WO2023001176A1 - 一种采用长春西汀治疗近视的方法 - Google Patents

一种采用长春西汀治疗近视的方法 Download PDF

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WO2023001176A1
WO2023001176A1 PCT/CN2022/106704 CN2022106704W WO2023001176A1 WO 2023001176 A1 WO2023001176 A1 WO 2023001176A1 CN 2022106704 W CN2022106704 W CN 2022106704W WO 2023001176 A1 WO2023001176 A1 WO 2023001176A1
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myopia
eye
vinpocetine
administration
ophthalmic
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PCT/CN2022/106704
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English (en)
French (fr)
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周翔天
张森
瞿佳
郑钦元
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温州医科大学附属眼视光医院
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Priority to EP22845341.1A priority Critical patent/EP4364736A1/en
Priority to AU2022314016A priority patent/AU2022314016B2/en
Priority to KR1020247004275A priority patent/KR20240050324A/ko
Publication of WO2023001176A1 publication Critical patent/WO2023001176A1/zh
Priority to US18/418,181 priority patent/US20240165089A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • the application relates to a method for treating myopia with vinpocetine, in particular to a method and application for controlling the progression of myopia, and provides corresponding drugs or preparations, belonging to the field of medicine.
  • Myopia is the most common refractive error, which refers to a refractive state in which parallel light rays are refracted through the refractive system of the eye and the focus falls in front of the retina in a relaxed state.
  • Myopia causes people to see distant objects blurred, which brings a lot of inconvenience to life.
  • corrective means such as frame glasses, such technologies or methods cannot improve the social phenomenon of high myopia rate and increasing myopia degree. Therefore, the number of myopic people in the world is increasing year by year, especially in East Asian countries, the situation of high myopia patients is not optimistic.
  • there are many types of myopia and the pathogenesis is still unclear. At present, there is still 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.
  • Vinpocetine is C 22 H 26 N 2 O 2 , with an average molecular weight of 350.46. It is a white crystalline powder, soluble in chloroform or 96% ethanol, almost insoluble in water, derived from Apocynaceae.
  • An indole alkaloid extracted from flowers, its structure is as follows:
  • vinpocetine has high fat solubility, the compound can enter the blood-brain barrier, blood-ocular barrier, placenta and milk, and has high pharmacological activity on cardiovascular and cerebrovascular and central nervous system functions.
  • vinpocetine is mainly used for the treatment of cerebrovascular-related diseases and cognitive impairment, and most of the recipients are the elderly. It is reported that after systemic administration, Vinpocetine can selectively act on the cerebrovascular system, inhibit the activity of phosphodiesterase in the brain (that is, act as a phosphodiesterase inhibitor), relax vascular smooth muscle, and increase blood supply to the brain. These drugs have the characteristics of rapid metabolism in vivo, short elimination half-life, and low human bioavailability in oral dosage forms.
  • vinpocetine for external use in the eyes can easily pass through physical barriers such as the cornea and lens
  • vinpocetine is also an auxiliary component of many ophthalmic drugs, and it is mainly used as a microcirculation accelerator to promote blood flow in the eye.
  • promoting blood circulation in the eye may make the eye feel more comfortable, thereby increasing the acuity of vision in patients with refractive errors, it is not equivalent to treating myopia, and there are even reports that the administration of vinpocetine may cause myopia instead (biosintez. com/en/catalog/product/283).
  • vinpocetine is not used as a supplement or auxiliary component, such as a microcirculation promoter (inhibiting phosphodiesterase activity), assisting, accompanying or assisting other active substances in the treatment of myopia to enhance (such as making more
  • a microcirculation promoter inhibiting phosphodiesterase activity
  • assisting, accompanying or assisting other active substances in the treatment of myopia to enhance such as making more
  • the active substance has the effect of treating myopia; it is used as a direct active component for treating myopia.
  • the present application also studies the mechanism of vinpocetine in treating myopia.
  • people used vinpocetine as a phosphodiesterase inhibitor to enhance blood flow but this application found through experiments that vinpocetine does not depend on choroidal blood when treating myopia and controlling the progression of myopia stream improvement. That is, vinpocetine does not treat myopia and inhibit the progression of myopia by dilating blood vessels or promoting blood circulation (that is, the known functions of phosphodiesterase inhibitors), but may rely more on an inherent, but still New pharmacological effects not known by people. Therefore, the present application actually utilizes an unknown function of vinpocetine, and this discovery is also the key basis for forming the present application.
  • vinpocetine alone can have a significant inhibitory effect on the progression of myopia, and thus it is believed that vinpocetine can effectively treat simple myopia or axial myopia (such as juvenile myopia), mild or moderate Myopia and other types of myopia.
  • simple myopia or axial myopia such as juvenile myopia
  • myopia or high myopia, or high myopia, or pathological myopia in the elderly
  • vinpocetine is used to treat myopia with continuous diopter decline (such as simple myopia, axial myopia, or axial myopia).
  • the effect of simple myopia, or low and moderate myopia, or children and adolescent myopia, or progressive myopia, etc. will be significantly better.
  • Vinpocetine can also be used for the prevention of various types of myopia.
  • the use of vinpocetine for drug intervention in the progressive stage of myopia can prevent and prevent the occurrence of myopia, high myopia, high myopia and pathological myopia in the elderly.
  • This application further studies the concentration, ratio and formula of vinpocetine in the medicine or preparation for treating myopia, as well as the frequency of administration of related medicines, combined treatment and other medication methods.
  • local (ocular) administration not only has good safety, but also has a better therapeutic effect than systemic administration.
  • the application provides vinpocetine, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract substance, or its crystalline compound, or a combination of these substances, the use of which is one of the following or two or more of the following:
  • systemic administration e.g., oral administration, intravenous infusion
  • topical administration eye drops, eye injections, ocular implants, skin ointment/cream application around the eyes, or eye ointment application
  • parenteral administration such as through mucosal administration, transdermal administration, microneedle administration
  • non-invasive administration such as administration by eye spray
  • the drug, preparation or composition can be injection, tablet, freeze-dried powder injection, capsule, effervescent tablet, chewable tablet, buccal tablet, granule, ointment, syrup, oral liquid , aerosol, nasal drops, external preparations, oral preparations, etc.; preferably ophthalmic dosage forms, including but not limited to eye drops (eye drops), eye ointment, eye spray, implants, ophthalmic gel , eye patches, eye microspheres, ophthalmic sustained-release preparations, eye injections, intraocular injections; can also be free solutions, oil-water mixtures, suspensions (agents), liniments, lotions, creams, drops Elixirs, granules, sprays, ointments, patches, pastes, pills, suppositories, emulsions, containing cellulose (such as methylcellulose), polyhydric alcohols, cyclodextrins (such as hydroxypropyl- ⁇ -cyclodextrin
  • the myopic individual or the individual prone to myopia are children and/or adolescents, preferably 3 to 26 years old, more preferably 6 to 18 years old; or minors, preferably ocular (eyeball) ) are still in the growth and development stages; or are school-age groups, preferably students in grades 1 to 12; or have parents with high myopia; or have insufficient hyperopia reserves.
  • myopia is regarded as refractive myopia or axial myopia; congenital myopia (myopia from birth or before school age), early-onset myopia (under 14 years old), late-onset myopia (16-18 years old) , late-onset myopia (after adulthood); low myopia (mild myopia), moderate myopia, high myopia (severe myopia); pseudomyopia, true myopia; children and/or adolescent myopia (preferred population age is 3- 26 years old, more preferably the crowd age is 6-18 years old), juvenile myopia, adult myopia, elderly myopia; simple myopia, pathological myopia; axial simple myopia, simple axial myopia; children and/or Or juvenile axial myopia (preferred population age is 3-26 years old, more preferably population age is 6-18 years old); school age and preschool population axial myopia; primary myopia, secondary myopia; children and/or adolescents Primary myopia (preferred population age is 3-26 years old, more preferably population age is 6-18 years old); or children and/or
  • myopia-related symptoms include complications caused by myopia, such as complications of high myopia, such as floaters, glaucoma, posterior staphyloma, retinal detachment, retinal tear, amblyopia, macular hemorrhage, choroidal neogenesis Vascular, choroidal atrophy, macular degeneration or macular degeneration, visual field defect, progressive or sudden loss of vision (especially near vision), eye soreness and/or pain, night blindness, astigmatism, anisometropia, blindness, vitreous liquefaction Vitreous opacity Strabismus Frequent blinking and eye rubbing Anisometropia Blurred vision when looking at distant objects Need to squint or partially close eyelids to see distant objects Clearly Headache from eyestrain Headache from nearsightedness Poor concentration, difficulty seeing while driving especially at night (nocturnal myopia), atrophic degeneration of the retina (bleeds and holes), new blood vessels under the retina, or shrinking of the eyeball.
  • myopia
  • the medicament, preparation, composition or device further comprises other medicaments or ophthalmic preparations, including but not limited to myopia treatment drugs (such as pirenzepine, muscarinic antagonists , ambenzylamine, yin polyamine, timolol maleate, epinephrine, pirenzepine, pyrazine, pirenzepine, perphenpine, pirenzepine, methylamine, closamide, acetylcholinesterase inhibitor , dopamine agonist, ⁇ -aminobutyric acid, naloxone, glucagon, retinoic acid, salidroside, formononetin, etc.), M receptor blockers (such as for M2 or M3 receptor blockers or antagonists or inhibitors), benzalic acid and its various salt forms (bendazine), atropine, dimethazole, polyunsaturated fatty acids (such as DHA, EPA), prazo
  • Vinpocetine, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related The compound or extract, or its crystalline compound, or the 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 administered simultaneously, or successively The form of administration, or the form of alternating administration, or the form of interval administration, or the form of single administration.
  • the vinpocetine related compound or extract is selected from vinpocetine metabolites (such as apovincaminic acid, hydroxyvinpocetine, hydroxyl-apovincaminic acid and dihydroxy-vinpocetine-glycinate), vinca alkaloids ( Vinca alkaloid), apovincamine, periwinkle, vincamine, voacanga africana, apovincamine plant extract, vincristine ( one of vincristine, tabersonine, vinblastine, vindoline, apovincaminic acid hydrochloride, catharanthine, ethyl vincaminate, methoxyvinpocetine, dihydrovinpocetine one or more substances.
  • vinpocetine metabolites such as apovincaminic acid, hydroxyvinpocetine, hydroxyl-apovincaminic acid and dihydroxy-vinpocetine-glycinate
  • vinca alkaloids Vinca alkaloid
  • apovincamine periwinkle
  • the preparation is oral products or cosmetics such as health products, foods, dietary supplements, nutritional products, drinks, etc.
  • Cosmetics can be a kind of free solution, oil-water mixture, suspension (agent), liniment, lotion, spray, cream, drop, granule, ointment, paste, pill, suppository, emulsion, and patch or a combination of several.
  • the device is an instrument, device, consumable, system, medical device, healthcare product, or product that can change the appearance of the eye, such as contact lenses, glasses, that can release drugs or have drug delivery functions or potential drug delivery capabilities , intraocular lens, suture, OK lens cleaning (maintenance) system, eye patch, eye patch, color contact lenses, microneedle, eye spray system, eye massager, eye fumigation device, ocular surface drug delivery device, eye Internal drug delivery device, fundus drug delivery device, implanted pump, wearable device, acupressure device, eye relaxation device, myopia treatment device or a combination of drugs and devices for myopia prevention and control.
  • intraocular lens suture
  • OK lens cleaning (maintenance) system eye patch
  • eye patch color contact lenses
  • microneedle microneedle
  • eye spray system eye massager
  • eye fumigation device ocular surface drug delivery device
  • eye Internal drug delivery device fundus drug delivery device, implanted pump, wearable device, acupressure device, eye relaxation device, myopia treatment device
  • Vinpocetine, or its optical isomer or its 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 as the sole active ingredient or main active ingredient or direct active ingredient; or vinpocetine, or its optical isomer or its racemate, or its
  • the content or efficacy of the solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline form compound, or the combination of these substances account for the said use 1% or less of all active ingredients, 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%, the percentage (%) can be mass ratio or molar ratio or potency ratio.
  • concentration of the compound or extract, or its crystalline compound, or a combination of these substances in said medicament, preparation, composition or device is 0.001 ⁇ M to 10 mM, preferably 0.01 ⁇ M to 1000 ⁇ M, preferably 0.05 ⁇ M to 100 ⁇ M, More preferably 0.1 ⁇ M to 25 ⁇ M, more preferably 0.1 ⁇ M to 15 ⁇ M; or the concentration or proportion of these substances or their combination in the drug, preparation, composition or device is lower than 25%, preferably lower than 5%, preferably less than 1%, more preferably less than 0.01%, more preferably less than 0.001%, said percentage (%) can be mass/volume concentration (gram per 100 milliliters) or mass percentage or mole ( number) ratio.
  • the present application provides a drug, preparation, composition or device for ophthalmic administration, vinpocetine, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, or
  • concentration of its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or the combination of these substances in the drug, preparation, composition or device is 0.001 ⁇ M to 10 mM, preferably 0.01 ⁇ M to 1000 ⁇ M, preferably 0.05 ⁇ M to 100 ⁇ M, more preferably 0.1 ⁇ M to 25 ⁇ M, more preferably 0.1 ⁇ M to 15 ⁇ M; or the concentration of said substances or combinations thereof in said medicament, preparation, composition or device Or account for 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 (gram per 100 ml) or mass percentage or mole (number) ratio.
  • the present application also provides a pharmaceutical composition or compound preparation containing at least two active substances, including vinpocetine, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrugs, or its metabolites, or its related compounds or extracts, or its crystalline compounds, or the combination of these substances and other active substances for the treatment of myopia.
  • active substances including vinpocetine, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrugs, or its metabolites, or its related compounds or extracts, or its crystalline compounds, or the combination of these substances and other active substances for the treatment of myopia.
  • Vinpocetine or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract
  • the added amount, concentration and/or drug effect of the substance, or its crystalline compound, or the combination of these substances is not lower than any other active substance for treating myopia, and the drug effect is aimed at treating myopia or controlling the progression of myopia.
  • the present application also provides a pharmaceutical composition or compound preparation, including vinpocetine, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolites, or its related compounds or extracts, or its crystalline compounds, or a combination of these substances and other active substances for the treatment of myopia, said other active substances for the treatment of myopia do not contain long-acting ⁇ -adrenergic receptor agonists agents, long-acting muscarinic antagonists and/or muscarinic antagonists.
  • the present application further provides an ophthalmic preparation or medicine, in which, Vinpocetine, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, Or its prodrugs, or its metabolites, or its related compounds or extracts, or its crystalline compounds, or a combination of these substances as the direct, sole, or main active ingredients.
  • the formulations or drugs include, but are not limited to, eye drops (eye drops), ophthalmic ointments, eye sprays, implants, ophthalmic gels, eye patches, ophthalmic microspheres, ophthalmic Sustained-release preparations, periocular injections, or intraocular injections.
  • concentration of the compound or extract, or its crystalline compound, or a combination of these substances is 0.001 ⁇ M to 10 mM, preferably 0.01 ⁇ M to 1000 ⁇ M, preferably 0.05 ⁇ M to 100 ⁇ M, more preferably 0.1 ⁇ M to 25 ⁇ M, more preferably 0.1 ⁇ M to 15 ⁇ M; or the concentration or proportion of vinpocetine is lower than 25%, preferably lower than 5%, preferably lower than 1%, more preferably lower than 0.01%, more preferably lower than 0.001%, said Percentage (%) can be mass/volume concentration (grams per 100 milliliters) or mass percentage or molar (number) ratio.
  • 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, Volume34, IssueS1, 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, 1017 4 Aug (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, 1, Front 2 0 2 Physiol; 543727.), Nimodipine
  • KS505a flunaronezinel, , zaprinast, 8-methoxymethyl IPMX, SCH 51866, Nimodipine, IC224 (Claire Lugnier, Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new targ et 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.
  • PDE Cyclic nucleotide phosphodiesterase
  • vinpocetine is a type I phosphodiesterase inhibitor (PDE1 inhibitor), perhaps other known type I phosphodiesterase inhibitors (whether specific or not) before the filing date have the same unknown activity or drug activity as vinpocetine. effects, such as being able to prevent and/or treat myopia and control the progression of myopia.
  • PDE1 inhibitor type I phosphodiesterase inhibitor
  • miRNAs and modifications thereof are MicroRNA-328 or MicroRNA-328 antisense compositions.
  • Vinpocetine, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related is administered simultaneously, such as a specific course of administration (treatment) at the same time or successively, on the same day, on the same week, on the same Monthly administration, administration in the same year; or alternate administration at intervals, such as alternate administration at intervals of 4 hours, alternate administration at intervals of 12 hours, alternate administration on every other day, alternate administration on every other week, alternate administration on every other month, and alternate administration on every other year medicine; or:
  • Vinpocetine, or its optical isomers or their racemates, or their solvates, or their pharmaceutically acceptable salts, or their prodrugs, or their metabolites, or their related compounds or extracts, or Its crystalline compound, 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, or administration in the same month in a specific course of administration (treatment) , dosing in the same year; or alternate dosing at intervals, such as alternating dosing at intervals of 4 hours, alternating dosing at intervals of 12 hours, alternating dosing at alternate days, alternately at every other week, alternately at every other month, alternately at every other year; or :
  • Vinpocetine or its optical isomers or their racemates, or their solvates, or their pharmaceutically acceptable salts, or their prodrugs, or their metabolites, or their related compounds or extracts, or Its crystalline compounds, or combinations of these substances, are used in combination with devices (eg contact lenses) and/or surgery (eg refractive surgery, myopia laser surgery, lens surgery).
  • devices eg contact lenses
  • surgery eg refractive surgery, myopia laser surgery, lens surgery.
  • the one or more other drugs are myopia prevention and control and/or myopia treatment drugs (such as bendalysine, atropine, dimethazole, polyunsaturated fatty acids, DHA, fish oil, prazol M-receptor blockers, niacin, pirenzepine, muscarinic antagonists, 7-methylxanthine (7MX), pirenzepine, ampicillin, dominoamine, timolol maleate , epinephrine, pyrazine, pirfenpine, perbiphenpine, pirenzepine, methylamine, closamide, acetylcholinesterase inhibitors, dopamine agonists, gamma-aminobutyric acid, naloxone, glucagon , retinoic acid, salidroside, formononetin, etc.), vasodilator drugs, smooth muscle relaxation drugs, drugs to prevent vasos
  • the device is a variety of glasses that delay the progression of myopia, OK mirrors, frame glasses, eye stickers, (myopia) acupoint massage equipment, eye relaxation equipment, myopia treatment equipment, etc., with vision protection function or treatment (correction) Apparatus, equipment, consumables, medical equipment or health care products for myopia.
  • the drug, one or more other drugs, myopia prevention and control drugs, myopia treatment drugs, or ophthalmic preparations may not be long-acting ⁇ -adrenoceptor agonist (long-acting ⁇ -adrenoceptor agonist, LABA ), long-acting muscarinic antagonists (long-acting muscarinic antagonists, LAMA) and / or muscarinic antagonists (muscarinic antagonists), such as not salmeterol and / or tiotropium bromide.
  • the dosage form for systemic administration such as oral tablet
  • the dosage form for topical administration such as eye drops
  • the abnormal development of the eyeball is mainly induced by environmental factors, or is mainly caused by human factors. Improper use of photocorrective glasses, drug side effects, obesity, trauma, poor light in the learning environment, lack of outdoor exercise), regardless of genetic factors, or genetic factors in which genetic factors are secondary factors, concomitant factors, or synergistic factors, the abnormal Development such as abnormal development of eyeball size in childhood and adolescent stages (eg, 3-26 years old).
  • abnormal development or dysplasia includes too long axial length of the eye or a mismatch between the length of the eye axis and the refractive system, resulting in the imaging focus of the parallel light rays being located in front of the retina after passing through the normal or abnormal refractive system of the eye.
  • Figure 1 Effects of high, medium and low concentrations of vinpocetine on refraction (degrees), vitreous cavity depth and eye axial length in the FDM group.
  • A is the diopter difference map between the experimental eye and the fellow eye
  • B is the vitreous cavity depth difference map between the experimental eye and the fellow eye
  • C is the axial length difference map between the experimental eye and the fellow eye.
  • Figure 2 Effects of high, medium and low concentrations of vinpocetine on refraction (degrees), vitreous cavity depth and eye axial length in the LIM group.
  • A is the diopter difference map between the experimental eye and the fellow eye
  • B is the vitreous cavity depth difference map between the experimental eye and the fellow eye
  • C is the axial length difference map between the experimental eye and the fellow eye.
  • Figure 3 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 eye choroidal thickness ChT
  • B is the effect of vinpocetine on choroidal blood flow ChBP.
  • Figure 4 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 eye choroidal thickness ChT
  • B is the effect of vinpocetine on choroidal blood flow ChBP.
  • Figure 5 Changes in diopter and axial parameters of myopic individuals under systemic administration of different doses of vinpocetine.
  • VPN vinpocetine
  • Vehicle solvent
  • Week week
  • Refraction diopter
  • VCD vitreous cavity depth
  • AL axial length
  • N sample size.
  • Repeated measures ANOVA ANOVA
  • Figure 6 Treatment of myopia with salmeterol and tiotropium bromide. Comparison of diopter (A), depth of vitreous cavity (B), axial length of eye (C), depth of anterior chamber (D), lens thickness (E) and corneal curvature between different drug groups before and after the experiment (F) The delta changes the effect.
  • VPN V: vinpocetine; T: tiotropium bromide; S: salmeterol; Vehicle: solvent; Week: week; Refraction: diopter; 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 ANOVA (A-F).
  • Figure 7 The intervention effect of vinpocetine eye drops on the diopter, vitreous cavity depth and axial length of myopic individuals. Compare the diopter (A), depth of vitreous cavity (B), axial length of the eye (C), depth of anterior chamber (D), and lens thickness (E ) and the difference in corneal curvature (F) changes.
  • VPN vinpocetine
  • Vehicle solvent
  • Refraction diopter
  • 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.
  • ANOVA ANOVA
  • Figure 8 Intervention effect of vinpocetine metabolite AVA on diopter, vitreous cavity depth and axial length of myopic individuals.
  • AVA Apovincaminic acid, a metabolite of vinpocetine; Vehicle: solvent; Week: week; Refraction: diopter; VCD: vitreous cavity depth; AL: axial length; N: sample size.
  • the present application provides a method for preventing and treating myopia, which involves topical administration of vinpocetine or related compounds in the eyes.
  • the present application further provides a drug for treating myopia and controlling the progression of myopia, which is locally administered to the eye and uses vinpocetine as the sole or main active ingredient.
  • vinpocetine is mainly tablet and injection, and is administered systemically.
  • BRB blood-retinal barrier
  • Vinpocetine or its metabolites reach the therapeutic concentration threshold, such a treatment strategy has the potential risk of systemic adverse reactions, especially for young people and requires continuous administration for a long time.
  • the present application has developed a vinpocetine drug for topical administration in the eye with better efficacy and safety.
  • This drug development strategy is aimed at the use of vinpocetine and its related compounds (such as fluorides) in the prevention and control of myopia in children and adolescents. Years, three years, five years, ten years), the growth and development of young individuals are less affected, and the ophthalmic dosage form is safe and reliable.
  • the present application also provides a method, the method is to administer an effective dose of vinpocetine or its related compounds to a suitable subject for treating myopia and/or inhibiting the elongation of the ocular axis.
  • the method or pharmaceutical composition of the present application can significantly inhibit myopia, especially 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 and middle-term myopia , or mild or moderate myopia, or non-pathological myopia, or simple axial myopia, or axial myopia in children and/or adolescents (preferred population age is 3-26 years old, more preferably population age is 6-18 years old) years old), or progressive myopia in children and/or adolescents (preferably 3-26 years old, more preferably 6-18 years old), or primary myopia, or non-senile myopia, or juvenile myopia , or progressive myopia, or non-refractive myopia.
  • the method or pharmaceutical composition of the present application can significantly inhibit and slow down the elongation of eye axis and/or the increase of vitreous cavity length in myopic individuals (including individuals who are not yet myopic but will develop myopia).
  • the applicable population of the method or the pharmaceutical composition of the present application includes children and/or adolescents with myopia (preferably aged 3-26, more preferably aged 6-18), or early and mid-term myopia , or mild or moderate myopia, or non-pathological myopia, or simple axial myopia, or axial myopia in children and/or adolescents (preferred population age is 3-26 years old, more preferably population age is 6-18 years old) years old), or progressive myopia in children and/or adolescents (preferably 3-26 years old, more preferably 6-18 years old), or primary myopia, or non-senile myopia, or juvenile myopia , or progressive myopia, or non-refractive myopia, the eye axis extension and/or vitreous cavity length increase of these myopic individuals (including individuals who are not yet myopic
  • the present application provides a method for treating, preventing or alleviating myopia and its related symptoms in a subject, comprising administering a therapeutically effective amount of vinpocetine or a therapeutically acceptable salt thereof or a related compound thereof to the subject.
  • the vinpocetine is administered alone, preferably, the vinpocetine is administered with other drugs simultaneously, sequentially or at intervals, alternately, preferably, the vinpocetine is administered in the form of a pharmaceutical composition, preferably, the
  • 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.
  • the present application also provides a pharmaceutical composition for treating, preventing or alleviating myopia and its related symptoms, said pharmaceutical composition comprising vinpocetine or its therapeutically acceptable salt or its related compounds.
  • 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.
  • the compound may be a vinpocetine metabolite (such as apovincaminic acid, apovincaminic acid), vinca alkaloid, apovincamine, periwinkle, vincamine, African potato fruit extract (voacanga africana), Apovincaminic Acid Hydrochloride, Vincristine, Tabersonine, Vinblastine, Vindoline, Apovincaminic Acid Hydrochloride, Catharanthine ), ethylvincamine (ethylvincaminate), etc.; preferably, the compound is vinpocetine or its therapeutically acceptable salts and derivatives thereof.
  • 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.
  • the myopia-related symptoms include, but are not limited to: floaters, glaucoma, posterior staphyloma, retinal detachment, amblyopia, macular hemorrhage, visual field defect, progressive or sudden decrease in vision (especially near vision), eye acid swelling and/or pain, night blindness.
  • the myopia is refractive myopia. According to another aspect of the present application, the myopia is axial myopia.
  • the application also provides vinpocetine or its salt form, in the process of preventing, slowing down and treating myopia, it can be used in combination or at intervals or alternately with other myopia prevention and control drugs (such as atropine) or optical prevention and control means (such as ok lens)
  • myopia prevention and control drugs such as atropine
  • optical prevention and control means such as ok lens
  • the present application also provides vinpocetine or its salt form, in the process of preventing, slowing down and treating myopia, systemic administration dosage forms (such as oral tablets) and local administration dosage forms (such as eye drops) are used in combination or alternately Myopia treatment (inhibition of myopia progression and/or axial lengthening) program.
  • systemic administration dosage forms such as oral tablets
  • local administration dosage forms such as eye drops
  • Myopia means that in the state of relaxation, parallel rays of light are gathered in front of the retina after passing through the refractive system of the eyeball. Myopia is usually manifested by subnormal distance vision and normal near vision.
  • the clinical concept of myopic individuals is: those with static refraction ⁇ -0.25D.
  • the clinical manifestations are blurred distance vision and good near-distance vision.
  • long-distance vision often fluctuates. Since no or less adjustment is used when seeing near, the collective function is correspondingly weakened, which may easily cause exophoria or exotropia.
  • there is no difference between the concepts represented by the word "myopia” and the word "myopia” and the two can be replaced by each other.
  • myopia There are four common classifications of myopia: (1) According to the diopter size, it can be divided into mild (300 degrees and below), moderate (300 degrees-600 degrees) and high (600 degrees or above -6D); (2) According to whether the refractive components are abnormal, it can be divided into refractive myopia and axial myopia; (3) according to whether pathological changes occur, it can be divided into pathological myopia and simple myopia; (4) according to the cause classification, it can be divided into Primary myopia and concurrent/secondary myopia.
  • the patient has no other symptoms except blurred vision of distant objects, that is, the main problem is that the distance vision gradually decreases, the vision of distant objects is blurred, and the near vision is normal. No special changes other than length.
  • the anterior chamber of the patient's eye is deep, the pupil is large, and the eyeball is slightly protruding due to the long anteroposterior axis.
  • White or off-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 elongates backwards, and the retinal pigment epithelium and choroid are separated from the temporal edge of the optic disc, exposing the sclera or part of the choroid and sclera. .
  • the sclera at the posterior pole continues to expand backwards, and genu-like streaks and subretinal neovascularization may appear in the macula, and plaque-like atrophy and degeneration of the nearby retina and choroid may occur, resulting in posterior staphyloma.
  • the macula often has hyperpigmentation and even hemorrhage, forming atrophic spots (Forster-Fuchs spots).
  • Such patients are often accompanied by vitreous liquefaction and opacity, and a few can also develop retinal detachment and concurrent cataract.
  • Refractive myopia is mainly due to the excessive curvature of the cornea or lens, the refractive power exceeds the normal range, and the axial length of the eye is in the normal range.
  • Axial myopia is that the axial length of the eye exceeds the normal range, while the curvature of the cornea and lens are basically within the normal range. Axial myopia is the main type of myopia in children and adolescents.
  • Pathological myopia also known as degenerative myopia, is a degenerative disease of the fundus. Patients with myopia usually have high diopters (such as greater than 600 degrees), visual function is significantly impaired, and distance vision is worse. In addition, visual field, light perception, contrast perception, etc. Mosquitoes, floating objects, flashes, etc. Thinning of the retinal pigment epithelium and choroid can be seen in the fundus of the patient, often accompanied by retinal pigment epithelial atrophy, choroidal neovascularization, retinal detachment, macular degeneration and other symptoms, and the pathological changes of the fundus are still developing after the development stops. This type of myopia is severe and can cause blind.
  • “Simple myopia” refers to the myopia that develops during the developmental period of the eyeball. When the development stops, the myopia also tends to be stable. For example, it often occurs at school age. The degree of myopia is below 600 degrees, and the fundus generally has no obvious pathological changes. Sexual myopia (eye). This kind of myopia develops progressively, and the axial length of the eye also gradually increases. Appropriate lenses can be used to correct the vision to normal, and most other visual function indicators are normal. On the contrary, it is non-simple myopia. Examples of non-simple myopia include pathological myopia, high myopia, and myopia in the elderly.
  • Primary myopia is the main type of myopia. “Primary” refers to a type of myopia with unknown causes such as the etiology and mechanism of occurrence that cannot be determined using existing diagnostic techniques. During its occurrence and development, there are pathological or physiological functional-structural changes specific to myopia, including congenital myopia and acquired simple myopia.
  • Concurrent/secondary myopia refers to temporary myopia (such as toxic myopia, drug-induced myopia, traumatic myopia, diabetic Myopia and initial cataract myopia), etc., this type of myopia is characterized by clear predisposing factors and repeated vision fluctuations. This type of myopia is often high in the elderly.
  • Axial simple myopia sometimes called simple axial myopia, is a group of simple myopia characterized by simple myopia in which the focus of imaging is in front of the retina due to axial lengthening and/or increased vitreous cavity depth.
  • This kind of myopic eye refractive tissue (such as the lens) is basically normal, and it is the most common type of myopia in children and adolescents. It mostly occurs in 3 to 26 years old, especially in 6-18 year olds (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.).
  • “Curvature myopia” is myopia caused solely by increased curvature of the cornea or lens.
  • Index myopia is mainly myopia formed by the increase of refractive power caused by the increase of the refractive index of aqueous humor and lens, which belongs to refractive myopia.
  • Progressive myopia refers to a type of myopia in which the diopter continues to decrease with time or as the individual ages. If this kind of myopia is not intervened, it will eventually develop into high myopia.
  • Chronic myopia is a kind of simple myopia caused by using eyes at close range for a long time. Most of these myopia patients have not developed into pathological myopia.
  • the eyeballs of children or adolescents are in the stage of growth and development, with a strong ability to adjust, and the stretchability of the sclera is relatively large.
  • close-distance work such as reading and writing, the eyeballs are in a defocused state. Over time, the front and rear axes of the eyeballs will become longer, and it is easy to form axial myopia in children and adolescents.
  • the degree of myopia in children and adolescents will gradually increase, and the corresponding axial length of the eye will further increase. Therefore, with the growth and learning rhythm of children or adolescents, the axial length of the eyes is always in a dynamic state, and the diopter continues to become negative. That is to say, it belongs to progressive myopia, rather than being in a static state like adults or elderly people with myopia. . Therefore, the clinical evaluation of the efficacy of this kind of myopia treatment drugs is to control the progression of myopia and inhibit the elongation of the eye axis as the main indicators.
  • Myopia of the elderly is usually more complex, easily affected by the aging of body organs and underlying diseases, often accompanied by blood sugar changes, hardening of the arteries, insufficient blood supply, eye microcirculation disorders and other symptoms, and most of them are high myopia.
  • a notable feature of adults or elderly myopia patients is that the degree of myopia generally does not increase with age. The main reason is that the growth and development of the eyes of these individuals basically stops, and the axial length of the eyes no longer decreases due to long-term near-sightedness. change. Therefore, the myopia of the elderly (including adults) and the myopia of children and adolescents (minors) are two completely different diseases, and it is necessary to clearly distinguish these two indications in the treatment of myopia.
  • the medicine or method of the present application is suitable for treating various types of myopia
  • simple myopia is preferred and non-simple myopia such as old people's myopia, high myopia, and pathological myopia are excluded, because the clinical intervention strategy of these myopia patients is no longer to inhibit the eye.
  • the extension of the axis is more to prevent blindness caused by serious eye diseases, such as blindness caused by retinal detachment.
