopia or myopic symptoms. In some embodiments, compared to the level observed in the absence of the composition or method of the present application (e.g., in a biologically matched control subject or specimen not exposed to the composition or compound of the present application method), "treating" myopia or myopia-related symptoms according to the present application method obtains prevention, alleviation, inhibition, and prevention of myopia progression of, for example, at least about 5%, at least about 10%, or at least about 20%. In some embodiments, compared to myopia or myopia-related symptoms in the absence of the compound of the present application method, myopia or myopia-related symptoms are treated by at least about 30%, at least about 40%, at least about 50%, or at least about 60%, at least about 70%, at least about 80%, at least about 90% or more (about 100%). Therefore, it can be understood by those skilled in the art that "treatment", "slowing down", "delaying", "inhibiting", "controlling" or "preventing and controlling" does not refer to eye health care effects or auxiliary therapeutic effects, etc., which are beneficial to myopia treatment by indirect means, such as enhancing blood circulation in the eye, improving comfort during eye application, etc.

[0098] The evaluation of the therapeutic effect of myopia involves many factors, such as whether the selection of the sample group is scientific, whether an objective control is set, whether an effective dose is applied, etc. Specifically, if the sample group is mostly elderly (whose eye development has stopped and who may have underlying diseases such as arteriosclerosis, etc.), it is difficult to prove that Vinpocetine has a therapeutic effect on myopia; if the efficacy is evaluated only through vision tests without designing any parallel control (such as a placebo group), it is also impossible to prove that Vinpocetine has a therapeutic effect on myopia. The present application uses two classic myopia disease models, form deprivation and negative mirror-induced guinea pig models, which are commonly used in the preclinical development stage of actual myopia drugs and whose eyes are still in the growth and development stage, as well as scientific experimental standards in the field to evaluate the efficacy of compounds in preventing and controlling myopia, especially preventing and controlling myopia in children and adolescents and / or simple myopia (DA Goss, Am J Optom Physiol Opt. 1981 Oct; 58(10): 859-69. and Hao Wu, Proc Natl Acad Sci U S A. 2018 Jul 24; 115(30): E7091-E7100. and Sen Zhang, Invest Ophthalmol Vis Sci. 2019 Jul 1; 60(8): 3074-3083.).

[0099] "Far vision" is also known as naked eye far vision. Medically, it refers to the vision measured when looking straight ahead with eyes open at a horizontal distance of 5 meters from the eye chart, without wearing glasses or any auxiliary equipment that can enhance vision (such as frame glasses, contact lenses, cosmetic contact lenses, pinhole lenses, etc.).

[0100] "Topical administration" refers to direct administration to the desired part of the body or a method of administration that can achieve local effect, including but not limited to: epidermal administration, inhalation administration, enema administration, ocular administration, and nasal administration.

[0101] "Systemic administration" is also called systemic administration, which includes intravenous administration, oral administration, intramuscular injection, subcutaneous injection and other administration methods. Drugs can be transported through the blood in the body and distributed throughout the body.

[0102] "Improved systemic drug delivery" refers to a safe, efficient and convenient systemic drug delivery method that can utilize specific drug targeting technologies to effectively reduce the toxicity of systemic drugs while enriching the vinpocetine drug in the eye.

[0103] "Directly active ingredient" is also called "(drug) active ingredient (Active pharmaceutical ingredient)", which refers to a substance that has a direct therapeutic effect on a disease (such as myopia). It is a sufficient condition for treating the disease or its parameters such as dosage and administration method directly affect the effect of treating the disease. There is a causal relationship between the administration of this ingredient and the effect of treating the disease.

[0104] "Sole active ingredient" means that there is only one ingredient in the final product (such as a drug) that exerts a medicinal effect, such as directly inhibiting, preventing and / or treating myopia.

[0105] "Main active ingredient" refers to an active ingredient whose added amount, proportion, concentration or efficacy is no less than other active ingredients (such as myopia treatment effects) in the final product (such as medicine).

[0106] “These substances” refer to vinpocetine, or its optical isomers or racemates, or solvates, or pharmaceutically acceptable salts, or prodrugs, or metabolites, or related compounds or extracts, or crystalline compounds thereof.

[0107] In this specification and the appended claims, singular forms, including the singular forms "a", "an", and "the", also specifically encompass plural referents of the terms to which they refer, unless the context clearly dictates otherwise. Additionally, as used herein, the word "or" is used in its "inclusive" sense of "and / or" rather than the "exclusive" sense of "either / or", unless specifically indicated otherwise.

[0108] As used herein, reference to variable numerical ranges is intended to convey that the application can be implemented with variables equal to any value in the range. Therefore, for inherent discontinuous variables, the variable can be equal to any integer value in the numerical range, including the endpoints of the range. Similarly, for inherent continuous variables, the variable can be equal to any real value in the numerical range, including the endpoints of the range. For example, the variable described as having a numerical value between 0 and 2 can be 0, 1 or 2 for inherent discontinuous variables, and can be 0.0, 0.1, 0.01, 0.001 or any other real value for inherent continuous variables.

[0109] As used herein, "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If the use of the term is not clear to one of ordinary skill in the art, then in the context in which the term is used, "about" will mean a value within the range of plus or minus 10% of the recited value.

[0110] As used herein, "administering" a compound, formulation or drug to a subject includes any route of introducing or delivering the compound to a subject to perform its intended function. "Administration" can be performed by any suitable route, including oral, intraocular, ocular surface, intranasal, parenteral (by intravenous, intramuscular, intraperitoneal or subcutaneous) or topical administration (such as topical administration of the skin of parts such as the eye). "Administration" includes self-administration and administration by others. When administering to the eye or periocular, it can be applied to the affected eye, the unaffected eye or both of the subject.

[0111] The term "effective amount" as used herein refers to an amount sufficient to obtain the desired therapeutic and / or preventive effect, such as an amount that causes the prevention or alleviation of a symptom associated with an ophthalmic condition. The amount of the composition administered to the subject will depend on the type and severity of the disease and the nature of the individual, such as general health, age, sex, weight, and tolerance to drugs. The amount also depends on the extent, severity, and type of the disease. A skilled person will be able to determine the appropriate dose based on these and other factors. The composition may also be administered in combination with one or more other therapeutic compounds. In the methods described herein, a vinpocetine compound or a pharmaceutical composition containing it may be administered to a subject having one or more symptoms or signs of an ophthalmic condition. For example, a "therapeutically effective amount" of vinpocetine refers to an average level of pharmacological effects that minimizes the ophthalmic condition.

[0112] As used herein, the terms "formulation" and "composition" are used interchangeably and refer to a mixture of two or more compounds, elements or molecules. In some aspects, the terms "formulation" and "composition" can be used to refer to a mixture of one or more active agents with a carrier or other excipient. A composition can take almost any physical form, including solid, liquid (e.g., solution), or gas.

[0113] In addition, the term "dosage form" may include one or more preparations or compositions provided in a form for administration to a subject. For example, an injectable dosage form may be a preparation or composition prepared in a manner suitable for administration by injection.

[0114] The term "pharmaceutically acceptable" as used herein means a drug carrier, a drug concentration, or a drug form, etc., approved for use in animals, preferably in humans, by regulatory authorities such as CFDA (China), EMEA (Europe) and / or FDA (US) and / or any other national regulatory authorities.

[0115] As used herein, the term "simultaneous" therapeutic use refers to the administration of at least two active ingredients (compounds) by the same route and at the same time or substantially at the same time.

[0116] As used herein, the term "separate" therapeutic application refers to the administration of at least two active ingredients (compounds) at the same time or at substantially the same time by different routes.

[0117] The term "sequential" therapeutic application as used herein refers to the administration of at least two active ingredients at different times, with the same or different routes of administration. More specifically, sequential application refers to the complete administration of one of the active ingredients before the administration of the other active ingredient begins. Thus, one active ingredient may be administered several minutes, hours or days before the other active ingredient is administered. In this case, no simultaneous treatment is performed.

[0118] As used herein, the term "preventing" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in treated samples relative to untreated control samples, or delays the onset of or reduces the severity of one or more symptoms of the disorder or condition relative to untreated control samples.

[0119] The term "related compounds" as used herein includes, but is not limited to, derivatives or structural analogs of vinpocetine.

[0120] The term "derivative" or "analog" of a compound as used herein includes any molecule related to the function and / or structure of the compound, such as an acid, amide, ester, ether, acetylated variant, hydroxylated variant, or alkylated variant of the compound. The term derivative also includes compounds related to the structure that have lost one or more substituents as listed above. Preferred derivatives of a compound are molecules with a significant degree of similarity to the compound, as determined by known methods. Similar compounds, together with their similarity index to the parent molecule, can be found in a large number of databases, such as PubChem (http: / / pubchem.ncbi.nlm.nih.gov / search / ) or DrugBank (http: / / www.drugbank.ca / ). In a more preferred embodiment, the derivative should have a Tanimoto similarity index greater than 0.4, preferably greater than 0.5, more preferably greater than 0.6, and even more preferably greater than 0.7 to the parent drug. The Tanimoto similarity index is widely used to measure the degree of structural similarity between two molecules. The Tanimoto similarity index can be calculated by software such as Small Molecule Subgraph Detector (http: / / www.ebi.ac.uk / thornton-srv / software / SMSD / ) available online. Preferred derivatives should be related to the parent compound in structure and function, that is, they should also retain at least part of the activity of the parent drug. Moreover, the term "derivative" also includes metabolites of the drug, for example, the molecule is produced by (biochemical) modification or processing of the drug, usually by a specialized catalytic system, after administration to an organism, and it exhibits or retains the biological activity of the drug. Moreover, the term "derivative" also includes halogenated (such as fluoro), protium-substituted, deuterium-substituted, tritiated compounds or combinations thereof in the form of vinpocetine or its salts.

[0121] In a specific embodiment, "metabolite" as used herein refers to a modified or processed drug that retains at least part of the activity of the parent drug, preferably has an inhibitory effect on phosphodiesterase activity or has a therapeutic, preventive or alleviating effect on myopia and related symptoms.

[0122] "Extract" or "Plant Extracts" refers to substances extracted or processed from plants (all or part of a plant) using appropriate chemical or physical methods, such as solvent extraction or pressing. The substance can be pure, contain a small amount of impurities, or be a mixture.

[0123] "Ophthalmic composition" or "ophthalmic preparation" or "ophthalmic preparation" refers to an ophthalmic composition, or an ophthalmic pharmaceutical composition, or an ophthalmic pharmaceutical product; or drugs, preparations, cosmetics, health products, drug-device combinations or devices used for the prevention and / or treatment of eye diseases, protection, maintenance, improvement of vision, avoidance, slowing down or reversal of vision damage; or it can be eye drops (eye drops), eye ointments, eye sprays, implants, eye gels, eye patches, eye microspheres, eye sustained-release preparations, periocular injections, intraocular injections, etc.

[0124] "Fish oil" refers to lipid substances derived from higher animals, especially fish (such as cod, salmon), squid, and seal, and especially refers to the polyunsaturated fatty acids therein, including but not limited to Omega-3 unsaturated fatty acids, DHA, EPA, DPA, ALA, nisinic acid, stearidonic acid, eicosatetraenoic acid or a combination thereof.

[0125] The present application discloses the identification of a compound, namely, vinpocetine, for the treatment, prevention or alleviation of myopia and its related symptoms to enhance the myopia reduction or myopia alleviation effect while avoiding or minimizing adverse side effects, such as those observed with atropine therapy.

[0126] The present application relates to a pharmaceutical composition or method for treating, preventing or alleviating myopia and its related symptoms in an individual, such as a toddler, a school-age child, a teenager or a younger adult. In some instances, treating, preventing or alleviating myopia and its related symptoms may include administering a therapeutically effective amount of a pharmaceutical composition or dosage form to a subject in need thereof.

[0127] The pharmaceutical composition comprises a therapeutically effective amount of vinpocetine compound or its salt or related compounds.

[0128] In another aspect, the present application provides an ophthalmic device containing a pharmaceutical composition, wherein the pharmaceutical composition comprises vinpocetine or a therapeutically acceptable salt thereof or a derivative thereof, preferably, wherein the ophthalmic device delivers the pharmaceutical composition in a sustained release manner; preferably, wherein the ophthalmic device delivers the pharmaceutical composition in a pulsed manner.

[0129] Through experiments, we unexpectedly found that the use of vinpocetine alone can significantly slow down the process of negative diopter in the guinea pig myopia model induced by form deprivation or lenses, and even completely inhibit (terminate) the process of negative diopter in some individuals, and can significantly inhibit the elongation of the axial length. Based on this, it can be confirmed that the vinpocetine compound has the effect of preventing or treating, preventing or controlling the progression of myopia in animals, especially humans, such as infants, school-age children, children and adolescents, minors, people aged 3 to 26 or young adults.

[0130] In some embodiments, the treatment object of the technical solution of the present application is a child or adolescent, with an age range of 3-26 years old, preferably 6-18 years old, or 12-18 years old. In some embodiments, the treatment object of the technical solution of the present application is an adult, for example, aged 16-65 years old, preferably 16-26 years old.

[0131] In the local administration experiment, no discomfort or eye abnormalities were observed in all the animals administered the drug, and there were no toxic manifestations such as weight loss and decreased food intake. Based on the existing clinical application of vinpocetine, those skilled in the art can expect that it will have good drug safety in the clinical treatment process of using it to treat, prevent or improve myopia and its related symptoms.

[0132] The pharmaceutical composition of the present application has a technical effect significantly superior to atropine in treating, preventing or alleviating myopia and its related symptoms, and no adverse reactions such as eye irritation, pupil dilation, inflammation or allergy were observed in the experiment.

[0133] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the patient is treated for a period of time between about 1 month and 20 years, such as a period of at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 5 years, at least 7 years, or at least 9 years.

[0134] In one embodiment, in the pharmaceutical composition, ophthalmic device or treatment method of the present application, the pharmaceutical composition comprises vinpocetine and a therapeutically acceptable salt thereof or a derivative thereof, and preferably comprises a pharmaceutically acceptable carrier.

[0135] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is an aqueous composition.

[0136] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is an ophthalmic preparation.

[0137] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is an ophthalmic aqueous formulation.

[0138] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is an eye drop formulation.

[0139] In other embodiments, according to any one of the above embodiments and any one or more of the other embodiments herein, the pharmaceutical composition, ophthalmic device, or method of treatment, wherein the pharmaceutical composition is an eye spray formulation. In other embodiments, according to any one of the above embodiments and any one or more of the other embodiments herein, the pharmaceutical composition, ophthalmic device, or method of treatment, wherein the pharmaceutical composition is an ocular pharmaceutical composition contained in a contact lens blister package.

[0140] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is a topical formulation.

[0141] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is an ophthalmic composition.

[0142] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is a topical ophthalmic composition.

[0143] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is an eye gel formulation.

[0144] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is an ophthalmic emulsion.

[0145] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is an ophthalmic liposome.

[0146] In other embodiments, according to the pharmaceutical composition, ophthalmic device, or method of treatment of any one of the above embodiments and any one or more of the other embodiments herein, the pharmaceutical composition is a nanodisk.

[0147] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is a nanoparticle suspension.

[0148] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is a cream or an ointment or an salve.

[0149] In other embodiments, according to any one of the above embodiments and any one or more of the other embodiments herein, the medicament, composition, ophthalmic device or method of treatment, wherein the medicament, composition is an ophthalmic ointment (such as eye ointment).

