WO2022228546A1 - 用于治疗近视的方法和药物组合物 - Google Patents

用于治疗近视的方法和药物组合物 Download PDF

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WO2022228546A1
WO2022228546A1 PCT/CN2022/090230 CN2022090230W WO2022228546A1 WO 2022228546 A1 WO2022228546 A1 WO 2022228546A1 CN 2022090230 W CN2022090230 W CN 2022090230W WO 2022228546 A1 WO2022228546 A1 WO 2022228546A1
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myopia
eye
administration
drugs
ophthalmic
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PCT/CN2022/090230
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English (en)
French (fr)
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周翔天
潘妙珍
瞿佳
郑钦元
吴昊
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温州医科大学附属眼视光医院
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Priority to AU2022265392A priority Critical patent/AU2022265392A1/en
Priority to EP22795016.9A priority patent/EP4324463A1/en
Priority to JP2023566974A priority patent/JP2024517782A/ja
Priority to CA3217324A priority patent/CA3217324A1/en
Priority to KR1020237039522A priority patent/KR20230170963A/ko
Publication of WO2022228546A1 publication Critical patent/WO2022228546A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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

Definitions

  • the present application relates to methods and medicaments for the treatment, prevention or control of myopia and related symptoms.
  • myopia (Paulus T V M de Jong, Br J Ophthalmol. 2018 Aug; 102(8):1021-102) to refer to a refractive error
  • Myopia is now one of the most serious public health problems in the world.
  • Early literature pointed out that in 2010, the number of myopia patients worldwide was close to 1.84 billion, accounting for 27% of the world's total population at that time, of which 170 million were highly myopic, accounting for 2.8%, especially in East Asia, such as China, Japan, South Korea and Singapore, myopia The prevalence is close to 50%, much higher than in Australia, Europe and the Americas. The global prevalence of myopia is projected to reach over 50% by 2050 (Brien A Holden, Ophthalmology.
  • myopia especially high myopia, may also cause glaucoma, cataract, retinal detachment, retinal tear, posterior scleral staphyloma, macular hemorrhage or myopic macular degeneration, choroidal neovascularization and other serious complications, damage Vision-related quality of life, increasing the difficulty of vision-related work leads to visual impairment and even blindness (Chen-Wei Pan, Ophthalmic Physiol Opt. 2012 Jan; 32(1): 3-16. and Seang-Mei Saw, Ophthalmic Physiol Opt. 2005 Sep;25(5):381-91.).
  • the only active ingredient or the main active ingredient is more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or 100% of the total active ingredient, and the percentage is by mass ratio or molar ratio.
  • these substances or combinations thereof and the one or more other drugs are formulated or designed for sequential administration, or simultaneous administration, or sequential administration, or alternating administration, or interval administration The form of administration, or the form of administration alone.
  • systemic administration eg, oral administration, intravenous infusion
  • topical administration eg, eye drops, intravitreal injection, skin ointment or ointment application
  • parenteral administration eg, mucosal administration drug, transdermal administration, microneedle administration
  • non-invasive administration such as applying ophthalmic ointment to the cornea or squeezing into the sac formed by stretching of the lower eyelid
  • non-invasive administration such as using ophthalmic spray.
  • the skin ointment or ointment is applied using a 3% skin ointment or ophthalmic ointment.
  • the above-mentioned modes of administration eg. eye drops, oral administration
  • formulations for topical administration include, but are not limited to, aqueous, oily, or suspension formulations, which may incorporate pharmacologically and/or physiologically active ingredients, such as mydriatic components, Decongestion components, eye muscle (such as ciliary muscle) regulating components, anti-inflammatory components, astringent components, antihistamine components, anti-allergic components, hepatoprotectives (avoid or reduce liver toxicity ) components, blood-retinal barrier enhancing components (making compounds more difficult to penetrate through this physiological barrier), vitamins, amino acids, antimicrobial components, carbohydrates, polymers or derivatives thereof, cellulose or derivatives thereof, topical Anesthetic components, glaucoma treatment components, cataract treatment components, etc.
  • pharmacologically and/or physiologically active ingredients such as mydriatic components, Decongestion components, eye muscle (such as ciliary muscle) regulating components, anti-inflammatory components, astringent components, antihistamine components, anti-allergic components, hepatoprotectives (avoid
  • the pharmaceutical composition or preparation can be injection, tablet, lyophilized powder for injection, capsule, effervescent tablet, chewable tablet, buccal tablet, granule, ointment, syrup, oral liquid, Aerosols, nasal drops, external preparations, oral preparations, etc.; preferably ophthalmic dosage forms, including but not limited to eye drops (eye drops), eye ointments, eye sprays, implants, eye gels, Eye patches, ophthalmic microspheres, ophthalmic sustained-release preparations, periocular injections or intraocular injections; can also be free solutions, oil-water mixtures, suspensions (agents), liniments, lotions, creams, drops , powder, spray, ointment, patch, paste, pill, suppository or emulsion.