  • Myopia-related symptoms include complications caused by myopia, such as complications of high myopia, floaters, glaucoma, posterior staphyloma, retinal detachment, retinal tear, amblyopia, macular hemorrhage, choroidal neovascularization, choroidal atrophy, macular Degeneration or macular degeneration, visual field defect, progressive or sudden loss of vision (especially near vision), eye soreness and/or pain, poor night vision (eg, night blindness), astigmatism, anisometropia, blindness, vitreous liquefaction Vitreous opacity Strabismus frequent blinking Flashes of light Frequent eye rubbing Anisometropia Blurred vision when looking at distant objects Need to squint or partially close eyelids to see distant objects Clear eye fatigue Headache Driving while driving Difficulty with vision especially at night (nocturnal myopia), retinal atrophy and degeneration (hemorrhage and hole), subretinal neovascularization, and eye
  • Adjustment tension myopia due to the overload of near vision of the eyeball and excessive adjustment of ciliary muscles, myopia caused by adjustment tension or adjustment spasm appears.
  • Astigmatism myopia is a type of myopia in which the cornea is damaged or has different degrees of curvature, and the external light is scattered in all directions and cannot form a focus on the retina.
  • the myopia of the present invention may or may not include pathological myopia, high myopia, elderly myopia, and astigmatism myopia. Ting can prevent, treat or slow down (control) the progression of myopia by an unknown mechanism.
  • Myopia intervention methods can be divided into myopia correction and myopia treatment, among which the main feature and purpose of myopia treatment is to inhibit (control) the progression of myopia.
  • Myopia correction is to correct or reduce the degree of myopia through optical methods.
  • Commonly used correction methods include wearing frame glasses, clear lens phacoemulsification, intraocular lens implantation, and corneal laser surgery.
  • this method only corrects the individual diopter, and cannot delay the progression of myopia or reverse the excessively long eye axis.
  • this type of myopia intervention method will not stop or slow down the continuous negative process of diopter, and cannot inhibit the progression of myopia. Therefore, myopia correction methods such as corneal laser surgery will compensate the patient's refractive error and restore their distance vision. They are suitable for improving vision for pathological myopia, high myopia or elderly myopia, but they are not suitable for treating axial myopia.
  • “Inhibiting (controlling) the progression of myopia” refers to delaying (slowing down) the continuous deepening of myopia, slowing down the negative speed of diopter, controlling the development of myopia and inhibiting (controlling) the continuous extension of eye axis through various methods or drugs.
  • the etiological treatment is also aimed at mostly minors who are still in the stage of eye development.
  • slowing down, controlling or even stopping the continuous negative change of diopter and inhibiting the corresponding increase in eye axial length are the primary goals to be achieved in the development of myopia treatment drugs. That is, the treatment of myopia should achieve the effect of controlling or inhibiting the development of myopia for children or adolescents with myopia, axial myopia, simple myopia and other myopia, rather than simply reversing or correcting this ametropic state.
  • treatment refers to inhibiting (controlling) the progression of myopia, not correcting myopia.
  • the terms “treat”, “mitigate”, “delay”, “inhibit”, “control”, or “control” refer to both therapeutic measures and prophylactic or preventive measures aimed at preventing or slowing down (mitigating) or to terminate the target condition or disorder.
  • the subject after receiving a therapeutic amount of a vinpocetine compound or a pharmaceutical composition containing the same according to the methods described herein, the subject exhibits observable and/or measurable one or more symptoms and signs of an ophthalmic disorder If the obtained is suppressed, delayed, reduced and disappeared, or the progress of the disease is slowed down and delayed, the ophthalmic disease of the subject is successfully treated.
  • the various modes of treatment or prevention of a medical condition described herein are intended to mean "significant", which includes complete treatment or prevention as well as less than complete treatment or prevention, wherein some biologically relevant or medically relevant result is achieved. "Treating" in some embodiments does not require 100% elimination of myopia or symptoms of myopia.
  • the level observed in the absence of a composition or method of the present application results in preventing, reducing, inhibiting, arresting, eg, at least about 5%, at least about 10%, or at least about 20% of the progression of myopia.
  • 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% compared to myopia or myopia-related symptoms in the absence of a compound of the methods of the present application.
  • % at least about 70%, at least about 80%, at least about 90%, or more (about 100%). Therefore, those skilled in the art can understand that “treating”, “slowing down”, “delaying”, “inhibiting”, “controlling” or “preventing and controlling” does not mean that eye health effects or adjuvant therapeutic effects are beneficial to The means of myopia treatment, such as enhancing eye blood circulation, improving the comfort of eye application, etc.
  • the evaluation of the effect of myopia treatment involves many factors, such as whether the selection of the sample group is scientific, whether an objective control is set up, and whether an effective dose is administered, etc. Specifically, if most of the sample population is elderly (eye development stops and there may be underlying diseases such as arteriosclerosis, etc.), it is difficult to prove that vinpocetine has a therapeutic effect on myopia; Any parallel control (such as placebo group) can not prove that vinpocetine has a therapeutic effect on myopia.
  • This application uses two classic myopia disease models, guinea pig form deprivation and negative mirror induction, which are usually used in the preclinical development stage of actual myopia drugs, and scientific test standards in this field to evaluate the prevention and control of compounds Myopia, especially the efficacy of drugs in the prevention and control of myopia and/or simple myopia in children and adolescents (D A 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.).
  • “Distance vision” is also known as uncorrected distance vision. In medicine, it refers to facing the eye chart at a horizontal distance of 5 meters, and staring straight ahead with normal eyes open, without wearing glasses or any auxiliary equipment that can increase vision (such as frame glasses, contact lenses, Visual acuity measured when using a color contact lens, a small hole lens, etc.).
  • Topical administration refers to direct administration to the body part to be affected or a method of administration that can satisfy a local effect, including but not limited to: epidermal administration, inhalation administration, enema administration, eye administration, nasal administration .
  • Systemic administration is also called systemic administration, including intravenous administration, oral administration, intramuscular injection, subcutaneous injection and other administration methods. Drugs can be distributed throughout the body through blood transport in the body.
  • Improved systemic drug delivery refers to safe, efficient and convenient systemic drug delivery that can effectively reduce the drug toxicity of systemic drug delivery and enrich vinpocetine in the eyes by using specific drug targeting technology Way.
  • Direct 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), which is a sufficient condition for the treatment of the disease or its dosage, administration Parameters such as the method directly affect the treatment effect of the disease, and there is a causal relationship between the application of the ingredient and the effect of the treatment of the disease.
  • the only active ingredient means that there is only one ingredient in the final product (such as a drug) that exerts medicinal effects, such as directly inhibiting, preventing and/or treating myopia.
  • Main active ingredient refers to an active ingredient whose added amount, ratio, concentration or medicinal effect is not lower than other active ingredients (such as myopia treatment effect) in the final product (such as a drug) .
  • These substances refer to vinpocetine, or its optical isomers or their racemates, or their solvates, or their pharmaceutically acceptable salts, or their prodrugs, or their metabolites, or their related compounds Or extract, or its crystalline compound.
  • a reference to a range of values for a variable is intended to convey that the application can be practiced with the variable equal to any value within the range.
  • that variable can be equal to any integer value within the numerical range, including the endpoints of that range.
  • the variable can be equal to any real value within the numerical range, including the endpoints of the range.
  • a variable described as having a value between 0 and 2 may be 0, 1, or 2 for an inherently discontinuous variable, and 0.0, 0.1, 0.01, 0.001, or any other real value for an inherently continuous variable .
  • administering includes any means by which the compound is introduced or delivered to the subject to perform its intended function.
  • administering can be performed by any suitable route, including oral, intraocular, superficial, intranasal, parenteral (by intravenous, intramuscular, intraperitoneal, or subcutaneous) or topical (e.g., periocular, etc. topical application to the skin).
  • administering includes self-administration and administration by another. Ocular or periocular administration may be administered to the subject's affected eye, the non-affected eye, or both.
  • the term "effective amount” as used herein refers to an amount sufficient to obtain the desired therapeutic and/or prophylactic effect, eg, causing prevention or alleviation of a condition associated with an ophthalmic condition.
  • the amount of the composition administered to a subject will depend on the type and severity of the disease and on the nature of the individual, such as general health, age, sex, weight and tolerance to drugs. The amount will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine the appropriate dosage based on these and other factors.
  • the compositions may also be administered in combination with one or more other therapeutic compounds.
  • a vinpocetine compound in the methods described herein, can be administered to a subject having one or more symptoms or signs of an ophthalmic disorder.
  • a "therapeutically effective amount" of vinpocetine refers to the average level of the pharmacological effect that minimally alleviates the ophthalmic condition.
  • composition As used herein, the terms “preparation” 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” may 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 (eg, solution), or gas.
  • an injectable dosage form may include one or more formulations or compositions presented in a form for administration to a subject.
  • an injectable dosage form may be a formulation or composition prepared in a manner suitable for administration by injection.
  • pharmaceutically acceptable means approved for use in animals by regulatory authorities such as CFDA (China), EMEA (Europe) and/or FDA (US) and/or any other national regulatory authorities, preferably with In humans, such as the carrier of the drug, the concentration of the drug, or the form of the drug.
  • therapeutic use refers to the administration of at least two active ingredients (compounds) by the same route and at the same or substantially the same time.
  • sequential therapeutic application refers to the administration of at least two active ingredients at different times, by the same or different routes of administration. More specifically, sequential application refers to the complete administration of one of the active ingredients before the start of administration of the other active ingredients. Thus, it is possible that one active ingredient is administered minutes, hours or days before the other active ingredient. Concurrent treatment was not performed in this case.
  • 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 a treated sample relative to an untreated control sample, or delays the disorder or condition relative to an untreated control sample Occurrence or lessening of the severity of one or more symptoms of a disorder or condition.
  • derivatives or “analogue” of a compound includes any molecule that is functionally and/or structurally related to said compound, such as an acid, amide, ester, ether, acetylated variant, hydroxylated variants or alkylated variants.
  • derivative also includes structurally related compounds that have lost one or more of the substituents listed above.
  • Preferred derivatives of compounds are molecules which share a significant degree of similarity to said 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.
  • the derivative should have a Tanimoto similarity index with the parent drug of greater than 0.4, preferably greater than 0.5, more preferably greater than 0.6, even more preferably greater than 0.7.
  • 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 available online such as the Small Molecule Subgraph Detector (http://www.ebi.ac.uk/thornton-srv/software/SMSD/).
  • Preferred derivatives should be both structurally and functionally related to the parent compound, ie they should also retain at least part of the activity of the parent drug.
  • the term “derivative” also includes metabolites of a drug, e.g. molecules which, after administration to an organism, result from (biochemical) modification or processing of said drug, usually by specialized catalytic systems, and which exhibit or retain The biological activity of the drug. Furthermore, the term “derivative” also includes halogenated (eg fluoro), protiumated, deuterated, tritiated compounds or combinations thereof in the form of vinpocetine or its salts.
  • a "metabolite” as used herein refers to a modification 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. or processed drugs.
  • Extracts or "Plant Extracts” refer to substances extracted or processed from plants (all or a part of plants) by appropriate chemical or physical methods, such as solvent extraction or pressing.
  • a substance can be pure, with minor impurities, or a mixture.
  • Optymic composition or “ophthalmic preparation” or “ophthalmic preparation” refers to an ophthalmic composition, or an ophthalmic pharmaceutical composition, or an ophthalmic pharmaceutical product; or used for the prevention and/or treatment of eye diseases, vision protection Drugs, preparations, cosmetics, health care products, drug-device combinations or devices that maintain, improve, avoid, slow down or reverse visual impairment; or may be eye drops (eye drops), eye ointments, eye sprays, implants, Ophthalmic gels, eye patches, ophthalmic microspheres, ophthalmic sustained-release preparations, periocular injections, intraocular injections, etc.
  • “Fish oil” refers to lipids derived from higher animals, especially fish (such as cod, salmon), squid, and seals, especially polyunsaturated fatty acids, including but not limited to Omega-3 unsaturated fatty acids, DHA , EPA, DPA, ALA, nisinic acid, stearidonic acid, eicosatetraenoic acid, or combinations thereof.
  • the present disclosure identifies compounds for the treatment, prevention or alleviation of myopia and its associated symptoms, namely vinpocetine, to enhance myopia reduction or myopia mitigation while avoiding or minimizing adverse side effects, as achieved by atropine therapy. observed adverse side effects.
  • treating, preventing, or alleviating myopia and its associated symptoms may include administering a therapeutically effective amount of a pharmaceutical composition or dosage form to a subject in need thereof.
  • the pharmaceutical composition comprises a therapeutically effective amount of a vinpocetine compound or a salt thereof or a related compound thereof.
  • the application provides an ophthalmic device comprising a pharmaceutical composition comprising vinpocetine or a therapeutically acceptable salt or derivative thereof, preferably wherein the ophthalmic device is in the form of sustained release Preferably, wherein the ophthalmic device delivers the pharmaceutical composition in a pulsatile manner.
  • vinpocetine alone can significantly slow down the negative progression of diopter in the guinea pig model of form deprivation or lens-induced myopia, and even completely inhibit (terminate) the negative progression of diopter in some individuals, and can significantly Inhibition of eye axis extension, based on this, it can be confirmed that vinpocetine compounds can prevent or prevent myopia in animals, especially humans, such as infants, school-age children, children and adolescents, minors, 3 to 26-year-old people or young adults. The effect of treating, preventing or controlling the progression of myopia.
  • the treatment objects of the technical solution of the present application are children or adolescents, whose age range is 3-26 years old, preferably 6-18 years old, or 12-18 years old.
  • the subject of the technical solution of the present application is an adult, for example, aged 16-65 years, preferably 16-26 years old.
  • the pharmaceutical composition of the present application has significantly better technical effects than atropine in treating, preventing or slowing down myopia and its related symptoms, and no adverse reactions such as eye irritation, pupil dilation, inflammation or allergy were observed in the experiment.
  • the patient is treated for a period of time between about 1 month and 20 years, such as at least 6 months, at least 1 year, at least A period of 2 years, at least 3 years, at least 5 years, at least 7 years, or at least 9 years.
  • the pharmaceutical composition comprises vinpocetine and its therapeutically acceptable salt or its derivatives, preferably, comprises pharmaceutically acceptable Carrier.
  • 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 salve or ointment or ointment.
  • the drug, composition, ophthalmic device or method of treatment wherein the drug, composition is ophthalmic Ointments (such as eye ointments).
  • the medicament, formulation, composition, 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 medicament, formulation, combination
  • the preparation is oral preparation, such as tablet or capsule or powder or syrup.
  • the medicament, formulation, composition, 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 medicament, formulation, combination
  • the formulations also contain one or more other ophthalmically acceptable excipients and additives, including carriers, stabilizers, osmolarity regulators, preservatives, antioxidants, buffers, tonicity regulators, thickeners or other excipients Forming agent.
  • the medicament, formulation, composition, 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 medicament, formulation, combination A substance, device or method of treatment comprising a polyhydric alcohol and/or an acidic co-solvent, optionally hydroxypropyl- ⁇ -cyclodextrin and citric or tartaric acid.
  • the medicament, formulation, composition, device or method of treatment wherein the carrier is selected from but not Limited to: water, mixtures of water and water-miscible solvents, vegetable or mineral oils containing 0.01% to 5% by weight hydroxyethylcellulose, ethyl oleate, carboxymethylcellulose, carboxymethylcellulose Cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, ethyl acrylate, polyacrylamide, pectin, alginate, starch derivatives, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyepoxide Ethane, cross-linked polyacrylic acid, carbopol, lecithin, polyethylene glycol stearate, polyhydric alcohols, acid co-solvents, cetyl alcohol or polyoxyethylene sorbitol mono Oleate.
  • the carrier is selected from but not Limited to: water, mixtures of water and water-miscible solvents, vegetable or mineral oils containing 0.0
  • the medicament, formulation, composition, device or method of treatment wherein the osmotic pressure regulator is Sodium chloride.
  • the medicament, formulation, composition, device or method of treatment wherein the preservative is selected from the group consisting of benzene Zalkonium Chloride, Cetrimonium, Sodium Perborate, Stabilized Oxychloro Complex, Sofia, Polyquaternium-1, Chlorobutanol, Disodium EDTA, Polyhexamethylene Biguanide, or combinations thereof .
  • the medicament, formulation, composition, device or method of treatment wherein the buffer is selected from boron Acid salts, borate-polyol complexes, phosphate buffers, citrate buffers, acetate buffers, carbonate buffers, organic buffers, amino acid buffers, or combinations thereof.
  • the medicament, formulation, composition, 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 tonicity modifier is selected from 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, monosodium hydrogen phosphate, monopotassium phosphate, dextrose, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, glycerin, or combinations thereof.
  • the tonicity modifier is selected from From sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, sodium bicarbonate,
  • Vinpocetine, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or Its metabolites, or its related compounds or extracts, or its crystalline compounds, or the combination of these substances have the effect on the prevention and control (treatment) of myopia or the inhibition of the axial length of the eye, and the sex, age, and The type of myopia, the speed of myopia progression and the severity of myopia were not related.
  • 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 subconjunctival reservoirs.
  • 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, ocular Inserts, corneal onlays, corneal inlays, nanodiscs, liposomes, nanoparticles, punctal plugs or hydrogel matrices with microfluidic reservoirs.
  • the ophthalmic device is a contact lens, ocular Inserts, corneal onlays, corneal inlays, nanodiscs, liposomes, nanoparticles, punctal plugs or hydrogel matrices with microfluidic reservoirs.
  • 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 for use in An ophthalmic composition for the treatment of an ophthalmic disorder or condition.
  • 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 for use in An ophthalmic composition for the treatment of anterior myopia, myopia, true myopia, pseudomyopia or myopia development.
  • 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 for use in An ophthalmic composition for treating high myopia, moderate myopia or low myopia.
  • 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 for use in Ophthalmic composition for the treatment of patients diagnosed with anterior myopia (or at risk of developing myopia).
  • 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 in a contact lens lens inside the cover package.
  • Suitable methods include in vitro, ex vivo or in vivo methods.
  • In vivo methods generally involve administering a vinpocetine compound of the present application or a pharmaceutical composition containing the same to a mammal, preferably a human.
  • a vinpocetine compound or a pharmaceutical composition containing the same can be administered to a subject in an effective amount (ie, an amount having the desired therapeutic effect).
  • Dosage and dosing regimen will depend on the extent of the ophthalmic condition in the subject, the subject and the subject's medical history.
  • the compounds disclosed herein may also exist as prodrugs.
  • Prodrugs of the compounds described herein are modified forms of vinpocetine or its related compounds that are susceptible to chemical changes under physiological conditions.
  • prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo setting.
  • prodrugs can be slowly converted to compounds when placed in a transdermal patch reservoir with suitable enzymes or chemical reagents.
  • Prodrugs are often useful because, in some cases, they may be easier to administer than the compound or parent drug. For example, they are bioavailable by oral administration whereas the parent drug is not.
  • Prodrugs may also be more soluble in pharmaceutical compositions than the parent drug.
  • 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 is then metabolically hydrolyzed to a carboxylic acid (the active entity).
  • the compounds disclosed herein may exist as therapeutically acceptable salts.
  • This application includes the compounds listed above in the form of salts, including acid addition salts.
  • Suitable salts include those formed with organic and inorganic acids.
  • Such acid addition salts are generally pharmaceutically acceptable.
  • non-pharmaceutically acceptable salts can be used in the preparation and purification of problematic compounds.
  • Base addition salts may also be formed and are pharmaceutically acceptable.
  • terapéuticaally acceptable salt means a salt or zwitterionic form of a compound disclosed herein that is water- or oil-soluble or dispersible and therapeutically acceptable, as defined herein. Salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate free base form of the compound with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate , butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate , Hemisulfate, Heptanoate, Hexanoate, Hippurate, Hydrochloride, Hydrobromide, Hydroiodide, 2-Hydroxyethanesulfonate (Isethionate), Lactate , maleate, malonate, DL-mandelate, mesitylene sulfonate, mesylate, naphthalene sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, oxalate salt, pectate, persul
  • basic groups in the compounds disclosed herein can be quaternized with: methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl sulfate, diethyl sulfate, dibutyl esters and dipentyl esters; decyl, lauryl, myristyl and steryl chlorides, bromides and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts may also be formed by complexation of the compounds with alkali metal or alkaline earth metal ions. Accordingly, this application includes the sodium, potassium, magnesium, and calcium salts, and the like, of the compounds disclosed herein.
  • the crystal form of Vinpocetine includes all known species, such as the crystal form 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.).
  • Base adducts can be prepared during the final isolation and purification of the compound by reacting the carboxyl group with a suitable base such as a hydroxide, carbonate or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as a hydroxide, carbonate or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary or tertiary amine.
  • Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium and aluminum as well as non-toxic quaternary ammonium cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, trimethylamine, Ethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, di Benzylamine, N,N-Dibenzylphenethylamine, 1-Diphenylhydroxymethylamine and N,N'-Dibenzylethylenediamine.
  • Other representative organic amines suitable for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • compositions comprising one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides or solvates thereof, together with one or more A pharmaceutically acceptable carrier thereof and optionally one or more other therapeutic components.
  • a carrier is "acceptable” in the sense that it is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent on the chosen route of administration. Any known techniques, carriers and excipients that are suitable and understood in the art may be used; see, for example, Remington's Pharmaceutical Sciences.
  • compositions disclosed herein can be produced in any manner known in the art, for example by means of conventional mixing, dissolving, granulating, sugar-coating, finely milling, emulsifying, encapsulating, entrapping or compression processes, and can also be Make medicine-device combination.
  • Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual, ocular , intranasal and intraocular) administration, the most suitable route may depend, for example, on the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Generally, these methods comprise bringing into association a compound of the present application, or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof (the "active ingredient") with the carrier which constitutes one or more accessory ingredients. step. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; Solutions or suspensions in aqueous liquids; or as oil-in-water emulsions or water-in-oil emulsions.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • compositions which can be used orally include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, inert diluent, or lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • the dosage of all formulations for oral administration should be suitable for the purpose of myopia prevention, treatment to be achieved by such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Furthermore, stabilizers may be added. Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • fillers or diluents used in oral pharmaceutical formulations such as capsules and tablets include, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, microcrystalline cellulose (MCC), powdered cellulose, corn starch, pregelatinized starch, dextrate, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate , magnesium carbonate, magnesium oxide, poloxamers (such as polyethylene oxide), methylcellulose, and hydroxypropylmethylcellulose.
  • Bulking agents may have complexed solvent molecules, as in the case where the lactose used is lactose monohydrate.
  • disintegrants used in oral pharmaceutical formulations such as capsules and tablets include, but are not limited to, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, polysaccharide Povidone, crospovidone (polyvinylpolypyrrolidone), methylcellulose, microcrystalline cellulose, powdered cellulose, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate.
  • glidants and lubricants can be used in oral pharmaceutical formulations to ensure uniform blending of the excipients upon mixing.
  • lubricants include, but are not limited to, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, benzene Sodium formate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
  • glidants include, but are not limited to, silicon dioxide ( Si02 ), talc corn starch, and poloxamers.
  • Poloxamers are ABA block copolymers in which the A segment is a hydrophilic polyethylene glycol homopolymer and the B segment is a hydrophobic polypropylene glycol homopolymer.
  • tablet binders include, but are not limited to, gum arabic, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oils, hydroxyethylcellulose , hydroxypropyl cellulose, hydroxypropyl methyl cellulose, copolyvidone (copolyvidone), methyl cellulose, liquid glucose, maltodextrin, polymethacrylate, povidone, pregelatinized starch, algae Sodium phosphate, starch, sucrose, tragacanth and zein.
  • the compounds may be formulated for parenteral administration by injection, eg, by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations are available in unit-dose 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 requires only the addition of a sterile liquid carrier immediately before use, such as a physiological Saline or sterile pyrogen-free water.
  • a sterile liquid carrier such as a physiological Saline or sterile pyrogen-free water.
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type previously described.
  • the pharmaceutical composition of the present application is in the form of an injection, especially a syringe.
  • the pharmaceutical composition is administered by intraocular injection, more preferably by intravitreal injection into the vitreous.
  • Formulations for parenteral administration include, but are not limited to, aqueous and non-aqueous (oily) sterile injectable solutions of the active compound, which may contain antioxidants, buffers, bacteriostats and agents that render the formulation isotonic with the blood of the intended recipient. solutes; and aqueous and nonaqueous 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 ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as methyl cellulose, sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally such as ethyl oleate or triglycerides) or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the compounds mentioned in this patent can also be formulated into storage preparations.
  • Such long-acting formulations may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (eg, as an emulsion in acceptable oils) or ion exchange resins, or as sparingly soluble derivatives, eg, as sparingly soluble salts.
  • compositions may take the form of tablets, troches, lozenges or gels formulated in conventional manner.
  • Such compositions may contain active ingredients, such as compounds such as vinpocetine mentioned in this patent, in a flavored base such as sucrose and gum arabic or tragacanth.
  • 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.
  • the compounds mentioned in this patent can also be formulated into disposable preparations for local application, devices, articles for changing the appearance of the eye, or medical consumables, such as single-use eye drops (each Package contains only one therapeutically effective dose), individually wrapped eye patches, color contact lenses, daily disposable contact lenses.
  • Vinpocetine and other referenced compounds disclosed herein may be administered topically, ie by non-systemic administration. This includes applying the compounds disclosed herein to the eye, epidermis or externally of the oral cavity, and instilling such compounds into the ears, eyes and nose such that the compound does not appreciably enter the bloodstream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin to the site of action (such as gels, liniments, lotions, creams, ointments or pastes) and formulations suitable for application to the eyes, ears or nose , such as drops, sprays.
  • the active ingredient for the treatment of myopia may comprise, for example, 0.0000001% to 99% w/w (by weight) of the total content of the preparation. In certain embodiments, the active ingredient may comprise up to more than 50% w/w. In other embodiments, it may comprise less than 1% w/w. In certain embodiments, the active ingredient may comprise from 0.01% w/w to 1% w/w.
  • the active ingredient for topical administration may comprise, for example, from 0.0000001% to 100% w/v (weight to volume) of the formulation; Alternatively, in certain embodiments, the active ingredient may comprise as much as 50% w/v or more. In other embodiments, it may comprise less than 1% w/v. In certain embodiments, the active ingredient may comprise from 0.01% w/v to 1% w/v. In other embodiments, it may comprise from 0.00001% to 0.001% w/v of the formulation.
  • Said gel preparation form comprises the preparation formed by linking vinpocetine or its prodrug or its related compound with hydrogel, preferably, the hydrogel of vinpocetine or its prodrug linked by hydrogel is biological Degradable hydrogel.
  • the hydrogel comprises, preferably consists of, at least one polymer, preferably selected from poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkoxy ) polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(asparagine), poly(butyric acid), poly(caprolactone), poly(carbonate ), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyloxazoline ), poly(glycolic acid), poly(hydroxyethyl acrylate) (poly(hydroxyethyl acrylate)), poly(hydroxyethyl oxazoline), poly(hydroxypropylmethacrylamide) (poly(hydroxypropylmethacrylamide)), poly (hydroxypropyl methacrylate) (poly(hydroxypropyl methacrylate)), poly(hydroxypropyl oxazoline), poly(
  • the hydrogel is a biodegradable polyethylene glycol (PEG) based hydrogel.
  • PEG polyethylene glycol
  • the polyethylene glycol (PEG) has a single molecular weight or a group of different molecular weights mixed in a certain proportion.
  • the hydrogel is a shaped article, preferably in the form of particles. More preferably, the hydrogel is in the shape of microbeads. Even more preferably, the microparticle beads have a diameter of 1-1000 ⁇ m, more preferably 5-500 ⁇ m, more preferably 10-100 ⁇ m, even more preferably 20-80 ⁇ m. Bead diameters are determined when microparticle beads are suspended in isotonic aqueous buffer.
  • the hydrogel-linked vinpocetine or prodrug thereof is in the shape of a bead. More preferably, said hydrogel-linked vinpocetine or prodrug thereof is in the shape of microbeads.
  • the microparticle beads have a diameter of 1-1000 ⁇ m, more preferably 5-500 ⁇ m, more preferably 10-100 ⁇ m, even more preferably 20-80 ⁇ m. Bead diameters are determined when microparticle beads are suspended in isotonic aqueous buffer. Such hydrogels can be polymerized in different ways, for example by free-radical polymerization, ionic polymerization or complex-forming reactions.
  • crosslinker reagents crosslinking macromers or crosslinking monomers
  • backbone reagents multifunctional macromonomers
  • the crosslinker reagent carries at least two interconnectable functional groups
  • the backbone reagent 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 or may not be present.
  • Useful interconnectable functional groups include, but are not limited to, radically polymerizable groups such as vinyl, vinyl-benzene, acrylate, acrylamide, methacrylate, methacrylamide, and ionically polymerizable groups Such as oxetane, azetidine and ethylene oxide.
  • the hydrogel is formed by a chemical complex forming reaction.
  • the starting material is at least one macromolecular starting material having complementary functionality for reactions such as condensation or addition reactions.
  • 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.
  • the topical ophthalmic, otic, and nasal formulations of the present application may contain excipients in addition to the active ingredient such as vinpocetine.
  • Excipients commonly used in such formulations include, but are not limited to, isotonic agents, preservatives, chelating agents, buffers and surfactants.
  • Other excipients include solubilizers, stabilizers, comfort enhancers, polymers, demulcents, pH adjusters and/or lubricants.
  • excipients can be used in the formulations of the present application, including water, mixtures of water and water-miscible solvents (such as C1-C7 alkanols), containing 0.5% to 5% non-toxic water-soluble polymers vegetable or mineral oils, natural products (such as alginate, pectin, tragacanth, karaya, guar, xanthan, carrageenan, agar and acacia), starch derivatives (such as starch acetate and hydroxypropyl starch) and other synthetic products (such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinylmethyl ether, polyethylene oxide, preferably crosslinked polyacrylic acid and mixtures of these products).
  • concentration of excipients is usually 1 to 100,000 times that of the active ingredient.
  • the excipients to be included in the formulation are generally selected on the basis of their inertness with respect to the active ingredient composition of the formulation.
  • suitable isotonicity adjusting agents include, but are not limited to, mannitol, dextrose, sodium chloride, glycerin, 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 preferably polysorbate 80, RLM 100, POE 20 cetyl stearyl ether (such as CS20) and porol Sham (such as F68).
  • the formulation may contain substances that increase the viscosity of the solution or suspension, such as sodium carboxymethylcellulose, hypromellose, microcrystalline cellulose, sorbitol or dextran.
  • the formulation also Suitable stabilizers or agents which increase the solubility of the compounds to allow the preparation of highly concentrated solutions may be included and include, but are not limited to, ethanol, benzyl alcohol, polyethylene glycol, phenylethyl alcohol, and glycerol.
  • the formulations presented herein may contain one or more preservatives.
  • preservatives include benzalkonium chloride, parabens, sodium perborate, sodium chlorite, alcohols (such as chlorobutanol, benzyl alcohol, or phenylethyl alcohol), guanidine derivatives (such as polyhexaethylene methyl biguanide), sodium perborate, polyquaternium-1, aminoalcohols (such as AMP-95), or sorbic acid.
  • the formulation itself may be preserved, whereby preservatives are not required.
  • packaging materials or packaging design can be used to avoid drug deterioration (such as changes in physical and chemical properties and/or changes in biological effects), so preservatives are not required.
  • the formulation may be a solution, suspension or gel.
  • formulations in aqueous solution or suspension for topical application to the eye or ear are in the form of drops.
  • Formulations for topical administration to the nose in aqueous solutions or suspensions are in the form of drops, spray or aerosol.
  • aqueous generally refers to aqueous formulations wherein the formulation contains >20%, >50%, more preferably >75% and especially >90% water by weight.
  • the drops may be delivered from a multi-dose eye drop bottle, which may preferably include a device, as is known in the art, for withdrawing any preservative therefrom as the formulation is delivered.
  • 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 hydrofluoroalkane-based propellants, or the active drug may be delivered as a dry powder Element.
  • 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 under the eyelid.
  • the formulations of the present application are administered once daily.
  • the formulation can also be formulated to be administered at any frequency of administration, 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, hourly, or any higher frequency.
  • This frequency of dosing is also maintained for varying durations depending on the treatment regimen.
  • the duration of a particular treatment regimen can vary from a single dose to regimens extending over months or years.
  • the formulations are administered in varying doses, but typical doses are one to two drops per application, or an equivalent amount of gel or other formulation (eg, tablet, eye ointment).
  • Those of ordinary skill in the art are familiar with how to determine a treatment regimen for a particular indication.
  • Gels for topical or transdermal application may generally contain a mixture of volatile solvents, non-volatile solvents and water.
  • the volatile solvent component of the buffered solvent system can include lower (C1-C6) alkyl alcohols, lower alkyl glycols, and lower glycol polymers.
  • the volatile solvent is ethanol.
  • the volatile solvent component is believed to act as a penetration enhancer while also having a cooling effect on the skin as it evaporates.
  • the non-volatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. In certain embodiments propylene glycol is used.
  • Nonvolatile solvents delay the evaporation of volatile solvents and lower the vapor pressure of buffered solvent systems.
  • the amount of this non-volatile solvent component is determined by the pharmaceutical compound or drug used.
  • the buffer component of the buffered solvent system can be selected from any buffer commonly used in the art; in certain embodiments water is used.
  • a common ingredient ratio is about 20% non-volatile solvent, about 40% volatile solvent, and about 40% water.
  • chelating and gelling agents include, but are not limited to, semi-synthetic cellulose derivatives (such as hydroxypropylmethylcellulose) and synthetic polymers, galactomannan polymers (such as guar gum and its derivatives), and cosmetic agent.