[0150] In other embodiments, according to any one of the above embodiments and any one or more of the other embodiments herein, the drug, formulation, composition, device or method of treatment, wherein the drug, formulation, composition is an oral formulation, such as a tablet or capsule or powder or syrup.

[0151] In other embodiments, according to any one of the above embodiments and any one or more of the other embodiments herein, the drug, formulation, composition, device or treatment method, wherein the drug, formulation, composition further comprises one or more other ophthalmologically acceptable excipients and additives, including carriers, stabilizers, osmotic pressure regulators, preservatives, antioxidants, buffers, tonicity regulators, thickeners or other excipients.

[0152] In other embodiments, according to any one of the above embodiments and any one or more of the other embodiments herein, the drug, formulation, composition, device or treatment method comprises a polyhydroxy alcohol and / or an acidic cosolvent, optionally hydroxypropyl-β-cyclodextrin and citric acid or tartaric acid.

[0153] In other embodiments, according to any one of the above embodiments and any one or more of the other embodiments herein, the carrier is selected from but not limited to: water, a mixture of water and a water-miscible solvent, a vegetable or mineral oil containing 0.01% to 5% by weight of hydroxyethylcellulose, ethyl oleate, carboxymethyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, ethyl acrylate, polyacrylamide, pectin, alginate, starch derivatives, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, cross-linked polyacrylic acid, carbopol, lecithin, polyethylene glycol stearate, polyhydroxy alcohol, acidic cosolvent, heptadecaethyleneoxy oxycetanol or polyoxyethylene sorbitan monooleate.

[0154] In other embodiments, according to any one of the above embodiments and any one or more of the other embodiments herein, the medicament, formulation, composition, device or method of treatment, wherein the osmotic pressure regulating agent is sodium chloride.

[0155] In other embodiments, according to any one of the above embodiments and any one or more of the other embodiments herein, the preservative is selected from benzalkonium chloride, cetrimonium, sodium perborate, stabilized oxychlorine complex, sofia, polyquaternium-1, chlorobutanol, disodium edetate, polyhexamethylene biguanide or a combination thereof.

[0156] In other embodiments, according to any one of the above embodiments and any one or more of the other embodiments herein, the buffer is selected from borate, borate-polyol complex, phosphate buffer, citrate buffer, acetate buffer, carbonate buffer, organic buffer, amino acid buffer or a combination thereof.

[0157] In other embodiments, according to any one of the above embodiments and any one or more of the other embodiments herein, the tonicity adjusting agent is selected from sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glucose, mannitol, sorbitol, glucose, sucrose, urea, propylene glycol, glycerol or a combination thereof.

[0158] In other embodiments, when it comes to the use of the present application, the prevention and control (treatment) effect of vinpocetine, or its optical isomers or racemic forms, or solvates, or pharmaceutically acceptable salts, or prodrugs, or metabolites, or related compounds or extracts, or crystalline compounds, or combinations of these substances on myopia or the inhibition of axial length is unrelated to the gender, age, type of myopia, myopia progression rate, and myopia severity of the subject.

[0159] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is a sustained release formulation or a subconjunctival reservoir.

[0160] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is a sustained release formulation.

[0161] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is a sustained release formulation contained within an ophthalmic device.

[0162] In other embodiments, according to any one of the above embodiments, and any one or more of the other embodiments herein, the pharmaceutical composition, ophthalmic device, or method of treatment, wherein the pharmaceutical composition is contained in an ophthalmic device, such as an eye patch, suture, or corneal contact lens.

[0163] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is an ophthalmic composition and the ophthalmic composition is contained within an ophthalmic device.

[0164] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the ophthalmic device is a contact lens, an ocular insert, a corneal onlay, a corneal inlay, a nanodisc, a liposome, a nanoparticle, a punctal plug, or a hydrogel matrix with a microfluidic reservoir.

[0165] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the ophthalmic device is a contact lens.

[0166] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the ophthalmic device is an ocular insert.

[0167] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the ophthalmic device is a corneal onlay.

[0168] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the ophthalmic device is a corneal inlay.

[0169] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the ophthalmic device is a nanodisk.

[0170] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the ophthalmic device is a liposome.

[0171] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the ophthalmic device is a nanoparticle.

[0172] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the ophthalmic device is a punctal plug.

[0173] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the ophthalmic device is a hydrogel matrix with microfluidic reservoirs.

[0174] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the ophthalmic device delivers the pharmaceutical composition in a sustained release manner.

[0175] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of an ophthalmic disorder or condition.

[0176] In other embodiments, according to any one of the above embodiments and any one or more of the other embodiments herein, the pharmaceutical composition, ophthalmic device or method of treatment is formulated as an ophthalmic composition for the treatment of pre-myopia, myopia, true myopia, pseudomyopia or myopia progression.

[0177] In other embodiments, according to the pharmaceutical composition, ophthalmic device or method of treatment of any one of the above embodiments and any one or more of the other embodiments herein, the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of high myopia, moderate myopia or low myopia.

[0178] In other embodiments, according to any one of the above embodiments and any one or more of the other embodiments herein, the pharmaceutical composition, ophthalmic device, or method of treatment is formulated as an ophthalmic composition for the treatment of patients diagnosed with pre-myopia (or at risk of developing myopia).

[0179] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is substantially uniformly distributed throughout the ophthalmic device.

[0180] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the ophthalmic device is contained within a contact lens blister pack.

[0181] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is immersed in an ophthalmic device within a contact lens blister pack.

[0182] Pharmaceutical Formulations, Modes of Administration and Dosages: Any method known to those skilled in the art can be used to contact cells, organs or tissues with the Vinpocetine compound. Suitable methods include in vitro methods, ex vivo methods or in vivo methods. In vivo methods generally include administering the Vinpocetine compound of the present application or a pharmaceutical composition containing it to a mammal, preferably to a human. When used in vivo for treatment, the Vinpocetine compound or a pharmaceutical composition containing it can be administered to the subject in an effective amount (i.e., an amount having the desired therapeutic effect). The dosage and dosing regimen will depend on the extent of the ophthalmic condition in the subject, the subject, and the subject's medical history.

[0183] Compounds disclosed herein may also exist as prodrugs. Prodrugs of compounds described herein are modified forms that are susceptible to chemical changes under physiological conditions to obtain vinpocetine or its related compounds. In addition, prodrugs can be converted into the compound in an ex vivo environment by chemical or biochemical methods. For example, when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, the prodrug can be slowly converted into a compound. Prodrugs are generally useful because, in some cases, they may be easier to administer than a compound or a parent drug. For example, they can be bioavailable by oral administration, while the parent drug cannot. The solubility of the prodrug in a pharmaceutical composition may also be higher than that of the parent drug. Many prodrug derivatives are known in the art, such as prodrug derivatives that rely on hydrolytic cleavage or oxidative activation of the prodrug. A non-limiting example of a prodrug is a compound that is administered as an ester ("prodrug") but then metabolically hydrolyzed into a carboxylic acid (active entity).

[0184] The compounds disclosed herein may exist as therapeutically acceptable salts. The present application includes the above listed compounds in salt form, including acid addition salts. Suitable salts include salts formed with organic acids and inorganic acids. Such acid addition salts are generally pharmaceutically acceptable. However, non-pharmaceutically acceptable salts can be used to prepare and purify problematic compounds. Base addition salts can also be formed and are pharmaceutically acceptable.

[0185] As used herein, the term "therapeutically acceptable salt" means a salt or zwitterionic form of a compound disclosed herein, which is water-soluble or oil-soluble or dispersible and therapeutically acceptable, as defined herein. Salts can be prepared during the final separation and purification of the compound, or prepared separately by reacting the compound in the form of an appropriate free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (benzenesulfonate, besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothionate), lactate, maleate , malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, citrate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (para-toluenesulfonate, p-tosylate) and undecanoate. In addition, the basic groups in the compounds disclosed herein can be quaternized with the following substances: methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; decyl, lauryl, myristyl and steryl chlorides, bromides and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid) and organic acids (such as oxalic acid, maleic acid, succinic acid and citric acid). Salts can also be formed by coordination of the compound with an alkali metal or alkaline earth metal ion. Thus, the present application includes sodium, potassium, magnesium and calcium salts of the compounds disclosed herein, etc.

[0186] The crystal forms of Vinpocetine include all known types, such as the crystal forms described by Samuel Golob in the literature (Samuel Golob, Improving Biopharmaceutical Properties of Vinpocetine Through Cocrystallization, J Pharm Sci. 2016 Dec; 105(12): 3626-3633).

[0187] Base addition salts can be prepared by reacting a carboxyl group with a suitable alkali (such as hydroxide, carbonate or bicarbonate of a metal cation) or with ammonia or an organic primary, secondary or tertiary amine during the final separation and purification of the compound. The cation of the acceptable salt for treatment includes lithium, sodium, potassium, calcium, magnesium and aluminum and nontoxic quaternary amine cations, such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N, N-dibenzylphenethylamine, 1-diphenylhydroxymethylamine and N, N'-dibenzylethylenediamine. Other representative organic amines suitable for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidines and piperazine.

[0188] Although it is possible to administer the compounds of the present application in the form of crude chemicals, it is also possible to provide them as pharmaceutical preparations. Therefore, pharmaceutical preparations are provided herein, which contain one or more certain compounds disclosed herein or one or more pharmaceutically acceptable salts, esters, prodrugs, amides or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier is "acceptable" in the sense that it is compatible with the other ingredients of the preparation and is harmless to its recipient. The appropriate formulation depends on the selected route of administration. Any known techniques, carriers and excipients that are suitable and understood in the art can be used; for example, see Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein can be produced in any manner known in the art, for example, by conventional mixing, dissolving, granulating, sugar coating, fine grinding, emulsification, encapsulation, embedding or compression processing, and can also be made into drug-mechanical combinations.

[0189] Preparations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including skin, oral, sublingual, ocular, intranasal and intraocular) administration, and the most suitable route may depend on, for example, the condition and illness of the recipient. Preparations can be conveniently provided in unit dosage form and can be prepared by any method known in the pharmaceutical field. Typically, these methods include the step of combining the compound of the present application or its pharmaceutically acceptable salt, ester, amide, prodrug or solvate ("active ingredient") with a carrier constituting one or more auxiliary ingredients. In general, the active ingredient is uniformly and closely combined with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, the product is formed into the desired preparation, thereby preparing the preparation.

[0190] Formulations of the compounds disclosed herein suitable for oral administration may be provided as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be provided as a bolus, electuary or paste.

[0191] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing a free-flowing form of active ingredients (such as powder or granules) optionally mixed with a binder, an inert diluent or a lubricant, a surfactant or a dispersant in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored and can be formulated so as to provide sustained or controlled release of the active ingredient therein. The dosage of all preparations for oral administration should be suitable for the purpose of myopia prevention and treatment achieved by such administration. Push-fit capsules can contain active ingredients mixed with fillers (such as lactose), binders (such as starches) and / or lubricants (such as talc or magnesium stearate) and optional stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid (such as fatty oil, liquid paraffin or liquid polyethylene glycol). In addition, a stabilizer can be added. A dragee core with a suitable coating is provided. For this purpose, a concentrated sugar solution can be used, which can optionally contain gum arabic, talcum, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture. Dyes or pigments can be added to tablets or dragee coatings for identification or in order to characterize the different combinations of active compound dosages.

[0192] Examples of fillers or diluents for oral pharmaceutical preparations such as capsules and tablets include, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugars, microcrystalline cellulose (MCC), powdered cellulose, corn starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamer (e.g., polyethylene oxide), methylcellulose, and hydroxypropylmethylcellulose. The filler may have complexed solvent molecules, such as in the case where the lactose used is lactose monohydrate.

[0193] Examples of disintegrants used in oral pharmaceutical preparations such as capsules and tablets include, but are not limited to, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, povidone, crospovidone (polyvinylpolypyrrolidone), methylcellulose, microcrystalline cellulose, powdered cellulose, low-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate.

[0194] In addition, glidants and lubricants can be used in oral pharmaceutical preparations to ensure uniform blending of excipients during mixing. Examples of lubricants include, but are not limited to, calcium stearate, glyceryl monostearate, stearyl palmitate, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. Examples of glidants include, but are not limited to, silicon dioxide (SiO2), talcum corn starch, and poloxamer. Poloxamer (or available from BASF Corporation) is an ABA block copolymer, wherein the A segment is a hydrophilic polyethylene glycol homopolymer, and the B segment is a hydrophobic polypropylene glycol homopolymer.

[0195] Examples of tablet binders include, but are not limited to, gum arabic, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oils, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, copolyvidone, methylcellulose, liquid dextrose, maltodextrin, polymethacrylates, povidone, pregelatinized starch, sodium alginate, starch, sucrose, tragacanth gum, and zein.

[0196] Compounds can be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. Preparations for injection can be provided in unit dosage forms, such as in ampoules or multi-dose containers with preservatives added. Compositions can take the form of suspensions, solutions or emulsions such as in oily or aqueous vehicles, and can contain preparatons, such as suspending agents, stabilizers and / or dispersants. Preparations can be provided in unit doses or multi-dose containers, such as sealed ampoules and vials, and can be stored in powder form or in a freeze-dried (lyophilized) state, which only requires the addition of sterile liquid carriers, such as saline or sterile pyrogen-free water, before use. Ready-to-use injection solutions and suspensions can be prepared by sterile powders, granules and tablets of the previously described types. In a preferred embodiment, the pharmaceutical composition of the present application is in the form of an injection, particularly a syringe. Preferably, the pharmaceutical composition is administered by intraocular injection, more preferably by intravitreal injection into the vitreous body.

[0197] Preparations for parenteral administration include, but are not limited to, aqueous and non-aqueous (oily) sterile injection solutions of active compounds, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils (such as sesame oil) or synthetic fatty acid esters (such as oleic acid ethyl, esters or triglycerides) or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as methylcellulose, sodium carboxymethylcellulose, sorbitol or dextran. Optionally, such as oleic acid ethyl ester or triglycerides) or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of high concentration solutions.

[0198] In addition to the aforementioned formulations, the compounds mentioned in this patent, such as Vinpocetine, can also be formulated into storage formulations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the compound can be formulated with a suitable polymeric material or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or formulated into a slightly soluble derivative, such as a slightly soluble salt.

[0199] For oral or sublingual administration, the composition may take the form of tablets, troches, lozenges or gels formulated in conventional manner. Such compositions may comprise active ingredients, such as compounds such as vinpocetine mentioned in this patent, in a flavored matrix such as sucrose and gum arabic or tragacanth.

[0200] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0201] In addition to the aforementioned preparations, the compounds mentioned in this patent, such as Vinpocetine, can also be formulated into disposable preparations, devices, products for changing the appearance of the eye, or medical consumables for topical administration, such as single-use eye drops (each package contains only one therapeutically effective dose), individually packaged eye patches, cosmetic contact lenses, and daily disposable contact lenses.