  • Lotions include those suitable for application to the skin or eyes.
  • Eye lotions may comprise sterile aqueous solutions, optionally containing an antiseptic, and may be prepared in a manner analogous to the preparation of drops.
  • Lotions or liniments for application to the skin may also include agents (such as alcohol or acetone) and/or moisturizers (such as glycerin) or oils (such as castor oil or peanut oil) to accelerate drying and cooling the skin.
  • agents such as alcohol or acetone
  • moisturizers such as glycerin
  • oils such as castor oil or peanut oil
  • the pharmaceutical composition of the present application may be a cream, ointment (such as 3% salve, ointment) or paste, which is a semi-solid formulation of the active ingredient for external application. They may be prepared by mixing, by means of suitable machines, the active ingredient in finely divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with an oleaginous or non-oily base.
  • the base may include hydrocarbons such as petrolatum, hard, soft or liquid paraffin, glycerin, beeswax, metallic soaps; mucilages; oils of natural origin such as fish oil, almond oil, corn oil, peanut oil, castor oil or olive oil ; lanolin or its derivatives or a fatty acid such as stearic acid or oleic acid together with an alcohol such as propylene glycol or macrogel or lanosterol or dihydrolanosterol.
  • the formulations may incorporate any suitable surfactant, such as anionic, cationic or nonionic surfactants, such as sorbitan esters or polyethylene oxide derivatives thereof.
  • Suspending agents such as natural gums, cellulose derivatives, or inorganic materials, such as siliceous silicon dioxide, and other ingredients, such as lanolin, lanosterol, may also be included.
  • Drops or sprays may comprise sterile aqueous or oily solutions or suspensions, and may be prepared by dissolving the active ingredient in a suitable bactericide and/or fungicide and/or any other suitable preservative and in certain embodiments
  • the protocol includes the preparation of surfactants in aqueous solution.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or at 98-100°C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by aseptic technique.
  • bactericides and fungicides suitable for inclusion in drops are azole compounds (such as econazole), phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%), and chlorhexidine acetate Thai (0.01%).
  • Suitable solvents for preparing oily solutions include glycerol, alcohol and propylene glycol.
  • Formulations for topical administration in the mouth include lozenges containing the active ingredient in a flavored base such as sucrose and acacia or tragacanth and in a medium such as gelatin and glycerin or sucrose and acacia.
  • a lozenge containing the active ingredient in a matrix e.g., buccal or sublingual.
  • compounds such as vinpocetine mentioned in this patent can be conveniently delivered from an insufflator, nebulizer pressurized pack, or other convenient device for delivering an aerosol spray.
  • Pressurized packs may contain a suitable propellant, such as hydrofluoroalkane, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the application may take the form of a dry powder composition, eg a powder mix of the compound with a suitable powder base such as lactose or starch.
  • Powder compositions may be presented in unit dosage form, eg, in capsules, cartridges, gelatin or blister packs, from which the powder may be administered by means of an inhaler or insufflator.
  • Preferred unit dosage formulations are those containing an effective dose, as herein described, or an appropriate fraction thereof, of the active ingredient.
  • formulations described above may 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 flavored agent).
  • the compounds 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 5mg to 100mg/day, and children or adolescents should reduce or maintain the same dosage.
  • Tablets or other presentations provided as discrete units may conveniently contain an amount of the compound or compounds which is effective at the dose or doses, for example containing from 0.1 mg to 1000 mg, Usually about 1 mg to 10 mg units, preferably 5 mg.
  • Compounds such as vinpocetine mentioned in this patent can be administered in various ways, such as oral administration, local administration or administration by injection, or systemic administration and local administration at the same time, or systemic administration and local administration alternately.
  • the precise amount of compound administered to a patient is the responsibility of the attending physician.
  • the particular dosage level for any particular patient will depend upon a variety of factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, the exact condition being treated, and The severity of the indication or condition being treated.
  • the route of administration may vary depending on the condition and its severity.
  • At least one compound described herein or a pharmaceutically acceptable salt, ester or prodrug thereof in combination with another therapeutic agent.
  • another therapeutic agent such as a pharmaceutically acceptable salt, ester or prodrug thereof.
  • an antihypertensive drug in combination with the initial therapeutic agent.
  • the efficacy of one of the compounds described herein may be potentiated by administration of an anti-allergic drug (i.e., an anti-allergic drug may have only minimal therapeutic benefit by itself, but when combined with a therapeutic agent mentioned herein has no effect on The overall therapeutic benefit of the patient is enhanced).
  • the benefit experienced by a patient may be augmented by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has a therapeutic benefit.
  • another therapeutic agent which also includes a therapeutic regimen
  • the therapeutic benefit may be enhanced by also providing the patient with another myopia treating agent.
  • the total benefit experienced by the patient may simply be additive of the two therapeutic agents, or the patient may experience a synergistic benefit.
  • compositions in dry or liquid form may be presented as single or multi-dose pharmaceutical compositions.
  • the liquid or dry pharmaceutical composition is provided as a single dose, which means that the container in which it is provided contains one pharmaceutical dose.
  • the liquid or dry pharmaceutical composition is a multidose pharmaceutical composition, which means that the container in which it is provided contains more than one therapeutic dose, ie the multidose composition contains at least 2 doses.
  • Such multi-dose compositions may be administered to different patients in need thereof, or may be administered to a single patient wherein, after the first dose is administered, the remaining dose is stored until needed.
  • the pharmaceutical composition is in a container.
  • Containers for liquid or dry pharmaceutical compositions are eg eye drops bottles, syringes, vials, vials with stoppers and closures, ampoules and cartridges.
  • liquid or dry pharmaceutical compositions are provided in syringes.
  • the container is preferably a dual chamber syringe.
  • the dry pharmaceutical composition is provided in the first chamber of a dual chamber syringe and the reconstituted solution is provided in the second chamber of the dual chamber syringe.
  • the dry composition is reconstituted prior to application of the dry composition to a patient in need thereof.
  • Reconstitution can be performed in the container in which the dry composition is provided, eg, in eye drop bottles, syringes, dual chamber syringes, ampoules, and cartridges.
  • Reconstitution is performed by adding a predetermined amount of reconstitution solution to the dry composition.
  • Reconstitution solutions are sterile liquids such as water or buffers, which may contain other additives such as preservatives and/or antimicrobial agents such as benzyl alcohol and cresol.
  • the reconstitution solution is sterile water.
  • Ophthalmic preparations the pharmaceutical composition of the present application can be administered in the form of ophthalmic preparations, and the ophthalmic preparations of the present application contain ophthalmologically acceptable carriers.
  • the amount of active ingredient which may be combined with a carrier material to produce a single dosage form may vary depending upon the host treated and the particular mode of administration.
  • an "ophthalmically acceptable carrier” is an ophthalmologically acceptable solvent, suspension, or vehicle for a pharmaceutical composition to the eye of a subject.
  • the carrier can be solid or liquid.
  • the carrier is "ophthalmically acceptable” in the sense that the carrier is suitable for administration to the eye without causing any major adverse reactions.
  • the ophthalmically acceptable carrier is or includes water.
  • ophthalmic formulations are in the form of eye drops or gels for application to the eye.
  • the majority of the formulation will be water.
  • formulations comprise greater than 50% by weight (such as greater than 60%, 65%, 70%, 75%, 80%, 85% or 90% by weight), more usually greater than 95% by weight (such as 96% by weight %, 97% by weight, 98% by weight or 99% by weight) of water.
  • the ophthalmically acceptable carrier is an oil-in-water emulsion or oil.
  • the ophthalmic formulation may be in the form of a cream for application to the eye.
  • the formulation may comprise greater than 10%, more typically greater than 20% by weight of oily ingredients.
  • the carrier can be a biodegradable polymer, such as a biodegradable polymer ocular implant for sustained release of the compound of the present application and optionally other compounds.
  • biodegradable, biocompatible polymer matrices examples include biodegradable, biocompatible polymer matrices.
  • compounds can be embedded in a polymer matrix while maintaining structural integrity.
  • the polymers may be natural, such as polypeptides, proteins or polysaccharides, or may be synthetic, such as poly alpha-hydroxy acids. Examples include carriers made of, for example, collagen, fibronectin, elastin, cellulose acetate, nitrocellulose, methylcellulose, polysaccharides, fibrin, gelatin, and combinations thereof.
  • the polymer is polylactic acid (PLA) or lactic-co-glycolic acid (PGLA).
  • Polymeric matrices, including microspheres and nanospheres, can be prepared and isolated in a variety of forms and sizes.
  • therapeutic compounds are prepared with carriers that will protect the therapeutic compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using known techniques.
  • Excipients suitable for ophthalmic formulations of the present application include, for example, demulcents, emollients, hypertonic agents, preservatives, buffers or pH adjusters.
  • suitable excipients include:
  • Moderators synthetic high molecular weight cross-linked acrylic polymers (such as Carbomer 974 and Carbomer 980); cellulose derivatives (such as hydroxypropyl methylcellulose (“HPMC” or “hypromellose”) cellulose”), hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose (carboxymethyl cellulose)) or sodium carboxymethyl cellulose (carboxymethyl cellulose sodium)); dextran (such as dextran Sugar 70); Gelatin; Polyols (such as Glycerin, Macrogol 300, Macrogol 400, Polysorbate 80, and Propylene Glycol); Polyvinyl Alcohol; Povidone (Polyvinylpyrrolidone); Poloxa Mu; and hyaluronic acid (a disaccharide polymer) or its sodium or potassium salt.
  • HPMC hydroxypropyl methylcellulose
  • HPMC hydroxypropyl methylcellulose
  • HPMC hydroxypropyl methylcellulose
  • cellulose derivatives such as hydroxypropy
  • Emollients 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.
  • 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
  • fish oil castor oil
  • Preservatives benzalkonium chloride; sodium perborate; Oxyd (sodium chlorite 0.05%, hydrogen peroxide 0.01%); polyquaternium-1 (ethanol, 2,2′,2′′-nitrilotri -polymer with 1,4-dichloro-2-butene and N,N,N′,N′-tetramethyl-2-butene-1,4-diamine); sodium silver chloride; hexa Methylenebiguanide; Oxyborate; and (Sodium Chlorite 0.005% m/v).
  • Ophthalmic hypertonic agent sodium chloride.
  • the ophthalmic formulations of the present application may also contain preservatives that inhibit the growth of microorganisms and extend the shelf life of the formulation.
  • Preservatives that can be used in ophthalmic preparations of the present application include, for example, benzalkonium chloride, sodium perborate, Oxyd (sodium chlorite 0.05%, hydrogen peroxide 0.01%), polyquaternium-1 (ethanol, 2,2', 2′′-nitrilotri-polymer with 1,4-dichloro-2-butene and N,N,N′,N′-tetramethyl-2-butene-1,4-diamine) , sodium silver chloride, hexamethylene biguanide, oxyborate.
  • Sodium chlorite (0.005% m/v) is a microbicide with broad-spectrum antimicrobial activity and very low toxicity to mammalian cells , which protect the formulation during storage but eventually dissociate 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 for long-term use. This preservative has no adverse effects on epithelial cells in vitro or on physical exertion, and is less disruptive to cellular integrity than many other preservatives in use.
  • the ophthalmic formulations of the present application may be prepared by any suitable method for preparing ophthalmic formulations.
  • Ophthalmic formulations are generally sterile, and thus the method may include the step of sterilizing the ophthalmic formulation.
  • ophthalmic formulations are clear and have a reflectance similar to tear fluid, a suitable pH (usually buffered to around pH 7.5) to avoid severe corneal irritation and to prevent microorganisms.
  • Formulations of the present application suitable for topical administration to the eye are preferably isotonic or slightly hypotonic in order to counteract any tear hyperosmolarity caused by evaporation and/or disease.
  • the formulations of the present application generally have an osmolality in the range of 220-320 mOsm/kg, preferably in the range of 235-300 mOsm/kg. Surface tension values close to or lower than those observed for tear films are generally preferred.
  • Ophthalmic preparations are generally formulated as sterile aqueous solutions.
  • the compositions of the present application are formulated with one or more tear substitutes.
  • tear substitutes are known in the art, including but not limited to: monomeric polyols, such as glycerin, propylene glycol, and ethylene glycol; polymeric polyols, such as polyethylene glycol; cellulose esters, such as hydroxy Propylmethylcellulose, sodium carboxymethylcellulose, and hydroxypropylcellulose; dextrans, such as Dextran 70; vinyl polymers, such as polyvinyl alcohol; and carbomers, such as Carbomer 934P, Carbomer 941, Carbomer 940 and Carbomer 974P.
  • the preparation or pharmaceutical composition of the present application can be used together with contact lenses, contact lenses or other ophthalmic products (such as frame glasses, myopia treatment apparatus).
  • Preferred formulations are prepared using a buffer system that maintains the pH of the formulation at a pH of about 4.5 to about 8. Most preferred formulations have a pH of 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 ZnCO 3 may also be used. Buffer capacity can be adjusted to match conditions most sensitive to pH stability.
  • the ophthalmic formulations of the present application may also contain cooling agents such as menthol, camphor, borneol, geraniol, eucalyptol, linalool and the like.
  • cooling agents such as menthol, camphor, borneol, geraniol, eucalyptol, linalool and the like.
  • concentration of the cooling agent is preferably 0.0001 to 0.1 w/v%.
  • the ophthalmic preparations of the present application may also contain other commonly used therapeutic components in ophthalmology, such as bentacic acid and its salt forms (such as bendax lysine), decongestant components (such as epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, Tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc.), anti-inflammatory/astringent agents (eg, neostigmine methylsulfate, ⁇ -Aminocaproic acid, allantoin, berberine hydrochloride hydrate, berberine sulfate hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozy
  • Active substance content of the pharmaceutical composition of the present application when the medicine is mixed, the concentration of the therapeutically active compound can be selected from an effective suitable amount of each substance.
  • Therapeutically active compounds may be present in high, medium or low concentrations, such as about 0.0000001-100%, about 0.00001-10%, about 0.001-20%, about 0.1- 30%, about 1-40%, about 10-50%, about 20-60%, about 30-70%, about 40-80%, about 50-90% (w/v), for example about 1 ⁇ M, about 0.1 ⁇ M, about 0.01 ⁇ M, about 5 ⁇ M, about 10 ⁇ M, about 15 ⁇ M, about 25 ⁇ M, about 50 ⁇ M, 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).
  • Ophthalmic formulations of the present application may be implanted in the eye as eye drops (in the form of single-dose or multi-dose droppers), ointments, gels, creams, or biodegradable polymers
  • the drug is delivered to the patient in the form of a drug (designed for sustained release) or via ocular moistening (eg, a multi-dose spray).
  • the packaging of ophthalmic formulations should relate to the retention or non-retention properties of the solution.
  • Packaging methods such as form-fill-seal technology, which combines blow molding, aseptic filling, and sealing into a single process, are particularly useful for packaging preservative-free formulations in unit-dose containers.
  • these single-dose containers are composed of low density polyethylene or polypropylene and include twist-off closures.
  • the formulations and methods of the present application are already in use with any subject who would benefit from the formulations and methods of the present application.
  • the subject is usually a mammal, more usually a human.
  • the present application is not limited to the treatment of humans, and may be adapted for veterinary use.
  • the terms "subject", “patient” or “subject in need” include humans as well as non-human animals, including, for example, farm animals such as sheep, pigs, cows and horses; pet animals, Such as dogs and cats; laboratory animals such as mice, rats and rabbits.
  • said mammal is a human.
  • the application provides an ophthalmic device comprising a pharmaceutical composition comprising vinpocetine or a therapeutically acceptable salt thereof or a derivative or combination thereof, preferably wherein the ophthalmic device
  • the pharmaceutical composition is delivered in a sustained release manner.
  • the pharmaceutical composition is a sustained release formulation or a subconjunctival depot.
  • the pharmaceutical composition is a sustained release formulation contained within the ophthalmic device.
  • the ophthalmic device is a contact lens, contact lens, ocular insert, corneal onlay, corneal inlay, nanodiscs, lipid Plastids, nanoparticles, punctal plugs, or hydrogel matrices with microfluidic reservoirs.
  • the ophthalmic device delivers the pharmaceutical composition in a sustained release manner.
  • the pharmaceutical composition is formulated as an ophthalmic composition, eg, as an ophthalmic composition for the treatment of an ophthalmic disorder or condition.
  • the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of anterior myopia, myopia, or myopia progression.
  • the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of high myopia, moderate myopia, or low myopia.
  • the pharmaceutical composition is formulated as an ophthalmic combination for the treatment of patients diagnosed with (or at risk of developing) myopia thing.
  • the pharmaceutical composition is substantially uniformly distributed throughout the ophthalmic device.
  • the ophthalmic device is contained within a contact lens or contact lens blister pack.
  • the pharmaceutical composition submerges the ophthalmic device within a contact lens or contact lens blister pack.
  • the pharmaceutical composition is administered to the eye of the patient.
  • the pharmaceutical compositions are administered topically.
  • the pharmaceutical composition is administered to the eye in the form of an eye drop formulation, an eye spray formulation, or an eye gel formulation.
  • the pharmaceutical compositions are formulated as ophthalmic emulsions, ophthalmic liposomes, nanodiscs, nanoparticle suspensions, or ophthalmic ointments. form for application to the eye.
  • the pharmaceutical compositions are ophthalmically administered to the eye of a patient via an ophthalmic device.
  • the pharmaceutical compositions are administered 1, 2, 3, 4, or 5 times per day.
  • a pharmaceutical composition as disclosed herein may be an aqueous ophthalmic formulation, such as in the form of eye drops.
  • an aqueous ophthalmic formulation as described herein may be packaged in an eye drop bottle and administered as drops.
  • an aqueous ophthalmic formulation may be administered as a single application (ie, a single dose), which may consist of one, two, three or more drops instilled into the eye of the patient.
  • one dose of the ophthalmic aqueous formulation described herein is one drop of the aqueous composition from said eye drop bottle.
  • a pharmaceutical composition as disclosed herein may be an ophthalmic gel formulation.
  • the ophthalmic gel formulation may be packaged in an eye drop bottle and administered as drops.
  • an ophthalmic gel formulation may be administered as a single application (ie, a single dose), which may consist of one, two, three or more drops instilled into the patient's eye.
  • one dose of the ophthalmic gel described herein is one drop of the gel composition from the eye drop bottle.
  • a pharmaceutical composition as disclosed herein may be an ophthalmic ointment formulation.
  • the ophthalmic ointment formulation may be packaged within a tube or other squeezable container having a dispensing nozzle through which a stick of ointment will be delivered.
  • an ophthalmic ointment formulation may be administered as a single application (ie, a single dose), which may include one or more strips into the patient's eye.
  • one dose of ophthalmic ointment is a stick of ointment composition dispensed through the nozzle of a dispenser tube.
  • Treatment of a subject with a therapeutically effective amount of a therapeutic composition or formulation described herein may comprise a single treatment or a series of treatments.
  • the methods prevent the progression of myopia in the treated patient.
  • the methods control the progression of myopia in the treated patient.
  • the methods reduce the progression of myopia in the treated patient.
  • the methods slow or reduce the progression of myopia in the treated patient.
  • the methods control, slow, reduce, delay, and/or alleviate the progression of myopia in the treated patient within the following ranges relative to no treatment Inside: about 5-95%, about 5-90%, about 5-80%, about 5-70%, about 5-60%, about 5-50%, About 5-40%, about 5-30%, about 5-20%, about 10-100%, about 20-90%, about 30-90%, about 40-90% %, between about 50-90%, or between about 75-90%.
  • use of the pharmaceutical compositions, formulations, ophthalmic devices, or methods of treatment limits the magnitude of negative diopter change in the subject's eye to within 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.
  • the methods reverse the progression of myopia in the treated patient.
  • the patient suffers from high myopia, moderate myopia, or low myopia.
  • the patient is anterior myopia (or is at risk of developing myopia).
  • the methods prevent, control, slow down, reduce, lessen, delay and/or reverse the axial (or longitudinal ) growth, i.e. axial prolongation and/or increased vitreous cavity length.
  • the pharmaceutical composition, ophthalmic device, or method of treatment will treat the eye of the patient (such as mild myopia, child or adolescent myopia) Axial elongation and/or increase in vitreous cavity length controlled, slowed, alleviated, decreased, delayed and/or reversed within the following ranges relative to no treatment: between about 5-95%, between about 5-90%, about 5 -80%, about 5-70%, about 5-60%, about 5-50%, about 5-40%, about 5-30%, about 5-20 %, about 10-100%, about 20-90%, about 30-90%, about 40-90%, about 50-90%, or about 75-90% .
  • the methods control, terminate, slow, reduce, delay, and/or reduce the risk of being diagnosed with myopia or having developed myopia Myopia occurrence, progression in patients at risk, increased choroidal thickness in the patient's eye (e.g., myopia, anterior myopia, or an eye at risk of developing myopia) and/or decreased the patient's eye (e.g., myopia
  • the axial (or longitudinal) growth velocity of the eye, an anterior myopic eye, or an eye at risk of developing myopia is inhibited.
  • the method controls, slows, reduces, delays, and/or axial (or longitudinal) growth of the treated patient's eye relative to untreated or between about 5-95%, between about 5-90%, between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50% , about 5-40%, about 5-30%, about 5-20%, about 10-100%, about 20-90%, about 30-90%, about Between 40-90%, about 50-90% or about 75-90%.
  • the pharmaceutical composition, ophthalmic device or method of treatment prevents, controls, slows, reduces, alleviates, alters, delays and/or reverses The myopic diopter of the treated patient's eye.
  • the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein result in less severe adverse reactions relative to atropine monotherapy.
  • the pharmaceutical composition, ophthalmic device or method of treatment produces a smaller increase in pupil size or no effect on pupil size relative to atropine monotherapy. influences.
  • the pharmaceutical composition, ophthalmic device, or method of treatment disclosed herein inhibits the progression of the normal eye's axial or diopter towards myopia relative to atropine monotherapy Degree.
  • Embodiment 1 myopia animal model and administration experiment
  • the guinea pig myopia model induced by form deprivation and lens is a classic and recognized animal model of myopia in the field, which can be used to evaluate the efficacy and safety of drugs for the treatment of myopia, and its construction method is well known to those skilled in the art.
  • the animal modeling and drug administration methods 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 application adopts an exemplary form deprivation and lens-induced guinea pig myopia model construction method as follows:
  • the myopia model adopts monocular form deprivation (FD) and lens induction (LI) modeling methods.
  • FD monocular form deprivation
  • LI lens induction
  • the right eye of the animal is completely covered by a special eye mask with a light transmittance of 1% that does not fall off automatically, and the other eye (left eye) obtains normal vision.
  • the -4D lens was fixed on the right eye of the animal, and the left eye obtained normal vision.
  • the above animals cleaned the lens twice a day to prevent the lens from blurring.
  • Animals in the experimental group were given medicine at 9:00-9:30 every morning.
  • negative, positive control group and experimental group animals take off goggles or lens respectively under red light, and give the solvent control of 0.1mL or test drug (vinpocetine of different concentrations), Or positive control (0.1% atropine), after the injection, it is confirmed that the animal is successfully administered without trauma and the eye patch or lens is restored immediately.
  • the administration process of each animal was controlled at about 10s.
  • the drug was administered on the day of modeling, and the form deprivation group was continuously administered for 2 weeks, and the lens induction group was continuously administered for 1 week. This experiment has been approved by the Experimental Animal Ethics Committee of Wenzhou Medical University.
  • the preparation method of Vinpocetine eye drops used in the experimental group is as follows:
  • the solubility of vinpocetine (VPN) in water at room temperature is 2.4 ⁇ g/mL
  • the inventor prepared 5 ⁇ M (being 1.75 ⁇ g/mL) vinpocetine storage solution, the solvent was physiological saline, and it was stored at -80 ° C. Diluted to 1 ⁇ M, 0.1 ⁇ M, 0.01 ⁇ M with physiological saline before administration experiment.
  • vinpocetine eye drops you can choose to use conventional physical dissolution methods such as heating and stirring, or use acids to adjust the pH value to increase solubility, and finally adjust the pH value to 7.31.
  • the above-mentioned vinpocetine eye drops are transparent and stable at normal temperature.
  • the difference between the solvent control group and the experimental group is that it does not contain active ingredients.
  • the diopter and eye axis parameters were respectively measured. detection.
  • the diopter was measured using an eccentric infrared refractometer (EIR) built in our laboratory, and the average value was taken as the final result after three tests for each eye.
  • EIR eccentric infrared refractometer
  • the axial parameters of the guinea pigs were measured using the A-ultrasound probe in the Cinescan A/B ultrasonic diagnostic instrument (QuantelMedical, Aviso, France).
  • the ultrasonic frequency was 11MHz, and the ultrasonic propagation speeds of different refractive media of the eyeball were set as: anterior chamber 1557.5m /s, lens 1723.3m/s, vitreous body 1540m/s.
  • the detection contents include vitreous chamber depth (VCD) and axial length (AL). 0.5% proparacaine hydrochloride eye drops (Alcon, Belgium) was used to anesthetize the ocular surface of the guinea pig test eyes about 2 minutes before the test. Each eye was measured 6 times, and the average value was taken as the final result.
  • the choroidal blood flow parameters and choroidal thickness were detected after the 1 week of continuous administration and after the end of the experiment for 2 weeks; the animals of the LIM group were tested for 7 days after the end of the experiment.
  • the detection of choroidal blood flow parameters and thickness adopts modified commercialized OCTA (Spectralis HRA+OCT, OCTA, Heidelberg, Germany) to make it more suitable for animal eyes.
  • the guinea pigs were fully anesthetized (the mixture of ketamine hydrochloride 60 mg/kg and xylazine hydrochloride 9 mg/kg, injected intraperitoneally), and then the OCTA images of the guinea pigs were obtained, and the measurement results were quantified by a self-programmed program (MatLab R2017a, MathWorks). 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).
  • Embodiment 2 the effect experiment of applying vinpocetine locally in the eye
  • the experimental method is as in Example 1.
  • the refraction, vitreous cavity and eye axis of all animals in the FDM group were tested before administration, 1 week after administration and 2 weeks after administration; All animals tested binocular refraction, vitreous cavity and eye axis. All data were analyzed by repeated-measures analysis of variance, where P values less than 0.05 were considered significant differences, and values less than 0.01 were considered extremely significant differences.
  • the myopia induced by the saline injection group was -4.94 ⁇ 2.35D, and the myopia induced by the same group was -6.74 ⁇ 1.90D two weeks later.
  • the myopia induced by the same group was -6.74 ⁇ 1.90D two weeks later.
  • FDM+VPN (1 ⁇ M): -4.94 ⁇ 2.35vs.-2.44 ⁇ 1.88D, p ⁇ 0.01, the refractive inhibition rate was 50.5%; the depth of the vitreous cavity was also suppressed accordingly, FDM+Vehicle vs. FDM+VPN (1 ⁇ M): 0.11 ⁇ 0.04vs.0.06 ⁇ 0.05mm, p ⁇ 0.01 , the depth inhibition rate of the vitreous cavity was 45.0%, and the axial length was also inhibited, FDM+Vehicle vs. FDM+VPN (1 ⁇ M): 0.11 ⁇ 0.05vs.0.07 ⁇ 0.05mm, p 0.09, the axial length inhibition rate was 39.8 %.
  • the corresponding indicators and results of myopia treatment in the medium-concentration vinpocetine administration group also suggest that vinpocetine and its related compounds can be used for myopia treatment.
  • the inventors even found that in the low-concentration vinpocetine administration group (only 0.01 ⁇ M) at two drug efficacy detection time points, although there was no statistical difference, the process of negative refraction and the prolongation of the vitreous cavity depth showed a trend of inhibition compared with the negative control group.
  • the myopia induced by the 0.1% atropine group after 1 week of medication was -3.20 ⁇ 1.73D
  • the refractive inhibition rate was 35.2%
  • the vitreous cavity depth was 0.08 ⁇ 0.05mm
  • the vitreous cavity depth inhibition rate was 31.5%
  • the axial length was 0.08 ⁇ 0.05
  • the axial length inhibition rate was 32.1%.
  • the induced myopia in the normal saline injection group was -3.25 ⁇ 1.20D
  • the induced myopia was -3.93 ⁇ 1.26D after 7 days, and the depth of the vitreous cavity and the axial length of the eye both increased or extended accordingly.
  • the myopia of the LIM model LIM+Vehicle vs.
  • the depth of the vitreous cavity also inhibited accordingly, LIM+Vehicle vs.
  • the inhibition rate of the vitreous cavity depth was 58.8%.
  • the axial length is also inhibited accordingly, LIM+Vehicle vs.
  • the induced myopia is -2.34 ⁇ 0.73D
  • the refractive inhibition rate is 30.0%
  • the vitreous cavity depth is 0.04 ⁇ 0.03mm
  • the vitreous cavity depth inhibition rate is 47.3%
  • the axial length 0.04 ⁇ 0.02mm
  • the axial length inhibition rate was 47.4%. It can be seen that all the myopia treatment indexes of the high concentration (1 ⁇ M) vinpocetine group are better than those of atropine.
  • the high, medium and low concentrations of vinpocetine administration groups all showed the effect of treating myopia (Fig. 2A-C).
  • Vinpocetine can also effectively inhibit the myopia of the LIM model after 7 days of administration.
  • the diopter results are LIM+Vehicle vs.LIM+VPN (1 ⁇ M): -3.93 ⁇ 1.26vs.-2.61 ⁇ 1.17D, p ⁇ 0.05, the refractive inhibition rate is 36.3%, and the depth of the vitreous cavity is also inhibited accordingly.
  • vinpocetine According to the data of two recognized animal models of myopia drug efficacy evaluation, vinpocetine has shown excellent myopia treatment effects, the inhibition and slowing down of the negative process of diopter and the corresponding inhibition of eye axis extension and increase of vitreous cavity depth It is consistent with the inhibition of vinpocetine, which proves that vinpocetine treats myopia mainly by controlling the lengthening of the eye axis and the increase of the depth of the vitreous cavity.
  • the inventor unexpectedly found that using vinpocetine alone, in the treatment of myopia, especially axial myopia, the efficacy of vinpocetine is even better than that of atropine (0.1% atropine). It is worth noting that the above-mentioned therapeutic effect of vinpocetine on myopia has nothing to do with the sex, age, type of myopia, speed of progression of myopia and severity of myopia of the subject.
  • vinpocetine can be used for the prevention, treatment and control of myopia, especially for the prevention and control of myopia in children and adolescents.
  • Embodiment 3 the mechanism of vinpocetine treatment myopia
  • Vinpocetine is known to improve blood circulation.
  • the inventor adopted the method of Example 1 to detect changes in the choroidal thickness ChT and choroidal blood flow ChBP index signals of FDM (administration for 1 week and 2 weeks) and LIM (administration for 1 week) at different time points within the administration cycle .
  • choroidal blood perfusion compared with the atropine group, was similar to the trend of the negative control group.
  • the concentration (0.1 ⁇ M) of vinpocetine in the form deprivation group exhibited a myopia treatment effect similar to that of atropine in terms of axial parameters, but its effect on choroidal vasodilation was not as good as that of atropine (Fig. 1B-C and Fig. 3B).
  • the pharmacology of vinpocetine in the treatment of myopia is not through the expansion of ocular blood vessels or the mechanism of improving ocular blood circulation or increasing choroidal blood flow, but may rely more on a mechanism that has never been recognized (ocular ) function, and the biological target corresponding to this function even has a competitive binding relationship with the known vasodilator target of vinpocetine.
  • Embodiment 4 Vinpocetine controls the effect of myopia progression by systemic administration
  • the purpose of this experiment is to evaluate the control effect of vinpocetine on myopia treatment, especially on the progression of myopia through systemic administration (such as intravenous infusion or gavage), and comprehensively analyze according to indicators such as diopter, axial length, vitreous cavity depth, and body weight. Drug effectiveness and safety.
  • the oral bioavailability of vinpocetine is 52% (Vereczkey et al., 1979a), and the LD50 value of oral administration is about 500mg/kg (Cholnoky and 1976).
  • Vinpocetine dosage forms currently on sale in China include tablets and injections. According to the normal living habits of guinea pigs and the requirements of form deprivation modeling and considering the principle of drug compliance in the future clinical use of myopia treatment, the inventor believes that the method of gavage administration should be used for evaluation.
  • the efficacy of systemic administration of vinpocetine in the treatment of myopia is similar to or better than that of intravenous infusion.
  • the dosage of a single oral administration of guinea pigs is formulated with reference to the oral bioavailability of vinpocetine in similar species and the corresponding toxic dosage of rodents by oral administration.
  • the dosage should basically maintain the normal physiological state of guinea pigs and not cause It presents with severe toxicities such as ataxia or clonic convulsions.
  • Form deprivation (FD) myopia modeling was performed on the guinea pigs at 8 am on the first day of the experiment.
  • the form deprivation myopia model adopts the mask method, and the headgear is made by the inventor using a 10-inch milky white non-toxic latex balloon.
  • FD induction continued throughout the cycle of vinpocetine gavage efficacy experiments, and the headgear was only briefly removed during eye detection (such as diopter detection).
  • the drug efficacy experiment started check the position of the headgear every day at 8:00 am, 12:00 noon, 7:00 pm and before administration, and eliminate individuals whose headgear fell off more than 3 times.
  • the solvent or drug corresponding to the FDM model was given between 9 and 10 am every day.
  • the actual administration is calculated according to the average body weight of each group of animals, and the intragastric volume of the solvent group is 5mL/kg/d.