[0202] Vinpocetine and other compounds disclosed herein can be administered topically, i.e., by non-systemic administration. This includes applying the compounds disclosed herein to the outside of the eye, epidermis, or oral cavity, and instilling such compounds into the ear, eye, and nose, so that the compounds do not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0203] Preparations suitable for topical application include liquid or semi-liquid preparations suitable for penetrating the skin to reach the site of action (such as gels, wipes, lotions, creams, ointments or pastes) and preparations suitable for application to the eyes, ears or noses, such as drops and sprays. The active ingredient used for myopia treatment may account for, for example, 0.0000001% to 99% w / w (by weight) of the total content of the preparation. In certain embodiments, the active ingredient may account for up to 50% w / w or more. In other embodiments, it may account for less than 1% w / w. In certain embodiments, the active ingredient may account for 0.01% w / w to 1% w / w. In other embodiments, it may account for 0.00001% to 0.001% w / w of the preparation; alternatively, the active ingredient for topical application may account for, for example, 0.0000001% to 100% w / v (by weight to volume) of the preparation; alternatively, the active ingredient may account for up to 50% w / v or more. In other embodiments, it may account for less than 1% w / v. In certain embodiments, the active ingredient may comprise 0.01% w / v to 1% w / v. In other embodiments, it may comprise 0.00001% to 0.001% w / v of the formulation.

[0204] The gel preparation form includes a preparation formed by connecting vinpocetine or its prodrug or its related compounds with a hydrogel. Preferably, the hydrogel of vinpocetine or its prodrug connected with the hydrogel is a biodegradable hydrogel.

[0205] The hydrogel comprises, preferably consists of, at least one polymer, preferably selected from the group consisting of poly(acrylic acid), poly(acrylates), poly(acrylamides), poly(alkoxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(asparagine), poly(butyric acid), poly(caprolactone), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamide), poly(esters), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl oxazoline), poly(hydroxypropylmethacrylamide), poly(hydroxypropyl methacrylate), poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(N-isopropylacrylamide), poly(lactic acid), poly(lactic-co-glycolic acid), poly(lactic-co-glycolic acid). acid), poly(methacrylamide), poly(methacrylate), poly(methyl oxazoline), poly(propylene fumarate), poly(organophosphorus cyanide), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinyl pyrrolidone), siloxane, ribonucleic acid, deoxynucleic acid, albumin, antibodies and fragments thereof, plasma proteins, collagen, elastin, fascin, fibrin, keratin, polyaspartic acid, polyglutamic acid, prolamin, transferrin, cytochrome, flavoprotein, glycoprotein, hemoprotein, lipoprotein, metalloprotein, phytochrome, phosphoprotein, opsin, agar, agarose, alginate, arabinan, arabinogalactan, carrageenan, cellulose, carbomethyl cellulose (carbomethyl cellulose) cellulose), hydroxypropyl methylcellulose and other carbohydrate-based polymers, chitosan, dextran, dextrin, gelatin, hyaluronic acid and its derivatives, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, xylan, and copolymers and functionalized derivatives thereof.

[0206] Preferably, the hydrogel is a biodegradable polyethylene glycol (PEG) based hydrogel.

[0207] Preferably, the polyethylene glycol (PEG) is of a single molecular weight or a group of polyethylene glycols of different molecular weights mixed in a certain ratio.

[0208] The hydrogel is a shaped article, preferably in the shape of microparticles. More preferably, the hydrogel is in the shape of microparticle beads. Even more preferably, the microparticle beads have a diameter of 1-1000 μm, more preferably 5-500 μm, more preferably 10-100 μm, and even more preferably 20-80 μm. The bead diameter is measured when the microparticle beads are suspended in an isotonic aqueous buffer. In a preferred embodiment, the hydrogel-connected vinpocetine or its prodrug is bead-shaped. More preferably, the hydrogel-connected vinpocetine or its prodrug is in the shape of microparticle beads. Even more preferably, the microparticle beads have a diameter of 1-1000 μm, more preferably 5-500 μm, more preferably 10-100 μm, and even more preferably 20-80 μm. The bead diameter is measured when the microparticle beads are suspended in an isotonic aqueous buffer. Such hydrogels can be polymerized in different ways, for example, by free radical polymerization, ionic polymerization or complex formation reaction.

[0209] If the hydrogel is processed by free radical polymerization or ionic polymerization, at least two raw materials are cross-linking macromonomers or cross-linking monomers (which are called cross-linking agent reagents) and multifunctional macromonomers (which are called backbone agents). The cross-linking agent reagent carries at least two interconnectable functional groups, and the backbone agent carries at least one interconnectable functional group and at least one chemical functional group that is not used to participate in the polymerization step. Additional diluent monomers may be present or absent. Useful interconnectable functional groups include, but are not limited to, free radical polymerizable groups such as vinyl, vinyl-benzene, acrylate, acrylamide, methacrylate, methacrylamide, and ionically polymerizable groups such as oxetane, azetidine and oxirane. In an alternative preparation method, the hydrogel is generated by a chemical complex formation reaction. In this type of reaction, the raw material is at least one macromolecular raw material having complementary functionality that undergoes reactions such as condensation or addition reactions. In one embodiment, only one macromolecular starting material is used, which is a heteromultifunctional backbone reagent comprising a large number of polymerizable functional groups which may be the same or different.

[0210] In addition to active ingredients such as vinpocetine, the topical eye, ear and nose preparations of the present application may also include excipients. Excipients commonly used in such preparations include, but are not limited to, isotonic agents, preservatives, chelating agents, buffers and surfactants. Other excipients include solubilizers, stabilizers, comfort enhancers, polymers, moderators, pH regulators and / or lubricants. Any of the various excipients can be used for the preparations of the present application, including water, a mixture of water and a water-miscible solvent (such as C1-C7 alkanol), a vegetable oil or mineral oil containing 0.5% to 5% non-toxic water-soluble polymers, natural products (such as alginate, pectin, tragacanth gum, karaya gum, guar gum, xanthan gum, carrageenan, agar and gum arabic), starch derivatives (such as acetic starch and hydroxypropyl starch) and other synthetic products (such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably cross-linked polyacrylic acid and a mixture of these products). The concentration of the excipient is generally 1 to 100,000 times the concentration of the active ingredient. In preferred embodiments, the excipients to be included in the formulation are generally selected based on their inertness toward the active ingredient composition of the formulation.

[0211] For eye, ear and nasal preparations, suitable isotonicity adjusting agents include but are not limited to mannitol, dextrose, sodium chloride, glycerol, sorbitol and the like. Suitable buffers include but are not limited to phosphates, citrates, borates, acetates and the like. Suitable surfactants include but are not limited to ionic and nonionic surfactants (although nonionic surfactants are preferred polysorbate 80, RLM 100, POE 20 cetyl stearyl ether (such as CS20) and poloxamer (such as F68). The preparation may contain substances that increase the viscosity of the solution or suspension, such as sodium carboxymethylcellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, sorbitol or dextran. Optionally, the preparation may also contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of high concentration solutions, which include but are not limited to ethanol, benzyl alcohol, polyethylene glycol, phenylethanol and glycerol.

[0212] The preparations given herein may include one or more preservatives. Examples of such preservatives include benzalkonium chloride, parabens, sodium perborate, sodium chlorite, alcohols (such as chlorobutanol, benzyl alcohol or phenylethyl alcohol), guanidine derivatives (such as polyhexamethylene biguanide), sodium perborate, polyquaternium-1, amino alcohols (such as AMP-95) or sorbic acid. In certain embodiments, the preparation itself can be preservative, so that no preservative is required. In certain embodiments, although the preparation itself is not preservative, packaging materials or packaging designs can be used to avoid drug deterioration (such as changes in physicochemical properties and / or changes in biological effects), so that no preservative is required.

[0213] For ocular, otic or nasal administration, the formulation may be a solution, suspension or gel. In a preferred aspect, the formulation for topical administration to the eye or ear in an aqueous solution or suspension is in the form of drops. The formulation for topical administration to the nose in an aqueous solution or suspension is in the form of drops, sprays or aerosols. The term "aqueous" generally refers to an aqueous formulation in which the formulation contains >20%, >50%, more preferably >75% and especially >90% water by weight. These drops can be delivered by a single-dose eye drop bottle, which may preferably be sterile, thereby enabling the antibacterial component of the formulation to be eliminated. Alternatively, the drops can be delivered by a multi-dose eye drop bottle, which may preferably include a device for extracting any preservatives from it when delivering the formulation, such a device being known in the art. Solution and suspension formulations can be administered nasally using a nebulizer. Intranasal delivery of solutions, suspensions, or dry powders may also be facilitated by aerosol systems based on propellants, including but not limited to hydrofluorocarbon-based propellants, or the active pharmaceutical ingredient may be delivered in dry powder form.

[0214] For ocular conditions, the components of the present application may be delivered to the eye as a concentrated gel or similar vehicle or as a dissolvable insert placed beneath the eyelid.

[0215] In a specific embodiment, the preparation of the application is used once a day. However, the preparation can also be formulated to use with any frequency of application, including once a week, once every 5 days, once every 3 days, once every 2 days, twice a day, three times a day, four times a day, five times a day, six times a day, eight times a day, per hour or with any higher frequency. According to the treatment plan, this administration frequency is also kept to a duration of varying lengths. The duration of a specific treatment plan can be extended to a plan of several months or years from a single administration. Preparations are applied with different dosages, but typical dosage is to use one to two drops at a time, or a considerable amount of gel or other preparations (such as tablets, eye ointments). Those of ordinary skill in the art are familiar with how to determine the treatment plan for specific indications.

[0216] Gels for topical or transdermal administration may generally include a mixture of volatile solvents, non-volatile solvents and water. In certain embodiments, the volatile solvent component of the buffered solvent system may include lower (C1-C6) alkyl alcohols, lower alkyl glycols and lower glycol polymers. In further embodiments, the volatile solvent is ethanol. The volatile solvent component is considered to act as a penetration enhancer, and as it evaporates, it also produces a cooling effect on the skin. The non-volatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. Propylene glycol is used in certain embodiments. The non-volatile solvent delays the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system. The amount of this non-volatile solvent component, like the volatile solvent, is determined by the drug compound or drug used. When there is too little non-volatile solvent in the system, the drug compound may crystallize due to the evaporation of the volatile solvent, and too much may cause a lack of bioavailability due to poor release of the drug from the solvent mixture. The buffer component of the buffered solvent system can be selected from any buffer commonly used in the art; water is used in certain embodiments. Common ratios of ingredients are about 20% non-volatile solvent, about 40% volatile solvent, and about 40% water. Several optional ingredients may be added to the topical composition. These include, but are not limited to, chelating agents and gelling agents. Suitable gelling agents may include, but are not limited to, semisynthetic cellulose derivatives (such as hydroxypropyl methylcellulose) and synthetic polymers, galactomannan polymers (such as guar gum and its derivatives), and cosmetic agents.

[0217] Lotions include those suitable for application to the skin or eyes. Eye lotions may comprise sterile aqueous solutions optionally containing bactericides and may be prepared by methods similar to those for preparing drops. Lotions or liniments for application to the skin may also include agents (such as alcohol or acetone) and / or humectants (such as glycerol) or oils (such as castor oil or peanut oil) to accelerate drying and cool the skin.

[0218] The pharmaceutical composition of the present application may be a cream, ointment (such as 3% ointment, ointment) or paste, which is a semisolid preparation of an active ingredient for external application. They can be prepared by mixing the active ingredient in finely divided or powdered form alone or in a solution or suspension in an aqueous or non-aqueous fluid with an oleaginous or non-oleaginous matrix with the aid of a suitable machine. The matrix may include hydrocarbons such as vaseline, hard paraffin, soft paraffin or liquid paraffin, glycerol, beeswax, metal soaps; mucilage; oils of natural origin such as fish oil, almond oil, corn oil, peanut oil, castor oil or olive oil; lanolin or its derivatives or fatty acids (such as stearic acid or oleic acid) together with alcohols (such as propylene glycol) or macrogranular gel or lanosterol or dihydrolanosterol. The preparation may be admixed with any suitable surfactant, such as anionic, cationic or nonionic surfactants, such as sorbitan esters or their polyethylene oxide derivatives. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as siliceous silica, and other ingredients such as lanolin and lanosterol may also be included.

[0219] Drops or sprays can include sterile aqueous or oily solutions or suspensions, and can be prepared by dissolving active ingredients in suitable bactericides and / or fungicides and / or any other suitable preservatives and in certain embodiments comprising an aqueous solution of a surfactant. The resulting solution can then be clarified by filtration, transferred to a suitable container, which is then sealed and sterilized by autoclaving or by keeping it for half an hour at 98-100°C. Alternatively, the solution can be sterilized by filtration and transferred to a container by aseptic technique. Examples of bactericides and fungicides suitable for inclusion in drops include azole compounds (such as econazole), phenylmercuric nitrate or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of oily solutions include glycerol, dilute alcohols and propylene glycol.

[0220] Formulations for topical administration in the mouth (eg, buccally or sublingually) include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.

[0221] For administration by inhalation, compounds such as Vinpocetine mentioned in this patent can be conveniently delivered by an insufflator, atomizer pressurized pack or other convenient device for delivering aerosol sprays. The pressurized pack may contain a suitable propellant, such as hydrofluorocarbons, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compound according to the present application can take the form of a dry powder composition, such as a powder mixture of the compound and a suitable powder matrix (such as lactose or starch). The powder composition can be provided in a unit dosage form in, for example, a capsule, cartridge, gelatin or blister pack, and the powder can be administered from the above by means of an insufflator or insufflator.

[0222] Preferred unit dosage formulations are those containing an effective dose, as herein recited, or an appropriate fraction thereof, of the active ingredient.

[0223] It should be understood that in addition to the ingredients specifically mentioned above, the above-mentioned formulations may also include other agents conventional in the art for the type of formulation concerned, such as microneedles, formulations suitable for oral or intranasal administration (which may include flavoring agents).

[0224] The compound can be administered orally or via injection at a dose of 0.001 to 300 mg / kg per day. The dosage range for adults and the elderly is generally 5 mg to 100 mg / day, and children or adolescents should reduce or maintain the same dosage. Tablets or other presentation forms provided in discrete units can conveniently contain a certain amount of one or more compounds, which are effective in the case of such a dose or multiple doses, for example, units containing 0.1 mg to 1000 mg, usually about 1 mg to 10 mg, preferably 5 mg.

[0225] The compounds such as Vinpocetine mentioned in this patent can be administered in various ways, such as orally, topically or by injection, or systemically and topically at the same time, or systemically and topically alternately. The exact amount of compound administered to the patient is the responsibility of the attending physician. The specific dosage level for any particular patient depends on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, administration route, excretion rate, drug combination, the exact condition treated, and the severity of the indication or condition treated. In addition, the route of administration may vary, depending on the condition and its severity.

[0226] In some cases, it may be appropriate to administer at least one compound described herein (or a pharmaceutically acceptable salt, ester or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient receiving one of the compounds herein is hypotension, it may be appropriate to administer an anti-hypotensive in combination with the initial therapeutic agent. Or by way of example only, the therapeutic effect of one of the compounds described herein may be enhanced by administering an anti-allergic drug (i.e., the anti-allergic drug itself may have only minimal therapeutic benefit, but when combined with the therapeutic agent mentioned herein, the total therapeutic benefit to the patient is enhanced). Or by way of example only, the benefit experienced by the patient may be enhanced by administering one of the compounds described herein with another therapeutic agent (which also includes a treatment regimen) that also has a therapeutic benefit. By way of example only, in a myopia treatment involving the administration of one of the compounds described herein, the therapeutic benefit may be enhanced by also providing the patient with another myopia therapeutic agent. In any case, regardless of the disease, disorder or condition being treated, the total benefit experienced by the patient may simply be the sum of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0227] The pharmaceutical composition in dry or liquid form may be provided as a single-dose or multi-dose pharmaceutical composition.

[0228] In one embodiment of the present application, the liquid or dry pharmaceutical composition is provided in a single dose, which means that the container in which it is provided contains one pharmaceutical dose. Alternatively, the liquid or dry pharmaceutical composition is a multi-dose pharmaceutical composition, which means that the container in which it is provided contains more than one therapeutic dose, that is, the multi-dose composition contains at least 2 doses. Such multi-dose compositions can be used for different patients who need them, or can be used for one patient, wherein the remaining dose is stored until needed after the first dose is applied.

[0229] In another aspect of the present application, the pharmaceutical composition is in a container. Containers for liquid or dry pharmaceutical compositions include, for example, eye drop bottles, syringes, vials, vials with stoppers and seals, ampoules and cartridges. In particular, the liquid or dry pharmaceutical composition is provided in a syringe. If the pharmaceutical composition is a dry pharmaceutical composition, the container is preferably a dual-chamber syringe. In this embodiment, the dry pharmaceutical composition is provided in a first chamber of the dual-chamber syringe, and the reconstitution solution is provided in a second chamber of the dual-chamber syringe.

[0230] Before applying the dry composition to a patient in need thereof, the dry composition is reconstituted. Reconstitution can be carried out in a container in which the dry composition is provided, such as an eye drop bottle, a syringe, a dual-chamber syringe, an ampoule, and a cartridge. Reconstitution is carried out by adding a predetermined amount of a reconstitution solution to the dry composition. The reconstitution solution is a sterile liquid such as water or a buffer, which may contain other additives such as preservatives and / or antimicrobials such as benzyl alcohol and cresol. Preferably, the reconstitution solution is sterile water. When the dry composition is reconstituted, it is referred to as a "reconstituted pharmaceutical composition" or "reconstituted pharmaceutical composition" or "reconstituted composition".

[0231] Ophthalmic preparations: The pharmaceutical composition of the present application can be administered in the form of an ophthalmic preparation. The ophthalmic preparation of the present application comprises an ophthalmologically acceptable carrier.

[0232] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form may vary depending upon the host treated and the particular mode of administration.

[0233] As used herein, an "ophthalmologically acceptable carrier" is an ophthalmologically acceptable solvent, suspending agent or vehicle for administering a pharmaceutical composition to the eye of a subject. The carrier may be a solid or a liquid. The carrier is "ophthalmologically acceptable" in the sense that the carrier is suitable for administration to the eye without causing any major adverse reaction.

[0234] Typically, ophthalmologically acceptable carriers are or include water. Typically, ophthalmic preparations are in the form of eye drops or gels for application to the eye. Typically, the major part of the preparation is water. Typically, the preparation includes greater than 50 wt % (such as greater than 60 wt %, 65 wt %, 70 wt %, 75 wt %, 80 wt %, 85 wt % or 90 wt %), more typically greater than 95 wt % (such as 96 wt %, 97 wt %, 98 wt % or 99 wt %) water.

[0235] In some embodiments, the ophthalmologically acceptable carrier is an oil-in-water emulsion or oil. In such embodiments, the ophthalmic formulation may be in the form of an ointment applied to the eye. In such embodiments, the formulation may contain greater than 10% by weight, more typically greater than 20% by weight of an oily component.

[0236] In other embodiments, the carrier may be a biodegradable polymer, such as a biodegradable polymer eye implant for sustained release of the compounds of the present application and optionally other compounds. For example, a biodegradable, biocompatible polymer matrix. In one embodiment, the compound can be embedded in a polymer matrix while maintaining structural integrity. The polymer can be natural, such as a polypeptide, protein, or polysaccharide; or it can be synthetic, such as poly-alpha-hydroxy acid. Examples include carriers made of, for example, collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, methylcellulose, polysaccharides, fibrin, gelatin, and combinations thereof. In one embodiment, the polymer is polylactic acid (PLA) or poly(lactic acid-co-glycolic acid) (PGLA). Polymer matrices can be prepared and isolated in various forms and sizes, including microspheres and nanospheres.

[0237] In some embodiments, the therapeutic compound is prepared with a carrier that will protect the therapeutic compound to prevent it from being rapidly discharged from the body, such as a controlled release agent, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Such preparations can be prepared using known techniques.

[0238] Excipients: Excipients suitable for use in the ophthalmic preparations of the present application include, for example, demulcents, emollients, hypertonicity agents, preservatives, buffers or pH adjusters. Examples of suitable excipients include:

[0239] A. Demulcents: synthetic high molecular weight cross-linked acrylic acid polymers (such as carbomer 974 and carbomer 980); cellulose derivatives (such as hydroxypropyl methylcellulose ("HPMC" or "hydroxypropyl methylcellulose"), hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose (carboxymethylcellulose)) or sodium carboxymethyl cellulose (sodium carboxymethylcellulose)); dextran (such as dextran 70); gelatin; polyols (such as glycerol, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80 and propylene glycol); polyvinyl alcohol; povidone (polyvinyl pyrrolidone); poloxamer; and hyaluronic acid (disaccharide polymer) or its sodium or potassium salt.

[0240] B. Softeners: lanolin (such as anhydrous lanolin); oily ingredients (such as light mineral oil, mineral oil, paraffin, petrolatum, liquid paraffin, white ointment, white petrolatum, white wax and yellow wax); and fish oil, castor oil.

[0241] C. Preservatives: benzalkonium chloride; sodium perborate; Oxyd (sodium chlorite 0.05%, hydrogen peroxide 0.01%); polyquaternium-1 (polymer of ethanol, 2,2′,2″-nitrilotris- with 1,4-dichloro-2-butene and N,N,N′,N′-tetramethyl-2-butene-1,4-diamine); sodium silver chloride; hexamethylene biguanide; oxyborate; and (sodium chlorite 0.005% m / v).

[0242] D. Ophthalmic hypertonicity agent: sodium chloride.

[0243] E. The ophthalmic preparations of the present application may also contain preservatives that inhibit the growth of microorganisms and extend the shelf life of the preparations. Preservatives that can be used in the ophthalmic preparations of the present application include, for example, benzalkonium chloride, sodium perborate, Oxyd (sodium chlorite 0.05%, hydrogen peroxide 0.01%), polyquaternium-1 (polymer of ethanol, 2,2′,2″-nitrilotri-with 1,4-dichloro-2-butene and N,N,N′,N′-tetramethyl-2-butene-1,4-diamine), sodium silver chloride, hexamethylene biguanide, and oxyborates. Sodium chlorite (.005% m / v) is a broad-spectrum antimicrobial Sodium chlorite is a microbicide that is biologically active and has very low toxicity to mammalian cells, which protects the formulation during storage but eventually dissociates into water, sodium ions, chloride ions and oxygen after exposure. Because they are also found in natural tears, the risk of preservative-induced eye irritation and corneal damage is minimized. Sodium chlorite is safe and effective to use in the long term. This preservative has no side effects on epithelial cells in vitro or in vivo, and is less disruptive to cell integrity than many other preservatives in use.

[0244] The ophthalmic preparation of the present application can be prepared by any suitable method for preparing an ophthalmic preparation. The ophthalmic preparation is generally sterile, and therefore the method may include a step of sterilizing the ophthalmic preparation. Preferably, the ophthalmic preparation is transparent and has a reflectivity similar to that of tears, a suitable pH (usually buffered to about pH 7.5) to avoid severe corneal irritation and prevent microorganisms. The preparation of the present application suitable for topical application to the eye is preferably isotonic or slightly hypotonic, so as to counteract any tear hyperosmoticity caused by evaporation and / or disease. This may require a tonicity agent to make the molar osmotic pressure concentration of the preparation reach or approach the level of 210-320 milliosmole / kilogram (mOsm / kg). The preparation of the present application generally has a molar osmotic pressure concentration in the range of 220-320mOsm / kg, preferably a molar osmotic pressure concentration in the range of 235-300mOsm / kg. Surface tension values ​​close to or lower than the surface tension values ​​of the observed tear film are generally preferred. Ophthalmic preparations are generally formulated into sterile aqueous solutions.

[0245] In certain ophthalmic embodiments, the composition of the present application is formulated with one or more tear substitutes. Various tear substitutes are known in the art, including but not limited to: monomeric polyols, such as glycerol, propylene glycol and ethylene glycol; polymeric polyols, such as polyethylene glycol; cellulose esters, such as hydroxypropyl methylcellulose, sodium carboxymethylcellulose and hydroxypropyl cellulose; dextran, such as dextran 70; vinyl polymers, such as polyvinyl alcohol; and carbomer, such as carbomer 934P, carbomer 941, carbomer 940 and carbomer 974P. The preparation or pharmaceutical composition of the present application can be used with contact lenses, corneal contact lenses or other ophthalmic products (such as frame glasses, myopia treatment devices).

[0246] Preferred formulations are prepared using a buffer system that maintains the pH of the formulation at about 4.5 to a pH of about 8. The most preferred formulation pH is 5.5 to 7.5. Optional buffers are physiologically tolerated buffers that maintain the pH in the desired range, such as sodium phosphate, bicarbonate, succinate, histidine, citrate and acetate, sulfate, nitrate, chloride, pyruvate. Antacids such as Mg(OH)2 or ZnCO3 may also be used. The buffer capacity may be adjusted to match the conditions most sensitive to pH stability.

[0247] The ophthalmic preparation of the present application may further include a cooling agent, such as menthol, camphor, borneol, geraniol, eucalyptol, linalool, etc. When the cooling agent is mixed, the concentration of the cooling agent is preferably 0.0001 to 0.1 W / V%.

[0248] The ophthalmic preparations of the present application may also contain other commonly used therapeutic components in ophthalmology, such as benzydric acid and its salt forms (such as benzydric lysine), decongestants (such as epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc.), anti-inflammatory / astringents (such as neostigmine methylsulfate, ε-aminocaproic acid, allantoin, berberine hydrochloride hydrate, berberine sulfate hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride, etc.), antihistamines (such as diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (flavin adenine dinucleoside, etc.). =The ingredients include sodium pantothenate, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, etc.), amino acids (such as potassium L-aspartate, magnesium L-aspartate, potassium and magnesium L-aspartate (equal mixture), aminoethylsulfonic acid, etc.), ingredients for relieving visual fatigue and / or dry eyes (such as taurine, vitamin A, hydroxypropyl methylcellulose and vitamin E), polyunsaturated fatty acids (such as fish oil, omega-3 unsaturated fatty acids, DHA, EPA), piracetam, sulfonamides, niacin, retinoic acid, lutein, salidroside, formononetin, atropine, dibazole, M receptor blockers (such as blockers or antagonists or inhibitors for M3 receptors), etc.

[0249] The content of active substance in the pharmaceutical composition of the present application: When the drugs are mixed, the concentration of the therapeutically active compound can be selected from the effective and suitable amount of each substance. From the perspective of irritation to the eye, stability of the preparation, etc., the therapeutically active compound (such as vinpocetine) in the pharmaceutical composition can be present in a high concentration, a medium concentration or a low concentration, for example, about 0.0000001-100%, about 0.00001-10%, about 0.001-20%, about 0.1-30%, about 1-40%, about 10-5 0%, about 20-60%, about 30-70%, about 40-80%, about 50-90% (W / V), for example, about 1 μM, about 0.1 μM, about 0.01 μM, about 5 μM, about 10 μM, about 15 μM, about 25 μM, about 50 μM, or about 0.0000001%, about 0.000001%, about 0.00001%, about 0.0001%, about 0.001%, about 0.01%, about 0.1%, about 1%, about 10% (W / V) of the total pharmaceutical composition.

[0250] Delivery of ophthalmic formulations: The ophthalmic formulations of the present application can be delivered to the patient in the form of eye drops (in the form of single-dose or multi-dose droppers), ointments, gels, creams or biodegradable polymer eye implants (designed for sustained release) or by eye moisturization (such as multi-dose spray).

[0251] The packaging of ophthalmic preparations should be related to the retention or non-retention properties of the solution. Packaging methods such as form-fill-encapsulate technology that combines blow molding, aseptic filling and sealing into a single process can be particularly useful for packaging preservative-free preparations in unit dose containers. Typically, these single dose containers are composed of low-density polyethylene or polypropylene and include twist-off caps.

[0252] The formulations and methods of the present application have been used for any subject that can benefit from the formulations and methods of the present application. The subject is usually a mammal, more usually a human. However, the present application is not limited to treating humans and can be applied to veterinary use. Therefore, according to the present application, the term "subject", "patient" or "subject in need" includes humans as well as non-human animals, for example, including farm animals such as sheep, pigs, cows and horses; pet animals such as dogs and cats; laboratory animals such as mice, rats and rabbits. In a preferred embodiment, the mammal is a human.

[0253] In another aspect, the present application provides an ophthalmic device containing a pharmaceutical composition, wherein the pharmaceutical composition comprises vinpocetine or a therapeutically acceptable salt thereof or a derivative thereof or a combination thereof, preferably, wherein the ophthalmic device delivers the pharmaceutical composition in a sustained release manner.

[0254] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is a sustained release formulation or a subconjunctival depot.

[0255] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is a sustained release formulation contained within an ophthalmic device.

[0256] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the ophthalmic device is a contact lens, a contact lens, an ocular insert, a corneal onlay, a corneal inlay, a nanodisc, a liposome, a nanoparticle, a punctal plug, or a hydrogel matrix with a microfluidic reservoir.

[0257] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the ophthalmic device delivers the pharmaceutical composition in a sustained release manner.

[0258] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is formulated as an ophthalmic composition, for example, as an ophthalmic composition for the treatment of an ophthalmic disorder or condition.

[0259] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions are formulated as ophthalmic compositions for the treatment of pre-myopia, myopia, or myopia progression.

[0260] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions are formulated as ophthalmic compositions for the treatment of high myopia, moderate myopia, or low myopia.

[0261] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions are formulated as ophthalmic compositions for the treatment of patients diagnosed with pre-myopia (or at risk of developing myopia).

[0262] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is substantially uniformly distributed throughout the ophthalmic device.

[0263] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the ophthalmic device is contained within a contact lens or contact lens blister pack.

[0264] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is immersed in an ophthalmic device within a contact lens or contact lens blister package.

[0265] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is administered to an eye of the patient.

[0266] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is administered topically.

[0267] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions are administered to the eye in the form of an eye drop formulation, an eye spray formulation, or an eye gel formulation.

[0268] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions are administered to the eye in the form of ophthalmic emulsions, ophthalmic liposomes, nanodisks, nanoparticle suspensions, or ophthalmic ointments.

[0269] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is ophthalmically administered to an eye of a patient via an ophthalmic device.

[0270] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is administered 1, 2, 3, 4, or 5 times per day.

[0271] In certain embodiments, the pharmaceutical composition as disclosed herein can be an ophthalmic aqueous preparation, such as in the form of eye drops. For example, an ophthalmic aqueous preparation as described herein can be packaged in an eye dropper and applied as drops. In certain embodiments, an ophthalmic aqueous preparation can be applied as a single application (i.e., a single dose), which can include one, two, three or more drops dropped into the patient's eye. In certain embodiments, a dose of an ophthalmic aqueous preparation as described herein is a drop of an aqueous composition from the eye dropper.