  • the diopter and eye axis parameters of the tested animals were detected at the time of 1 week and 2 weeks. .2019 Jul 1; 60(8):3074-3083; Pan Miaozhen, Proc Natl Acad Sci USA.2021 Oct 26; 118(43):e2104689118), the statistical basis is the difference between the experimental eye and the fellow eye of the same subject At the same time, the body weight of all subjects was recorded during the experimental period.
  • the preparation method of the vinpocetine intragastric solution used by the present embodiment inventor is as follows: it is reported that the solubility of vinpocetine in 0.5% methylcellulose can reach 200mg/mL (Waidyanatha S et al, Systemic exposure of vinpocetine in pregnant) Sprague Dawley rats following repeated oral exposure: An investigation of fetal transfer, Toxicol Appl Pharmacol, 338:83-92, 15 Nov 2017). Under the condition of not 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 10mg/mL respectively And 20mg/mL of vinpocetine preparation (gavage solution). At room temperature, the overall appearance of the preparation is clear, transparent, and uniform without visible suspended matter.
  • the preparation process of the preparation may use conventional physical and chemical aids such as heating, stirring, and pH adjustment as appropriate, and no compound precipitation occurs before the preparation is administered.
  • the body weight of the vinpocetine-administered group in the 50mg/kg group was significantly lower than that in the solvent group at one week of administration, FDM+Vehicle vs.
  • FDM+VPN (50mg/kg): 208.5 ⁇ 14.9 vs.188.0 ⁇ 22.9mg, p ⁇ 0.05, the mean body weight decreased by 9.9%; at 2 weeks of administration, the weight gain of the vinpocetine administration group in the 50mg/kg group was significantly inhibited, FDM+Vehicle vs.FDM+VPN (50mg /kg): 229.6 ⁇ 21.4vs.210.2 ⁇ 21.9mg, p ⁇ 0.05, and the mean body weight decreased by 8.4%. It can be seen that when the daily dosage reaches 50mg/kg, it has already produced substantial toxicity to experimental animals, and continues to increase. The dose of cetine will increase the risk of toxicity to the tested individual.
  • vinpocetine by intragastric administration has a definite dose-effect relationship for the treatment of myopia, especially for the inhibition of myopia progression: that is, as the amount of intragastric administration increases, vinpocetine can be cured by systemic administration.
  • the effect of the method on the treatment of myopia is more obvious.
  • the diopter and eye axis parameters of the three groups of animals at the end of the drug treatment are explained, among which the diopter: FDM+Vehicle vs.
  • FDM+VPN 50mg/kg vs. FDM+VPN (100mg/kg): -6.59 ⁇ 1.42vs.- 5.71 ⁇ 2.41vs.-5.223 ⁇ 2.20D; Glass cavity depth: FDM+Vehicle vs. FDM+VPN (50mg/kg) vs. FDM+VPN (100mg/kg): 0.12 ⁇ 0.05vs.0.13 ⁇ 0.07vs.0.10 ⁇ 0.06mm; axial length: FDM+Vehicle vs. FDM+VPN (50mg/kg) vs. FDM+VPN (100mg/kg): 0.14 ⁇ 0.05vs.0.13 ⁇ 0.05vs.0.11 ⁇ 0.05mm.
  • systemic administration of vinpocetine also has the potential to inhibit the progression of myopia and achieve a significant effect on the treatment of myopia, but compared with topical administration, systemic administration should require a larger dose or a longer duration. Medication time.
  • direct systemic administration such as direct intravenous infusion or oral tablet
  • side effects such as weight loss or increased risk of miscarriage
  • vinpocetine can be used for the prevention and treatment of myopia.
  • local administration of vinpocetine is a better choice for the prevention and control of myopia progression.
  • systemic administration such as the use of specific drug targeting technology to effectively reduce the drug toxicity of systemic administration, and at the same time enrich the vinpocetine drug in the eye, etc. Realize safe, efficient and convenient systemic drug delivery to treat or inhibit myopia.
  • Embodiment 5 salmeterol and tiotropium bromide treat myopia
  • guinea pig form deprivation myopia model described in the present invention Utilize the guinea pig form deprivation myopia model described in the present invention to evaluate drug efficacy, all individuals pass through diopter and ocular axis detection, after removing unqualified animals, divide into 5 groups at random: use vinpocetine treatment group alone, salmeterol+ Tiotropium bromide + vinpocetine combined treatment group, salmeterol + tiotropium bromide combined treatment group, negative control group (solvent group) and 0.1% atropine group (positive control group), wherein salmeterol (salmeterol, S ) and tiotropium bromide (tiotropium, T) were used at concentrations of 1 ⁇ 10 -5 M and 1 ⁇ 10 -6 M, respectively, and vinpocetine was used at a concentration of 1 ⁇ M whether administered alone or in combination.
  • salmeterol + tiotropium bromide + vinpocetine combined treatment group and vinpocetine alone (1 ⁇ M) have similar therapeutic effects, and the diopter, axial length and glass There was no statistical difference in the body cavity depth indicators, suggesting that neither salmeterol nor tiotropium bromide showed a synergistic or promoting effect on the treatment of myopia with vinpocetine.
  • Comprehensive analysis of salmeterol + tiotropium bromide + vinpocetine combined administration has no significant difference in effectiveness compared with vinpocetine alone in the treatment of myopia.
  • the purpose of this experiment is to evaluate the effect of vinpocetine on myopia through non-invasive administration route. All the tested drugs are made into eye drops.
  • Utilize the guinea pig form deprivation myopia model described in the present invention to evaluate drug efficacy all individuals pass through diopter and ocular axis detection, after removing unqualified animals, divide into 4 groups at random: Vinpocetine low concentration (1 ⁇ M) group, Vinpocetine low concentration (1 ⁇ M) group, Vinpocetine Tin high concentration (5 ⁇ M) group, negative control group (solvent group) and 0.1% atropine group (positive control group).
  • Vinpocetine low concentration (1 ⁇ M) group Vinpocetine low concentration (1 ⁇ M) group
  • Vinpocetine Tin high concentration 5 ⁇ M
  • negative control group solvent group
  • 0.1% atropine group positive control group
  • the actual effective therapeutic dose of the drug obtained by eye drops in each test eye is lower than the same dose.
  • the volume of the peribulbar injection of the eye is lower than the 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, regardless of the low-concentration vinpocetine eye drop group or the 0.1% atropine group in this embodiment, the drug effect (diopter index) of the eye drop directly administered into the eye is inferior to the effect of its peribulbar injection on myopia.
  • FDM+VPN 0.14 ⁇ 0.05vs.0.09 ⁇ 0.04mm (actual value 0.0869 ⁇ 0.0448mm, after rounding), p ⁇ 0.01, vitreous cavity depth suppression rate was 38.6%; axial length was also suppressed
  • FDM+Vehicle vs.FDM+ VPN 0.16 ⁇ 0.04vs.0.09 ⁇ 0.04mm (the actual value is 0.0925 ⁇ 0.0406mm, after rounding), p ⁇ 0.001, and the inhibition rate of eye axis length is 41.4%.
  • Low-concentration 1 ⁇ M vinpocetine administration group can also effectively control the progression of myopia: FDM+Vehicle vs.
  • the myopia induced by the 0.1% atropine eye drop group model after 2 weeks of medication was -3.93 ⁇ 1.75D
  • the refractive inhibition rate was 40.0%
  • the depth of the vitreous cavity was 0.11 ⁇ 0.05mm (actual value 0.1107 ⁇ 0.0502mm, rounded off)
  • the vitreous cavity depth inhibition rate was 21.8%
  • the axial length of the eye was 0.11 ⁇ 0.05mm (the actual value was 0.1093 ⁇ 0.0530mm, rounded off), and the axial length inhibition rate was 30.7%.
  • This example proves that vinpocetine eye drops can significantly inhibit myopia diopter negative, prolong the axial length of the myopic eye, and increase the depth of vitreous cavity in the same way as juxtabulbar subconjunctival injection.
  • This administration method also has a positive dose-effect relationship, that is, the higher the dosage of vinpocetine, the more obvious the effect of myopia treatment.
  • the comprehensive performance of vinpocetine in the treatment of myopia is also better than that of the positive control atropine, especially the control effect on the progression of myopia.
  • Example 7 Vinpocetine metabolite Avicaminic acid (Apovincaminic acid, AVA) can effectively prevent and control myopia
  • avicaminic acid alone group avicaminic acid alone group
  • negative control group solvent group
  • atropine group positive control group
  • the modeling method of myopia individuals was the same as that of other embodiments of the present invention. All groups were administered by juxtabulbar subconjunctival injection with an injection volume of 100 ⁇ L, administered once a day for 1 week.
  • the diopter and eye axis parameters of the animals were detected before the drug effect experiment started and at the end of the 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 fellow eye of the same individual subject. Both AVA injection and atropine injection used in this example were prepared by the inventors themselves with 0.9% normal saline, without adding other active substances or auxiliary materials.
  • the experimental results show that the changes in the diopter and axial parameters of the animals in the negative control group are in line with the expectations of the myopia model, and the positive control drug atropine has shown the expected drug effect in the experiment. effectiveness evaluation.
  • Continuous administration of 1 ⁇ M AVA for 1 week can effectively inhibit the development of myopia and the corresponding extension of the eye axis and vitreous cavity depth (see Figure 8).
  • vinpocetine can not only significantly slow down the process of negative diopter change in individuals with myopia or individuals prone to myopia, but also significantly inhibit the increase in the depth of the vitreous cavity and the elongation of the eye axis. It can significantly improve the symptoms related to myopia and achieve myopia prevention. , the effect of treating and controlling the progression of myopia, and no ocular abnormalities were observed during the administration of all test individuals, and no obvious changes were observed in the pupil size of the test eyes during the administration.
  • vinpocetine can be used in the prevention and treatment of myopia, delaying the development of myopia, controlling the progress of myopia, especially in children and adolescents with myopia or simple axial myopia or progressive myopia or primary myopia and these myopia Treatment, prevention or improvement of related symptoms.

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Abstract

本申请涉及一种采用长春西汀治疗近视的方法，不仅能够有效预防近视和/或控制近视进展，并且安全无明显副作用，具有良好的临床应用前景。

Description

一种采用长春西汀治疗近视的方法 技术领域
本申请涉及一种采用长春西汀治疗近视的方法，尤其是涉及控制近视进展的方法和用途，并提供相应的药物或制剂，属于医药领域。
背景技术
近视是一种最常见的屈光不正，是指在调节放松状态下，平行光线通过眼的屈光系统屈折后，焦点落在视网膜之前的一种屈光状态。近视导致人看远处物体时模糊不清，给生活带来许多不便。虽然可以通过框架眼镜等矫正手段提高近视患者远视力，但该类技术或方法不能改善近视率高发、近视程度不断加重的社会现象。因此，世界范围内近视人群数量逐年增加，尤其在东亚各国高度近视患者情况不容乐观。然而，近视的种类多且发病机制还不清楚，目前尚缺乏疗效显著且安全的治疗近视、尤其是控制近视进展的药物，因此，该疾病存在着未被满足的临床需求。
长春西汀(Vinpocetine)的化学式为C 22H 26N 2O 2，平均分子量350.46，为白色晶状粉末，溶于氯仿或96％乙醇，几乎不溶于水，衍生于夹竹桃科小蔓长春花中提取出的一种吲哚类生物碱，其结构如下：
Figure PCTCN2022106704-appb-000001
长春西汀在水中溶解性呈现pH酸性依赖，发现其更易溶于胃环境pH(1.2)和肠道环境pH(6.8)，且具有比长春胺更高的生物活性和更小的毒副作用。长春西汀具有高脂溶性，该化合物可以进入血脑屏障、血眼屏障、胎盘和乳汁，对心脑血管和中枢神经系统功能具有较高的药理活性。
目前，长春西汀主要用于脑血管相关疾病和认知障碍的治疗，受用人群多为老年人。据报道全身给药后长春西汀能选择性地作用于脑血管系统，抑制脑内磷酸二酯酶活性(即作为一种磷酸二酯酶抑制剂)，舒张血管平滑肌，增加脑部血液供应。该类药物存在着体内代谢迅速、消除半衰期短、口服剂型人体生物利用度低等特点。由于眼部外用长春西汀能够较容易地穿越角膜、晶状体等物理屏障，因此，长春西汀也是很多眼科用药的辅助成分，其主要用作微循环促进剂来促进眼部血液流动等。尽管促进眼部血液循环可能使眼部感觉更为舒适，从而增加屈光不正患者视力的敏锐性，但这并不能等同于治疗近视，甚至有报道表明施用长春西汀反而可能导致近视(biosintez.com/en/catalog/product/283)。
发明内容
本申请意外地发现了长春西汀的全新用途并通过反复试验证明了：长春西汀能够治疗近视和控制近视进展。即长春西汀不是作为补充或辅助成分，例如作为微循环促进剂(抑制磷酸二酯酶活性)，在近视治疗的药物中辅助、伴随或协助其他治疗近视的活性物质以增强(如使更多药物主要成分到达起效靶细胞)该活性物质治疗近视的效果；而是作为治疗近视的直接活性成分。
本申请还研究了长春西汀治疗近视的机理。在本申请前，人们使用长春西汀都是将其作为磷酸二酯酶抑制剂来增强血流，但本申请通过实验发现，长春西汀治疗近视和控制近视进展时，并不依赖于脉络膜血流的改善。也就是说，长春西汀不是通过扩张血管或促进血液循 环(即磷酸二酯酶抑制剂的已知功能)来治疗近视和抑制近视进展的，而可能更依赖于一种其固有的、但还未被人们所知的新药理作用。因此，本申请实际上是利用了长春西汀的一种不为人知的功能，而该发现也是形成本申请的关键基础。
本申请首次证明了单独的长春西汀即可对近视进展具有显著的抑制效果，并由此确信长春西汀可以有效地治疗包括单纯性近视或轴性近视(如青少年近视)、轻度或中度近视等各类近视。相比采用长春西汀治疗老年人近视、或高度近视、或老年人高度近视、或病理性近视，长春西汀用于治疗屈光度持续下降的近视(如单纯性近视、轴性近视、或轴性单纯性近视、或低度和中度近视、或儿童及青少年近视、或渐进式近视等)的效果会显著地更好一些。
长春西汀同样可以用于各类近视的预防，例如，在近视进展期利用长春西汀进行药物干预，可以预防和阻止老年人近视、高度近视、老年人高度近视和病理性近视的发生。
本申请进一步研究了长春西汀在治疗近视药物或制剂中的浓度、配比和配方，以及相关药物施用频次、联合治疗等用药方法。其中，局部(眼部)施用不仅安全性良好且治疗效果明显好于全身施用的效果。
本申请提供长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合的用途，所述用途为如下之一或同时满足两项及以上：
①预防和/或治疗近视及其相关症状，和/或近视矫正；或者
②抑制(控制)近视的进展；或者
③用于近视防控或延缓近视(眼)发生发展；或者
④抑制、减缓近视个体或有近视发生倾向个体的眼轴延长和/或眼玻璃体腔长度(深度)增加；或者
⑤预防、减缓、减弱或治疗与视觉障碍相关的眼球的异常发育；或者
⑥使个体不用佩戴眼镜(如框架眼镜或OK镜)或不依靠视力矫正手段(如屈光手术)获得比使用这些物质或手段前和/或比未经使用这些物质或手段更清晰的远视力；或者
⑦抑制、延缓或减缓近视个体或有近视发生倾向个体屈光度变负的进程或速度；或者
⑧用于制备药物、制剂、组合物或装置，所述药物、制剂、组合物或装置用于实现前述第①-⑦中的至少一项用途。
在一些实施方式中，采用全身给药(如口服、静脉滴注)、和/或局部给药(滴眼、眼部注射、眼部植入、皮肤膏/乳剂眼周涂抹或眼药膏涂抹)、和/或肠胃外给药(如通过粘膜给药、透皮给药、微针给药)、和/或无创给药(如利用眼用喷剂给药)的方式。
在一些实施方式中，药物、制剂或组合物可以为注射液、片剂、冻干粉针剂、胶囊剂、泡腾片、咀嚼片、含化片、颗粒剂、软膏剂、糖浆剂、口服液、气雾剂、滴鼻剂、外用制剂、口服制剂等；优选是眼用剂型，包括但不限于滴眼液(眼药水)、眼药膏、眼部喷剂、植入片、眼用凝胶、眼贴、眼用微球、眼用缓释制剂、眼周注射剂、眼内注射剂；还可以为自由溶液、油水混合液、混悬液(剂)、擦剂、洗剂、霜剂、滴剂、冲剂、喷剂、膏剂、贴剂、糊剂、丸剂、栓剂、乳剂，含有纤维素(如甲基纤维素)、多羟基醇、环糊精(如羟丙基-β-环糊精)、酸性助溶剂(如柠檬酸)、树枝状高分子、纳米材料、缓释材料、脂质体或其组合配制的组。
在一些实施方式中，近视个体或有近视发生倾向个体为儿童和/或青少年，优选为3至26岁人群，更优选为6至18岁人群；或为未成年人群，优选为眼部(眼球)尚处于生长、发育阶段的人群；或为学龄人群，优选为一至十二年级学生人群；或为父母是高度近视的人群；或为远视储备不足。
在一些实施方式中，近视为屈光性近视或轴性近视；先天性近视(生下来或学龄前就是近视)、早发性近视(14岁以下)、迟发性近视(16～18岁)、晚发性近视(成年以后)；低度近视(轻度近视)、中度近视、高度近视(重度近视)；假性近视、真性近视；儿童和/或青少年近视(优选人群年龄为3-26岁，更优选人群年龄为6-18岁)、未成年人近视、成 年人近视、老年人近视；单纯性近视、病理性近视；轴性单纯性近视、单纯性轴性近视；儿童和/或青少年轴性近视(优选人群年龄为3-26岁，更优选人群年龄为6-18岁)；学龄及学龄前人群轴性近视；原发性近视、继发性近视；儿童和/或青少年原发性近视(优选人群年龄为3-26岁，更优选人群年龄为6-18岁)；或儿童和/或青少年渐进式近视(优选人群年龄为3-26岁，更优选人群年龄为6-18岁)；曲率性近视、指数性近视、散光性近视、位置性近视、弯曲性近视；屈光度持续变负的轴性近视；因长时间近距离用眼导致的近视、视疲劳引发的近视及假性近视、药物不良反应造成的屈光度变负、近视眼、看书导致的近视、使用手机等电子产品导致的近视、屈光介质(成分)不匹配导致的近视、屈光近视、屈光发育异常导致的近视、眼球生长过大导致的近视、用眼不卫生导致的近视、各种原因造成的远处物体成像焦点落于视网膜前方、对阿托品治疗效果不佳或无效的近视、户外运动不足导致的近视、调节紧张性近视、儿童近视、婴幼儿近视、遗传性近视、环境因素主导的近视。
在一些实施方式中，近视相关症状包括近视引起的并发症，如高度近视的并发症，再如飞蚊症、青光眼、后巩膜葡萄肿、视网膜脱落、视网膜撕裂、弱视、黄斑出血、脉络膜新生血管、脉络膜萎缩、黄斑变性或黄斑病变、视野缺损、视力(尤其是近视力)进行性或突发性下降、眼部酸胀和/或疼痛、夜盲、散光、屈光参差、失明、玻璃体液化、玻璃体混浊、斜视、频繁眨眼、经常揉眼睛、屈光参差、看远处物体时视野模糊、需要眯眼或部分闭上眼睑才能看清楚远处物体、眼睛疲劳引起的头痛、近视导致的注意力不集中、驾车时视力困难尤其是在夜间(夜间近视眼)、视网膜萎缩变性(出血和裂孔)、视网膜下新生血管、或眼球萎缩。
在一些实施方式中，药物、制剂、组合物或装置中还包含其他的药物或眼科用制剂，所述药物或眼科用制剂包括但不限于近视治疗药物(如哌仑西平、毒蕈碱拮抗剂、氨苄胺、阴多胺、马来酸噻莫洛尔、肾上腺素、皮伦西平、吡嗪、吡苯平、哌苯平、吡恩西平、甲胺、氯松胺、乙酰胆碱酯酶抑制剂、多巴胺激动剂、γ-氨基丁酸、纳洛酮、胰高血糖素、维甲酸、红景天苷、芒柄花黄素等)、M受体阻断剂(如针对M2或M3受体的阻断剂或拮抗剂或抑制剂)、苄达酸及其各种盐形式(苄达赖氨酸)、阿托品、地巴唑、多不饱和脂肪酸(如DHA、EPA)、哌唑嗪、后马托品、山莨菪碱(消旋)、托吡卡胺、7-甲基黄嘌呤、烟酸、吡拉西坦(Piracetam)、丹参提取物、红花提取物、鱼油、熊胆提取物、维生素、三磷酸腺苷(ATP)、平滑肌舒张药物、防止血管痉挛药物、非选择性腺苷酸拮抗剂、扩血管药物、扩瞳组分、充血去除组分、眼肌(如睫状肌)调节组分、抗(消)炎剂组分、收敛剂组分、抗组胺剂组分、抗过敏剂组分、抑制胶原蛋白降解组分、护肝类(避免或减弱肝毒性)组分、增强血-视网膜屏障组分(使化合物更加难以渗透通过该生理屏障)、氨基酸、抗菌剂组分、抗氧化组分、糖类、聚合物或其衍生物、纤维素或其衍生物、局部麻醉剂组分、弱视治疗组分、青光眼治疗组分、白内障治疗组分、I型磷酸二酯酶抑制剂(特异或非特异)、miRNA及其修饰物、眼科疾病的治疗性组分、辅料等。
在一些实施方式中，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合与一种或多种近视防控药物和/或近视治疗药物被配制成或设计成连续施用形式，或者同时施用的形式，或者先后施用形式，或者交替施用的形式，或者间隔施用的形式，或者单独施用的形式。