[0272] In certain embodiments, the pharmaceutical composition as disclosed herein can be an ophthalmic gel preparation. For example, the ophthalmic gel preparation can be packaged in an eye dropper and applied as drops. In certain embodiments, the ophthalmic gel preparation can be applied as a single application (i.e., a single dose), which can include one, two, three or more drops dropped into the patient's eye. In certain embodiments, one dose of the ophthalmic gel described herein is a drop of the gel composition from the eye dropper.

[0273] In certain embodiments, the pharmaceutical composition as disclosed herein can be an ophthalmic ointment preparation. For example, the ophthalmic ointment preparation can be packaged in a tube or other squeezable container having a dispensing nozzle through which the ointment strip is delivered. In certain embodiments, the ophthalmic ointment preparation can be applied as a single application (i.e., a single dose), which can include one or more strips entering the patient's eye. In certain embodiments, a dose of an ophthalmic ointment is a strip of ointment composition dispensed through a dispensing tube nozzle.

[0274] Treating a subject with a therapeutically effective amount of a therapeutic composition or formulation described herein can include a single treatment or a series of treatments.

[0275] In certain embodiments of the pharmaceutical compositions, ophthalmic devices or methods of treatment disclosed herein, the methods prevent the progression of myopia in the treated patient.

[0276] In certain embodiments of the pharmaceutical compositions, ophthalmic devices or methods of treatment disclosed herein, the methods control the progression of myopia in the treated patient.

[0277] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods reduce the progression of myopia in the treated patient.

[0278] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods slow down or reduce the progression of myopia in the treated patient.

[0279] In certain embodiments of the pharmaceutical compositions, ophthalmic devices or methods of treatment disclosed herein, the methods control, slow, reduce, delay and / or alleviate the progression of myopia in a treated patient within the following ranges relative to untreated: between about 5-95%, between about 5-90%, between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50%, between about 5-40%, between about 5-30%, between about 5-20%, between about 10-100%, between about 20-90%, between about 30-90%, between about 40-90%, between about 50-90%, or between about 75-90%.

[0280] In certain embodiments of the pharmaceutical compositions, formulations, ophthalmic devices or methods of treatment disclosed herein, use of the pharmaceutical compositions, formulations, ophthalmic devices or methods of treatment limits the magnitude of negative refractive power change in the eye of the subject to be administered to about 1.0-6.0D, 1.0-5.0D, 1.0-4.0D, 1.0-3.0D, 1.0-2.0D, less than 6.0D, less than 5.0D, less than 4.0D, less than 3.0D, less than 2.0D and less than 1.0D.

[0281] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods reverse the progression of myopia in the treated patient.

[0282] In certain embodiments of the pharmaceutical composition, ophthalmic device or method of treatment disclosed herein, the patient suffers from high myopia, moderate myopia or low myopia.

[0283] In certain embodiments of the pharmaceutical compositions, ophthalmic devices or methods of treatment disclosed herein, the patient is pre-myopic (or is at risk of developing myopia).

[0284] In certain embodiments of the pharmaceutical compositions, ophthalmic devices or therapeutic methods disclosed herein, the methods prevent, control, slow, reduce, alleviate, delay and / or reverse the axial (or longitudinal) growth of the eye of the treated patient, i.e., elongation of the axial length and / or increase in vitreous cavity length.

[0285] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions, ophthalmic devices, or methods of treatment control, slow, mitigate, reduce, delay, and / or reverse axial elongation and / or increase in vitreous cavity length in a treated patient (e.g., mild myopia, childhood or adolescent myopia) in the following range relative to untreated: between about 5-95%, between about 5-90%, between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50%, between about 5-40%, between about 5-30%, between about 5-20%, between about 10-100%, between about 20-90%, between about 30-90%, between about 40-90%, between about 50-90%, or between about 75-90%.

[0286] In certain embodiments of the drugs, formulations, compositions, ophthalmic devices or treatment methods disclosed herein, the methods control, terminate, slow down, reduce, delay and / or alleviate the occurrence and progression of myopia in a patient diagnosed with myopia or at risk of developing myopia, increase the choroidal thickness of the patient's eye (e.g., a myopic eye, a pre-myopic eye, or an eye at risk of developing myopia) and / or reduce the axial (or longitudinal) growth rate of the patient's eye (e.g., a myopic eye, a pre-myopic eye, or an eye at risk of developing myopia), that is, the elongation of the axial length and / or the increase in vitreous cavity length are inhibited.

[0287] In certain embodiments of the pharmaceutical compositions, ophthalmic devices or treatment methods disclosed herein, the methods control, slow, reduce, delay and / or alleviate the axial (or longitudinal) growth of the eye of a treated patient by between about 5-95%, between about 5-90%, between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50%, between about 5-40%, between about 5-30%, between about 5-20%, between about 10-100%, between about 20-90%, between about 30-90%, between about 40-90%, between about 50-90% or between about 75-90%.

[0288] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions, ophthalmic devices, or methods of treatment prevent, control, slow, reduce, alleviate, alter, delay, and / or reverse myopic refraction in the eye of the treated patient.

[0289] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions, ophthalmic devices, or methods of treatment result in less severe adverse reactions relative to atropine monotherapy.

[0290] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions, ophthalmic devices, or methods of treatment produce a smaller increase in pupil size or no effect on pupil size relative to atropine monotherapy.

[0291] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions, ophthalmic devices, or methods of treatment inhibit the extent to which the axial length or refractive power of a normal eye progresses toward myopia relative to atropine monotherapy.

[0292] Example 1: Myopia animal model and drug administration experiment

[0293] The form deprivation and lens-induced guinea pig myopia model is a classic and recognized myopia animal model in the field, which can be used for the efficacy and safety evaluation of myopia treatment drugs, and its construction method is well known to those skilled in the art. The animal modeling and administration method of this application refer to the scientific literature previously published by this research group (Sen Zhang, Invest Ophthalmol Vis Sci. 2019 Jul 1; 60 (8): 3074-3083.; Miaozhen Pan, Exp Eye Res. 2021 Jan; 202: 108332.), specifically, the exemplary form deprivation and lens-induced guinea pig myopia model construction method used in this application is as follows:

[0294] Three-week-old tricolor guinea pigs (both male and female, simulating humans aged 3-26 years) were used and kept in the experimental animal room of Wenzhou Medical University, with 12 hours of light (400-500 lux) / 12 hours of darkness, free access to water and food. The myopia model was established using monocular form deprivation (FD) and lens induction (LI) modeling. Form deprivation used a special 1% transmittance, non-self-falling eye mask to completely cover the right eye of the animal, and the other eye (left eye) obtained normal vision. The lens induction group used a -4D lens fixed in front of the right eye of the animal, and the left eye obtained normal vision. The above animals cleaned the lenses twice a day to prevent blurring of the lenses. The animals in the experimental group were given medication every day from 9:00 to 9:30 am. When administering the drug, the animals in the negative and positive control groups and the experimental groups removed their eye masks or lenses under red light, and injected 0.1 ml of solvent control, or test drug (vinpocetine at different concentrations), or positive control (0.1% atropine) around the right eyeball. After the injection, it was confirmed that the animal was successfully administered without trauma and the eye mask or lens was immediately restored. The administration process for each animal was controlled within about 10 seconds. The drug administration began on the day of modeling, and the form deprivation group was administered for 2 consecutive weeks, and the lens induction group was administered for 1 consecutive week. This experiment has been reviewed by the Experimental Animal Ethics Committee of Wenzhou Medical University.

[0295] The preparation method of Vinpocetine eye drops used in the experimental group is as follows:

[0296] It is reported that the solubility of VPN in water at room temperature is 2.4 μg / mL. The inventor prepared a 5 μM (i.e., 1.75 μg / mL) storage solution of VPN, the solvent is normal saline, stored at -80°C, and diluted to 1 μM, 0.1 μM, and 0.01 μM with normal saline before the administration experiment. During the preparation process of VPN eye drops, conventional physical dissolution methods such as heating and stirring can be selected, and acids can also be used to adjust the pH value to increase solubility, and finally the pH value is adjusted to 7.31. The above-mentioned VPN eye drops are transparent and stable at room temperature.

[0297] The animals were grouped as follows:

[0298] 1. Form deprivation group (FDM) :

[0299] 1. Form deprivation plus solvent injection group: One eye was patched and the patched eye was injected with solvent saline for 2 weeks, sample size = 20.

[0300] 2. Form deprivation plus drug injection group:

[0301] One eye was patched and vinpocetine (0.01 μM: 0.1 ml / day) was injected into the patched eye for 2 weeks, sample size = 15;

[0302] One eye was patched and vinpocetine (0.1 μM: 0.1 ml / day) was injected into the patched eye for 2 weeks, sample size = 20;

[0303] One eye was patched and vinpocetine (1.00 μM: 0.1 ml / day) was injected into the patched eye for 2 weeks, sample size = 22;

[0304] 3. Form deprivation plus positive control group: One eye was covered with an eye patch and atropine (0.1%: 0.1 ml / day) was injected into the eye for 2 weeks, sample size = 15.

[0305] 2. Lens Induction Group (LIM) :

[0306] 1. Lens-induced solvent injection group: monocularly wearing -4D lenses and injecting solvent saline into the wearing eye for 1 week, sample size = 10.

[0307] 2. Lens induction plus drug injection group:

[0308] One eye wore a -4D lens and the wearing eye was injected with vinpocetine (0.01 μM: 0.1 ml / day) for 1 week, sample size = 12;

[0309] One eye wore a -4D lens and the wearing eye was injected with vinpocetine (0.1 μM: 0.1 ml / day) for 1 week, sample size = 12;

[0310] Wearing 4D lenses in one eye and injecting vinpocetine (1.00 μM: 0.1 ml / day) into the wearing eye for 1 week, sample size = 13;

[0311] 3. Lens-induced positive control group: One eye was covered with an eye patch and atropine (0.1%: 0.1 ml / day) was injected into the eye for 1 week, sample size = 11.

[0312] The difference between the solvent control group and the experimental group is that the solvent control group does not contain active ingredients.

[0313] Measurement of refractive power and eye parameters of enrolled animals

[0314] All animals in the same model efficacy experiment were measured in the same time period, and the first measurement time was 3 weeks of age, that is, before drug administration. The refractive power and axial length parameters of the animals in the FDM group were tested before the experiment, 1 week after drug administration, and 2 weeks after drug administration; the animals in the LIM group were tested before the experiment, 3 days after drug administration, and 7 days after drug administration. The refractive power was measured using an eccentric infrared photoretinoscope (EIR) built in this laboratory, and each eye was tested 3 times and the average value was taken as the final result. The axial length parameters of guinea pigs were measured using the A-ultrasound probe in the Cinescan A / B ultrasound diagnostic instrument (Quantel Medical, Aviso, France). The ultrasound frequency was 11MHz, and the ultrasound propagation speeds of different refractive media of the eyeball were set as: 1557.5m / s in the anterior chamber, 1723.3m / s in the lens, and 1540m / s in the vitreous. The test content included vitreous chamber depth (VCD) and axial length (AL). About 2 minutes before the test, the guinea pig's test eye was anesthetized with 0.5% proparacaine hydrochloride eye drops (Alcon, Belgium). Each eye was measured 6 times, and the average value was taken as the final result.

[0315] Measurement of choroidal blood flow and thickness

[0316] Choroidal blood flow parameters and choroidal thickness were measured for the FDM group animals after continuous administration for 1 week and 2 weeks of administration; and for the LIM group animals after 7 days of administration. Choroidal blood flow parameters and thickness were measured using a modified commercial OCTA (Spectralis HRA+OCT, OCTA, Heidelberg, Germany) to make it more suitable for animal eyes. Guinea pigs were fully anesthetized before testing (a mixture of 60 mg / kg ketamine hydrochloride and 9 mg / kg xylazine hydrochloride, intraperitoneal injection), after which guinea pig OCTA images were obtained, and the measurement results were quantified by a self-written program (MatLab R2017a, MathWorks), realizing real-time quantitative detection of choroidal blood flow and thickness in guinea pigs (Sen Zhang, Invest Ophthalmol Vis Sci. 2019 Jul 1; 60 (8): 3074-3083).

[0317] Example 2: Experimental study on the effect of topical application of vinpocetine on the eye

[0318] The experimental method is as in Example 1. The refraction, vitreous cavity and axial length of all test animals were measured before administration, 1 week after administration and 2 weeks after administration in the FDM group; the refraction, vitreous cavity and axial length of all test animals were measured before administration, 3 days after administration and 7 days after administration in the LIM group. All data were analyzed by repeated measures analysis of variance, where P values ​​less than 0.05 were considered significant differences, and less than 0.01 were considered extremely significant differences.

[0319] Experimental results:

[0320] 1. Vinpocetine alone can effectively inhibit the occurrence and development of FDM-induced myopia (F3,73=14.66, p<0.001). One week after administration of FDM, the saline injection group induced myopia of -4.94±2.35D, and two weeks later, the group induced myopia of -6.74±1.90D. The vitreous cavity depth and axial length were correspondingly extended, indicating that the model was successfully established. After one week of continuous administration of 1μM vinpocetine, FDM myopia and the corresponding extension of the axial length and vitreous cavity depth can be effectively inhibited. Specifically: FDM+Vehicle vs.FDM+VPN(1μM): -4.94±2.35 vs.-2.44±1.88D, p<0.01, the refractive inhibition rate was 50.5%; the vitreous cavity depth was also inhibited accordingly, FDM+Vehicle vs.FDM+VPN(1μM): 0.11±0.04 vs.0.06±0.05mm, p<0.01, the vitreous cavity depth inhibition rate was 45.0%, and the axial length was also inhibited, FDM+Vehicle vs.FDM+VPN(1μM): 0.11±0.05 vs.0.07±0.05mm, p=0.09, and the axial length inhibition rate was 39.8%. In addition, the corresponding indicators and results of myopia treatment in the medium-concentration vinpocetine-administered group also suggest that vinpocetine and its related compounds can be used for myopia treatment. The inventors even found that at two efficacy detection time points in the low-concentration vinpocetine-administered group (only 0.01 μM), although there was no statistical difference, the negative process of refraction and the extension of vitreous cavity depth showed an inhibitory trend compared with the negative control group. Compared with the myopia treatment results of the positive control group, after one week of medication, the myopia induced by the 0.1% atropine group model was -3.20±1.73D, the refraction suppression rate was 35.2%, the vitreous cavity depth was 0.08±0.05mm, the vitreous cavity depth suppression rate was 31.5%, the axial length was 0.08±0.05, and the axial length suppression rate was 32.1%. It can be seen from the above results that high-concentration vinpocetine is more effective than atropine in the prevention and control of myopia, and the efficacy of medium-concentration vinpocetine in myopia treatment is similar to that of atropine ( Figure 1 AC).

[0321] After two weeks of continuous administration of Vinpocetine, myopia in the FDM model can also be effectively inhibited. FDM+Vehicle vs.FDM+VPN(1μM): -6.74±1.90 vs.-3.36±2.21D, p<0.001, the refractive index was 50.1%, and the refractive index of some animals was almost unchanged compared with the last test. The depth of the vitreous cavity was also inhibited accordingly, FDM+Vehicle vs.FDM+VPN(1μM): 0.16±0.07 vs.0.09±0.05mm, p<0.001, the inhibition rate of the vitreous cavity depth was 43.4%, and the axial length was also inhibited accordingly, FDM+Vehicle vs. FDM+VPN (1μM): 0.16±0.06 vs. 0.08±0.05 mm, p<0.001, axial length inhibition rate was 48.2%; while at this time, 0.1% atropine-induced myopia was -3.38±2.79D, refractive inhibition rate was 49.8%, vitreous cavity depth was 0.10±0.05 mm, vitreous cavity depth inhibition rate was 38.2%, axial length was 0.10±0.05 mm, axial length inhibition rate was 41.0% ( Figure 1 AC), pupil dilation was observed in animals during atropine administration.