在一些实施方式中，长春西汀相关化合物或提取物选自长春西汀代谢物(如阿朴长春胺酸apovincaminic acid，hydroxyvinpocetine,hydroxyl-apovincaminic acid和dihydroxy-vinpocetine-glycinate)、长春花生物碱(Vinca alkaloid)、阿扑长春胺(apovincamine)、长春花提取物(periwinkle)、长春蔓胺(vincamine)、非洲马铃果提取物(voacanga africana)、夹竹桃科植物提取物、长春新碱(vincristine)、它勃宁(tabersonine)、长春花碱(Vinblastine)、文多灵(Vindoline)、Apovincaminic Acid Hydrochloride、长春质碱(catharanthine)、乙基长春胺(ethyl vincaminate)、methoxyvinpocetine、dihydrovinpocetine中的一种或多种物质。
在一些实施方式中，制剂为保健品、食品、膳食补充剂、营养品、饮品等口服制品或化妆品。化妆品可以是自由溶液、油水混合液、混悬液(剂)、擦剂、洗剂、喷剂、霜剂、滴剂、冲剂、膏剂、糊剂、丸剂、栓剂、乳剂、贴剂的一种或几种的组合。
在一些实施方式中，装置为可以释放药物或具有药物递送功能或具备潜在药物递送能力的仪器、设备、耗材、系统、医疗器械、保健用品或改变眼部外观的用品，如角膜接触镜、眼镜、人工晶体、缝合线、OK镜清洁(维护)系统、眼贴、明目贴、美瞳、微针、眼部喷雾系统、眼部按摩仪、眼部熏蒸仪、眼表药物递送装置、眼内药物递送装置、眼底药物递送装置、植入泵、可穿戴设备、穴位按摩仪、眼部放松设备、近视治疗仪或用于近视防控的药械组合。
在一些实施方式中，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合，作为唯一活性成分或主要活性成分或直接活性成分；或者长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合的含量或药效占所述用途全部活性成分的1％及以下，或1％以上、10％以上、20％以上、30％以上、40％以上，或50％以上、60％以上、70％以上、80％以上、90％以上，或100％，所述百分比(％)可以为质量比或摩尔比或效价比。
在一些实施方式中，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合在所述药物、制剂、组合物或装置中的浓度为0.001μM至10mM，优选为0.01μM至1000μM，优选为0.05μM至100μM，更优选为0.1μM至25μM，更优选为0.1μM至15μM；或者所述这些物质或其组合在所述药物、制剂、组合物或装置中的浓度或占比低于25％，优选为低于5％，优选为低于1％，更优选为低于0.01％，更优选为低于0.001％，所述百分比(％)可以为质量/体积浓度(克每100毫升)或质量百分比或摩尔(数)比。
本申请提供一种眼部施用的药物、制剂、组合物或装置，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合在所述药物、制剂、组合物或装置中的浓度为0.001μM至10mM，优选为0.01μM至1000μM，优选为0.05μM至100μM，更优选为0.1μM至25μM，更优选为0.1μM至15μM；或者所述这些物质或其组合在所述药物、制剂、组合物或装置中的浓度或占比低于25％，优选为低于5％，优选为低于1％，更优选为低于0.01％，更优选为低于0.001％，所述百分比(％)可以为质量/体积浓度(克每100毫升)或质量百分比或摩尔(数)比。
本申请还提供含至少2个活性物质的药物组合物或复方制剂，包括长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合及其他治疗近视的活性物质。优选的，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合的添加量、浓度和/或药效不低于任一其他治疗近视的活性物质，所述药效针对近视治疗或控制近视进展。
本申请还提供一种药物组合物或复方制剂，包括长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合及其他治疗近视的活性物质，所述其他治疗近视的活性物质不含长效β肾上腺素受体激动剂、长效毒蕈碱拮抗剂和/或毒蕈碱拮抗剂。
本申请进一步提供一种眼部制剂或药物，所述制剂或药物中，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合作为直接的、唯一的、或主要的 活性成分。
在一些实施方式中，所述制剂或药物包括但不限于滴眼液(眼药水)、眼药膏、眼部喷剂、植入片、眼用凝胶、眼贴、眼用微球、眼用缓释制剂、眼周注射剂、或眼内注射剂。
在一些实施方式中，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合的浓度为0.001μM至10mM，优选为0.01μM至1000μM，优选为0.05μM至100μM，更优选为0.1μM至25μM，更优选为0.1μM至15μM；或者长春西汀的浓度或占比低于25％，优选为低于5％，优选为低于1％，更优选为低于0.01％，更优选为低于0.001％，所述百分比(％)可以为质量/体积浓度(克每100毫升)或质量百分比或摩尔(数)比。
在一些实施方式中，I型磷酸二酯酶抑制剂为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，Volume34,IssueS1,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,Cyclic nucleotide 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.)等。由于长春西汀属于I型磷酸二酯酶抑制剂(PDE1抑制剂)，或许其他申请日前已知的I型磷酸二酯酶抑制剂(无论是否特异)与长春西汀具有相同未知的活性或药效，如同样能够预防和/或治疗近视以及控制近视进展。
在一些实施方式中，miRNA及其修饰物为MicroRNA-328或MicroRNA-328反股組合物。
在一些实施方式中，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物中的两种或多种物质的组合被同期给药，如具体一次用药(治疗)过程同时或先后给药、同一天给药、同一周给药、同一月给药、同一年给药；或间隔交替给药，如间隔4小时交替给药、间隔12小时交替给药、隔天交替给药、隔周交替给药、隔月交替给药、隔年交替给药；或者：
长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合与一种或多种其他药物同期给药，如具体一次用药(治疗)过程同时或先后给药、同一天给药、同一周给药、同一月给药、同一年给药；或间隔交替给药，如间隔4小时交替给药、间隔12小时交替给药、隔天交替给药、隔周交替给药、隔月交替给药、隔年交替给药；或者：
长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合与装置(如角膜接触镜)和/或手术(如屈光矫正手术、近视角膜激光手术、晶状体手术)联合被采用。
在一些实施方式中，所述一种或多种其他药物是近视防控和/或近视治疗药物(如苄达赖氨酸、阿托品、地巴唑、多不饱和脂肪酸、DHA、鱼油、哌唑嗪、M受体阻断剂、烟酸、哌仑西平、毒蕈碱拮抗剂、7-甲基黄嘌呤(7MX)、皮伦西平、氨苄胺、阴多胺、马来酸噻莫洛尔、肾上腺素、吡嗪、吡苯平、哌苯平、吡恩西平、甲胺、氯松胺、乙酰胆碱酯酶抑制剂、多巴 胺激动剂、γ-氨基丁酸、纳洛酮、胰高血糖素、维甲酸、红景天苷、芒柄花黄素等)，扩血管药物，平滑肌舒张药物，防止血管痉挛药物，调控胶原蛋白代谢药物，吡拉西坦(Piracetam)，抗过敏药物，护肝类药物，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或其组合等。
在一些实施方式中，装置为各种延缓近视进展的眼镜、OK镜、框架眼镜、眼贴、(近视)穴位按摩仪、眼部放松设备、近视治疗仪等具有保护视力功能或治疗(矫正)近视作用的仪器、设备、耗材、医疗器械或保健用品。
在一些实施方式中，药物、一种或多种其他药物、近视防控药物、近视治疗药物、或眼科用制剂可以不是长效β肾上腺素受体激动剂(long-acting β-adrenoceptor agonist，LABA)、长效毒蕈碱拮抗剂(long-acting muscarinic antagonists，LAMA)和/或毒蕈碱拮抗剂(muscarinic antagonists)，例如不是沙美特罗和/或噻托溴铵。
在一些实施方式中，在实现所述用途的过程中，将全身给药剂型(如口服片剂)和局部给药剂型(如滴眼液)同时使用、或联合使用、或交替使用、或间隔使用、或单独使用。
在一些实施方式中，眼球的异常发育为主要由环境因素诱发的、或者主要是人为因素导致的屈光发育异常(如长时间近距离阅读、频繁使用电子屏幕、持续视近缺乏远视机会、屈光矫正眼镜使用不当、药物副作用、肥胖、外伤、学习环境光线不佳、缺少户外运动)，而与遗传因素无关，或者遗传因素在其中是次要因素、伴随因素、或协同因素，所述异常发育例如儿童及青少年阶段(如3-26岁)眼球的大小发育异常。
在一些实施方式中，异常发育或发育异常包括眼轴长度过长或眼轴延长速度与屈光系统不匹配，导致平行光线通过眼部正常或异常屈光系统后成像焦点位于视网膜前方。
附图说明
图1：在FDM组施用高、中、低3个浓度的长春西汀对屈光(度)、玻璃体腔深度和眼轴长度的影响。其中，A为实验眼和对侧眼屈光度差值图；B为实验眼和对侧眼的玻璃体腔深度差值图；C为实验眼和对侧眼的眼轴长度差值图。
图2：在LIM组施用高、中、低3个浓度的长春西汀对屈光(度)、玻璃体腔深度和眼轴长度的影响。其中，A为实验眼和对侧眼屈光度差值图；B为实验眼和对侧眼的玻璃体腔深度差值图；C为实验眼和对侧眼的眼轴长度差值图。
图3：在FDM组施用高、中、低3个浓度的长春西汀对脉络膜厚度和血流的影响。其中，A为长春西汀对眼脉络膜厚度ChT的影响；B为长春西汀对脉络膜血流ChBP的影响。
图4：在LIM组施用高、中、低3个浓度的长春西汀对脉络膜厚度和血流的影响。其中，A为长春西汀对眼脉络膜厚度ChT的影响；B为长春西汀对脉络膜血流ChBP的影响。
注：*代表p<0.05,**代表p<0.01,***代表p<0.001。
在每个不同时间段(LIM组：给药前、给药3天和给药7天或FDM组：给药前、给药1周和给药2周)，用5个柱状图例显示测定的结果。在图1、图3中，每连续5个柱状图从左到右依次为FDM+Vehicle、FDM+Atropine(0.1％)、FDM+VPN(0.01μM)、FDM+VPN(0.1μM)、FDM+VPN(1μM)。在图2、图4中，每连续5个柱状图从左到右依次为LIM+Vehicle、LIM+Atropine(0.1％)、LIM+VPN(0.01μM)、LIM+VPN(0.1μM)、LIM+VPN(1μM)。VPN＝vinpocetine。
图5：近视个体不同剂量长春西汀全身给药方式下的屈光度和眼轴参数变化。比较实验前、实验1周和实验2周时受试个体双眼之间屈光度(A)、玻腔深度(B)和眼轴长度(C)的差值。VPN：长春西汀；Vehicle：溶剂；Week：周；Refraction：屈光度；VCD：玻腔深度；AL：眼轴长度；N：样本量。重复测量方差分析(A-C)。
图6：沙美特罗及噻托溴铵治疗近视。比较实验前和实验结束后不同药物组就近视个体双眼之间屈光度(A)、玻腔深度(B)、眼轴长度(C)、前房深度(D)、晶体厚度(E)和角膜曲率(F)的差值改变影响。VPN＝V：长春西汀；T：噻托溴铵；S：沙美特罗；Vehicle： 溶剂；Week：周；Refraction：屈光度；VCD：玻腔深度；AL：眼轴长度；ACD：前房深度；LT：晶体厚度；RCC：角膜曲率；N：样本量。*P<0.05，**P<0.01,***P<0.001。重复测量方差分析(A-F)。
图7：长春西汀滴眼液对近视个体的屈光度、玻腔深度和眼轴长度的干预效果。比较不同给药组实验前和给药2周后同一受试个体双眼之间屈光度(A)、玻腔深度(B)、眼轴长度(C)、前房深度(D)、晶体厚度(E)和角膜曲率(F)的差值改变。VPN：长春西汀；Vehicle：溶剂；Refraction：屈光度；VCD：玻腔深度；AL：眼轴长度；ACD：前房深度；LT：晶体厚度；RCC：角膜曲率；N：样本量。*P<0.05，**P<0.01,***P<0.001。重复测量方差分析(A-F)。
图8：长春西汀代谢产物AVA对近视个体的屈光度、玻腔深度和眼轴长度的干预效果。比较实验前和实验给药1周时受试个体双眼之间屈光度(A)、玻腔深度(B)和眼轴长度(C)的差值。AVA：长春西汀代谢产物阿维卡明酸(Apovincaminic acid)；Vehicle：溶剂；Week：周；Refraction：屈光度；VCD：玻腔深度；AL：眼轴长度；N：样本量。*P<0.05，**P<0.01,***P<0.001。重复测量方差分析(A-C)。
具体实施方式
下文将示例性地展示本申请的实施例。尽管已结合这些特定实施方案对本申请进行了描述，但应当理解并非意在将本申请限定为此类特定实施方案。相反，本申请意在覆盖如可包括在由随附权利要求所限定的本申请的精神和范围内的替换物、修改、取代、变型和等效物。
本申请提供一种预防、治疗近视的方法，涉及在眼部局部施用长春西汀或其相关化合物。
本申请进一步提供在眼部局部施用的、以长春西汀作为唯一的、或主要的活性成分的近视治疗和控制近视进展药物。现有技术中，长春西汀主要是片剂和注射剂，并全身施用。而长春西汀用于治疗近视时，如果进行全身给药，必将受到药物首过效应、血-视网膜屏障(blood-retinal barrier，BRB)等影响，需要给予大剂量的药物才能保证进入眼部的长春西汀或其代谢产物达到治疗浓度阈值，这样的治疗策略存在发生全身不良反应的潜在风险，尤其对象是低年龄人群且需要长时间连续给药。同时，全身给药受更多个体差异影响，增加了长春西汀防控近视疗效的不确定性。因此，本申请开发了有效性和安全性更好的、在眼部局部施用的长春西汀药物。这种药物开发策略针对长春西汀及其相关化合物(如氟代物)在儿童、青少年近视防控的用途，优势是患者用药方便、依从度高，可以长期给药(如一个月、半年、一年、三年、五年、十年)，幼龄个体生长和发育受影响小，眼用剂型安全、可靠。
本申请还提供了一种方法，所述方法为给合适的对象施用有效剂量的长春西汀或其相关化合物，用于治疗近视和/或抑制其眼轴延长。
本申请的方法或药物组合物能够显著地抑制近视，尤其是抑制儿童和/或青少年近视(优选人群年龄为3-26岁，更优选人群年龄为6-18岁)、或者早期、中期的近视、或者是轻度或中度近视、或者非病理性近视、或者轴性单纯性近视、或者儿童和/或青少年轴性近视(优选人群年龄为3-26岁，更优选人群年龄为6-18岁)、或者儿童和/或青少年渐进式近视(优选人群年龄为3-26岁，更优选人群年龄为6-18岁)、或者原发性近视、或者非老年性近视、或者未成年人近视、或者渐进性近视、或者非屈光性近视。
本申请的方法或药物组合物能够显著地抑制、减缓近视个体(包括还未近视但将要发展为近视的个体)眼轴延长和/或玻璃腔长度增加。优选的，本申请的方法或药物组合物适用的人群包括患有儿童和/或青少年近视(优选人群年龄为3-26岁，更优选人群年龄为6-18岁)、或者早期、中期的近视、或者是轻度或中度近视、或者非病理性近视、或者轴性单纯性近视、或者儿童和/或青少年轴性近视(优选人群年龄为3-26岁，更优选人群年龄为6-18岁)、或者儿童和/或青少年渐进式近视(优选人群年龄为3-26岁，更优选人群年龄为6-18岁)、或者原发性近视、或者非老年性近视、或者未成年人近视、或者渐进性近视、或者非屈光性近视，这些近视个体(包括还未近视但将要发展为近视的个体)的眼轴延长和/或玻璃腔长度增加被本申请的方法或药物组合物抑制甚至终止。
本申请提供了一种治疗、预防或减缓受试者近视及其相关症状的方法，包括向受试者施用治疗有效量的长春西汀或其治疗上可接受的盐或其相关化合物。优选地，所述长春西汀单独施用，优选地，所述长春西汀与其他药物同时、顺序或间隔、交替施用，优选地，所述长春西汀以药物组合物形式施用，优选地，所述药物组合物被制备成眼用制剂，优选地，所述眼用制剂还包含药学上可接受的载体，优选地，所述载体是眼科上可接受的载体。
本申请还提供了一种用于治疗、预防或减缓近视及其相关症状的药物组合物，所述药物组合物包含长春西汀或其治疗上可接受的盐或其相关化合物。优选地，所述药物组合物被制备成眼用制剂，优选地，所述眼用制剂还包含药学上可接受的载体，优选地，所述载体是眼科上可接受的载体。
本申请还提供了化合物或其治疗上可接受的盐及其衍生物在制备用于治疗、预防或减缓近视及其相关症状的药物组合物中的用途，所述化合物可以为长春西汀代谢物(如阿朴长春胺酸，apovincaminic acid)、长春花生物碱(Vinca alkaloid)、阿扑长春胺(apovincamine)、长春花提取物(periwinkle)、长春蔓胺(vincamine)、非洲马铃果提取物(voacanga africana)、夹竹桃科植物提取物、长春新碱(vincristine)、它勃宁(tabersonine)、长春花碱(Vinblastine)、文多灵(Vindoline)、Apovincaminic Acid Hydrochloride、长春质碱(catharanthine)、乙基长春胺(ethylvincaminate)等；优选的，所述化合物为长春西汀或其治疗上可接受的盐及其衍生物。优选地，所述药物组合物被制备成眼用制剂，优选地，所述眼用制剂还包含药学上可接受的载体，优选地，所述载体是眼科上可接受的载体。
所述近视相关症状包括但不限于：飞蚊症、青光眼、后巩膜葡萄肿、视网膜脱落、弱视、黄斑出血、视野缺损、视力(尤其是近视力)进行性或突发性下降、眼部酸胀和/或疼痛、夜盲。
根据本申请的一个方面，所述近视为屈光性近视。根据本申请的另一个方面，所述近视为轴性近视。
本申请还提供了长春西汀或其盐形式，在预防、减缓和治疗近视过程中，和其他近视防控药物(如阿托品)或光学防控手段(如ok镜)联合使用或间隔使用或交替使用的近视治疗(抑制近视进展)方案。
本申请还提供了长春西汀或其盐形式，在预防、减缓和治疗近视过程中，全身给药剂型(如口服片剂)和局部给药剂型(如滴眼液)联合使用或交替使用的近视治疗(抑制近视进展和/或眼轴延长)方案。
术语和定义
“近视”是指在调节放松状态下，平行光线经眼球屈光系统后聚集在视网膜之前。近视通常的表现是远视力低于正常水平而近视力正常。近视个体的临床概念是：静态屈光呈现≥-0.25D者。临床表现为远距离视物模糊，近距离视力好，近视初期常有远距离视力波动，由于看近时不用或少用调节，所以集合功能相应减弱，易引起外隐斜或外斜视。在本文的某些段落中，词语“近视”和词语“近视眼”所代表的概念无区别，二者可以相互替换。本领域研究者应该通过其所在上下文正确理解本专利中“近视”或“近视眼”所表达的含义。
常见的近视分类有四种：(1)根据屈光度大小，可分为轻度(300度及以下)、中度(300度-600度)及高度(600度或-6D以上)；(2)根据屈光成分是否异常，可分为屈光性近视和轴性近视；(3)根据是否发生病理学改变，可分为病理性近视和单纯性近视；(4)根据原因分类，可分为原发性近视和并发性/继发性近视。
对于“轻度或中度近视”而言，患者除视远物模糊外，并无其它症状，即主要是远视力逐渐下降，视远物模糊不清，近视力正常，通常眼部除眼轴长度外无特殊改变。
对于“高度近视”(如-6D)而言，患者眼的前房较深，瞳孔较大，眼球因前后轴过长而显得稍有突出。在视盘颞侧可见白色或灰白色新月形斑，称为近视半月斑，这是由于巩膜向后伸长，视网膜色素上皮及脉络膜与视盘颞侧边缘脱开，露出巩膜或部分脉络膜与巩膜之故。后极部巩膜不断向后扩张在黄斑部可出现膝裂样条纹和视网膜下新生血管，附近视网膜、脉 络膜出现斑块状萎缩变性，导致后巩膜葡萄肿。黄斑部常有色素增生，甚至出血，形成萎缩斑(Forster-Fuchs spot)。此种患者常伴有玻璃体液化、混浊，少数还可发生视网膜脱离及并发性白内障。此外，高度近视常因屈光间质混浊及视网膜、脉络膜变性，其远、近视力都不好，有时还伴有眼前黑影浮动。如果有这样的病变出现，这类近视就不再是单纯的近视。
“屈光性近视”主要由于角膜或晶状体曲率过大，屈光力超出正常范围，而眼轴长度在正常范围。
“轴性近视”是眼轴长度超出正常范围，而角膜和晶状体曲率基本在正常范围。轴性近视是儿童及青少年近视的主要类型。
“病理性近视”又称变性近视，是一种眼底的退行性病变。患者近视屈光度数通常较高(如大于600度)，视功能明显受损，远视力更差，此外视野、光觉、对比度感觉等也多见异常，常伴有夜间视力差(夜盲)、飞蚊症、漂浮物、闪光感等。患者眼底可见视网膜色素上皮和脉络膜变薄，常伴有视网膜色素上皮萎缩、脉络膜新生血管和视网膜脱离、黄斑变性等症状，并且发育停止后眼底病理性变化仍在发展，这种近视类型严重可致盲。
“单纯性近视”是指眼球在发育期发展的近视，发育停止，近视也趋于稳定，如多在学龄期发病，近视度数在600度以下，眼底一般无明显病理变化的近视，也称获得性近视(眼)。这类近视进行性发展，眼轴长度也渐进性增加，可用适当的镜片将视力矫正至正常，其他视功能指标多属正常。相反的，即为非单纯性近视，非单纯性近视的例子有病理性近视、高度近视、老年人近视等。
“原发性近视”为近视的主要类型。“原发性”系指运用现有诊断技术尚不能确定病因及发生机制等一类原因不明的近视。在其发生发展过程中，表现有近视特异性的病理性或生理性功能-结构改变，包括先天性近视及后天单纯性近视。
“并发性/继发性近视”是指由于内外因素作用下引起的眼调节功能障碍，或屈光指数异常而出现的一时性近视(如中毒性近视、药物性近视、外伤性近视、糖尿病性近视及初发期白内障性近视)等，这类近视的特点是多有明确的诱发因素，视力波动反复。这类近视常在老年人群中高发。
“轴性单纯性近视”有时也称为单纯性轴性近视，属于单纯性近视，其特征为由于眼轴延长和/或玻璃体腔深度增加造成成像焦点位于视网膜前方的单纯性近视。这种近视眼部屈光组织(如晶状体)基本正常，是儿童及青少年最常见的近视类型，多发于3至26岁，尤其是6-18岁的人群(Paul N Baird，Nat Rev Dis Primers.2020 Dec 17；6(1):99.和A J Adams，Am J Optom Physiol Opt.1987 Feb；64(2):150-2和Seang-Mei Saw，Ophthalmic Physiol Opt.2005 Sep；25(5):381-91.)。
“曲率性近视”是单纯由于角膜或晶状体曲率增大造成的近视。
“指数性近视”，主要是由房水、晶状体屈光指数的增高而导致的屈光力增加形成的近视，其属于屈光性近视。
“渐进式近视”指屈光度随时间或个体年龄增长而持续下降的一种近视，这种近视如果不加以干预，一般最终将发展成为高度近视。
“儿童和青少年近视”是由于长时间近距离用眼而引起的一种单纯性近视，这类近视患者绝大多数未发展为病理性近视。儿童或青少年的眼球正处在生长发育阶段，调节能力很强，巩膜的伸展性也比较大。当阅读、书写等近距离工作时，眼球处于离焦状态，久而久之，眼球的前后轴就会变长，容易形成儿童和青少年轴性近视。如果用眼习惯不改变或者对近视眼不采取医学干预，儿童及青少年的近视程度会逐渐加重，相应的眼轴长度也会进一步增加。因此，这类近视随着儿童或青少年生长发育和学习节奏，眼轴长度一直处于动态中，屈光度也持续变负，即属于渐进式近视，而非像成年人或老年人近视那样大多处于静止状态。因此，临床上对这类近视治疗药物的药效评价以控制近视进展和抑制眼轴延长为主要指标。
“老年人近视”通常比较复杂，容易受身体器官老化及基础疾病的影响，时常伴有血糖改变、血管硬化、供血不足、眼部微循环失调等症状，且大多是高度近视。成年人或老年人近 视患者的一个显著特征是近视程度一般不会随年龄加重，其中的主要原因是这类个体的眼部生长发育基本停止，眼轴长度不再因长时间近距离视物而发生变化。因此，老年人(包括成年人)近视和儿童及青少年(未成年人)近视是截然不同的两类疾病，在近视治疗方法上需要明确区分这两种适应症。尽管本申请的药物或方法适于治疗各种近视类型，但优选单纯性近视而排除老年人近视、高度近视、病理性近视等非单纯性近视，因为这些近视患者临床干预策略不再是抑制眼轴延长，更多是阻止眼部严重病变造成的失明，如视网膜脱落引起的失明。
“近视相关症状”包括近视引起的并发症，如高度近视的并发症、飞蚊症、青光眼、后巩膜葡萄肿、视网膜脱落、视网膜撕裂、弱视、黄斑出血、脉络膜新生血管、脉络膜萎缩、黄斑变性或黄斑病变、视野缺损、视力(尤其是近视力)进行性或突发性下降、眼部酸胀和/或疼痛、夜间视力差(如夜盲)、散光、屈光参差、失明、玻璃体液化、玻璃体混浊、斜视、频繁眨眼、闪光感、经常揉眼睛、屈光参差、看远处物体时视野模糊、需要眯眼或部分闭上眼睑才能看清楚远处物体、眼睛疲劳引起的头痛、驾车时视力困难尤其是在夜间(夜间近视眼)、视网膜萎缩变性(出血和裂孔)、视网膜下新生血管、及眼球萎缩；还可发生程度不等的眼底改变，近视弧形板、黄斑部出血或形成视网膜下新生血管瘤，可发生形状不规则的白色萎缩斑，或有色素沉着呈圆形黑色斑(Fuchs斑)，视网膜周边格子状变性、囊样变性，在年龄较轻时即出现玻璃体液化、浑浊和玻璃体后脱离等，发生视网膜裂孔和脱离的风险高于正常人，常由于眼球前后径边长，眼球较突出，眼球后部极扩张，形成巩膜葡萄肿。
“调节紧张性近视”，由于眼球的视近负荷过重，睫状肌等调节过度，出现了调节紧张或调节痉挛所造成的近视。
“散光性近视”，是因角膜受损或有不同程度的弯曲度，外来的光线弥散四方，不能在视网膜上结成焦点的一类近视。
在一些实施方式中，本发明的近视可以包括或不包括病理性近视、高度近视、老年人近视、散光性近视，这些近视能够通过长春西汀改善血流的功能得以矫正，也可以通过长春西汀未知的机制得以预防、治疗或减缓(控制)其近视的进展。
近视的干预手段可分为近视矫正和近视治疗，其中近视治疗以抑制(控制)近视进展为主要特征和目的。
“近视矫正”是通过光学的方法矫正或减少近视度数。常用的矫正手段包括佩戴框架眼镜、透明晶状体超声乳化术、人工晶体植入、角膜激光手术等。但是，这种手段只是矫正了个体的屈光度，并不能延缓近视进展或逆转过长的眼轴。也就是说，这类近视干预方法不会起到终止或减缓屈光度持续变负进程的作用，不能抑制近视进展。因此，如角膜激光手术等近视矫正方法会使患者的屈光不正发生补偿，恢复其远视力，适用于病理性近视、高度近视或老年人近视人群提高视力，但并不适用于治疗轴性近视或单纯性近视，如儿童或青少年近视，原发性近视，或轻度、中度近视等。事实上，轴性近视个体在佩戴框架眼镜后虽然远视力暂时恢复，但该矫正方式不会抑制其眼轴进一步延长或控制其近视发展速度，在未有其它药物治疗的情况下，其结果是近视度数会进一步增加，患者每隔一段时间就需要更换度数更大的框架眼镜来继续对其视力进行矫正。
“抑制(控制)近视进展”是指通过各种方法或药物来延缓(减缓)近视度数的不断加深、减慢屈光度变负速度、控制近视的发展和抑制(控制)眼轴的不断延长，属于病因学上的治疗，针对的患者也大都为尚处于眼部发育阶段的未成年人群。对于儿童或青少年近视的治疗，减缓、控制甚至终止其屈光度持续变负及抑制相应的眼轴长度增加，是近视治疗药物开发要达到的首要目的。即治疗近视对于儿童或青少年近视、轴性近视、单纯性近视等近视类型，应达到控制或抑制近视发展的效果，而不是简单的逆转或矫正这种屈光不正状态。
除非特别说明，本申请的“治疗(近视)”指抑制(控制)近视进展，而不是矫正近视。本文中使用的术语“治疗”、“减缓”、“延缓”、“抑制”、“控制”、或“防控”指的是治疗处理措施和预防或防止措施，目的是防止或减缓(减轻)或终止目标病症或失调。例如在接受了根据本 文所述的方法的治疗量的长春西汀化合物或含有其的药物组合物后，对象显示出眼科病症的一种或多种症状和症候的可以观察到的和/或测定到的被抑制、延缓、减少和消失，或者是病情进展的减缓和延缓，则对象的眼科病症得到成功地治疗。还应当理解，本文描述的治疗或预防医学病症的各种模式意在表示“显著”，其包括完全治疗或者预防以及小于完全治疗或者预防，其中达到了某种生物学相关或医学相关的结果。在一些实施方式中“治疗”并不需要100％消除近视或近视症状。在一些实施方案中，与不存在本申请组合物或方法时(例如，在未暴露于本申请组合物或本申请方法的化合物的生物学匹配的对照受试者或标本中)观察到的水平相比，根据本申请方法“治疗”近视或近视相关症状获得了预防、减轻、抑制、阻止例如至少约5％、至少约10％或至少约20％的近视进展。在一些实施方案中，与不存在本申请方法的化合物时的近视或近视相关症状相比，近视或近视相关症状被治疗了至少约30％、至少约40％、至少约50％或至少约60％、至少约70％、至少约80％、至少约90％或更多(约100％)。因此，本领域技术人员可以理解，“治疗”、“减缓”、“延缓”、“抑制”、“控制”或“防控”并不是指眼部保健作用或辅助治疗作用等通过间接方式有益于近视治疗的手段，如增强眼部血液循环、提高眼部施用时的舒适度等。
近视治疗效果的评估涉及多种因素，比如样本群体的选择是否科学，是否设置了客观的对照，是否施用了有效的剂量等。具体而言，如果样本群体大都为老年人(眼部发育停止且可能存在基础疾病如动脉硬化等)，很难证明长春西汀对近视具有治疗作用；如果仅通过视力测试评价药效而没有设计任何平行对照(如安慰剂组)，也无法证明长春西汀对近视具有治疗作用。本申请使用了在实际近视药物临床前开发阶段通常使用的眼部尚在生长发育阶段的豚鼠形觉剥夺和负镜诱导两种经典近视疾病模型、以及本领域的科学试验标准来评估化合物防控近视、尤其是防控儿童和青少年近视和/或单纯性近视的药效(D A Goss，Am J Optom Physiol Opt.1981 Oct；58(10):859-69.和Hao Wu，Proc Natl Acad Sci U S A.2018 Jul 24；115(30):E7091-E7100.和Sen Zhang，Invest Ophthalmol Vis Sci.2019 Jul 1；60(8):3074-3083.)。
“远视力”又称裸眼远视力，医学上指正对视力表水平距离5米处，正常睁眼向正前方注视，不戴眼镜及任何有增加视力作用的辅助设备(如框架眼镜，隐形眼镜，美瞳镜，小孔镜等)时测得的视力。
“局部给药”指直接用药于要影响的身体部位或可以满足局部起效的给药方式，包括但不限于：表皮给药、吸入给药、灌肠给药、眼部给药、鼻腔给药。
“全身给药”又称系统给药，包括静脉给药、口服、肌内注射、皮下注射等给药方式，药物可在体内经过血液运输分布于全身。
“改良的全身给药”指可以利用特定的药物靶向技术等在有效降低全身给药的药物毒性的同时又可以在眼部使长春西汀药物富集等安全、高效、方便的全身给药方式。
“直接活性成分”也称“(药物)活性成分(Active pharmaceutical ingredient)”，指对疾病(如近视)具有直接的治疗作用的物质，其是治疗疾病的充分条件或其给药剂量、给药方式等参数直接影响疾病治疗效果，施用该成分与获得治疗疾病的效果之间存在因果关系。
“唯一活性成分”指最终产品(如药物)中有且仅有一种成分发挥药效，如直接对近视起抑制、预防和/或治疗作用。
“主要活性成分”指与最终产品(如药物)中的其他活性成分(如近视治疗作用)相比，其添加量、占比、浓度或所发挥的药效不低于其他活性成分的活性成分。
“这些物质”指长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物。
在本说明书和随附权利要求书中，除非上下文中另外明确指定，否则单数形式，包括单数形式“一种(a)”、“一个(an)”和“该/所述(the)”还特别涵盖它们所指代的术语的复数个指示物。另外，如本文所用，除非另外特别指出，否则词“或”以其“和/或”的“包括性”涵义使用而不是“或者/或”的“排他性”涵义。
如本文所用，对变量数值范围的引用旨在传达本申请可以用等于该范围内任意值的变量 实施。因此，对于内在不连续的变量，所述变量可等于所述数值范围内的任何整数值，包括所述范围的端点。类似地，对于内在连续的变量，所述变量可等于所述数值范围内的任何实值，包括所述范围的端点。举例而言，被描述为具有0至2之间数值的变量对于内在不连续的变量可为0、1或2，并且对于内在连续的变量可为0.0、0.1、0.01、0.001或任何其它实值。
本文中使用的“约”将被本领域的普通技术人员所理解，且将根据其被使用的上下文而在一定程度上变化。如果该术语的使用对本领域的一般技术人员而言不清楚，则在使用该术语的上下文中，“约”将表示所列举的值加上10％或减去10％范围内的数值。
本文中使用的将化合物、制剂或药物“给药”至对象包括将化合物引入到或给送至对象以执行其预期功能的任何途径。可以通过任何合适的途径来执行“给药”，包括口服、眼内、眼表、鼻内、肠胃外(通过静脉内、肌内、腹腔内或皮下)或者局部给药(如眼周等部位皮肤的局部施药)。“给药”包括自己给药和由其他人给药。眼部给药或眼周给药时可施用于受试者的患眼，未患眼或两者。
本文中使用的术语“有效量”指的是足以获得所需的治疗和/或预防效果，例如引起预防或减轻与眼科病症关联的病症的量。给药至对象的组合物的量将取决于疾病的类型和严重性以及个体的性质，比如平常健康情况、年龄、性别、体重和对药物的耐受力。所述量还取决于疾病的程度、严重性和类型。专业的技术人员将能够根据这些因素和其他因素来确定合适的剂量。所述组合物还可结合一种或多种其他的治疗化合物来给药。在本文描述的方法中，长春西汀化合物或含有其的药物组合物可以给药至具有眼科病症的一种或多种症状或症候的对象。例如，长春西汀的“治疗有效量”是指最小程度地减轻眼科病症的药理作用的平均水平。
本文中使用的术语“制剂”和“组合物”可互换使用并指两种或更多种化合物、元素或分子的混合物。在一些方面，术语“制剂”和“组合物”可用于指一种或多种活性剂与载体或其他赋形剂的混合物。组合物几乎可以采取任何物理形态，包括固体、液体(例如溶液)或气体。
此外，术语“剂型”可以包括以用于施用于受试者的形式提供的一种或多种制剂或组合物。例如，注射剂型可以是以适合通过注射来施用的方式制备的制剂或组合物。
本文中使用的术语“药学上可接受的”意指被管理部门例如CFDA(中国)、EMEA(欧洲)和/或FDA(US)和/或任意其它国家管理部门批准用于动物的、优选用于人的例如药物的载体、药物的浓度、或药物的存在形式等。
本文中使用的术语“同时”治疗应用指的是通过相同的途径且在同一时间或基本上在同一时间将至少两种活性成分(化合物)给药。
本文中使用的术语“单独”治疗应用指的是在同一时间或者基本上相同的时间通过不同的途径将至少两种有效成分(化合物)给药。
本文中使用的术语“顺序”治疗应用指的是在不同的时间将至少两种活性成分给药，给药途径相同或不同。更具体地，顺序应用指的是在其它活性成分给药开始之前，将所述活性成分中的一种活性成分完全给药。因此，可能在将其它的活性成分给药之前的若干分钟、若干小时或若干天之前，将一种活性成分给药。在这种情况下没有进行同时治疗。
本文中使用的术语“预防”失调或病症指的是化合物在统计样本中，相对于未治疗的对照样本降低治疗的样本的失调或病症的发生，或者相对于未治疗的对照样本延迟失调或病症的一种或多种症候的发生或者减轻失调或病症的一种或多种症候的严重程度。