[0322] In addition, by Figure 1 It can be seen that there is a positive dose-effect relationship in the treatment of form deprivation myopia model with vinpocetine. With the increase of the dosage, the myopia treatment effect is stronger, and the axial length and vitreous cavity depth also show the same inhibitory effect. Compared with the control group, vinpocetine can significantly inhibit the negative refractive power of form deprivation myopia, significantly inhibit the extension of axial length of form deprivation myopia, and the extension of vitreous cavity depth. At the same time, the comprehensive performance of vinpocetine in the treatment of myopia in the FDM model is also better than atropine, especially the inhibitory effect on the negative refractive power process.

[0323] 2. Vinpocetine can effectively inhibit the occurrence and development of LIM-induced myopia (F3,43=4.073, p=0.012). After 3 days of LIM experiment, the saline injection group induced myopia of -3.25±1.20D, and after 7 days, it induced myopia of -3.93±1.26D. The vitreous cavity depth and axial length increased or prolonged accordingly. After 3 days of administration of 1μM vinpocetine, myopia in the LIM model can be effectively inhibited, LIM+Vehicle vs.LIM+VPN(1μM): -3.25±1.20 vs.-2.00±0.82D, p<0.05, the refractive inhibition rate was 38.5%, and the vitreous cavity depth also had a corresponding inhibition, LIM+Vehicle vs.LIM+VPN(1μM): 0.07±0.03 vs.0.03±0.03mm, p<0.01, the vitreous cavity depth inhibition rate was 58.8%, and the axial length also had a corresponding inhibition, LIM+Vehicle vs.LIM+VPN(1μM): 0.07±0.03 vs.0.03±0.03mm, p<0.01, the vitreous cavity depth inhibition rate was 58.8%, and the axial length also had a corresponding inhibition, LIM+Vehicle vs.LIM+VPN(1μM): 0.08±0.02vs.0.04±0.02mm, p<0.001, axial length inhibition rate was 55.5%; while at this time, the myopia induced by 0.1% atropine was -2.34±0.73D, the refractive inhibition rate was 30.0%, the vitreous cavity depth was 0.04±0.03mm, the vitreous cavity depth inhibition rate was 47.3%, the axial length was 0.04±0.02mm, and the axial length inhibition rate was 47.4%. It can be seen that all myopia treatment indicators of the high concentration (1μM) vinpocetine group were better than atropine. Compared with the negative control group, the high, medium and low concentrations of vinpocetine groups all showed the effect of myopia treatment ( Figure 2 AC).

[0324] After 7 days of administration, vinpocetine can also effectively inhibit myopia in the LIM model. By comparing the changing trends of the negative refractive power process in different experimental groups during the entire administration period, it was found that vinpocetine can significantly slow down the rate of myopia progression in the lens-induced myopia model. The refractive power results were LIM+Vehicle vs.LIM+VPN(1μM): -3.93±1.26 vs.-2.61±1.17D, p<0.05, the refractive power suppression rate was 36.3%, and the vitreous cavity depth also had a corresponding inhibition, LIM+Vehicle vs.LIM+VPN(1μM): 0.09±0.04 vs.0.05±0.02mm, p<0.001, the vitreous cavity depth inhibition rate was 49.8%, and the axial length also had a corresponding inhibition, LIM+Vehicle vs.LIM+VPN(1μM): 0.09±0.04 vs.0.05±0.02mm, p<0.001, the vitreous cavity depth inhibition rate was 49.8%, and the axial length also had a corresponding inhibition, LIM+Vehicle vs.LIM+VPN(1μM): 0.10±0.04 vs.0.05±0.02 mm, p<0.001, axial length inhibition rate was 53.8%; while at this time, 0.1% atropine-induced myopia was -2.61±1.17D, refractive inhibition rate was 33.4%, vitreous cavity depth was 0.05±0.03 mm, vitreous cavity depth inhibition rate was 45.7%, axial length was 0.06±0.03 mm, axial length inhibition rate was 41.8% ( Figure 2 AC), the pupil dilation phenomenon was observed in the animals during the use of atropine. It can be seen that the comprehensive performance of high-concentration vinpocetine in the treatment of myopia in the LIM model is better than that of (high-concentration) atropine, especially from the perspective of drug safety and efficacy.

[0325] Depend on Figure 2 It can also be seen that different concentrations of vinpocetine also have a positively correlated dose-effect relationship in the treatment of lens-induced myopia models. At the same time, vinpocetine can have a high inhibitory effect in the early stages of myopia and can maintain such an inhibitory effect. That is, the excellent myopia prevention and control efficacy shown by vinpocetine has nothing to do with the severity of myopia or the speed of negative refractive power. In addition, compared with the saline group, all vinpocetine treatment groups significantly inhibited the process of negative refractive power of lens-induced myopia, delayed the occurrence and development of myopia, and significantly inhibited the extension of axial length and increase in vitreous cavity depth in lens-induced myopia during the entire dosing cycle.

[0326] According to the data of two recognized animal models for evaluating the efficacy of myopia drugs, Vinpocetine showed excellent myopia treatment effects. The inhibition and slowing down of the process of negative refractive power were consistent with the corresponding inhibition of axial lengthening and the inhibition of the increase of vitreous cavity depth, proving that Vinpocetine mainly treats myopia by controlling axial lengthening and the increase of vitreous cavity depth. The inventor unexpectedly found that when Vinpocetine is used alone, the efficacy of Vinpocetine in the treatment of myopia, especially axial myopia, is even better than that of atropine (0.1% atropine). It is worth noting that the above-mentioned Vinpocetine treatment effect on myopia is unrelated to the gender, age, type of myopia, myopia progression rate and myopia severity of the subjects.

[0327] No eye abnormalities were observed in all the test animals in the vinpocetine group during the administration period. No significant changes in pupil size were observed in the test eyes of young guinea pigs during the topical administration of vinpocetine, and no allergic reactions were observed. At the same time, no common clinical adverse reactions of vinpocetine or toxic manifestations such as weight loss were observed in any of the test animals in the vinpocetine group during the administration period.

[0328] From the perspective of pharmacodynamic evaluation and the safety of long-term continuous medication, vinpocetine can be used to prevent, treat and control myopia, especially in children and adolescents.

[0329] Example 3: Mechanism of Vinpocetine in the Treatment of Myopia

[0330] It is well known that vinpocetine has the effect of improving blood circulation. The inventors used the method of Example 1 to detect the changes in the choroidal thickness ChT and choroidal blood flow ChBP index signals of FDM (1 week and 2 weeks of administration) and LIM (1 week of administration) at different time points during the administration cycle. It was found that compared with the solvent injection group, the therapeutically effective amount of vinpocetine only slightly increased the increase in choroidal thickness and choroidal blood perfusion, but there was no statistical significance (in the FDM model, ChBP: F 3,59 =1.294,p=0.285, Figure 3 In the AB;LIM model, ChBP:F 3,44 =0.383,p=0.766, Figure 4AB). In addition, a comprehensive investigation of the drug's inhibition of myopia treatment indicators such as refraction and axial length, and the effects of vinpocetine on the increase in choroidal thickness and choroidal blood perfusion at the corresponding time points revealed that the actual efficacy of its myopia treatment and control of myopia progression and the assumed pharmacology of vasodilation (increasing choroidal blood flow) are not logically corresponding, and there are contradictions. The relevant test data of the form deprivation group after one week of administration, that is, different concentrations of vinpocetine can effectively inhibit indicators such as negative refraction and increased vitreous cavity depth, showing a significant myopia treatment effect and a positively correlated dose-effect relationship, but the effect of vinpocetine on choroidal blood perfusion showed a negatively correlated dose-effect relationship, and the effects of vinpocetine at various concentrations on choroidal blood perfusion, compared with the atropine group, are similar to the negative control group. In particular, the high-concentration group of vinpocetine (1μM), although the effect of improving choroidal blood flow is the worst, has the strongest effect on inhibiting the progression of negative refraction in myopia ( Figure 1 AB and Figure 3 B); For example, at 2 weeks, the medium concentration (0.1 μM) of vinpocetine in the form deprivation group showed similar myopia treatment effects in terms of axial parameters as atropine, but its effect on choroidal vasodilation was not as good as atropine ( Figure 1 BC and Figure 3 B).

[0331] In summary, the pharmacological mechanism of Vinpocetine in treating myopia is not through the mechanism of dilating ocular blood vessels, improving ocular blood circulation or increasing choroidal blood flow, but may be more dependent on a (ocular) function that has never been recognized by people. The biological target corresponding to this function even has a competitive binding relationship with the known vasodilator target of Vinpocetine.

[0332] Example 4: Effect of Vinpocetine on Controlling Myopia Progression by Systemic Administration

[0333] The purpose of this study is to evaluate the effect of systemic administration of vinpocetine (such as intravenous drip or oral gavage) on the treatment of myopia, especially the control of myopia progression, and to comprehensively analyze the efficacy and safety of the drug based on indicators such as refraction, axial length, vitreous cavity depth, and body weight. In rats, the oral bioavailability of vinpocetine is 52% (Vereczkey et al., 1979a), and the oral gavage LD50 value is about 500 mg / kg (Cholnoky and 1976). The literature also reported that after giving rodents a lethal dose of vinpocetine, the animals often showed clinical manifestations of ataxia and clonic convulsions (Cholnoky and 1976). According to the safety evaluation data of Vinpocetine on rodents published by the FDA, it is administered by gavage to animals of childbearing age. Rats were given 20 mg / kg per day without obvious abnormalities, and 40 mg / kg and above showed toxicity such as weight loss and reduced food intake; rabbits were given 75 mg / kg per day without obvious abnormalities, and 150 mg / kg began to show toxicity such as weight loss and reduced food intake. Currently, the dosage forms of Vinpocetine sold in China include tablets and injections. Based on the normal living habits of guinea pigs and the requirements of form deprivation modeling, as well as the principle of drug compliance for future clinical use of myopia treatment, the inventor believes that the efficacy of systemic administration of Vinpocetine in myopia treatment is similar to or better than that of intravenous drip administration by gavage. The single gavage dose of guinea pigs is formulated with reference to the oral bioavailability of Vinpocetine in similar species and the corresponding gavage toxic dose of rodents. The dosage should basically maintain the normal physiological state of guinea pigs and prevent them from experiencing severe toxic reactions such as ataxia or clonic convulsions.

[0334] Continuous daily administration evaluates the inhibitory effect of vinpocetine on myopia progression by systemic administration, and observes the toxicity of the dose used. The form deprivation myopia animal model and the method for evaluating the efficacy of vinpocetine for myopia treatment used in this experiment are the same as those in other related embodiments (topical administration) in this application, wherein the guinea pig form deprivation myopia model (FDM) modeling and oral administration are operated and performed with reference to the literature published by the inventor's laboratory (Pan Miaozhen, Proc Natl Acad Sci US A. 2021 Oct 26; 118 (43): e2104689118). Specifically, healthy 3-week-old tricolor guinea pigs (male or female) were selected after eliminating individuals with obvious eye diseases or abnormalities. After refraction (infrared eccentric photorefractometer) and axial length (A-ultrasound) detection, animals with refractive power between 3-8 diopter (D) and binocular anisometropia not exceeding 2D were selected and randomly divided into the following 3 groups: form deprivation (FDM) + solvent control (Vehicle) group, FDM + low-dose vinpocetine group (VPN) and FDM + high-dose VPN group. The mean weights of the three groups of animals before administration were basically the same and there was no statistical difference between them. Guinea pigs were given form deprivation (FD) myopia model at 8 am on the first day of the experiment. The form deprivation myopia model adopts the mask method. The headgear is made by the inventor using a 10-inch milky white non-toxic latex balloon. The right eye of the guinea pig model is covered with the headgear (experimental eye), and the left eye is not covered with the headgear (contralateral eye). FD induction continued throughout the vinpocetine gavage efficacy experiment cycle, and the headgear was only briefly removed for eye testing (such as refractive testing). After the start of the efficacy experiment, the position of the headgear was checked at 8 am, 12 noon, 7 pm and before administration, and individuals whose headgear fell off more than 3 times were eliminated. Starting from the day of modeling, the solvent or drug corresponding to the FDM model was administered between 9 and 10 am every day. The administration method was gavage, and the dosage was 50 mg / kg / d (low dose) and 100 mg / kg / d (high dose), respectively. The actual administration was calculated according to the mean body weight of each group of animals, and the gavage volume of the solvent group was 5 ml / kg / d. The drug was administered once a day for 2 consecutive weeks. The refractive power and axial length parameters of the test animals were tested at the beginning, 1 week and 2 weeks of the efficacy experiment of this model. All data collection and processing methods were the same as those published in the literature by the inventor's laboratory (Sen Zhang, Invest Ophthalmol Vis Sci. 2019 Jul 1; 60 (8): 3074-3083; Pan Miaozhen, Proc Natl Acad Sci USA. 2021 Oct 26; 118 (43): e2104689118). The statistical basis was the difference between the experimental eye and the contralateral eye of the same subject. At the same time, the weight of all subjects was recorded during the experimental period.The preparation method of the vinpocetine gavage solution used by the inventors of this embodiment is as follows: It is reported that the solubility of vinpocetine in 0.5% methylcellulose at room temperature can reach 200 mg / mL (Waidyanatha S et al, Systemic exposure of vinpocetine in pregnant SpragueDawley rats following repeated oral exposure: An investigation of fetal transfer, Toxicol Appl Pharmacol, 338: 83-92, 15Nov 2017). Without adding other pharmaceutical excipients or other compounds, the inventors directly and completely dissolved the vinpocetine compound powder in 0.5% methylcellulose solvent (sterile water + methylcellulose) to prepare 10 mg / mL and 20 mg / mL vinpocetine preparations (gavage solutions) respectively. At room temperature, the overall appearance of the preparation is clear, transparent, uniform, and there is no visible suspended matter. The preparation preparation process may use conventional physical and chemical solubilizing means such as heating, stirring, and pH adjustment as appropriate, and no compound precipitation occurs before the preparation is administered.