本文中使用的术语“相关化合物”包括但不限于长春西汀的衍生物或结构类似物。
本文中使用的术语化合物的“衍生物”或“类似物”包括与所述化合物功能和/或结构相关的任何分子，如该化合物的酸、酰胺、酯、醚、乙酰化变体、羟基化变体或烷基化变体。术语衍生物还包括失去了如上列出的一个或多个取代基的结构相关的化合物。化合物的优选衍生物是与所述化合物具有显著相似性程度的分子，如通过已知的方法确定的。类似化合物连同它们与母体分子的相似性指数可以在大量的数据库中找到，如PubChem(http://pubchem.ncbi.nlm.nih.gov/search/)或DrugBank(http://www.drugbank.ca/)。在更优选的实施方案中，衍生物应具有与母体药物的大于0.4、优选大于0.5、更优选大于0.6、甚 至更优选大于0.7的Tanimoto相似性指数。Tanimoto相似性指数广泛用来测量两种分子之间的结构相似性程度。Tanimoto相似性指数可以通过可在线获得的软件如Small Molecule Subgraph Detector(http://www.ebi.ac.uk/thornton-srv/software/SMSD/)计算。优选的衍生物应在结构和功能上均与母体化合物相关，即它们还应保留母体药物的至少部分活性。而且，术语“衍生物”还包括药物的代谢物，例如，该分子在施用至有机体后，通常通过专门的催化系统由所述药物的(生化)改性或加工而产生，并且其显示或保留药物的生物学活性。而且，术语“衍生物”还包括长春西汀或其盐形式的卤代(如氟代)、氕代、氘代、氚代化合物或其组合物。
在具体实施方案中，如本文所用的“代谢物”是指保留母体药物的至少部分活性、优选针对磷酸二酯酶活性具有抑制作用或对于近视及相关症状具有治疗、预防或减缓作用的改性或加工的药物。
“提取物”或“植物提取物”(Plant Extracts)是指采用适当的化学或物理方法，如溶剂萃取或压榨，以植物(植物全部或者某一部分)为原料提取或加工而成的物质，该物质可以是纯品，也可以含有少量杂质，也可以是混合物。
“眼科组合物”或“眼用制剂”或“眼科用制剂”是指眼科用组合物、或眼科用药物组合物、或眼科药物产品；或用于眼部疾病预防和/或治疗，视力保护、维持、提高，避免、减缓或逆转视力损伤的药物、制剂、化妆品、保健品、药械组合或装置；或可以是滴眼液(眼药水)、眼药膏、眼部喷剂、植入片、眼用凝胶、眼贴、眼用微球、眼用缓释制剂、眼周注射剂、眼内注射剂等。
“鱼油”是指来源于高等动物，尤其是鱼类(如鳕鱼、鲑鱼)、鱿鱼、海豹的脂类物质，特别指其中的多不饱和脂肪酸，包括但不限于Omega-3不饱和脂肪酸、DHA、EPA、DPA、ALA、nisinic acid、stearidonic acid、eicosatetraenoic acid或其组合。
本申请公开鉴别了用于近视及其相关症状的治疗、预防或减缓的化合物，即长春西汀，以提高近视减低或近视减缓效果，同时避免或最大程度减小不良副作用，如通过阿托品疗法所观察到的那些不良副作用。
本申请涉及在个体例如幼儿、学龄儿童、青少年或年龄较小的成年人中治疗、预防或减缓近视及其相关症状的药物组合物或方法。在一些实例中，治疗、预防或减缓近视及其相关症状可包括对有需要的受试者使用治疗有效量的药物组合物或剂型。
所述药物组合物包含治疗有效量的长春西汀化合物或其盐或其相关化合物。
在另一个方面，本申请提供了含有药物组合物的眼科装置，所述药物组合物包含长春西汀或其治疗上可接受的盐或其衍生物，优选地，其中所述眼科装置以缓释方式递送所述药物组合物；优选地，其中所述眼科装置以脉冲方式递送所述药物组合物。
我们经过实验出人意料地发现，单独使用长春西汀可显著减缓形觉剥夺或镜片诱导的豚鼠近视模型的屈光度变负进程，甚至在一些个体上屈光度变负进程被完全抑制(终止)，并且可以显著抑制眼轴延长，基于此，可证实长春西汀化合物对于动物体尤其是人类，如幼儿、学龄儿童、儿童及青少年、未成年人、3至26岁人群或年轻的成年人的近视具有预防或治疗、防止或控制近视进展的效果。
在一些实施方式中，本申请的技术方案的治疗对象为儿童或青少年，年龄范围3-26岁，优选6-18岁、或12-18岁。在一些实施方式中，本申请的技术方案的治疗对象为成年人，例如年龄为16-65岁，优选为16-26岁。
在局部给药实验中，所有给药的动物中都没有观察到出现任何不适或眼部异常现象，也没有体重减轻、进食减少等毒性表现，基于长春西汀已有的临床应用基础，本领域技术人员可以预期：在将其用于治疗、防止或改善近视及其相关症状的临床治疗过程中将具有良好的药物安全性。
本申请的药物组合物在治疗、预防或减缓近视及其相关症状方面具有显著优于阿托品的技术效果，且实验中没有观察到眼部刺激、瞳孔扩张、炎症或过敏等不良反应。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，将所述患者治疗 约1个月至20年之间的一段时间，如至少6个月、至少1年、至少2年、至少3年、至少5年、至少7年或者至少9年的一段时间。
在一个实施方式中，本申请的药物组合物、眼科装置或治疗方法中，所述药物组合物包含长春西汀及其治疗上可接受的盐或其衍生物，优选地，包含药学上可接受的载体。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是水性组合物。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是眼科制剂。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是眼科水性制剂。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是滴眼剂制剂。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是眼喷雾制剂。在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是包含在隐形眼镜泡罩包装内的眼部药物组合物。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是局部制剂。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是眼科组合物。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是局部眼科组合物。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是眼凝胶制剂。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是眼科乳剂。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是眼科脂质体。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是纳米圆片。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是纳米颗粒混悬剂。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是药膏或软膏或油膏。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物、组合物、眼科装置或治疗方法，其中所述药物、组合物是眼科软膏剂(如眼药膏)。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物、制剂、组合物、装置或治疗方法，其中所述药物、制剂、组合物是口服制剂，如片剂或胶囊剂或散剂或糖浆剂。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物、制剂、组合物、装置或治疗方法，其中所述药物、制剂、组合物还包含一种或多种其它眼科可用的赋形剂和添加剂，其包括载体、稳定剂、渗透压调节剂、防腐剂、抗氧化剂、缓冲剂、张度调节剂、增稠剂或其它赋形剂。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个 或多个所述的药物、制剂、组合物、装置或治疗方法，其中所述药物、制剂、组合物、装置或治疗方法包含多羟基醇和/或酸性助溶剂，可选羟丙基-β-环糊精和柠檬酸或酒石酸。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物、制剂、组合物、装置或治疗方法，其中所述载体选自但不限于：水、水和水可混溶的溶剂的混合物、包含按重量计0.01％至5％的羟乙基纤维素的植物或矿物油、油酸乙酯、羧甲基纤维素、羧基甲基纤维素、羟甲基纤维素、羟乙基纤维素、丙烯酸乙脂、聚丙烯酰胺、果胶、海藻酸盐、淀粉衍生物、聚乙烯醇、聚乙烯吡咯烷酮、聚乙烯甲醚、聚环氧乙烷、交联聚丙烯酸、卡巴浦尔、卵磷脂、聚乙二醇硬脂酸酯、多羟基醇、酸性助溶剂、十七乙烯氧基氧化十六烷醇或者聚氧乙烯山梨糖醇单油酸酯。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物、制剂、组合物、装置或治疗方法，其中所述渗透压调节剂是氯化钠。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物、制剂、组合物、装置或治疗方法，其中所述防腐剂选自苯扎氯铵、西曲铵、高硼酸钠、稳定的氧氯复合物、索非亚、聚季铵盐-1、氯代丁醇、乙二胺四乙酸二钠、聚六亚甲基双胍或其组合。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物、制剂、组合物、装置或治疗方法，其中所述缓冲剂选自硼酸盐、硼酸盐-多元醇复合物、磷酸盐缓冲剂、柠檬酸盐缓冲剂、乙酸盐缓冲剂、碳酸盐缓冲剂、有机缓冲剂、氨基酸缓冲剂或其组合。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物、制剂、组合物、装置或治疗方法，其中所述张度调节剂选自氯化钠、硝酸钠、硫酸钠、硫酸氢钠、氯化钾、氯化钙、氯化镁、氯化锌、乙酸钾、乙酸钠、碳酸氢钠、碳酸钠、硫代硫酸钠、硫酸镁、磷酸氢二钠、磷酸二氢钠、磷酸二氢钾、葡萄糖、甘露糖醇、山梨糖醇、葡萄糖、蔗糖、脲、丙二醇、甘油或其组合。
在其他实施方式中，涉及本申请的用途时，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合，对于近视的防控(治疗)效果或对眼轴长度的抑制，与施药对象的性别、年龄、近视种类、近视进展速度和近视严重程度无关。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是缓释制剂或结膜下储库。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是缓释制剂。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是包含在眼科装置内的缓释制剂。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物包含在眼科装置内，如眼贴、缝合线、角膜接触镜。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物是眼科组合物并且所述眼科组合物包含在眼科装置内。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述眼科装置是隐形眼镜、眼插入物、角膜覆盖物、角膜镶嵌物、纳米圆片、脂质体、纳米颗粒、泪点塞或具有微流体储库的水凝胶基质。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述眼科装置是隐形眼镜。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述眼科装置是眼插入物。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述眼科装置是角膜覆盖物。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述眼科装置是角膜镶嵌物。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述眼科装置是纳米圆片。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述眼科装置是脂质体。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述眼科装置是纳米颗粒。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述眼科装置是泪点塞。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述眼科装置是具有微流体储库的水凝胶基质。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述眼科装置以缓释方式递送所述药物组合物。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中将所述药物组合物配制为用于眼科病症或病况治疗的眼科组合物。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中将所述药物组合物配制为用于前近视、近视、真性近视、假性近视或近视发展治疗的眼科组合物。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中将所述药物组合物配制为用于高度近视、中度近视或低度近视治疗的眼科组合物。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中将所述药物组合物配制为用于诊断为前近视(或者具有出现近视的风险)的患者的治疗的眼科组合物。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物基本均一地分布在整个眼科装置中。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述眼科装置包含在隐形眼镜泡罩包装内。
在其它实施方式中，根据以上实施方式中的任一个和本文中其它实施方式中的任何一个或多个所述的药物组合物、眼科装置或治疗方法，其中所述药物组合物浸没在隐形眼镜泡罩包装内的眼科装置内。
药物制剂形式、给药模式和剂量：可以使用本领域的技术人员所知的任何方法来将细胞、器官或组织与长春西汀化合物接触。适当的方法包括体外法、间接体内法或体内法。体内法通常包括将本申请的长春西汀化合物或含有其的药物组合物给药至哺乳动物、优选地给药至 人。当用在体内以治疗时，长春西汀化合物或含有其的药物组合物可以以有效的量(即具有期望的治疗效果的量)给药至对象。剂量和给药方案将取决于对象中的眼科病症的程度、该对象以及该对象的病史。
本文公开的化合物也可作为前药存在。本文所述的化合物的前药是在生理条件下易于产生化学变化以得到长春西汀或其相关化合物的修改形式。此外，前药可通过化学或生物化学方法在离体环境中转化成该化合物。例如，当置于具有合适的酶或化学试剂的透皮贴剂储器(reservoir)中时，前药可缓慢地转化成化合物。前药通常是有用的，因为在一些情况下，它们可能比化合物或母体药物更容易施用。例如，它们可通过口服施用而具有生物利用性，而母体药物则不能。前药在药物组合物中的溶解度也可高于母体药物。许多前药衍生物是本领域中已知的，如依赖于前药的水解分裂或氧化活化的前药衍生物。前药的一个非限制性例子是作为酯(“前药”)施用但然后代谢水解成羧酸(活性实体)的化合物。
本文公开的化合物可作为治疗上可接受的盐存在。本申请包括盐形式的上列化合物，包括酸加成盐。合适的盐包括与有机酸和无机酸形成的盐。这种酸加成盐通常是药学上可接受的。然而，非药学上可接受的盐可用于制备和纯化有问题的化合物。也可以形成碱加成盐，并且是药学上可接受的。
如本文所用，术语“治疗上可接受的盐”表示本文公开的化合物的盐或两性离子形式，其为水溶或油溶性的或可分散和治疗上可接受的，如本文所定义。盐可在化合物的最终分离和纯化期间制备，或者通过使适当的游离碱形式的化合物与合适的酸反应来单独地制备。代表性的酸加成盐包括乙酸盐、己二酸盐、藻酸盐、L-抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐(benzenesulfonate，besylate)、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡糖酸盐、甲酸盐、富马酸盐、龙胆酸盐、戊二酸盐、甘油磷酸盐、乙醇酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(羟乙磺酸盐)、乳酸盐、马来酸盐、丙二酸盐、DL-扁桃酸盐、均三甲苯磺酸盐、甲磺酸盐、萘磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、膦酸盐、枸橼酸盐、苦味酸盐、新戊酸盐、丙酸盐、焦谷氨酸盐、琥珀酸盐、磺酸盐、酒石酸盐、L-酒石酸盐、三氯乙酸盐、三氟乙酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐(para-toluenesulfonate，p-tosylate)和十一烷酸盐。此外，本文公开的化合物中的碱性基团可用以下物质来季铵化：甲基、乙基、丙基和丁基氯化物、溴化物和碘化物；硫酸二甲酯、二乙酯、二丁酯和二戊酯；癸基、月桂基、肉豆蔻基和甾醇基氯化物、溴化物和碘化物；及苄基和苯乙基溴化物。可用于形成治疗上可接受的加成盐的酸的例子包括无机酸(如盐酸、氢溴酸、硫酸和磷酸)和有机酸(如草酸、马来酸、琥珀酸和柠檬酸)。也可通过化合物与碱金属或碱土金属离子的配位作用形成盐。因此，本申请包括本文公开的化合物的钠、钾、镁和钙盐等。
长春西汀的晶型包括人们已知的全部种类，例如Samuel Golob在文献中所描述的晶型(Samuel Golob，Improving Biopharmaceutical Properties of Vinpocetine Through Cocrystallization,J Pharm Sci.2016 Dec；105(12):3626-3633.)。
可在化合物的最终分离和纯化期间，通过使羧基与合适的碱(如金属阳离子的氢氧化物、碳酸盐或碳酸氢盐)或者与氨或有机伯、仲或叔胺反应来制备碱加成盐。治疗上可接受的盐的阳离子包括锂、钠、钾、钙、镁和铝以及无毒的季胺阳离子，如铵、四甲铵、四乙铵、甲胺、二甲胺、三甲胺、三乙胺、二乙胺、乙胺、三丁胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二环己基胺、普鲁卡因、二苄胺、N,N-二苄基苯乙胺、1-二苯羟甲胺和N,N’-二苄基乙二胺。适用于形成碱加成盐的其它代表性有机胺包括乙二胺、乙醇胺、二乙醇胺、哌啶和哌嗪。
虽然有可能以粗化学品的形式施用本申请的化合物，但也有可能将它们作为药物制剂提供。因此，本文提供了药物制剂，其包含一种或多种本文公开的某些化合物或一种或多种其药学上可接受的盐、酯、前药、酰胺或溶剂化物，连同一种或多种其药学上可接受的载体和 任选一种或多种其它治疗成分。载体是“可接受的”意义是，与制剂的其它成分相容，并且对其接受者无害。适当的制剂取决于选定的施用途径。可以使用合适且为本领域中所理解的任何公知的技术、载体和赋形剂；例如见于Remington’s Pharmaceutical Sciences。可以按本领域中已知的任何方式生产本文公开的药物组合物，例如借助于常规的混合、溶解、粒化、包糖衣、细磨、乳化、胶囊包封、包埋或压制处理，还可以制成药械组合。
制剂包括适合口服、肠胃外(包括皮下、皮内、肌内、静脉内、关节内和髓内)、腹膜内、经粘膜、透皮、直肠和局部(包括皮肤、口腔、舌下、眼部、鼻内和眼内)施用的制剂，最合适的途径可取决于例如接受者的病状和病症。可以方便地以单位剂型提供制剂，并且可通过药学领域中公知的任何方法来进行制备。通常情况下，这些方法包括使本申请的化合物或其药学上可接受的盐、酯、酰胺、前药或溶剂化物(“活性成分”)与构成一种或多种辅助成分的载体相结合的步骤。一般来说，均匀且紧密地使活性成分与液体载体或细碎的固体载体或两者相结合，然后如果必要的话，使产品成形为所需的制剂，由此制备制剂。
本文公开的适于口服施用的化合物的制剂可提供成分离的单位，如胶囊剂、扁囊剂或片剂，各含有预定量的活性成分；提供成粉剂或颗粒；提供成在水性液体或非水液体中的溶液剂或混悬剂；或提供成水包油型乳液或油包水型乳液。活性成分还可以提供成大丸剂、药糖剂或糊剂。
可口服使用的药物制剂包括片剂、由明胶制成的推入配合胶囊以及由明胶和增塑剂(如甘油或山梨醇)制成的密封软胶囊。可通过任选与一种或多种辅助成分进行压制或模制来制备片剂。可通过在合适的机器中压制任选与粘结剂、惰性稀释剂或润滑剂、表面活性剂或分散剂混合的自由流动形式的活性成分(如粉末或颗粒)来制备压制的片剂。可通过在合适的机器中模制用惰性液体稀释剂润湿的粉状化合物的混合物来制备模制的片剂。片剂可任选被包衣或刻痕并且可被配制，以便提供其中的活性成分的缓释或控释。用于口服施用的所有制剂的剂量应适合这种施用所到达的近视预防、治疗目的。推入配合胶囊可含有与填充剂(如乳糖)、粘结剂(如淀粉)和/或润滑剂(如滑石或硬脂酸镁)及任选稳定剂混合的活性成分。在软胶囊中，活性化合物可溶解或悬浮在合适的液体(如脂肪油、液体石蜡或液体聚乙二醇)中。此外，可以添加稳定剂。提供具有合适包衣的糖衣丸核。为此目的，可以使用浓糖溶液，其可任选含有阿拉伯树胶、滑石、聚乙烯吡咯烷酮、卡波普凝胶、聚乙二醇和/或二氧化钛、漆溶液及合适的有机溶剂或溶剂混合物。可将染料或颜料加到片剂或糖衣丸包衣中用于识别或用以表征活性化合物剂量的不同组合。
用于口服药物制剂(如胶囊和片剂)的填充剂或稀释剂的例子包括但不限于乳糖、甘露醇、木糖醇、右旋糖、蔗糖、山梨醇、可压缩糖、微晶纤维素(MCC)、粉状纤维素、玉米淀粉、预胶化淀粉、葡萄糖结合剂(dextrate)、右旋糖酐、糊精、右旋糖、麦芽糖糊精、碳酸钙、磷酸氢钙、磷酸三钙、硫酸钙、碳酸镁、氧化镁、泊洛沙姆(如聚环氧乙烷)、甲基纤维素和羟丙基甲基纤维素。填充剂可具有络合的溶剂分子，如在使用的乳糖为一水合乳糖的情况下。
用于口服药物制剂(如胶囊和片剂)的崩解剂的例子包括但不限于乙醇酸淀粉钠、羧甲基纤维素钠、羧甲基纤维素钙、交联羧甲纤维素钠、聚维酮、交聚维酮(聚乙烯基聚吡咯烷酮)、甲基纤维素、微晶纤维素、粉状纤维素、低取代羟丙基纤维素、淀粉、预胶化淀粉和藻酸钠。
此外，在口服药物制剂中可使用助流剂和润滑剂以确保混合时赋形剂的均匀共混。润滑剂的例子包括但不限于硬脂酸钙、单硬酯酸甘油酯、硬脂酸棕榈酸甘油酯、氢化植物油、轻质矿物油、硬脂酸镁、矿物油、聚乙二醇、苯甲酸钠、月桂基硫酸钠、硬脂酰富马酸钠、硬脂酸、滑石和硬脂酸锌。助流剂的例子包括但不限于二氧化硅(SiO 2)、滑石玉米淀粉和泊洛沙姆。泊洛沙姆(或可得自BASF Corporation)是A-B-A嵌段共聚物，其中A区段是亲水聚乙二醇均聚物，B区段是疏水聚丙二醇均聚物。
片剂粘结剂的例子包括但不限于阿拉伯树胶、藻酸、卡波姆、羧甲基纤维素钠、糊精、乙基纤维素、明胶、瓜尔胶、氢化植物油、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、共聚维酮(copolyvidone)、甲基纤维素、液体葡萄糖、麦芽糖糊精、聚甲基丙烯酸酯、聚 维酮、预胶化淀粉、藻酸钠、淀粉、蔗糖、黄蓍胶和玉米蛋白。
可配制化合物用于通过注射的肠胃外施用，例如通过弹丸注射或连续输注。用于注射的制剂可提供成例如在添加有防腐剂的安瓿或多剂量容器中的单位剂型。组合物可采取诸如在油性或水性媒介物中的混悬液、溶液或乳液的形式，并且可含有配制剂，如悬浮剂、稳定剂和/或分散剂。制剂可提供在单位剂量或多剂量容器中，例如密封的安瓿和小瓶中，并且可以粉末形式或以冷冻干燥(冻干)状态储存，其仅需要在临使用前添加无菌液体载体，例如生理盐水或无菌无热原水。可由先前描述类型的无菌粉末、颗粒和片剂制备即用的注射溶液和混悬液。在一个优选的实施方案中，本申请的药物组合物是注射剂、特别是注射器的形式。优选地，通过眼内注射、更优选通过玻璃体内注射入玻璃体施用药物组合物。
用于肠胃外施用的制剂包括但不限于：活性化合物的水性及非水(油性)无菌注射溶液，其可含有抗氧化剂、缓冲剂、抑菌剂和使制剂与预定接受者的血液等渗的溶质；和水性及非水无菌混悬液，其可包括悬剂和增稠剂。合适的亲脂性溶剂或媒介物包括脂肪油(如芝麻油)或合成脂肪酸酯(如油酸乙、酯或甘油三酯)或脂质体。水性注射混悬液可含有提高混悬液粘度的物质，如甲基纤维素、羧甲基纤维素钠、山梨醇或右旋糖酐。任选如油酸乙酯或甘油三酯)或脂质体。水性注射混悬液可含有提高混悬液粘度的物质，如羧甲基纤维素钠、山梨醇或右旋糖酐。任选地，混悬液还可含有合适的稳定剂或提高化合物溶解度的试剂，以使得能够制备高浓度的溶液。
除了前述的制剂外，还可以将长春西汀等本专利提及的化合物配制成储存制剂。这种长效制剂可通过植入(例如皮下或肌内)或通过肌内注射来施用。因此，举例来说，化合物可用合适的聚合材料或疏水材料(例如作为可接受的油中的乳液)或离子交换树脂进行配制，或配制成微溶的衍生物，例如为微溶的盐。
对于口腔或舌下施用，组合物可采取按常规方式配制的片剂、糖锭、锭剂或凝胶的形式。这种组合物可在有味道的基质(如蔗糖和阿拉伯树胶或黄蓍胶)中包含活性成分，如本专利提及的长春西汀等化合物。
也可将化合物配制成直肠用组合物，如栓剂或保留灌肠剂，例如含有常规的栓剂基质，如可可脂、聚乙二醇或其它甘油酯。
除了前述的制剂外，还可以将长春西汀等本专利提及的化合物配制成局部施用的一次性制剂、装置、改变眼部外观用品或医药耗材，如单次使用的滴眼液(每个包装仅含有一份治疗有效剂量)、独立包装的眼贴、美瞳、日抛型隐形眼镜。
本文公开的长春西汀等提及的化合物可局部施用，即通过非全身性施用。这包括将本文公开的化合物施加于眼部、表皮或口腔的外部，和将这种化合物滴注到耳、眼和鼻里，使得化合物不会明显地进入血液。相反，全身施用是指口服、静脉内、腹膜内和肌内施用。
适合局部施用的制剂包括适合穿透皮肤到达起效部位的液体或半液体制剂(如凝胶、擦剂、洗剂、霜剂、膏剂或糊剂)和适合施用于眼、耳或鼻的制剂，如滴剂、喷剂。用于近视治疗的活性成分可占制剂总含量的例如0.0000001％至99％w/w(按重量计)。在某些实施方案中，活性成分可占多达50％w/w以上。在其它实施方案中，其可占不到1％w/w。在某些实施方案中，活性成分可占0.01％w/w至1％w/w。在其它实施方案中，其可占制剂的0.00001％至0.001％w/w；或者，用于局部施用的活性成分可占制剂的例如0.0000001％至100％w/v(按重量比体积计)；或者在某些实施方案中，活性成分可占多达50％w/v以上。在其它实施方案中，其可占不到1％w/v。在某些实施方案中，活性成分可占0.01％w/v至1％w/v。在其它实施方案中，其可占制剂的0.00001％至0.001％w/v。
所述凝胶制剂形式包括长春西汀或其前体药物或其相关化合物与水凝胶连接形成的制剂，优选地，水凝胶连接的长春西汀或其前体药物的水凝胶是生物可降解的水凝胶。
所述水凝胶包含至少一种聚合物，优选由至少一种聚合物组成，所述聚合物优选选自聚(丙烯酸)、聚(丙烯酸酯)、聚(丙烯酰胺)、聚(烷氧基)聚合物、聚(酰胺)、聚(酰氨基胺)、聚(氨基酸)、聚(酸酐)、聚(天冬酰胺)、聚(丁酸)、聚(己内酯)、聚(碳酸酯)、聚(氰基丙烯酸酯)、 聚(二甲基丙烯酰胺)、聚(酯)、聚(乙烯)、聚(乙二醇)、聚(环氧乙烷)、聚(乙基唑啉)、聚(乙醇酸)、聚(丙烯酸羟乙酯)(poly(hydroxyethyl acrylate))、聚(羟基乙基唑啉)、聚(羟丙基甲基丙烯酰胺)(poly(hydroxypropylmethacrylamide))、聚(甲基丙烯酸羟丙酯)(poly(hydroxypropyl methacrylate))、聚(羟丙基唑啉)、聚(亚氨基碳酸酯)、聚(N-异丙基丙烯酰胺)、聚(乳酸)、聚(乳酸-共-乙醇酸)(poly(lactic-co-glycolic acid))、聚(甲基丙烯酰胺)、聚(甲基丙烯酸酯)、聚(甲基唑啉)、聚(富马酸丙二醇酯)、聚(有机磷氰)、聚(原酸酯)、聚(唑啉)、聚(丙二醇)、聚(硅氧烷)、聚(氨基甲酸酯)、聚(乙烯醇)、聚(乙烯基胺)、聚(乙烯基甲基醚)、聚(乙烯基吡咯烷酮)、硅氧烷、核糖核酸、脱氧核酸、白蛋白、抗体及其片段、血浆蛋白、胶原蛋白、弹性蛋白、成束蛋白(fascin)、纤维蛋白、角蛋白、聚天冬氨酸、聚谷氨酸、谷醇溶蛋白(prolamin)、运铁蛋白、细胞色素、黄素蛋白、糖蛋白、血红素蛋白、脂蛋白、金属蛋白、植物光敏素、磷蛋白、视蛋白、琼脂、琼脂糖、藻酸盐、阿拉伯聚糖、阿拉伯半乳聚糖、角叉菜胶、纤维素、羧甲基纤维素(carbomethyl cellulose)、羟丙基甲基纤维素和其它基于碳水化合物的聚合物、脱乙酰壳多糖、右旋糖酐、糊精、明胶、透明质酸及其衍生物、甘露聚糖、果胶、鼠李糖半乳糖醛酸聚糖、淀粉、羟烷基淀粉、木聚糖、及其共聚物和官能化衍生物。
优选地，所述水凝胶是基于生物可降解的聚乙二醇(PEG)的水凝胶。
优选地，所述聚乙二醇(PEG)是单一分子量的或不同分子量按一定比例混合而成的组。
所述水凝胶是成形制品，优选是微粒的形状。更优选地，所述水凝胶是微粒珠的形状。甚至更优选地，所述微粒珠具有1-1000μm、更优选5-500μm、更优选10-100μm、甚至更优选20-80μm的直径。珠直径是在将微粒珠混悬于等渗水性缓冲液中时测定的。在一个优选的实施方案中，所述水凝胶连接的长春西汀或其前体药物是珠形状的。更优选地，所述水凝胶连接的长春西汀或其前体药物是微粒珠形状的。甚至更优选地，所述微粒珠具有1-1000μm、更优选5-500μm、更优选10-100μm、甚至更优选20-80μm的直径。珠直径是在将微粒珠混悬于等渗水性缓冲液中时测定的。这类水凝胶可以以不同的方式被聚合，例如通过自由基聚合、离子聚合或络合物形成反应被聚合。
如果水凝胶是通过自由基聚合或离子聚合加工的，则至少两种原料是交联大分子单体或交联单体(其被称为交联剂试剂)和多官能大分子单体(其被称为骨架试剂)。交联剂试剂携带至少两个可相互连接的官能团，骨架试剂携带至少一种可相互连接的官能团和至少一种不用于参与聚合步骤的化学官能团。另外的稀释剂单体可以存在，也可以不存在。有用的可相互连接的官能团包括但不限于可自由基聚合的基团如乙烯基、乙烯基-苯、丙烯酸酯、丙烯酰胺、甲基丙烯酸酯、甲基丙烯酰胺，和可离子聚合的基团如氧杂环丁烷、氮杂环丁烷和环氧乙烷。在一种供替代选择的制备方法中，所述水凝胶是通过化学络合物形成反应生成的。在这类反应中，原料是至少一种大分子原料，其具有进行诸如缩合或加成反应等反应的互补官能团(complementary functionality)。在一个实施方案中，仅使用一种大分子原料，其是异型多官能(heteromultifunctional)骨架试剂，包含大量可以相同或不同的可聚合的官能团。
除了长春西汀等活性成分之外，本申请的局部眼、耳和鼻用制剂还可包含赋形剂。在这种制剂中常用的赋形剂包括但不限于等渗剂、防腐剂、螯合剂、缓冲剂和表面活性剂。其它赋形剂包括增溶剂、稳定剂、舒适增强剂、聚合物、缓和剂、pH调节剂和/或润滑剂。各种赋形剂中的任何一种均可用于本申请的制剂，包括水、水与水混溶性溶剂(如C1-C7烷醇)的混合物、包含0.5％至5％无毒水溶性聚合物的植物油或矿物油、天然产物(如藻酸盐、果胶、黄蓍胶、梧桐胶、瓜尔胶、黄原胶、角叉菜胶、琼脂和阿拉伯树胶)、淀粉衍生物(如醋酸淀粉和羟丙基淀粉)以及其它合成产物(如聚乙烯醇、聚乙烯吡咯烷酮、聚乙烯基甲基醚、聚环氧乙烷、优选交联聚丙烯酸及这些产物的混合物)。赋形剂的浓度通常是活性成分浓度的1至100,000倍。在优选的实施方案中，要包括在制剂中的赋形剂通常是根据它们对制剂的活性成分组成的惰性来选择的。
关于眼、耳和鼻用制剂，合适的等渗调节剂包括但不限于甘露醇、右旋糖、氯化钠、甘油、山梨醇等。合适的缓冲剂包括但不限于磷酸盐、柠檬酸盐、硼酸盐、醋酸盐等。合适的 表面活性剂包括但不限于离子和非离子表面活性剂(虽然非离子表面活性剂是优选的聚山梨醇酯80、RLM 100、POE 20鲸蜡基硬脂酰基醚(如CS20)和泊洛沙姆(如F68)。制剂可含有提高溶液或混悬液粘度的物质，如羧甲基纤维素钠、羟丙甲纤维素、微晶纤维素、山梨醇或右旋糖酐。任选地，制剂还可含有合适的稳定剂或提高化合物溶解度的试剂以使得能够制备高浓度的溶液，这包括但不限于乙醇、苯甲醇、聚乙二醇、苯乙醇和甘油。
本文给出的制剂可包含一种或多种防腐剂。这种防腐剂的例子包括苯扎氯铵、对羟基苯甲酸酯、过硼酸钠、亚氯酸钠、醇(如氯丁醇、苄醇或苯乙醇)、胍衍生物(如聚六亚甲基双胍)、过硼酸钠、聚季铵盐-1、氨基醇(如AMP-95)或山梨酸。在某些实施方案中，制剂本身可以是防腐的，从而不需要防腐剂。在某些实施方案中，制剂本身虽然不是防腐的，但可以使用包装材质或包装设计来避免药物变质(如理化性质改变和/或生物效应改变)，从而不需要防腐剂。
对于眼、耳或鼻部施用，制剂可以是溶液、混悬液或凝胶。在优选方面，在水溶液或混悬液中用于局部施用到眼或耳的制剂是滴剂形式的。在水溶液或混悬液中用于局部施用到鼻的制剂是滴剂、喷雾剂或气溶胶形式的。术语“水性”通常表示其中按重量计制剂含＞20％、＞50％、更优选＞75％且特别是＞90％水的水性制剂。这些滴剂可由单剂量滴眼液瓶递送，所述单剂量滴眼液瓶可优选为无菌的，因此使得能够不需要制剂的抑菌组分。或者，滴剂可由多剂量滴眼液瓶递送，所述多剂量瓶可优选包括在递送制剂时从其中抽出任何防腐剂的设备，这种设备是本领域中已知的。溶液和混悬液制剂可使用雾化器进行鼻部施用。也可通过基于推进剂的气溶胶系统促进溶液、混悬液或干粉剂的鼻内递送，所述推进剂包括但不限于基于氢氟烷的推进剂，或者可以以干粉剂的形式递送活性药物成分。
对于眼部病症，可将本申请的组分作为浓缩的凝胶或类似的媒介物或作为置于眼睑下方的可溶性插入物递送到眼部。
在特定的实施方案中，本申请的制剂每天施用一次。然而，也可以将制剂配制成以任何施用频度进行施用，包括每周一次、每5天一次、每3天一次、每2天一次、每天两次、每天三次、每天四次、每天五次、每天六次、每天八次、每小时施用或以任何更高的频度施用。根据治疗方案，还将这种给药频度保持长短不一的持续时间。特定治疗方案的持续时间可从一次给药到延长至数月或数年的方案不等。以不同的剂量施用制剂，但典型的剂量是每次施用一至两滴，或相当量的凝胶或其它制剂(如片剂、眼药膏)。本领域的普通技术人员熟悉如何针对具体的适应症确定治疗方案。
用于局部或透皮施用的凝胶一般可包含挥发性溶剂、非挥发性溶剂和水的混合物。在某些实施方案中，缓冲溶剂系统的挥发性溶剂组分可包括低级(C1-C6)烷基醇、低级烷基二醇和低级二醇聚合物。在进一步的实施方案中，挥发性溶剂是乙醇。挥发性溶剂组分被认为是充当渗透促进剂，同时随着其蒸发，也对皮肤产生冷却效果。缓冲溶剂系统的非挥发性溶剂部分选自低级亚烷基二醇和低级二醇聚合物。在某些实施方案中使用丙二醇。非挥发性溶剂延缓挥发性溶剂的蒸发并降低缓冲溶剂系统的蒸汽压。此非挥发性溶剂组分的量，如同挥发性溶剂，是由所用的药物化合物或药物决定的。当系统中非挥发性溶剂太少时，药物化合物可能会由于挥发性溶剂的蒸发而结晶，而过多的话则可能会由于药物从溶剂混合物中释放较差而导致缺乏生物利用度。缓冲溶剂系统的缓冲组分可选自任何本领域中常用的缓冲剂；在某些实施方案中使用水。常见的成分比为约20％的非挥发性溶剂、约40％的挥发性溶剂和约40％的水。可将若干可选的成分添加到局部用组合物中。这些包括但不限于螯合剂和胶凝剂。适当的胶凝剂可包括但不限于半合成纤维素衍生物(如羟丙基甲基纤维素)及合成聚合物、半乳甘露聚糖聚合物(如瓜尔胶及其衍生物)和美容剂。
洗剂包括适合施加于皮肤或眼的洗剂。眼用洗剂可包含任选含有杀菌剂的无菌水溶液，并且可通过类似于制备滴剂的方法进行制备。用于施加到皮肤的洗剂或擦剂还可以包括用以加速干燥和冷却皮肤的试剂(如醇或丙酮)和/或保湿剂(如甘油)或油(如蓖麻油或花生油)。
本申请的药物组合物可以是霜剂、膏剂(如3％油膏、软膏)或糊剂，其为用于外部施加 的活性成分的半固体制剂。它们可通过借助于合适的机器将以单独或在水性或非水流体的溶液或混悬液中的细碎或粉状形式的活性成分与油脂性或非油脂性基质进行混合来制备。所述基质可包括烃，如凡士林、硬石蜡、软石蜡或液体石蜡、甘油、蜂蜡、金属皂；胶浆；天然来源的油，如鱼油、杏仁油、玉米油、花生油、蓖麻油或橄榄油；羊毛脂或其衍生物或脂肪酸(如硬脂酸或油酸)连同醇(如丙二醇)或大粒凝胶或羊毛甾醇或二氢羊毛甾醇。制剂可掺混任意合适的表面活性剂，如阴离子、阳离子或非离子表面活性剂，如失水山梨醇酯或其聚氧化乙烯衍生物。还可以包括悬浮剂，如天然树胶、纤维素衍生物或无机材料，如硅质二氧化硅，以及其它成分，如羊毛脂、羊毛甾醇。
滴剂或喷雾剂可包含无菌水性或油性溶液或混悬液，并且可通过将活性成分溶解在合适的杀菌剂和/或杀真菌剂和/或任何其它合适的防腐剂并且在某些实施方案中包括表面活性剂的水溶液中来制备。然后可通过过滤使所得到的溶液澄清，转移到合适的容器中，然后将其密封，并通过高压灭菌法或在98-100℃下保持半小时来灭菌。或者，可通过过滤将溶液灭菌，并通过无菌技术转移到容器中。适合包含在滴剂中的杀菌剂和杀真菌剂的例子有唑类化合物(如益康唑)、硝酸苯汞或醋酸苯汞(0.002％)、苯扎氯铵(0.01％)和醋酸洗必泰(0.01％)。用于制备油性溶液的合适溶剂包括甘油、稀醇和丙二醇。
用于在口中(例如口腔或舌下)局部施用的制剂包括在有味道的基质(如蔗糖和阿拉伯树胶或黄蓍胶)中包含活性成分的糖锭和在诸如明胶和甘油或蔗糖和阿拉伯树胶的基质中包含活性成分的锭剂。
对于通过吸入施用，可由吹入器、雾化器加压包或其它递送气溶胶喷雾剂的方便装置方便地递送本专利提及的长春西汀等化合物。加压包可包含合适的推进剂，如氢氟烷、二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体。在加压气溶胶的情况下，可以通过提供阀以递送计量的量来确定剂量单位。或者，对于通过吸入或吹入施用，根据本申请的化合物可采取干粉组合物的形式，例如化合物与合适粉末基质(如乳糖或淀粉)的粉末混合物。粉末组合物可以在例如胶囊、药筒、明胶或泡罩包装中的单位剂型提供，粉末可借助于吸入器或吹入器从上述当中施用。
优选的单位剂量制剂是含有如本文所述的有效剂量或其适当份额的活性成分的制剂。
应理解的是，除了上面特别提到的成分外，上述制剂还可包括本领域中针对所关注的制剂类型为常规的其它试剂，例如微针剂、适合口服或鼻内施用的制剂(可包括调味剂)。
可以按每天0.001至300mg/kg的剂量口服或经由注射施用化合物。成人及老年人的剂量范围一般是5mg至100mg/天，儿童或青少年应该减量或维持不变。以分立的单位提供的片剂或其它呈现形式可方便地含有一定量的一种或多种化合物，其在这种剂量或多个此剂量的情况下是有效的，例如含有0.1mg至1000mg、通常大约1mg至10mg的单位，优选是5mg。
可以按各种方式施用本专利提及的长春西汀等化合物，例如口服施用、局部施用或通过注射施用，或者同时进行全身给药和局部给药，或者交替进行全身给药和局部给药。施用于患者的化合物的精确量由巡诊医生负责。针对任何特定患者的具体剂量水平取决于多种因素，包括所用具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、施用时间、施用途径、排泄速度、药物组合、治疗的确切病症和所治疗的适应症或病状的严重程度。此外，施用途径可有所不同，这取决于病状及其严重程度。
在某些情况下，可能适当的是施用至少一种本文所述的化合物(或其药学上可接受的盐、酯或前药)与另一种治疗剂相组合。仅作为例子，如果患者经接受本文中的一种化合物而经受的副作用之一是低血压，则可能适当的是施用抗低血压药与初始的治疗剂相组合。或仅作为例子，可通过施用抗过敏药而使本文所述的化合物之一的疗效得到加强(即抗过敏药本身可能仅具有最小的治疗益处，但与本文提及的治疗剂组合时，对患者的总治疗益处得到加强)。或仅作为例子，可通过施用本文所述的化合物之一与也具有治疗益处的另一种治疗剂(其还包括治疗方案)使患者经受的益处得到加强。仅作为例子，在涉及施用本文所述的化合物之一的近视治疗中，通过还对患者提供另一种近视治疗剂可以使治疗益处得到加强。在任何情况下， 无论所治疗的疾病、病症或病状如何，患者经受的总益处均可简单地为两种治疗剂的加合，或者患者可经受协同的益处。
干燥或液体形式的药物组合物可以以单剂量或多剂量药物组合物的形式被提供。
在本申请的一个实施方案中，液体或干燥药物组合物以单剂量被提供，这意指提供其的容器含有一个药物剂量。或者，液体或干燥药物组合物是多剂量药物组合物，这意指提供其的容器含有多于一个治疗剂量，即，多剂量组合物含有至少2个剂量。这类多剂量组合物可以用于需要其的不同患者，或者可以用于一名患者，其中在应用第一个剂量之后将剩余剂量贮存至需要时。
在本申请的另一方面，药物组合物在容器中。用于液体或干燥药物组合物的容器有例如滴眼液瓶、注射器、小瓶、具有塞子和密封物的小瓶、安瓿和药筒。特别地，液体或干燥药物组合物在注射器中被提供。如果药物组合物是干燥药物组合物，则容器优选是双室注射器。在该实施方案中，所述干燥药物组合物在双室注射器的第一个室中被提供，重构溶液在双室注射器的第二个室中被提供。
在将干燥组合物应用于需要其的患者之前，将干燥组合物重构。重构可以在提供所述干燥组合物的容器中进行，例如在滴眼液瓶、注射器、双室注射器、安瓿和药筒中进行。通过向干燥组合物中加入预定量的重构溶液进行重构。重构溶液是无菌液体如水或缓冲液，其可以含有其它添加剂如防腐剂和/或抗微生物剂例如苄醇和甲酚。优选地，重构溶液是无菌水。当干燥组合物被重构时，其被称为“重构的药物组合物”或“重构的药物组合物”或“重构的组合物”。
眼用制剂：本申请的药物组合物可以以眼用制剂的形式给药，本申请的眼用制剂包含眼科上可接受的载体。
可与载体材料组合以产生单一剂型的活性成分的量可能有所不同，这取决于受治疗的宿主和具体的施用方式。
如本文所用，“眼科上可接受的载体”是用于药物组合物到受试者眼部的眼科上可接受的溶剂、混悬剂或媒介物。所述载体可为固体或液体。所述载体在某种意义上是“眼科上可接受的”，即载体适于施用于眼部而不引起任何大的不利反应。
通常，眼科上可接受的载体是或包括水。通常，眼用制剂的形式为用于向眼部施加的滴眼剂或凝胶剂。通常，制剂的大部分是水。通常，制剂包括大于50重量％(如大于60重量％、65重量％、70重量％、75重量％、80重量％、85重量％或90重量％)，更通常大于95重量％(如96重量％、97重量％、98重量％或99重量％)的水。
在一些实施方案中，眼科上可接受的载体为水包油乳液或油。在此类实施方案中，眼用制剂的形式可为向眼部施加的乳膏剂。在此类实施方案中，制剂可包含大于10重量％，更通常大于20重量％的油性成分。
在其它实施方案中，载体可为可生物降解的聚合物，例如用于缓释本申请的化合物和任选的其它化合物的可生物降解的聚合物眼睛植入物。比如可生物降解的、可生物相容的聚合物基质。在一个实施方式中，化合物可以嵌入到聚合物基质中，同时保持结构完整性。所述聚合物可以是天然的，比如多肽、蛋白质或多糖；或者可以是合成的，比如聚α-羟酸。示例包括由例如以下物质制成的载体：胶原蛋白、纤连蛋白、弹性蛋白、乙酸纤维素、硝酸纤维素、甲基纤维素、多糖、纤维蛋白、明胶及其组合。在一个实施方式中，所述聚合物是聚乳酸(PLA)或乳酸羟基乙酸共聚物(PGLA)。可以以各种形式和尺寸来制备并分离聚合物基体，包括微球和纳米球。
在一些实施方式中，治疗性化合物与将保护所述治疗化合物以防止其从身体中快速排出的载体一起制备，所述载体比如控释剂，包括植入体和微胶囊化的输送体系。可以使用可生物降解的、生物相容的聚合物，比如乙烯醋酸乙烯酯、聚酐、聚乙醇酸、胶原质、聚原酸酯和聚乳酸。可以利用已知的技术来制备这样的制剂。
赋形剂：适用于本申请眼用制剂的赋形剂包括例如缓和剂、软化剂、张力亢进剂、防腐 剂、缓冲剂或pH调节剂。适合的赋形剂的实例包括：
A.缓和剂：合成的高分子量交联丙烯酸聚合物(如卡波姆974和卡波姆980)；纤维素衍生物(如羟丙基甲基纤维素(“HPMC”或“羟丙甲纤维素”)、羟乙基纤维素、甲基纤维素、羧甲基纤维素(羧甲纤维素))或羧甲基纤维素钠(羧甲纤维素钠))；葡聚糖(如葡聚糖70)；明胶；多元醇(如甘油、聚乙二醇300、聚乙二醇400、聚山梨醇酯80和丙二醇)；聚乙烯醇；聚维酮(聚乙烯基吡咯烷酮)；泊洛沙姆；和透明质酸(二糖聚合物)或者其钠盐或钾盐。
B.软化剂：羊毛脂(如无水羊毛脂)；油性成分(如轻矿物油、矿物油、石蜡、凡士林、液体石蜡、白软膏、白凡士林、白蜡和黄蜡)；和鱼油、蓖麻油。
C.防腐剂：苯扎氯铵；过硼酸钠；Oxyd(亚氯酸钠0.05％，过氧化氢0.01％)；聚季铵-1(乙醇、2,2′,2″-次氮基三-与1,4-二氯-2-丁烯和N,N,N′,N′-四甲基-2-丁烯-1,4-二胺的聚合物)；氯化银钠；六亚甲基双胍；氧合硼酸盐；和(亚氯酸钠0.005％m/v)。
D.眼用张力亢进剂：氯化钠。
E.本申请的眼用制剂还可含有抑制微生物生长并延长制剂的保质期的防腐剂。可用于本申请眼用制剂的防腐剂包括例如苯扎氯铵、过硼酸钠、Oxyd(亚氯酸钠0.05％，过氧化氢0.01％)、聚季铵-1(乙醇、2,2′,2″-次氮基三-与1,4-二氯-2-丁烯和N,N,N′,N′-四甲基-2-丁烯-1,4-二胺的聚合物)、氯化银钠、六亚甲基双胍、氧合硼酸盐。亚氯酸钠(0.005％m/v)是具有广谱的抗微生物活性并对哺乳动物细胞具有非常低毒性的杀微生物剂，其在贮存期间保护制剂但最终在曝光之后解离为水、钠离子、氯离子和氧。因为它们还在天然泪液中发现，因此将防腐剂诱导的眼部刺激的风险和角膜损伤最小化。长期来说，亚氯酸钠使用安全且有效。这种防腐剂在体外或体力对上皮细胞无副作用，并且比许多其它正在使用的防腐剂对细胞完整性的破坏更小。
可通过任何适合的制备眼用制剂的方法来制备本申请的眼用制剂。眼用制剂通常为无菌的，并因此所述方法可包括对眼用制剂灭菌的步骤。优选地，眼用制剂是透明的并且具有类似于泪液的反射率、适合的pH(通常缓冲至pH7.5左右)以避免严重的角膜刺激和预防微生物。适于对眼部局部施用的本申请制剂优选为等渗的或略微低渗的，以便对抗由蒸发和/或疾病引起的任何泪液高渗性。这可能需要张度剂以使制剂的摩尔渗透压浓度达到或接近210-320毫渗摩尔/千克(mOsm/kg)的水平。本申请制剂一般具有220-320mOsm/kg范围的摩尔渗透压浓度，优选具有235-300mOsm/kg范围的摩尔渗透压浓度。接近或低于观察到的泪膜的表面张力值的表面张力值通常为优选的。一般将眼用制剂配制成无菌水溶液。
在某些眼用实施方案中，本申请的组合物与一种或多种泪液代替物一起配制。各种泪液代替物是本领域中已知的，包括但不限于：单体性多元醇，如甘油、丙二醇和乙二醇；聚合性多元醇，如聚乙二醇；纤维素酯，如羟丙基甲基纤维素、羧甲基纤维素钠和羟丙基纤维素；右旋糖酐，如右旋糖酐70；乙烯基聚合物，如聚乙烯醇；和卡波姆，如卡波姆934P、卡波姆941、卡波姆940和卡波姆974P。本申请的制剂或药物组合物可与隐形眼镜、角膜接触镜或其它眼科产品(如框架眼镜、近视治疗仪)一起使用。
使用维持制剂的pH值在约4.5至pH值约8的缓冲系统制备优选的制剂。最优选的制剂pH值为5.5至7.5。可选的缓冲剂为将pH维持在所需范围的生理学耐受的缓冲剂，例如磷酸钠、碳酸氢盐、琥珀酸盐、组氨酸、柠檬酸盐和乙酸盐、硫酸盐、硝酸盐、氯化物、丙酮酸盐。还可以使用抗酸剂，例如Mg(OH) 2或ZnCO 3。可以调节缓冲容量以匹配对pH稳定性最敏感的条件。
本申请的眼用制剂还可以包含清凉剂，例如薄荷脑、樟脑、冰片、香叶醇、桉叶素、芳樟醇等。混合清凉剂时，清凉剂的浓度优选0.0001～0.1w/v％。
本申请的眼用制剂还可以包含其他眼科常用治疗性组分，例如苄达酸及其盐形式(如苄达赖氨酸)、充血除去成分(例如肾上腺素、盐酸肾上腺素、盐酸麻黄碱、盐酸四氢唑啉、盐酸萘甲唑啉、硝酸萘甲唑啉、盐酸去氧肾上腺素、dl-盐酸甲基麻黄碱等)、消炎/收敛剂(例如，甲基硫酸新斯的明、ε-氨基己酸、尿囊素、盐酸小檗碱水合物、硫酸小檗碱水合物、薁磺酸 钠、甘草酸二钾、硫酸锌、乳酸锌、溶菌酶盐酸盐等)、抗组胺剂(例如盐酸苯海拉明、马来酸氯苯那敏等)、水溶性维生素类(黄素腺嘌呤二核苷酸钠、氰钴胺素、盐酸吡哆醇、泛醇、泛酸钙、泛酸钠等)、氨基酸类(例如L-天冬氨酸钾、L-天冬氨酸镁、L-天冬氨酸钾·镁(等量混合物)、氨基乙基磺酸等)、缓解视疲劳和/或眼睛干涩成分(如牛磺酸、维生素A、羟丙甲纤维素和维生素E类)、多不饱和脂肪酸(如鱼油、欧米伽-3不饱和脂肪酸、DHA、EPA)、吡拉西坦(Piracetam)、磺胺类药物、烟酸、维甲酸以及叶黄素、红景天苷、芒柄花黄素、阿托品、地巴唑、M受体阻断剂(如针对M3受体的阻断剂或拮抗剂或抑制剂)等。
本申请药物组合物的活性物质含量：药物混合时，治疗活性化合物的浓度可以选择各物质的有效的适合量，从对眼的刺激性、制剂的稳定性等的角度考虑，药物组合物中的治疗活性化合物(如长春西汀)可以以高浓度、中浓度或低浓度存在，例如占药物组合物总量的约0.0000001-100％、约0.00001-10％、约0.001-20％、约0.1-30％、约1-40％、约10-50％、约20-60％、约30-70％、约40-80％、约50-90％(w/v)，例如约1μM、约0.1μM、约0.01μM、约5μM、约10μM、约15μM、约25μM、约50μM，或者占药物组合物总量的约0.0000001％、约0.000001％、约0.00001％、约0.0001％、约0.001％、约0.01％、约0.1％、约1％、约10％(w/v)。
眼用制剂的递送：可将本申请的眼用制剂以滴眼剂(以单剂量或多剂量滴管的形式)、软膏剂、凝胶剂、乳膏剂或可生物降解的聚合物眼睛植入物(设计为缓释)的形式或通过眼睛增湿(如多剂量喷雾)递送给患者。
眼用制剂的包装应该与溶液的保留或不保留性质相关。包装方法诸如将吹塑模制、无菌填充和密封融合为单一工艺的成型-填充-封装技术可特别用于将不含防腐剂的制剂包装于单位剂量容器中。通常，这些单剂量容器是由低密度的聚乙烯或聚丙烯组成，并且包括拧开式罩盖。
本申请的制剂和方法已在用于任何可从本申请的制剂和方法中受益的受试者。受试者通常为哺乳动物，更通常为人。然而，本申请不限于治疗人，并可适用于兽医用途。因此，根据本申请，术语“受试者”、“患者”或“有需要的受试者”包括人以及非人动物，例如，包括农场动物，如羊、猪、牛和马；宠物动物，如狗和猫；实验室里的动物，如小鼠、大鼠和兔。在优选的实施方式中，所述哺乳动物是人。
在另一个方面，本申请提供了含有药物组合物的眼科装置，所述药物组合物包含长春西汀或其治疗上可接受的盐或其衍生物或其组合，优选地，其中所述眼科装置以缓释方式递送所述药物组合物。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述药物组合物是缓释制剂或结膜下储库(depot)。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述药物组合物是包含在眼科装置内的缓释制剂。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述眼科装置是隐形眼镜、角膜接触镜、眼插入物、角膜覆盖物、角膜镶嵌物、纳米圆片、脂质体、纳米颗粒、泪点塞或具有微流体储库的水凝胶基质。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述眼科装置以缓释方式递送所述药物组合物。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，将所述药物组合物配制为眼科组合物，例如，配制为用于眼科病症或病况治疗的眼科组合物。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，将所述药物组合物配制为用于前近视、近视或近视发展治疗的眼科组合物。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，将所述药物组合物配制为用于高度近视、中度近视或低度近视治疗的眼科组合物。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，将所述药物组合物配制为用于诊断为前近视(或者具有出现近视的风险)的患者的治疗的眼科组合物。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述药物组合物基本均一地分布在整个眼科装置中。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述眼科装置包含在隐形眼镜或角膜接触镜泡罩包装内。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述药物组合物将眼科装置浸没在隐形眼镜或角膜接触镜泡罩包装内。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，将所述药物组合物施用于所述患者的眼。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，局部施用所述药物组合物。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，将所述药物组合物以滴眼剂制剂、眼喷雾制剂或眼凝胶制剂的形式施用于眼。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，将所述药物组合物以眼科乳剂、眼科脂质体、纳米圆片、纳米颗粒混悬剂或眼科软膏剂的形式施用于眼。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，通过眼科装置将所述药物组合物眼科施用于患者的眼。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，每天施用所述药物组合物1、2、3、4或5次。
在某些实施方式中，如本文所公开的药物组合物可以是眼科水性制剂，如处于滴眼剂的形式。例如，如本文所述的眼科水性制剂可以包装在滴眼瓶中并作为滴剂施用。在某些实施方式中，眼科水性制剂可以作为单次施用(即，单次剂量)施用，其可以包括滴入患者眼中的一滴、两滴、三滴或更多滴。在某些实施方式中，本文所述的眼科水性制剂的一个剂量是来自所述滴眼瓶的一滴水性组合物。
在某些实施方式中，如本文所公开的药物组合物可以是眼科凝胶制剂。例如，所述眼科凝胶制剂可以包装在滴眼瓶中并作为滴剂施用。在某些实施方式中，眼科凝胶制剂可以作为单次施用(即，单次剂量)施用，其可以包括滴入患者眼中的一滴、两滴、三滴或更多滴。在某些实施方式中，本文所述的眼科凝胶的一个剂量是来自所述滴眼瓶的一滴凝胶组合物。
在某些实施方式中，如本文所公开的药物组合物可以是眼科软膏剂制剂。例如，所述眼科软膏剂制剂可以包装在管或其它可挤压容器内，所述管或其它可挤压容器具有通过其将递送软膏剂条的分配管口。在某些实施方式中，眼科软膏剂制剂可以作为单次施用(即，单次剂量)施用，其可以包括进入患者眼中的一条或多条。在某些实施方式中，眼科软膏剂的一个剂量是通过分散管管口分配的一条软膏剂组合物。
利用本文描述的治疗有效量的治疗组合物或制剂来治疗一对象可以包括单次治疗或一系列治疗。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述方法预防受治疗患者的近视发展。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述方法控制受治疗患者的近视发展。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述方法减轻受治疗患者的近视发展。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述方法减缓或降低受治疗患者的近视发展。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述方法将受治疗患者的近视发展控制、减缓、降低、延迟和/或减轻在相对于未治疗的以下范围内：约5-95％之间，约5-90％之间，约5-80％之间，约5-70％之间，约5-60％之间，约5-50％之间，约5-40％之间，约5-30％之间，约5-20％、约10-100％之间，约20-90％之间，约30-90％之间， 约40-90％之间，约50-90％之间，或约75-90％之间。
在本文所公开的药物组合物、制剂、眼科装置或治疗方法的某些实施方式中，所述药物组合物、制剂、眼科装置或治疗方法的使用将被施用对象眼的屈光度变负幅度限制在约1.0-6.0D、1.0-5.0D、1.0-4.0D、1.0-3.0D、1.0-2.0D、小于6.0D、小于5.0D、小于4.0D、小于3.0D、小于2.0D和小于1.0D。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述方法逆转了受治疗患者中的近视发展。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述患者患有高度近视、中度近视或低度近视。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述患者是前近视(或者具有发展为近视的风险)。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述方法预防、控制、减缓、降低、减轻、延迟和/或逆转了受治疗患者眼的轴向(或纵向)生长，即眼轴延长和/或玻璃腔长度增加。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述药物组合物、眼科装置或治疗方法将受治疗的患者(如轻度近视、儿童或青少年近视)的眼轴延长和/或玻璃腔长度增加控制、减缓、减轻、降低、延迟和/或逆转在相对于未治疗的以下范围内：约5-95％之间，约5-90％之间，约5-80％之间，约5-70％之间，约5-60％之间，约5-50％之间，约5-40％之间，约5-30％之间，约5-20％、约10-100％之间，约20-90％之间，约30-90％之间，约40-90％之间，约50-90％之间，或约75-90％之间。
在本文所公开的药物、制剂、组合物、眼科装置或治疗方法的某些实施方式中，所述方法控制、终止、减缓、降低、延迟和/或减轻了诊断为患有近视或者具有发展为近视的风险的患者的近视发生、发展，提高了所述患者眼(例如，近视眼、前近视眼或者具有出现近视的风险的眼)的脉络膜厚度和/或降低了所述患者眼(例如，近视眼、前近视眼或者具有出现近视的风险的眼)的轴向(或纵向)生长速度，即眼轴延长和/或玻璃腔长度增加被抑制。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述方法将受治疗患者眼的轴向(或纵向)生长相对于未治疗控制、减缓、降低、延迟和/或减轻了约5-95％之间，约5-90％之间，约5-80％之间，约5-70％之间，约5-60％之间，约5-50％之间，约5-40％之间，约5-30％之间，约5-20％之间，约10-100％之间，约20-90％之间，约30-90％之间，约40-90％之间，约50-90％之间或约75-90％之间。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述药物组合物、眼科装置或治疗方法预防、控制、减缓、降低、减轻、改变、延迟和/或逆转了受治疗患者眼的近视屈光度。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述药物组合物、眼科装置或治疗方法相对于阿托品单一疗法导致了不太严重的不良反应。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述药物组合物、眼科装置或治疗方法相对于阿托品单一疗法产生了较小的瞳孔尺寸增加或者对瞳孔大小没有影响。
在本文所公开的药物组合物、眼科装置或治疗方法的某些实施方式中，所述药物组合物、眼科装置或治疗方法相对于阿托品单一疗法抑制了正常眼的眼轴或屈光度向近视眼发展的程度。
实施例1、近视动物模型和给药实验
形觉剥夺和镜片诱导豚鼠近视模型是本领域经典且公认的近视动物模型，可用于近视治疗药物的疗效和安全性评估，其构建方式是本领域技术人员熟知的。本申请动物造模和给药方式参考本课题组之前已发表科学文献(Sen Zhang，Invest Ophthalmol Vis Sci.2019 Jul 1；60(8):3074-3083.；Miaozhen Pan，Exp Eye Res.2021 Jan；202:108332.)，具体的，本申请采 用示例性的形觉剥夺和镜片诱导豚鼠近视模型构建方式如下：
采用3周龄三色豚鼠(雌雄均用，模拟人3-26岁)，饲养于温州医科大学实验动物房，12小时光照(400-500lux)/12小时黑暗环境，自由饮水、取食。近视模型采用单眼形觉剥夺(FD)和镜片诱导(LI)造模方式。形觉剥夺使用特制透光率1％、不自行脱落眼罩完全遮盖动物右眼睛，另一只眼(左眼)获得正常的视觉。镜片诱导组使用-4D镜片固定于动物右眼前，左眼获得正常的视觉，以上动物每天两次清洁镜片防止镜片模糊。实验组动物每日上午9:00-9:30给药。给药时，阴性、阳性对照组及实验组动物分别在红光下取下眼罩或镜片，并给以右眼眼球周注射0.1mL的溶剂对照、或受试药物(不同浓度长春西汀)、或阳性对照(0.1％阿托品)，注射后确定动物给药成功无创伤并立即复原眼罩或镜片。每只动物给药过程控制在10s左右。造模当天开始给药，形觉剥夺组连续给药2周，镜片诱导组连续给药1周。本实验已通过温州医科大学实验动物伦理委员会审议。
实验组中所用长春西汀滴眼液配制方法如下：
据报道长春西汀(VPN)室温时在水中的溶解度为2.4μg/mL，发明人配制5μM(即为1.75μg/mL)的长春西汀储存液，溶剂为生理盐水，于-80℃保存，给药实验前用生理盐水分别稀释至1μM、0.1μM、0.01μM。长春西汀的滴眼液在配制过程中可以选择使用加热、搅拌等常规物理助溶方法，也可以使用酸类调整PH值以增加溶解度，最后将PH值调整到7.31即可。上述长春西汀滴眼液在常温时透明、稳定。
动物分组如下：
一、形觉剥夺组(FDM)：
1、形觉剥夺加溶剂注射组：单眼佩戴眼罩并给佩戴眼注射溶剂生理盐水2周，样本量＝20。
2、形觉剥夺加药物注射组：
单眼佩戴眼罩并给佩戴眼注射长春西汀(0.01μM:0.1mL/天)2周，样本量＝15；
单眼佩戴眼罩并给佩戴眼注射长春西汀(0.1μM:0.1mL/天)2周，样本量＝20；
单眼佩戴眼罩并给佩戴眼注射长春西汀(1.00μM:0.1mL/天)2周，样本量＝22；
3、形觉剥夺加阳性对照组：单眼佩戴眼罩并给佩戴眼注射阿托品(0.1％：0.1mL/天)2周，样本量＝15。
二、镜片诱导组(LIM)：
1、镜片诱导加溶剂注射组：单眼佩戴-4D镜片并给佩戴眼注射溶剂生理盐水1周，样本量＝10。
2、镜片诱导加药物注射组：
单眼佩戴-4D镜片并给佩戴眼注射长春西汀(0.01μM:0.1mL/天)1周，样本量＝12；
单眼佩戴-4D镜片并给佩戴眼注射长春西汀(0.1μM:0.1mL/天)1周，样本量＝12；
单眼佩戴-4D镜片并给佩戴眼注射长春西汀(1.00μM:0.1mL/天)1周，样本量＝13；
3、镜片诱导加阳性对照组：单眼佩戴眼罩并给佩戴眼注射阿托品(0.1％：0.1mL/天)1周，样本量＝11。
其中，溶剂对照组与实验组的区别在于不含活性成分。
入组动物屈光度和眼球参数测量
同一模型药效实验所有动物在同一时间段内测量，第一次测量时间为3周龄，即给药前。对上述FDM组动物在实验前、实验1周给药后和实验2周给药后；LIM组动物在实验前、实验3天给药后和实验7天给药后分别进行屈光度和眼轴参数的检测。屈光度的测量采用本实验室搭建的红外偏心验光仪(eccentricinfraredphotoretinoscope，EIR)，每只眼检测3次取平均值作为最终结果。豚鼠眼轴参数的测量采用CinescanA/B超声诊断仪(QuantelMedical，Aviso，France)中的A超探头测量，超声频率为11MHz，眼球不同屈光介质的超声传播速度分别设定为：前房1557.5m/s，晶状体1723.3m/s，玻璃体1540m/s。检测内容包括玻璃体腔深度(vitrous chamber depth，VCD)和眼轴长度(axial length，AL)。检测前2min左右用0.5％盐酸丙美卡因滴眼液(Alcon，Belgium)对豚鼠检测眼进行眼表面麻醉，每只眼测量6次， 取其平均值作为最终结果。
脉络膜血流和厚度的测量
对上述FDM组动物在连续给药1周时和给药2周实验结束后；LIM组动物在给药7天实验结束后分别进行脉络膜血流参数和脉络膜厚度的检测。脉络膜血流参数和厚度的检测采用经改造的商品化OCTA(Spectralis HRA+OCT,OCTA，海德堡，德国)，使之更适应于动物眼球。检测前将豚鼠充分麻醉(盐酸氯胺酮60mg/kg与盐酸甲苯噻嗪9mg/kg的混合物，腹腔注射)，之后获取豚鼠OCTA图像，并通过自编程序(MatLab R2017a,MathWorks)对测量结果进行量化，实现了对豚鼠的脉络膜血流量和厚度的实时定量检测(Sen Zhang，Invest Ophthalmol Vis Sci.2019 Jul 1；60(8):3074-3083)。
实施例2、在眼部局部施用长春西汀的效果实验
实验方法如实施例1。FDM组给药前、给药1周和给药2周后分别进行所有受试动物双眼屈光、玻璃体腔和眼轴检测；LIM组给药前、给药3天和给药7天后分别进行所有受试动物双眼屈光、玻璃体腔和眼轴检测。所有数据采用重复测量的方差分析进行分析，其中P值小于0.05为显著性差异，小于0.01为差异极显著。
实验结果：
一、单独施用长春西汀就能有效的抑制FDM诱导近视的发生发展(F3,73＝14.66,p<0.001)。FDM组给药一周后，生理盐水注射组诱导近视-4.94±2.35D，两周后该组诱导近视-6.74±1.90D，玻璃体腔深度和眼轴长度都有相应的延长，显示造模成功。1μM长春西汀连续给药一周后，就能有效的抑制FDM近视和相应眼轴、玻璃体腔深度延长，具体的：FDM+Vehicle vs.FDM+VPN(1μM)：-4.94±2.35vs.-2.44±1.88D,p<0.01,屈光抑制率为50.5％；玻璃体腔深度也得到相应的抑制，FDM+Vehicle vs.FDM+VPN(1μM)：0.11±0.04vs.0.06±0.05mm,p<0.01,玻璃体腔深度抑制率为45.0％，眼轴长度也被抑制，FDM+Vehicle vs.FDM+VPN(1μM)：0.11±0.05vs.0.07±0.05mm,p＝0.09,眼轴长度抑制率为39.8％。另外的中浓度长春西汀给药组近视治疗的相应指标及结果也提示长春西汀及其相关化合物可以用于近视治疗。发明人甚至在低浓度长春西汀给药组(仅0.01μM)两个药效检测时间点发现，虽然没有统计学差异，但屈光度变负进程和玻璃体腔深度延长较阴性对照组出现抑制趋势。比较阳性对照组近视治疗结果，用药1周后0.1％阿托品组模型诱导的近视为-3.20±1.73D，屈光抑制率为35.2％，玻璃体腔深度为0.08±0.05mm,玻璃体腔深度抑制率为31.5％，眼轴长度为0.08±0.05,眼轴长度抑制率为32.1％。从上述结果可以看出，高浓度的长春西汀在近视防控方面药效优于阿托品，中浓度长春西汀近视治疗与阿托品疗效近似(图1A-C)。
长春西汀连续给药两周后，也能有效的抑制FDM模型近视。FDM+Vehicle vs.FDM+VPN(1μM)：-6.74±1.90vs.-3.36±2.21D,p<0.001,屈光抑制率为50.1％，个别动物甚至屈光度较上次检测几乎没有变化，玻璃体腔深度也起到相应的抑制，FDM+Vehicle vs.FDM+VPN(1μM)：0.16±0.07vs.0.09±0.05mm,p<0.001,玻璃体腔深度抑制率为43.4％，眼轴长度也起到相应的抑制，FDM+Vehicle vs.FDM+VPN(1μM)：0.16±0.06vs.0.08±0.05mm,p<0.001,眼轴长度抑制率为48.2％；而此时0.1％阿托品诱导的近视为-3.38±2.79D，屈光抑制率为49.8％，玻璃体腔深度为0.10±0.05mm,玻璃体腔深度抑制率为38.2％，眼轴长度为0.10±0.05mm,眼轴长度抑制率为41.0％(图1A-C)，阿托品使用过程中观察到动物瞳孔放大现象。
此外，由图1可以看出，长春西汀在形觉剥夺近视模型治疗中存在正相关的量效关系，随着给药量的增加，近视治疗效果更强，眼轴长度和玻璃体腔深度也表现出同样的抑制效果。相较于对照组，长春西汀可以明显抑制形觉剥夺性近视屈光度变负、明显抑制形觉剥夺性近视眼轴长度延长、以及玻璃体腔深度延长。同时，长春西汀在FDM模型近视治疗方面的综合表现也优于阿托品，尤其是针对屈光度变负进程的抑制效果。
二、长春西汀能有效的抑制LIM诱导近视的发生发展(F3,43＝4.073,p＝0.012)。LIM组实验3天后，生理盐水注射组诱导近视-3.25±1.20D，7天后诱导近视-3.93±1.26D，玻璃体腔 深度和眼轴长度都有相应的增加或延长。1μM长春西汀给药3天后，就能有效的抑制LIM模型近视，LIM+Vehicle vs.LIM+VPN(1μM)：-3.25±1.20vs.-2.00±0.82D,p<0.05,屈光抑制率为38.5％，玻璃体腔深度也起到相应的抑制，LIM+Vehicle vs.LIM+VPN(1μM)：0.07±0.03vs.0.03±0.03mm,p<0.01,玻璃体腔深度抑制率为58.8％，眼轴长度也起到相应的抑制，LIM+Vehicle vs.LIM+VPN(1μM)：0.08±0.02vs.0.04±0.02mm,p<0.001,眼轴长度抑制率为55.5％；而此时0.1％阿托品诱导的近视为-2.34±0.73D，屈光抑制率为30.0％，玻璃体腔深度为0.04±0.03mm,玻璃体腔深度抑制率为47.3％，眼轴长度为0.04±0.02mm,眼轴长度抑制率为47.4％。可见，高浓度(1μM)长春西汀组的所有近视治疗指标均好于阿托品。相较于阴性对照组，高、中、低三个浓度的长春西汀给药组都表现出近视治疗的效果(图2A-C)。