[0335] The experimental results showed that the changes in the refractive power and axial length parameters of the animals in the negative control group were consistent with the expectations of the myopia model, proving that the form deprivation myopia model was successfully established and can be used for the efficacy evaluation of the tested drugs. Figure 5As shown in the figure, during the entire treatment period, the systemic administration of vinpocetine showed a trend of treating myopia and inhibiting myopia progression compared with the solvent control group, regardless of the refractive power or axial length parameters. At the same time, the weight gain of the vinpocetine group was significantly inhibited. Taking the low-concentration oral gavage group as an example: after 1 week of administration, the body weight of the 50 mg / kg vinpocetine group was significantly lower than that of the solvent group, FDM+Vehicle vs. FDM+VPN (50 mg / kg): 208.5±14.9 vs. 188.0±22.9 mg, p<0.05, and the mean body weight decreased by 9.9%; after 2 weeks of administration, the body weight gain of the 50 mg / kg vinpocetine group was significantly inhibited, FDM+Vehicle vs. FDM+VPN (50 mg / kg): 229.6±21.4 vs. 210.2±21.9 mg, p<0.05, and the mean body weight decreased by 8.4%. It can be seen that substantial toxicity has been produced to the experimental animals when the daily dose reaches 50 mg / kg, and further increasing the dosage of vinpocetine will increase the risk of toxicity to the subjects. However, it is worth emphasizing that the inventors have observed that oral administration of vinpocetine has a definite dose-effect relationship for myopia treatment, especially for inhibiting myopia progression: that is, as the oral administration amount increases, the efficacy of vinpocetine for myopia treatment through systemic administration becomes more obvious. Compared with the 50 mg / kg dose, when the dose is administered by oral administration at 100 mg / kg, the degree of negative refraction and the extension of axial length of the test subjects are further inhibited. The refractive index and axial length parameters of the three groups of animals at the end of the drug treatment are as follows: refractive index: FDM+Vehicle vs.FDM+VPN(50mg / kg) vs.FDM+VPN(100mg / kg): -6.59±1.42 vs.-5.71±2.41 vs.-5.223±2.20D; vitreous cavity depth: FDM+Vehicle vs.FDM+VPN(50mg / kg) vs.FDM+VPN(100mg / kg): 0.12±0.05 vs.0.13±0.07 vs.0.10±0.06mm; axial length: FDM+Vehicle vs.FDM+VPN(50mg / kg) vs.FDM+VPN(100mg / kg): 0.14±0.05 vs.0.13±0.05 vs.0.11±0.05mm. From the above results, it can be concluded that systemic administration of Vinpocetine also has the potential to inhibit the progression of myopia and achieve a significant effect in treating myopia, but compared with local administration, systemic administration should require a larger dose or a longer treatment time.In terms of safety evaluation, the use of direct systemic administration (such as direct intravenous infusion or oral tablets) of vinpocetine for the treatment of myopia will bring about certain side effects (such as weight loss or increased risk of miscarriage), so local administration is more recommended, because patients will bear additional clinical risks when using vinpocetine to treat myopia through systemic administration such as oral administration.

[0336] It can be seen that whether it is systemic administration or topical administration, vinpocetine can be used for the prevention and treatment of myopia. Compared with systemic administration, topical administration of vinpocetine is a better choice for preventing and controlling the progression of myopia. It should be understood that the results of this embodiment are not inconsistent with the conclusions of this application, but are intended to prompt: when vinpocetine is directly applied for myopia prevention and treatment, it is preferred to adopt a safer, more efficient and convenient topical administration method (preferably ocular administration), but it does not exclude the use of systemic administration routes, such as using specific drug targeting technology, while effectively reducing the drug toxicity of systemic administration, vinpocetine drug enrichment in the eye can be achieved to treat or inhibit myopia.

[0337] Example 5: Treatment of myopia with salmeterol and tiotropium bromide

[0338] The guinea pig form deprivation myopia model described in the present invention was used to evaluate the efficacy of the drug. All individuals were tested for diopter and axial length. After removing the animals that did not meet the conditions, they were randomly divided into 5 groups: a vinpocetine treatment group alone, a salmeterol+tiotropium+vinpocetine combined treatment group, a salmeterol+tiotropium combined treatment group, a negative control group (solvent group) and a 0.1% atropine group (positive control group). The concentrations of salmeterol (S) and tiotropium (T) were 1×10 -5 M and 1×10 -6 M, the concentration of vinpocetine used is 1 μM whether it is administered alone or in combination. Guinea pigs were subjected to form deprivation at 8 a.m. on the first day of the experiment, using the mask method, with the right eye covered (experimental eye) and the left eye uncovered (contralateral eye). Starting from the day of modeling, the solvent or drug of the corresponding group of the experimental eye was given at 9-10 a.m. every day, by juxtabulbar subconjunctival injection, with an injection volume of 100 μl, once a day for 2 consecutive weeks. The animal refractive power and axial length parameters were detected before and at the end of the efficacy experiment. All data collection and processing methods are the same as those in other embodiments of the present invention, and the statistical basis is the difference between the experimental eye and the contralateral eye of the same individual subject.

[0339] The experimental results showed that the changes in the refractive index and axial length parameters of the animals in the negative control group were in line with the expectations of the myopia model, and the positive control drug atropine showed the expected efficacy in the experiment. These all proved that the myopia model was successfully established and can be used for the efficacy evaluation of the tested drugs. After the drug intervention, there was no statistical difference in the refractive index or axial length parameters between the salmeterol + tiotropium combined treatment group and the negative control group. The specific data were as follows: refractive index: FDM + Vehicle vs. FDM + S + T (salmeterol, 10 -5 M+tiotropium,10 -6 M): -6.00±1.61 vs. -5.09±1.80 D, p>0.05, vitreous cavity depth: FDM+Vehicle vs.FDM+S+T (salmeterol, 10 -5 M+tiotropium,10 - 6 M): 0.12±0.05 vs. 0.12±0.06 mm, p>0.05, axial length: FDM+Vehicle vs. FDM+S+T (salmeterol, 10 -5 M+tiotropium,10 -6 M): 0.13±0.04 vs. 0.13±0.08 mm, p>0.05. The above results can fully prove that salmeterol and tiotropium bromide have no therapeutic effect on myopic individuals and cannot effectively control the progression of myopia. Compared with the negative control group, the vinpocetine (1 μM) treatment group and the 0.1% atropine group at the end of two weeks of administration were consistent with the myopia treatment results of other embodiments of the present invention. Both significantly inhibited the negative refractive power, axial length extension and vitreous cavity depth increase (such as Figure 6 As shown, there was a statistically significant difference between the vinpocetine (1 μM) treatment group and the solvent control group. No eye abnormalities were observed in the vinpocetine treatment group, while mydriasis was observed in the atropine group. The corneal curvature (RCC), anterior chamber depth (ACD) and lens thickness (LT) related indicators of the two groups of test animals were not affected by the drugs (see Figure 6 ). Therefore, under the premise of meeting the ocular safety of young individuals, vinpocetine as the only active ingredient, the main active ingredient or the direct active ingredient can effectively prevent and control myopia, and significantly inhibit, control and slow down the progression of myopia.

[0340] In addition, the combined treatment group of salmeterol + tiotropium bromide + vinpocetine and the single use of vinpocetine (1 μM) have similar therapeutic effects. During the entire medication period, there is no statistical difference in the diopter, axial length and vitreous cavity depth index of the guinea pig myopia model between the two, suggesting that neither salmeterol nor tiotropium bromide shows a synergistic or promoting effect on the treatment of vinpocetine myopia. Comprehensive analysis of the combined administration of salmeterol + tiotropium bromide + vinpocetine has no significant difference in effectiveness compared with the single use of vinpocetine to treat myopia. Combined with the salmeterol + tiotropium bromide treatment group, there is no significant pharmacodynamic effect on myopia. It is concluded that the combined administration of salmeterol + tiotropium bromide + vinpocetine is only the effect of vinpocetine in treating myopia, that is, vinpocetine can be used for myopia prevention and control as the only active ingredient or the main active ingredient or the direct active ingredient, which can effectively control myopia progression. Vinpocetine alone is superior to the drug combination treatment group of this embodiment in terms of safety, effectiveness and drugability in the treatment of myopia.

[0341] Example 6: Vinpocetine can effectively prevent and control myopia under non-invasive administration (eye drops)

[0342] The purpose of this experiment is to evaluate the effect of vinpocetine on myopia through non-invasive administration, and all the tested drugs are made into eye drops. The guinea pig form deprivation myopia model described in the present invention is used to evaluate the efficacy. All individuals are tested for diopter and axial length. After removing the animals that do not meet the conditions, they are randomly divided into 4 groups: a low concentration of vinpocetine (1μM) group, a high concentration of vinpocetine (5μM) group, a negative control group (solvent group) and a 0.1% atropine group (positive control group). Guinea pigs were subjected to form deprivation at 8 am on the first day of the experiment, using the mask method, with the right eye covered (experimental eye) and the left eye uncovered (contralateral eye). Starting from the day of modeling, the solvent or drug corresponding to all experimental eyes was given at 9-10 am and 14-15 pm every day, and the drug was directly administered by eye drops. The volume of a single eye drop was 25μl, and the drug was administered twice a day for 2 weeks. The animal refractive power and axial length parameters were detected before and after the efficacy experiment. All data collection and processing methods were the same as those in other embodiments of the present invention, and the statistical basis was the difference between the experimental eye and the contralateral eye of the same subject. The vinpocetine eye drops and atropine eye drops used in this embodiment were prepared by the inventor using 0.9% saline, and no other active substances or excipients were added to the eye drops.

[0343] The experimental results showed that the changes in the refractive power and axial length parameters of the animals in the negative control group were consistent with the expectations of the myopia model, and the positive control drug atropine showed the expected efficacy in the experiment. These all proved that the myopia model was successfully established in this experiment and can be used for the efficacy evaluation of Vinpocetine (eye drop dosage form).

[0344] Through non-invasive drug delivery, Vinpocetine eye drops can effectively inhibit the occurrence and development of myopia (refractive: F 2,42 =9.115,p<0.001; glass cavity: F 2,42 =6.243,p=0.04; Axis: F 2,42 =8.986, p<0.001), and there is a dose-effect relationship, that is, the higher the drug concentration, the better the myopia (eye) treatment effect, and there are statistical differences in the axial length parameter indicators in myopia treatment between different concentrations of vinpocetine drug groups. Due to the modeling method, the structure of the guinea pig eye (the eyeball is relatively convex compared to humans and will not actively close the eyes) and the normal blinking of the animals, the effective therapeutic dose of the drug actually obtained by eye drops for each test eye is lower than the peribulbar injection dose of the eye with the same volume, and the total volume of eye drops administered to the test animals per day is also less than the injection volume of Example 2. Therefore, in this example, whether it is the low-concentration vinpocetine eye drop group or the 0.1% atropine group, the efficacy (refractive index) of direct eye drops is inferior to the therapeutic effect of peribulbar injection on myopia. The specific results are as follows: Figure 7As shown: Continuous administration of 5μM vinpocetine for 2 weeks in the high-concentration group can effectively inhibit the development of FDM myopia and the corresponding extension of the axial length and vitreous cavity depth. Specifically: FDM+Vehicle vs.FDM+VPN(5μM): -6.56±1.70 vs.-3.80±1.16D, p<0.001, the refractive inhibition rate was 42.1%; the vitreous cavity depth was also inhibited accordingly, FDM+Vehicle vs.FDM+VPN(5μM): 0.14±0.05 vs.0.09±0.04mm (actual value 0.0869±0.0448mm, rounded off), p<0.01, the vitreous cavity depth inhibition rate was 38.6%; the axial length was also inhibited, FDM+Vehicle vs.FDM+VPN(5μM): 0.14±0.05 vs.0.09±0.04mm (actual value 0.0869±0.0448mm, rounded off), p<0.01, the vitreous cavity depth inhibition rate was 38.6%; vs.FDM+VPN(5μM): 0.16±0.04 vs.0.09±0.04 mm (actual value 0.0925±0.0406 mm, rounded), p<0.001, axial length inhibition rate was 41.4%. Low concentration 1μM vinpocetine administration group can also effectively control myopia progression: FDM+Vehicle vs.FDM+VPN(1μM): -6.56±1.70 vs.-4.81±1.72D, p<0.05, refractive inhibition rate was 26.7%. Compared with the progression of myopia in the negative control group, the myopia induced by the 0.1% atropine eye drops group was -3.93±1.75D after 2 weeks of medication, the refractive inhibition rate was 40.0%, the vitreous cavity depth was 0.11±0.05mm (the actual value was 0.1107±0.0502mm, rounded off), the vitreous cavity depth inhibition rate was 21.8%, the axial length was 0.11±0.05mm (the actual value was 0.1093±0.0530mm, rounded off), and the axial length inhibition rate was 30.7%. The atropine group experienced the adverse reaction of pupil dilation during medication, while the vinpocetine group did not show obvious eye abnormalities. Regardless of whether it was atropine or vinpocetine for myopia intervention, the corneal curvature, anterior chamber, and lens-related indicators of the subjects were not affected (see Figure 7 ). In the inventor's laboratory, for the 0.01% atropine eye drops that are currently used in clinical trials, under the same dosing conditions in this embodiment (myopia model, dosing method, dosing frequency and dosing volume, etc. are kept consistent), this concentration of atropine did not observe any therapeutic effect on the guinea pig myopia model, whether it is the refractive index or the axial parameter index, 0.01% atropine has no significant intervention effect, which may be related to the short time that the eye drops dosage form stays on the surface of the eyeball after the animal drops are administered. Therefore, from the perspective of efficacy and safety, the risk-benefit ratio of vinpocetine for the treatment of myopia individuals is better than that of atropine (such as the use of vinpocetine during the day will not cause photophobia caused by myopia dilation similar to atropine at the same time as myopia treatment), and is particularly suitable for myopia treatment in children and adolescents and myopia prevention and control in school-age populations.

[0345] This example proves that the administration of vinpocetine eye drops by eye drops can significantly inhibit the negative myopia refraction, significantly inhibit the extension of myopia axial length, and increase the depth of the vitreous cavity, just like the administration by juxtaconjunctival injection. This administration method also has a positively correlated dose-effect relationship, that is, the higher the dosage of vinpocetine, the more obvious the myopia treatment effect. At the same time, in the case of non-invasive administration, the comprehensive performance of vinpocetine in myopia treatment is also better than the positive control atropine, especially the control effect on myopia progression.

[0346] Example 7: Apovincaminic acid (AVA), a metabolite of vinpocetine, can effectively prevent and treat myopia

[0347] The guinea pig form deprivation myopia model described in the present invention is used to evaluate the efficacy of the drug. All individuals are tested for diopter and axial length. After removing the animals that do not meet the conditions, they are randomly divided into 3 groups: a group using avicamine acid alone, a negative control group (solvent group) and a 0.1% atropine group (positive control group), wherein the concentration of avicamine acid (AVA) is 1 μM. The method for modeling myopia individuals is the same as that of other embodiments of the present invention. All groups are administered by juxtaconjunctival injection, the injection volume is 100 μl, and the drug is administered once a day for 1 week. The animal diopter and axial length parameters are detected before and after the efficacy experiment. All data collection and processing methods are the same as those of other embodiments of the present invention, and the statistical basis is the difference between the experimental eye and the contralateral eye of the same subject. The AVA injection and atropine injection used in this embodiment are prepared by the inventor using 0.9% saline without adding other active substances or excipients.

[0348] The experimental results showed that the changes in the refractive index and axial length parameters of the animals in the negative control group were consistent with the expectations of the myopia model, and the positive control drug atropine showed the expected efficacy in the experiment, which proved that the myopia model was successfully established and can be used for the evaluation of the efficacy of AVA. The experimental results showed that the metabolite of vinpocetine, AVA, can effectively inhibit the occurrence and development of FDM-induced myopia (refractive index: F 2,36 =7.914,P=0.001; glass cavity: F 2,36 =3.904,p=0.029; Axis: F 2,36 =4.539, p=0.017). Continuous administration of 1 μM AVA for 1 week can effectively inhibit the progression of myopia and the corresponding extension of the axial length and vitreous cavity depth (see Figure 8), specifically: FDM+Vehicle vs.FDM+AVA(1μM): -4.39±1.73 vs.-2.65±1.18D, p<0.01, refractive suppression rate was 39.6%; vitreous cavity depth was also suppressed accordingly, FDM+Vehicle vs.FDM+AVA(1μM): 0.09±0.04 vs.0.06±0.02mm, p<0.05, vitreous cavity depth suppression rate was 34.7%; axial length was also suppressed, FDM+Vehicle vs.FDM+AVA(1μM): 0.10±0.04 vs.0.07±0.03mm, p<0.01, axial length suppression rate was 36.4%. Mydriasis occurred in the atropine group during administration, while no eye abnormalities were observed in the AVA group. From the above results, it can be seen that the metabolite AVA of Vinpocetine also has significant therapeutic effects in the prevention, control and treatment of myopia.

[0349] In summary, Vinpocetine can not only significantly slow down the process of negative refraction in myopic individuals or individuals with myopia tendency, but also significantly inhibit the increase of vitreous cavity depth and axial lengthening. It can significantly improve the symptoms related to myopia, achieve the effect of myopia prevention, treatment and control of myopia progression, and no eye abnormalities were observed in all subjects during the administration period, and no significant changes were observed in the pupil size of the subjects during the administration period. Therefore, Vinpocetine can be used for the prevention, control and treatment of myopia, delay the development of myopia, control the progression of myopia, especially for the treatment, prevention or improvement of myopia in children and adolescents or simple axial myopia or progressive myopia or primary myopia and these myopia-related symptoms.

Claims

1. Use of apovincine in the preparation of a medicament, a preparation, a composition or a device, characterized in that: The medicine, preparation, composition or device is used in one or two or more of the following aspects: Prevention and / or treatment of myopia, and / or myopia prevention; or inhibit or control the progression of myopia; or For the prevention and control of myopia or delaying the occurrence and development of myopia; or Inhibit or slow down the elongation of the eye axis and / or the increase of the vitreous cavity length in myopic individuals or individuals with myopia tendency; or Prevent, slow, reduce or treat abnormal eye development associated with myopia; or Providing a myopic individual or an individual at risk of developing myopia with better distance vision without the use of glasses or other vision correction methods than before and / or without the use of the substance or method; or Inhibit, delay or slow down the progression or speed of negative refraction in myopic individuals or individuals prone to myopia; or Treat anisometropia.

2. The use according to claim 1, characterized in that The myopia described herein includes myopia in children and adolescents, refractive myopia, congenital myopia, early-onset myopia, delayed myopia, late-onset myopia, low myopia, moderate myopia, high myopia, pseudomyopia, true myopia, infant myopia, adult myopia, elderly myopia, pathological myopia, axial myopia, semi-true and semi-pseudomyopia, simple myopia, primary myopia, secondary myopia, progressive myopia, curvature myopia, exponential myopia, astigmatism myopia, positional myopia, tortuosity myopia, myopia caused by long-term nearsightedness, etc. Myopia caused by distance use, myopia caused by visual fatigue, myopia caused by adverse drug reactions, myopia caused by refractive medium mismatch, myopia caused by refractive development abnormalities, myopia caused by reading, myopia caused by using electronic products, myopia caused by excessive growth of the eyeball, myopia caused by unhygienic eye use, myopia that is poorly responded to or is ineffective with atropine treatment, myopia caused by insufficient outdoor exercise, accommodative tension myopia, myopia dominated by genetic factors or hereditary myopia, or myopia caused mainly by environmental factors.

3. The use according to claim 1, characterized in that The myopic individuals or individuals with myopia tendency are adults, infants, children and / or adolescents; or people whose eyeballs are still in the growth and development stage; or school-age people; or people whose parents are highly myopic; or people with insufficient hyperopia reserve.

4. The use according to claim 1, characterized in that The myopia described is axial simple myopia, such as axial simple myopia in children and adolescents.

5. The use according to any one of claims 1 to 4, characterized in that The drug, preparation, composition or device also contains other drugs or ophthalmic preparations, which include but are not limited to vinpocetine, or its optical isomers or racemates, or solvates, or pharmaceutically acceptable salts, or prodrugs, or metabolites, or related compounds or extracts, or crystalline compounds, or combinations of these substances, muscarinic antagonists, ampicillin, anidopyramine, timolol maleate, epinephrine, pilanzepine, pyrazine, pyrifenepine, pyrifenepine, pyrenzepine, methylamine, chloranilamide, acetylcholinesterase inhibitors, dopamine agonists, γ-aminobutyric acid, naloxone, salmeterol, glucagon, retinoic acid, M receptor blockers, atropine, tiotropium bromide, dibazole, polyunsaturated fatty acids, homatocrit products, scopolamine, 7-methylxanthine, niacin, piracetam, salvia miltiorrhiza extract, safflower extract, fish oil, bear bile extract, vitamins, adenosine triphosphate, smooth muscle relaxants, drugs to prevent vasospasm, non-selective adenylate antagonists, vasodilators, mydriatic components, congestion removal components, eye muscle regulation components, anti-inflammatory components, astringent components, antihistamine components, antiallergic components, long-acting beta-adrenergic receptor agonists, collagen degradation inhibition components, liver protection components, blood-retinal barrier enhancement components, amino acids, antibacterial components, antioxidant components, sugars, polymers or their derivatives, cellulose or its derivatives, local anesthetic components, amblyopia treatment components, glaucoma treatment components, type I phosphodiesterase inhibitors, or miRNA and its modifications.

6. The use according to any one of claims 1 to 4, characterized in that The drug, preparation, composition or device further comprises other drugs or ophthalmic preparations, and the other drugs or ophthalmic preparations do not include an effective amount of a long-acting beta-adrenergic receptor agonist.

7. The use according to any one of claims 1 to 6, characterized in that The concentration of apovincine in the drug, preparation, composition or device is 0.001 μM to 100 mM or the concentration or proportion is less than 25%, and the percentage is mass / volume, or mass ratio, or molar ratio.

8. The use according to any one of claims 1 to 7, characterized in that The content or efficacy of apovincine accounts for 1% or less of all active ingredients in the use, and the percentage refers to mass ratio, or molar ratio, or potency ratio, or contribution rate to the efficacy of the use; or the concentration of apovincine in the drug, preparation, composition or device is 0.001 μM to 50 mM or the concentration or proportion is less than 0.001%, and the percentage is mass / volume, or mass ratio, or molar ratio.

9. The use according to any one of claims 1 to 8, wherein the drug, preparation or composition is administered systemically, topically, parenterally, or non-invasively.

10. The use according to any one of claims 1 to 9, wherein the medicine, preparation or composition is a tablet, injection, lyophilized powder injection, aerosol, ointment, lotion, cream, drops, granules, sprays, ointments, patches, pastes, emulsions, ophthalmic preparations (such as eye drops, eye ointments, eye sprays, implants, eye gels, eye patches, eye microspheres, eye sustained-release preparations, periocular injections, or intraocular injections), or oral preparations.

11. The use according to any one of claims 1 to 10, wherein the device is an instrument, equipment, consumables, system, medical device, health care product, or product that changes the appearance of the eye that can release drugs or has a drug delivery function or potential drug delivery capability, such as corneal contact lenses, glasses, intraocular lenses, sutures, OK lens cleaning (maintenance) systems, eye patches, eye patches, cosmetic contact lenses, microneedles, eye spray systems, eye massagers, eye fumigators, ocular surface drug delivery devices, intraocular drug delivery devices, fundus drug delivery devices, implantable pumps, wearable devices, acupoint massagers, eye relaxation devices, myopia therapeutic devices, or drug-device combinations for myopia prevention and control.

12. A drug, preparation, composition or device, characterized in that: Contains apovincine.

13. The drug, preparation, composition or device according to claim 12, characterized in that: The medicine, preparation, composition or device is used to treat myopia and / or delay the progression of myopia; the myopia is preferably simple myopia, childhood and adolescent myopia, axial myopia, primary myopia, progressive myopia, low myopia or moderate myopia.

14. The drug, preparation, composition or device according to claim 12 or 13, wherein the content or efficacy of apovincine accounts for 1% or less of all active ingredients in the drug, and the percentage refers to mass ratio, or molar ratio, or potency ratio, or contribution rate of efficacy to the use; or the concentration of apovincine in the drug, preparation, composition or device is 0.001 μM to 50 mM or the concentration or proportion is less than 0.001%, and the percentage is mass / volume, or mass ratio, or molar ratio.

15. The drug, preparation, composition or device according to any one of claims 12 to 14, wherein the drug, preparation or composition is a tablet, injection, lyophilized powder injection, aerosol, ointment, lotion, cream, drops, granules, sprays, ointments, patches, pastes, emulsions, ophthalmic preparations (such as eye drops, eye ointments, eye sprays, implants, eye gels, eye patches, eye microspheres, eye sustained-release preparations, periocular injections, or intraocular injections), or oral preparations.

16. A drug, preparation, composition or device as claimed in any one of claims 12 to 15, wherein the device is an instrument, equipment, consumables, system, medical device, health care product or product for changing the appearance of the eye that can release drugs or has drug delivery function or potential drug delivery ability, such as corneal contact lenses, glasses, intraocular lenses, sutures, OK lens cleaning (maintenance) systems, eye patches, eye patches, cosmetic contact lenses, microneedles, eye spray systems, eye massagers, eye fumigators, ocular surface drug delivery devices, intraocular drug delivery devices, fundus drug delivery devices, implantable pumps, wearable devices, acupoint massagers, eye relaxation devices, myopia treatment devices or drug-device combinations for myopia prevention and control.

17. The drug, preparation, composition or device according to any one of claims 12 to 16, characterized in that: The drug, preparation, composition or device also contains other drugs or ophthalmic preparations, which include but are not limited to vinpocetine, or its optical isomers or racemates, or solvates, or pharmaceutically acceptable salts, or prodrugs, or metabolites, or related compounds or extracts, or crystalline compounds, or combinations of these substances, muscarinic antagonists, ampicillin, anidopyramine, timolol maleate, epinephrine, pilanzepine, pyrazine, pyrifenepine, pyrifenepine, pyrenzepine, methylamine, chloranilamide, acetylcholinesterase inhibitors, dopamine agonists, γ-aminobutyric acid, naloxone, salmeterol, glucagon, retinoic acid, M receptor blockers, atropine, tiotropium bromide, dibazole, polyunsaturated fatty acids, homatocrit products, scopolamine, 7-methylxanthine, niacin, piracetam, salvia miltiorrhiza extract, safflower extract, fish oil, bear bile extract, vitamins, adenosine triphosphate, smooth muscle relaxants, drugs to prevent vasospasm, non-selective adenylate antagonists, vasodilators, mydriatic components, congestion removal components, eye muscle regulation components, anti-inflammatory components, astringent components, antihistamine components, antiallergic components, long-acting beta-adrenergic receptor agonists, collagen degradation inhibition components, liver protection components, blood-retinal barrier enhancement components, amino acids, antibacterial components, antioxidant components, sugars, polymers or their derivatives, cellulose or its derivatives, local anesthetic components, amblyopia treatment components, glaucoma treatment components, type I phosphodiesterase inhibitors, or miRNA and its modifications.

18. The drug, preparation, composition or device according to any one of claims 12 to 16, characterized in that: The drug, preparation, composition or device further comprises other drugs or ophthalmic preparations, and the other drugs or ophthalmic preparations do not include an effective amount of a long-acting beta-adrenergic receptor agonist.

19. Use of an effective amount of vinpocetine, or a pharmaceutically acceptable salt thereof, or a combination of these substances as the sole active ingredient, the main active ingredient, or the direct active ingredient in the preparation of a drug, a preparation, a composition, or a device, characterized in that: The medicine, preparation, composition or device is used in one or two or more of the following aspects: ①Prevention and / or treatment of myopia, and / or myopia prevention and treatment; or ②Inhibit or control the progression of myopia; or ③ Used for myopia prevention and control or delaying the occurrence and development of myopia; or ④ Inhibit or slow down the elongation of the eye axis and / or the increase of the length of the vitreous cavity of myopic individuals or individuals with myopia tendency; or ⑤Prevent, slow down, weaken or treat abnormal development of the eyeball related to myopia; or ⑥ Enable myopic individuals or individuals with myopia tendency to obtain clearer distance vision than before and / or without using these substances or means without wearing glasses or relying on other vision correction methods; or 7. Inhibit, delay or slow down the process or speed of negative refraction in myopic individuals or individuals with myopia tendency; or ⑧Treatment of anisometropia. Among them, the myopia described in items ① to ⑧ is simple myopia or non-pathological myopia.

20. The use according to claim 19, characterized in that The simple myopia or non-pathological myopia includes childhood and adolescent myopia, axial myopia, progressive myopia, low myopia, moderate myopia, myopia with a continuous decrease in refractive power, myopia that develops during the development of the eyeball, or myopia with a progressive increase in the axial length of the eye.

21. The use according to claim 19 or 20, characterized in that The drug, preparation, composition or device also contains other drugs or ophthalmic preparations, and the other drugs or ophthalmic preparations include but are not limited to muscarinic antagonists, ampicillin, anidrin, timolol maleate, epinephrine, pilanzepine, pyrazine, pyropenem, pyropenem, pyropenem, methylamine, chlorambucil, acetylcholinesterase inhibitors, dopamine agonists, γ-aminobutyric acid, naloxone, salmeterol, glucagon, retinoic acid, M receptor blockers, atropine, tiotropium bromide, dibazole, polyunsaturated fatty acids, homatropine, scopolamine, 7-methylxanthine, niacin, piracetam, salvia miltiorrhiza extract, safflower extract, fish oil, bear Bile extract, vitamins, adenosine triphosphate, smooth muscle relaxant, anti-vasospasm drug, non-selective adenylate antagonist, vasodilator, mydriatic component, decongestant component, eye muscle regulating component, anti-inflammatory component, astringent component, antihistamine component, antiallergic component, long-acting beta-adrenergic receptor agonist, collagen degradation inhibition component, liver protection component, blood-retinal barrier enhancement component, amino acid, antibacterial component, antioxidant component, sugar, polymer or its derivative, cellulose or its derivative, local anesthetic component, amblyopia treatment component, glaucoma treatment component, type I phosphodiesterase inhibitor, or miRNA and its modified products.

22. The use according to any one of claims 19 to 21, wherein the concentration of vinpocetine, or a pharmaceutically acceptable salt thereof, or a combination of these substances in the medicament, preparation, composition or device is 0.01 μM to 1000 μM.

23. The use according to any one of claims 19 to 22, characterized in that The medicine, preparation or composition is a tablet, injection, lyophilized powder injection, aerosol, ointment, lotion, cream, drops, granules, sprays, ointments, patches, pastes, emulsions, ophthalmic preparations (such as eye drops, eye ointments, eye sprays, implants, eye gels, eye patches, eye microspheres, eye sustained-release preparations, periocular injections, or intraocular injections), or oral preparations.

24. A drug, preparation, composition or device as claimed in any one of claims 19 to 23, wherein the device is an instrument, equipment, consumables, system, medical device, health care product or product for changing the appearance of the eye that can release drugs or has drug delivery function or potential drug delivery capability, such as corneal contact lenses, glasses, intraocular lenses, sutures, OK lens cleaning (maintenance) systems, eye patches, eye patches, cosmetic contact lenses, microneedles, eye spray systems, eye massagers, eye fumigators, ocular surface drug delivery devices, intraocular drug delivery devices, fundus drug delivery devices, implantable pumps, wearable devices, acupoint massagers, eye relaxation devices, myopia therapeutic devices or drug-device combinations for myopia prevention and control.

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