长春西汀给药7天后，也能有效的抑制LIM模型近视。通过整个给药周期内不同实验组中屈光度变负进程的变化趋势比较，发现长春西汀可以显著减缓镜片诱导近视模型中近视加重速度。屈光度结果为LIM+Vehicle vs.LIM+VPN(1μM)：-3.93±1.26vs.-2.61±1.17D,p<0.05,屈光抑制率为36.3％，玻璃体腔深度也起到相应的抑制，LIM+Vehicle vs.LIM+VPN(1μM)：0.09±0.04vs.0.05±0.02mm,p<0.001,玻璃体腔深度抑制率为49.8％，眼轴长度也起到相应的抑制，LIM+Vehicle vs.LIM+VPN(1μM)：0.10±0.04vs.0.05±0.02mm,p<0.001,眼轴长度抑制率为53.8％；而此时0.1％阿托品诱导的近视为-2.61±1.17D，屈光抑制率为33.4％，玻璃体腔深度为0.05±0.03mm,玻璃体腔深度抑制率为45.7％，眼轴长度为0.06±0.03mm,眼轴长度抑制率为41.8％(图2A-C)，阿托品使用过程中观察到动物瞳孔放大现象。可见，高浓度长春西汀在LIM模型近视治疗方面的综合表现都优于(高浓度)阿托品，尤其是从药物安全性和有效性角度去评价二者的成药性。
由图2还可以看出，不同浓度长春西汀在镜片诱导近视模型治疗中也存在正相关的量效关系。同时，长春西汀能在近视出现的早期就起到很高的抑制效果，且能一直维持这样的抑制效果，即长春西汀所表现出的优异的近视防控药效与近视严重程度或屈光度变负速度无关。此外，相较于生理盐水组，所有长春西汀治疗组在整个给药周期中几乎都明显抑制镜片诱导性近视屈光度变负进程、延缓了近视的发生发展、明显抑制镜片诱导性近视眼轴长度延长、以及玻璃体腔深度增加。
针对两种公认的近视药效评价动物模型数据，长春西汀都表现出优异的近视治疗效果，对屈光度变负进程的抑制及减缓程度与相应的对眼轴延长的抑制和对玻璃体腔深度增加的抑制一致，证明长春西汀主要通过控制眼轴延长和玻璃体腔深度的增加来治疗近视。发明人意外发现单独使用长春西汀，在近视尤其是轴性近视的治疗中，长春西汀表现出的药效甚至优于高度的阿托品(0.1％阿托品)。值得注意的是，上述长春西汀对于近视的治疗效果，与施药对象的性别、年龄、近视种类、近视进展速度和近视严重程度无关。
所有长春西汀组受试动物给药期间未观察到眼部异常，长春西汀对幼龄豚鼠局部给药期间受试眼瞳孔大小未观察到明显改变，也没有过敏现象。同时，所有长春西汀组受试动物给药期间未观察到有个体出现长春西汀常见临床不良反应或体重减轻等毒性表现。
从药效学结果评价和长期连续用药的安全性角度考虑，长春西汀可以被用于预防、治疗和控制近视，尤其是儿童及青少年近视的防控。
实施例3、长春西汀治疗近视的机制
长春西汀具有改善血液循环的作用已被人们熟知。发明人采用实施例1的方法，在给药周期内不同时间点检测FDM(给药1周和2周)和LIM(给药1周)的脉络膜厚度ChT和脉络膜血流ChBP指标信号变化的情况。发现：与溶剂注射组相比，治疗有效量的长春西汀对脉络膜厚度增加和脉络膜血流灌注仅有轻微增加但是没有统计学意义(FDM模型中，ChBP：F 3,59＝1.294,p＝0.285,图3A-B；LIM模型中，ChBP：F 3,44＝0.383,p＝0.766,图4A-B)。另外，综合考察药物对屈光度、眼轴长度等近视治疗指标抑制情况和对应时间点长春西汀对脉络膜厚度增加和脉络膜血流灌注影响，发现其近视治疗和控制近视进展真实药效和扩张血管(增加脉络膜血流)的假定药理这两者也不是逻辑对应关系，存在矛盾之处有给药1周后 形觉剥夺组的相关检测数据，即不同浓度长春西汀都可以有效抑制屈光度变负、玻璃体腔深度增加等指标，表现出显著的近视治疗效果并有正相关的量效关系，但长春西汀对脉络膜血流灌注影响却表现出负相关的量效关系，并且各浓度长春西汀对脉络膜血流灌注的影响，相较于阿托品组，都与阴性对照组趋势相近。特别是高浓度组长春西汀(1μM)，虽然改善脉络膜血流效果最差，但对近视抑制屈光度变负进程却药效最强(图1A-B和图3B)；再如在2周时，形觉剥夺组中浓度(0.1μM)的长春西汀表现出的眼轴参数方面的近视治疗效果和阿托品相仿，但其对脉络膜血管扩张作用却不及阿托品(图1B-C和图3B)。
综上，长春西汀治疗近视的药理并不是通过扩张眼部血管或改善眼部血液循环或增加脉络膜血流量的机制，而是可能更依赖于一种其从未被人们认识到的(眼部)功能，该功能对应的生物学靶点甚至跟长春西汀已知的扩张血管作用靶点存在竞争结合关系。
实施例4、长春西汀通过全身给药控制近视进展的效果
本实验目的是评估长春西汀通过全身给药(如静脉滴注或灌胃)对近视治疗、尤其是对近视进展的控制效果，根据屈光度、眼轴长度、玻璃体腔深度、体重等指标综合分析药物的有效性和安全性。在大鼠中，长春西汀的口服生物利用度为52％(Vereczkey et al.,1979a)，灌胃LD50值约为500mg/kg(Cholnoky and
Figure PCTCN2022106704-appb-000002
1976)。文献同时报道对啮齿类动物给予致死剂量的长春西汀后，动物多出现共济失调和阵挛性惊厥(ataxia and clonic convulsions)的临床表现(Cholnoky and
Figure PCTCN2022106704-appb-000003
1976)。根据FDA公布的长春西汀就啮齿类动物安全性评价数据，其采取灌胃给药生育龄动物，大鼠每天给药20mg/kg没有明显异常，给药40mg/kg及以上出现体重减轻摄食减少毒性表现；兔子每天给药75mg/kg没有明显异常，给药150mg/kg开始出现体重减轻摄食减少毒性表现。目前中国在售长春西汀剂型包括片剂和注射液，根据豚鼠正常生活习性和形觉剥夺造模要求以及考虑未来近视治疗临床使用用药依从性原则，发明人认为采取灌胃给药方式来评价长春西汀全身给药在近视治疗中的药效近似或优于静脉滴注给药方式。豚鼠灌胃单次给药量同时参考长春西汀在相近物种中的口服生物利用度和相应的啮齿类动物灌胃毒性剂量来制定，该给药量应基本保持豚鼠正常的生理状态且不使其出现如共济失调或阵挛性惊厥等严重毒性反应。
每天连续给药评估长春西汀按照全身给药方式对近视进展的抑制效果，同时观察使用剂量毒性表现。本实验使用的形觉剥夺近视动物模型及长春西汀近视治疗药效评估方法与本申请中其它相关的实施例(局部给药)相同，其中豚鼠形觉剥夺近视模型(FDM)造模及灌胃给药均参考发明人所在实验室已经发表文献操作及执行(Pan Miaozhen,Proc Natl Acad Sci U S A.2021 Oct 26；118(43):e2104689118)。具体为健康的3周龄三色豚鼠(雌雄不限)在剔除有明显眼部疾病或异常个体后，经过屈光度(红外偏心摄影验光仪)和眼轴(A超)检测，选取屈光力在3-8diopter(D)间且双眼屈光参差不超过2D动物，将其随机分成以下3组：形觉剥夺(FDM)+溶剂对照(Vehicle)组、FDM+低剂量长春西汀组(VPN)和FDM+高剂量VPN组，三组动物给药前体重均值基本相同且彼此间没有统计学差异。实验第一天上午8点开始给豚鼠进行形觉剥夺(FD)近视造模。形觉剥夺近视模型采用面罩法，头套由发明人利用10寸乳白色无毒乳胶气球制作，豚鼠造模个体右眼遮盖头套(实验眼)，左眼不遮盖头套(对侧眼)。FD诱导在整个长春西汀灌胃药效实验周期中持续进行，仅眼部检测(如屈光度检测)时短暂取下头套。药效实验开始后的每日早8点、中午12点、晚7点及给药前检查头套位置，淘汰头套脱落3次以上的个体。造模当日开始每日上午9-10点间给予FDM模型对应的溶剂或药物，给药方式是灌胃，给药量分别为50mg/kg/d(低剂量)和100mg/kg/d(高剂量)，实际给药按照每组动物体重均值计算，溶剂组灌胃体积按照5mL/kg/d。每日给药1次连续给药2周。该模型药效实验开始时、进行1周和2周时检测受试动物屈光度和眼轴参数，所有数据收集及处理方式均与发明人所在实验室已经发表文献相同(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)，统计依据为同一受试个体实验眼和对侧眼的差值，同时在实验周期内记录所有受试个体体重。本实施例发明人使用的长春西汀灌胃液配制方法如下：据报道 长春西汀室温时在0.5％的甲基纤维素中溶解度可达200mg/mL(Waidyanatha S et al，Systemic exposure of vinpocetine in pregnant Sprague Dawley rats following repeated oral exposure:An investigation of fetal transfer，Toxicol Appl Pharmacol,338:83-92,15 Nov 2017)。在不添加其它药学辅料或其它化合物的条件下，发明人将长春西汀化合物粉剂直接完全溶解于0.5％的甲基纤维素溶剂(无菌水+甲基纤维素)中分别配制成10mg/mL和20mg/mL的长春西汀制剂(灌胃液)。室温下该制剂整体外观澄清、透明、均一且无肉眼可见悬浊物质。所述制剂制备过程视情况可能使用加热、搅拌、pH调节等常规物理及化学助溶手段，所述制剂给药前无化合物析出情况出现。
实验结果发现阴性对照组动物的屈光度和眼轴参数变化均符合近视模型预期，证明本次实验形觉剥夺近视模型造模成功，可用于受试药物药效评价。如图5所示，在整个治疗周期中，无论从屈光度还是眼轴参数判断，长春西汀全身给药组相对溶剂对照组都有治疗近视和抑制近视进展的趋势。同时，长春西汀组的体重增长明显被抑制。以低浓度灌胃组为例说明：给药1周时，50mg/kg组长春西汀给药组体重明显低于溶剂组，FDM+Vehicle vs.FDM+VPN(50mg/kg)：208.5±14.9vs.188.0±22.9mg,p<0.05,体重均值减小9.9％；给药2周时，50mg/kg组长春西汀给药组体重增长明显被抑制，FDM+Vehicle vs.FDM+VPN(50mg/kg)：229.6±21.4vs.210.2±21.9mg,p<0.05,体重均值减少8.4％，可见，在每日给药剂量达50mg/kg时就已经对实验动物产生了实质毒性，继续增加长春西汀用量将会加大对受试个体的毒害风险。然而值得强调的是，发明人观察到灌胃给药长春西汀对近视治疗尤其是抑制近视进展存在确定的量效关系：即随着灌胃给药量的增加，长春西汀通过全身给药方式对近视治疗的药效越加明显。相比于50mg/kg剂量给药，当按照100mg/kg剂量灌胃给药时，受试个体屈光度变负程度和眼轴长度延长进一步被抑制。以给药治疗结束时三组动物屈光度和眼轴参数说明，其中屈光度：FDM+Vehicle vs.FDM+VPN(50mg/kg)vs.FDM+VPN(100mg/kg)：-6.59±1.42vs.-5.71±2.41vs.-5.223±2.20D；玻腔深度：FDM+Vehicle vs.FDM+VPN(50mg/kg)vs.FDM+VPN(100mg/kg)：0.12±0.05vs.0.13±0.07vs.0.10±0.06mm；眼轴长度：FDM+Vehicle vs.FDM+VPN(50mg/kg)vs.FDM+VPN(100mg/kg)：0.14±0.05vs.0.13±0.05vs.0.11±0.05mm。由上述结果可以得出结论：长春西汀通过全身给药同样有潜能抑制近视进展和达到显著治疗近视的效果，但与局部用药相比，全身给药应该需要采用更大的剂量或更长的用药治疗时间。安全性评价方面，采用直接全身施用(如直接静脉输注或口服片剂)长春西汀用于近视治疗的方案将会带来一定程度的副作用(比如体重下降或增大流产风险)，所以更推荐采用局部施用的方式，因为患者通过口服等全身给药方式利用长春西汀来治疗近视将承担额外的临床风险。
可见，无论是全身给药或是局部给药，长春西汀都可以用于近视的预防和治疗。相比于全身给药，长春西汀局部给药对于防控近视进展是更优的选择。应当理解，本实施例结果与本申请的结论并不矛盾，而是意在提示：直接施用长春西汀进行近视防控和治疗时，优选采用更加安全、高效、方便的局部给药方式(优选为眼部给药)，但并不排除通过全身给药途径，例如利用特定的药物靶向技术等在有效降低全身给药的药物毒性的同时又可以在眼部使长春西汀药物富集等实现安全、高效、方便的全身给药方式来治疗或抑制近视。
实施例5、沙美特罗及噻托溴铵治疗近视
利用本发明所描述的豚鼠形觉剥夺近视模型评价药效，所有个体经过屈光度和眼轴检测，去除不符合条件的动物后，随机分成5组：单独使用长春西汀治疗组、沙美特罗+噻托溴铵+长春西汀联合治疗组、沙美特罗+噻托溴铵联合治疗组、阴性对照组(溶剂组)和0.1％阿托品组(阳性对照组)，其中沙美特罗(salmeterol,S)和噻托溴铵(tiotropium,T)使用浓度分别为1×10 -5M和1×10 -6M，长春西汀使用浓度无论是单独给药还是联合给药都是1μM。实验第一天上午8点给豚鼠进行形觉剥夺，采用面罩法，右眼遮盖(实验眼)，左眼不遮盖(对侧眼)。造模当天开始每日上午9-10点给予实验眼对应组的溶剂或药物，球旁结膜下注射，注射体积为100μL，每日1次连续给药2周。药效实验开始前和实验结束时检测动物屈 光度和眼轴参数，所有数据收集及处理方式均与本发明其它实施例相同，统计依据为同一受试个体实验眼和对侧眼的差值。
实验结果显示阴性对照组动物的屈光度和眼轴参数变化符合近视模型预期，并且阳性对照药物阿托品在实验中表现出应有药效，这些都证明本次实验近视模型造模成功，可用于受试药物药效评价。在给药干预后，不论是屈光度还是眼轴参数，沙美特罗+噻托溴铵联合治疗组相较于阴性对照组都没有统计学差异，具体数据为给药2周后，屈光度：FDM+Vehicle vs.FDM+S+T(salmeterol,10 -5M+tiotropium,10 -6M)：-6.00±1.61vs.-5.09±1.80D,p>0.05，玻腔深度：FDM+Vehicle vs.FDM+S+T(salmeterol,10 -5M+tiotropium,10 -6M)：0.12±0.05vs.0.12±0.06mm,p>0.05，眼轴长度：FDM+Vehicle vs.FDM+S+T(salmeterol,10 -5M+tiotropium,10 -6M)：0.13±0.04vs.0.13±0.08mm,p>0.05。上述结果可以充分证明沙美特罗和噻托溴铵对近视个体没有任何治疗作用，其不能有效控制近视进展。相较阴性对照组，在二周给药结束时单独使用长春西汀(1μM)治疗组和0.1％阿托品组与本发明其它实施例近视治疗结果一致，二者都显著地抑制了近视个体的屈光度变负、眼轴长度延长以及玻璃体腔深度增加(如图6所示，长春西汀(1μM)治疗组与溶剂对照组存在统计学差异)。长春西汀治疗组眼部未见异常，阿托品组出现扩瞳现象，该两组受试动物角膜曲率(RCC)、前房深度(ACD)和晶体厚度(LT)相关指标亦没有受到药物影响(见图6)。因此，在同时满足幼龄个体用药眼部安全性的前提下，长春西汀作为唯一活性成分或主要活性成分或直接活性成分可以有效防控近视，显著抑制、控制和减缓近视进展。
除此之外，沙美特罗+噻托溴铵+长春西汀联合治疗组和单独使用长春西汀(1μM)治疗效果相近，整个用药期间二者就豚鼠近视模型的屈光度、眼轴长度以及玻璃体腔深度指标都不存在统计学差异，提示沙美特罗和噻托溴铵都没有表现出对长春西汀近视治疗有协同作用或促进作用。综合分析沙美特罗+噻托溴铵+长春西汀三者联合给药在有效性方面与单独使用长春西汀治疗近视无显著性差异，再结合沙美特罗+噻托溴铵治疗组对近视无显著药效作用，得出沙美特罗+噻托溴铵+长春西汀联合给药仅是其中长春西汀发挥治疗近视的效果，即长春西汀作为唯一活性成分或主要活性成分或直接活性成分可用于近视防控，其可以有效控制近视进展。单独使用长春西汀治疗近视在安全性方面、有效性方面和成药性方面都优于本实施例药物联合治疗组。
实施例6、无创给药(滴眼液剂型)条件下长春西汀可以有效防控近视
本实验目的是评估长春西汀通过无创给药途径对近视的影响，所有的受试药物制成滴眼液剂型。利用本发明所描述的豚鼠形觉剥夺近视模型评价药效，所有个体经过屈光度和眼轴检测，去除不符合条件的动物后，随机分成4组：长春西汀低浓度(1μM)组、长春西汀高浓度(5μM)组、阴性对照组(溶剂组)和0.1％阿托品组(阳性对照组)。实验第一天上午8点给豚鼠进行形觉剥夺，采用面罩法，右眼遮盖(实验眼)，左眼不遮盖(对侧眼)。造模当天开始每日上午9-10点和下午14-15点给予所有实验眼对应组的溶剂或药物，直接滴眼给药，单次滴眼液施用体积均为25μL，每日2次连续给药2周。药效实验开始前和实验结束时检测动物屈光度和眼轴参数，所有数据收集及处理方式均与本发明其它实施例相同，统计依据为同一受试个体实验眼和对侧眼的差值。本实施例使用的长春西汀滴眼液和阿托品滴眼液都由发明人利用0.9％生理盐水自行配制，上述滴眼液没有添加其它活性物质或辅料。
实验结果显示阴性对照组动物的屈光度和眼轴参数变化符合近视模型预期，并且阳性对照药物阿托品在实验中表现出应有药效，这些都证明本次实验近视模型造模成功，可用于长春西汀(滴眼液剂型)药效评价。
通过无创给药的方式，长春西汀眼药水能够有效的抑制近视的发生发展(屈光：F 2,42＝9.115,p<0.001；玻腔：F 2,42＝6.243,p＝0.04；眼轴：F 2,42＝8.986,p<0.001)，且存在量效关系，即给药浓度越高，近视(眼)治疗效果越好，并且不同浓度长春西汀药物组之间在近视治疗中的眼轴参数指标存在统计学差异。由于造模方式、豚鼠眼部结构(眼球相对人来说比较凸而且不会主动闭眼)和动物正常眨眼，每个受试眼通过滴眼给药实际获得的药物有效治疗剂量都低 于相同体积下眼部的球周注射给药量，而且受试动物每天滴眼液给药总体积也小于实施例2的注射给药体积。因此，本实施例中不论低浓度长春西汀滴眼液组还是0.1％的阿托品组，滴眼液直接滴眼给药的药效(屈光度指标)都逊于其球周注射给药对近视的治疗效果，具体结果如图7所示：高浓度组5μM长春西汀连续给药2周，可以有效的抑制FDM近视度数发展和相应眼轴、玻璃体腔深度延长，具体的：FDM+Vehicle vs.FDM+VPN(5μM)：-6.56±1.70vs.-3.80±1.16D,p<0.001,屈光抑制率为42.1％；玻璃体腔深度也得到相应的抑制，FDM+Vehicle vs.FDM+VPN(5μM)：0.14±0.05vs.0.09±0.04mm(实际数值0.0869±0.0448mm，经四舍五入),p<0.01,玻璃体腔深度抑制率为38.6％；眼轴长度也被抑制，FDM+Vehicle vs.FDM+VPN(5μM)：0.16±0.04vs.0.09±0.04mm(实际数值0.0925±0.0406mm，经四舍五入),p<0.001,眼轴长度抑制率为41.4％。低浓度1μM长春西汀给药组也同样能有效控制近视进展：FDM+Vehicle vs.FDM+VPN(1μM)：-6.56±1.70vs.-4.81±1.72D,p<0.05,屈光抑制率为26.7％。比较阴性对照组近视进展，用药2周后0.1％阿托品滴眼液组模型诱导的近视为-3.93±1.75D，屈光抑制率为40.0％，玻璃体腔深度为0.11±0.05mm(实际数值0.1107±0.0502mm，经四舍五入),玻璃体腔深度抑制率为21.8％，眼轴长度为0.11±0.05mm(实际数值0.1093±0.0530mm，经四舍五入),眼轴长度抑制率为30.7％。阿托品组给药期间出现瞳孔扩张不良反应而长春西汀组未见明显眼部异常。无论是阿托品还是长春西汀近视干预，受试个体的角膜曲率、前房、晶体相关指标均没有受到影响(见图7)。在发明人所在实验室，针对目前临床试验浓度使用较多的0.01％阿托品滴眼液，在本实施例相同给药条件下(近视模型、给药方式、给药频率和给药体积等保持一致)，该浓度阿托品对豚鼠近视模型没有观察到任何治疗效果，无论是屈光度指标还是眼轴参数指标0.01％阿托品都无显著干预效果，这可能和滴眼液剂型动物滴眼给药后停留在眼球表面的时间短有关。因此，从药效和安全性角度评价，长春西汀对近视个体治疗的用药风险收益比优于阿托品(如白天使用长春西汀不会出现在近视治疗的同时类似阿托品扩瞳引起的畏光现象)，尤其适用于儿童及青少年人群近视治疗和学龄阶段人群近视防控。
本实施例证明：长春西汀眼药水采取滴眼给药方式和球旁结膜下注射给药一样可以明显抑制近视屈光度变负、明显抑制近视眼轴长度延长、以及玻璃体腔深度增加。这种给药方式同样存在正相关的量效关系，即长春西汀给药量越高，近视治疗效果越明显。同时，在采取无创给药的情况下，长春西汀在近视治疗方面的综合表现也优于阳性对照阿托品，尤其是针对近视进展的控制效果。
实施例7、长春西汀代谢产物阿维卡明酸(Apovincaminic acid,AVA)可以有效防控近视
利用本发明所描述的豚鼠形觉剥夺近视模型评价药效，所有个体经过屈光度和眼轴检测，去除不符合条件的动物后，随机分成3组：单独使用阿维卡明酸组、阴性对照组(溶剂组)和0.1％阿托品组(阳性对照组)，其中阿维卡明酸(AVA)的使用浓度为1μM。近视个体造模方法与本发明其它实施例相同，所有组采取球旁结膜下注射给药，注射体积为100μL，每日1次连续给药1周。药效实验开始前和实验结束时检测动物屈光度和眼轴参数，所有数据收集及处理方式均与本发明其它实施例相同，统计依据为同一受试个体实验眼和对侧眼的差值。本实施例使用的AVA注射液和阿托品注射液都由发明人利用0.9％生理盐水自行配制，无添加其它活性物质或辅料。
实验结果显示阴性对照组动物的屈光度和眼轴参数变化符合近视模型预期，并且阳性对照药物阿托品在实验中表现出应有药效，这些都证明本次实验近视模型造模成功，可用于AVA药效评价。实验结果证明长春西汀代谢物AVA能够有效的抑制FDM诱导近视的发生发展(屈光：F 2,36＝7.914,P＝0.001；玻腔：F 2,36＝3.904,p＝0.029；眼轴：F 2,36＝4.539,p＝0.017)。1μM的AVA连续用药1周，可以有效的抑制近视度数发展和相应眼轴、玻璃体腔深度延长(见图8)，具体的：FDM+Vehicle vs.FDM+AVA(1μM)：-4.39±1.73vs.-2.65±1.18D,p<0.01,屈光抑制率为39.6％；玻璃体腔深度也得到相应的抑制，FDM+Vehicle vs.FDM+AVA(1μM)：0.09±0.04vs.0.06±0.02mm,p<0.05,玻璃体腔深度抑制率为34.7％；眼轴长度也被抑制， FDM+Vehicle vs.FDM+AVA(1μM)：0.10±0.04vs.0.07±0.03mm,p<0.01,眼轴长度抑制率为36.4％。阿托品组在给药期间出现扩瞳现象而AVA组没有观察到眼部异常。从上述结果可以看出，长春西汀的代谢产物AVA在近视防控和治疗中也有显著疗效。
综上，长春西汀不仅可以显著减缓近视个体或有近视发生倾向个体屈光度变负进程，还可以显著抑制其玻璃体腔深度增加和眼轴延长，其能够显著改善近视疾病的相关症状，达到近视预防、治疗和控制近视进展的效果，且所有受试个体给药期间未观察到眼部异常，给药期间受试眼瞳孔大小未观察到明显改变。因此，长春西汀可应用于近视的防控与治疗，延缓近视发生发展，控制近视进展，尤其是应用于儿童及青少年近视或单纯性轴性近视或渐进性近视或原发性近视及这些近视相关症状的治疗、防控或改善。

Claims (18)

  1. 长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合的用途，其特征在于，所述用途为如下之一或同时满足两项及以上：
    ①预防和/或治疗近视及其相关症状，和/或近视矫正；或者
    ②抑制(控制)近视进展；或者
    ③用于近视防控或延缓近视(眼)发生发展；或者
    ④抑制、减缓近视个体或有近视发生倾向个体的眼轴延长和/或眼玻璃体腔长度(深度)增加；或者
    ⑤预防、减缓、减弱或治疗与视觉障碍相关的眼球的异常发育；或者
    ⑥使个体不用佩戴眼镜(如框架眼镜或OK镜)或不依靠视力矫正手段(如屈光手术)获得比使用这些物质或手段前和/或比未经使用这些物质或手段更清晰的远视力；或者
    ⑦抑制、延缓或减缓近视个体或有近视发生倾向个体屈光度变负的进程或速度；或者
    ⑧用于制备药物、制剂、组合物或装置，所述药物、制剂、组合物或装置用于实现前述第①-⑦中的至少一项用途。
  2. 如权利要求1所述的用途，采用全身给药(如口服、静脉滴注)、和/或局部给药(滴眼、眼部注射、眼部植入、皮肤膏/乳剂眼周涂抹或眼药膏涂抹)、和/或肠胃外给药(如通过粘膜给药、透皮给药、微针给药)、和/或无创给药(如利用眼用喷剂给药)的方式。
  3. 如权利要求1或2所述的用途，所述药物、制剂或组合物可以为注射液、片剂、冻干粉针剂、胶囊剂、泡腾片、咀嚼片、含化片、颗粒剂、软膏剂、糖浆剂、口服液、气雾剂、滴鼻剂、外用制剂、口服制剂等；优选是眼用剂型，包括但不限于滴眼液(眼药水)、眼药膏、眼部喷剂、植入片、眼用凝胶、眼贴、眼用微球、眼用缓释制剂、眼周注射剂、眼内注射剂；还可以为自由溶液、油水混合液、混悬液(剂)、擦剂、洗剂、霜剂、滴剂、冲剂、喷剂、膏剂、贴剂、糊剂、丸剂、栓剂、乳剂，含有纤维素(如甲基纤维素)、多羟基醇、环糊精(如羟丙基-β-环糊精)、酸性助溶剂(如柠檬酸)、树枝状高分子、纳米材料、缓释材料、脂质体或其组合配制的组。
  4. 如前述权利要求之一所述的用途，近视个体或有近视发生倾向个体为儿童和/或青少年，优选为3至26岁人群，更优选为6至18岁人群；或为未成年人群，优选为眼部(眼球)尚处于生长、发育阶段的人群；或为学龄人群，优选为一至十二年级学生人群；或为父母是高度近视的人群；或为远视储备不足人群。
  5. 如前述权利要求之一所述的用途，所述近视为屈光性近视或轴性近视；先天性近视(生下来或学龄前就是近视)、早发性近视(14岁以下)、迟发性近视(16～18岁)、晚发性近视(成年以后)；低度近视(轻度近视)、中度近视、高度近视(重度近视)；假性近视、真性近视；儿童和/或青少年近视(优选人群年龄为3-26岁，更优选人群年龄为6-18岁)、未成年人近视、成年人近视、老年人近视；单纯性近视、病理性近视；轴性单纯性近视、单纯性轴性近视；儿童和/或青少年轴性近视(优选人群年龄为3-26岁，更优选人群年龄为6-18岁)；学龄及学龄前人群轴性近视；原发性近视、继发性近视；儿童和/或青少年原发性近视(优选人群年龄为3-26岁，更优选人群年龄为6-18岁)；或儿童和/或青少年渐进式近视(优选人群年龄为3-26岁，更优选人群年龄为6-18岁)；曲率性近视、指数性近视、散光性近视、位置性近视、弯曲性近视；屈光度持续变负的轴性近视；因长时间近距离用眼导致的近视、视疲劳引发的近视及假性近视、药物不良反应造成的屈光度变负、近视眼、看书导致的近视、使用手机等电子产品导致的近视、屈光介质(成分)不匹配导致的近视、屈光近视、屈光发育异常导致的近视、眼球生长过大导致的近视、用眼不卫生导致的近视、各种原因造成的远处物体成像焦点落于视网膜前方、对阿托品治疗效果不佳或无效的近视、户外运动不足导致的近视、调节紧张性近视、儿童近视、婴幼儿近视、遗传性近视、环境因素主导的近 视。
  6. 如前述权利要求之一所述的用途，所述近视相关症状包括近视引起的并发症，如高度近视的并发症，再如飞蚊症、青光眼、后巩膜葡萄肿、视网膜脱落、视网膜撕裂、弱视、黄斑出血、脉络膜新生血管、脉络膜萎缩、黄斑变性或黄斑病变、视野缺损、视力(尤其是近视力)进行性或突发性下降、眼部酸胀和/或疼痛、夜盲、散光、屈光参差、失明、玻璃体液化、玻璃体混浊、斜视、频繁眨眼、经常揉眼睛、屈光参差、看远处物体时视野模糊、需要眯眼或部分闭上眼睑才能看清楚远处物体、眼睛疲劳引起的头痛、近视导致的注意力不集中、驾车时视力困难尤其是在夜间(夜间近视眼)、视网膜萎缩变性(出血和裂孔)、视网膜下新生血管、或眼球萎缩。
  7. 如前述权利要求之一所述的用途，所述药物、制剂、组合物或装置中还包含其他的药物或眼科用制剂，所述药物或眼科用制剂包括但不限于近视治疗药物(如哌仑西平、毒蕈碱拮抗剂、氨苄胺、阴多胺、马来酸噻莫洛尔、肾上腺素、皮伦西平、吡嗪、吡苯平、哌苯平、吡恩西平、甲胺、氯松胺、乙酰胆碱酯酶抑制剂、多巴胺激动剂、γ-氨基丁酸、纳洛酮、胰高血糖素、维甲酸、红景天苷、芒柄花黄素等)、M受体阻断剂(如针对M2或M3受体的阻断剂或拮抗剂或抑制剂)、苄达酸及其各种盐形式(苄达赖氨酸)、阿托品、地巴唑、多不饱和脂肪酸(如DHA、EPA)、哌唑嗪、后马托品、山莨菪碱(消旋)、托吡卡胺、7-甲基黄嘌呤、烟酸、吡拉西坦(Piracetam)、丹参提取物、红花提取物、鱼油、熊胆提取物、维生素、三磷酸腺苷(ATP)、平滑肌舒张药物、防止血管痉挛药物、非选择性腺苷酸拮抗剂、扩血管药物、扩瞳组分、充血去除组分、眼肌(如睫状肌)调节组分、抗(消)炎剂组分、收敛剂组分、抗组胺剂组分、抗过敏剂组分、抑制胶原蛋白降解组分、护肝类(避免或减弱肝毒性)组分、增强血-视网膜屏障组分(使化合物更加难以渗透通过该生理屏障)、氨基酸、抗菌剂组分、抗氧化组分(如维生素C、茶多酚、谷胱甘肽等)、糖类、聚合物或其衍生物、纤维素或其衍生物、局部麻醉剂组分、弱视治疗组分、青光眼治疗组分、白内障治疗组分、I型磷酸二酯酶抑制剂(特异或非特异)、miRNA及其修饰物、眼科疾病的治疗性组分、辅料等。
  8. 如前述权利要求之一所述的用途，其中长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合与一种或多种近视防控药物和/或近视治疗药物被配制成或设计成连续施用形式，或者同时施用的形式，或者先后施用形式，或者交替施用的形式，或者间隔施用的形式，或者单独施用的形式。
  9. 如前述权利要求之一所述的用途，所述长春西汀相关化合物或提取物选自长春西汀代谢物(如阿朴长春胺酸apovincaminic acid，hydroxyvinpocetine,hydroxyl-apovincaminic acid和dihydroxy-vinpocetine-glycinate)、长春花生物碱(Vinca alkaloid)、阿扑长春胺(apovincamine)、长春花提取物(periwinkle)、长春蔓胺(vincamine)、非洲马铃果提取物(voacanga africana)、夹竹桃科植物提取物、长春新碱(vincristine)、它勃宁(tabersonine)、长春花碱(Vinblastine)、文多灵(Vindoline)、Apovincaminic Acid Hydrochloride、长春质碱(catharanthine)、乙基长春胺(ethyl vincaminate)、methoxyvinpocetine、dihydrovinpocetine中的一种或多种物质。
  10. 如前述权利要求之一所述的用途，其特征在于，所述制剂为保健品、食品、膳食补充剂、营养品、饮品等口服制品或化妆品。
  11. 如前述权利要求之一所述的用途，其特征在于，所述装置为可以释放药物或具有药物递送功能或具备潜在药物递送能力的仪器、设备、耗材、系统、医疗器械、保健用品或改变眼部外观的用品，如角膜接触镜、眼镜、人工晶体、缝合线、OK镜清洁(维护)系统、眼贴、明目贴、美瞳、微针、眼部喷雾系统、眼部按摩仪、眼部熏蒸仪、眼表药物递送装置、眼内药物递送装置、眼底药物递送装置、植入泵、可穿戴设备、穴位按摩仪、眼部放松设备、近视治疗仪或用于近视防控的药械组合。
  12. 如前述权利要求之一所述的用途，其特征在于，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合，作为唯一活性成分或主要活性成分或直接活性成分；或者长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合的含量或药效占所述用途全部活性成分的1％及以下，或1％以上、10％以上、20％以上、30％以上、40％以上，或50％以上、60％以上、70％以上、80％以上、90％以上，或100％，所述百分比(％)可以为质量比、或摩尔比、或效价比、或对所述用途的药效贡献率。
  13. 如前述权利要求之一所述的用途，其特征在于，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合在所述药物、制剂、组合物或装置中的浓度为0.001μM至100mM，优选为0.005μM至50mM，优选为0.01μM至1000μM，优选为0.05μM至100μM，更优选为0.1μM至25μM，更优选为0.1μM至15μM；或者所述这些物质或其组合在所述药物、制剂、组合物或装置中的浓度或占比低于25％，优选为低于5％，优选为低于1％，更优选为低于0.01％，更优选为低于0.001％，所述百分比(％)可以为质量/体积浓度(克每100毫升)或质量百分比或摩尔(数)比。
  14. 一种局部施用的用于近视治疗或控制近视进展的药物、制剂、组合物或装置，其特征在于，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合在所述药物、制剂、组合物或装置中的浓度为0.001μM至50mM，优选为0.01μM至1000μM，优选为0.05μM至100μM，更优选为0.1μM至25μM，更优选为0.1μM至15μM；或者所述这些物质或其组合在所述药物、制剂、组合物或装置中的浓度或占比低于25％，优选为低于5％，优选为低于1％，更优选为低于0.01％，更优选为低于0.001％，所述百分比(％)可以为质量/体积浓度(克每100毫升)或质量百分比或摩尔(数)比。
  15. 一种含至少2个活性物质的药物组合物或复方制剂，其特征在于，包括长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合及其他治疗近视的活性物质。
  16. 如权利要求15所述的药物组合物或复方制剂，其特征在于，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合的添加量、浓度和/或药效不低于任一所述其他治疗近视的活性物质的添加量、浓度和/或药效，所述药效针对近视治疗或控制近视进展。
  17. 一种眼用制剂，其特征在于，所述制剂中，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合作为治疗近视直接的、唯一的、或主要的活性成分；其中，长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合的浓度为0.001μM至50mM，优选为0.01μM至1000μM，优选为0.05μM至100μM，更优选为0.1μM至25μM，更优选为0.1μM至15μM；或者长春西汀、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐、或其前药、或其代谢产物、或其相关化合物或提取物、或其晶体型化合物、或这些物质的组合的浓度或占比低于25％，优选为低于5％，优选为低于1％，更优选为低于0.01％，更优选为低于0.001％，所述百分比(％)可以为质量/体积浓度(克每100毫升)或质量百分比或摩尔(数)比。
  18. 如权利要求17所述的制剂，其特征在于，所述制剂包括但不限于滴眼液(眼药水)、 眼药膏、眼部喷剂、植入片、眼用凝胶、眼贴、眼用微球、眼用缓释制剂、眼周注射剂、或眼内注射剂。
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