  • the myopic individual or the individual who is prone to myopia is a human, which can be a child, a teenager, a middle-aged person or an elderly person, preferably a group of 3 to 26 years old, more preferably a group of 6 to 18 years old; or an adult , or a minor, preferably a group of people whose eyes (eyeballs) are still in the growth and development stage; or a school-age group, preferably a group of students in grades 1 to 12.
  • myopia is refractive myopia or axial myopia; congenital myopia (myopia at birth or before school age), early-onset myopia (under 14 years of age), late-onset myopia (16-18 years of age) , late-onset myopia (after adulthood); low-grade myopia (mild myopia), moderate myopia, high myopia (severe myopia); pseudo-myopia, true myopia, half-true (mixed) myopia; children and/or Or juvenile myopia (preferably the age of the crowd is 3-26 years old, more preferably the age of the crowd is 6-18 years old), juvenile myopia, juvenile myopia, adult myopia, elderly myopia; simple myopia, pathological myopia; axial myopia Simple myopia, simple axial myopia; axial myopia in children and/or adolescents (preferably the age group is 3-26 years old, more preferably the age group is 6-18 years old); school-aged and preschool-aged population axial myopia; primary sexual myopia, secondary myopia; primary myopia in children and/or adolescents (
  • myopia-related symptoms include complications caused by myopia, such as complications of high myopia, floaters, glaucoma, posterior scleral staphyloma, retinal detachment, retinal tear, amblyopia, macular hemorrhage, choroidal neovascularization, Choroidal atrophy, macular degeneration or macular degeneration, visual field defect, progressive or sudden decrease in vision (especially near vision), eye soreness and/or pain, night blindness, astigmatism, anisometropia, blindness, vitreous liquefaction, vitreous Cloudiness, strabismus, frequent blinking, frequent eye rubbing, anisometropia, blurred vision when looking at distant objects, need to squint or partially close eyelids to see distant objects clearly, headaches from eye strain, trouble seeing when driving especially At night (nocturnal myopia), retinal atrophy (bleeds and holes), subretinal neovascularization, and ocular atrophy.
  • myopia such as complications of high myopia
  • the pharmaceutical composition, formulation or device further comprises medical preparations or drugs, including but not limited to myopia treatment drugs (such as atropine, dibazole, pirenzepine, muscarinic antagonists) Agents, 7-Methylxanthine (7MX), Ampicillin, Indolamine, Timolol Maleate, Epinephrine, Pirenzepine, Pyrazine, Piramphenic, Pirenzepine, Pirenzepine, Methylphenidate amines, chloramphenicol, acetylcholinesterase inhibitors, dopamine agonists, gamma-aminobutyric acid, naloxone, glucagon, retinoic acid, etc.), M receptor blockers (such as M3 receptor blockers) (blocking agent or antagonist or inhibitor), benzylic acid or its various salt forms, benzylic acid or its various salt forms, polyunsaturated fatty acids (such as DHA, EPA), salid
  • the one or more other drugs include, but are not limited to, myopia treatment drugs (eg, atropine, dibazole, pirenzepine, muscarinic antagonists, 7-methylxanthine (7MX), piren zepine, ampicillin, indopamine, timolol maleate, epinephrine, pyrazine, piramphene, piramphene, pirenzepine, methylamine, chlorazolamide, acetylcholinesterase inhibitor, dopamine agonist agents, gamma-aminobutyric acid, naloxone, glucagon, retinoic acid, etc.), M receptor blockers (such as M3 receptor blockers or antagonists or inhibitors), benzylic acid or Its various salt forms, benzyl lysine or its various salt forms, polyunsaturated fatty acids (such as DHA, EPA), salidroside, formononetin
  • the preparation can also be oral products or cosmetics such as health products, food, dietary supplements, nutritional products, drinks; wherein, the cosmetics can be free solutions, oil-water mixtures, suspensions (agents), One or a combination of liniments, lotions, sprays, creams, drops, granules, ointments, pastes, pills, suppositories, emulsions, and patches.
  • cosmetics can be free solutions, oil-water mixtures, suspensions (agents), One or a combination of liniments, lotions, sprays, creams, drops, granules, ointments, pastes, pills, suppositories, emulsions, and patches.
  • Figure 1 Benzyl lysine controls myopia progression.
  • Figure 3 Benzedalysine eye drops at different concentrations for the prevention and control of myopia.
  • Figure 5 Benzyl lysine increases choroidal thickness in myopic individuals.
  • Figure 6 Therapeutic effects of benidalysine eye drop eye administration and benidalysine ointment eye smear administration.
  • Figure 7 Safety of benidalysine eye drops for eye drop administration and benzylic acid ointment for eye application.
  • Figure 8 Lysine alone cannot treat myopia, the difference between #BDL and normal saline solvent group, # represents p ⁇ 0.05, ## represents p ⁇ 0.01, ### represents p ⁇ 0.001.
  • Figure 9 Bendylic acid eye drops alone have the same therapeutic effect on myopia as benzdalysine eye drops. Among them, the difference between #BDL and normal saline solvent group, *bendazac and vehicle solvent group. * represents p ⁇ 0.05, *** represents p ⁇ 0.001, ## represents p ⁇ 0.01, and ### represents p ⁇ 0.001.
  • Figure 13 Sorbinil and Zopolrestat do not treat myopia.
  • Figure 15 Meta-hydroxymethylaniline does not treat myopia. #Statistical difference between the atropine administration group and the negative control group, ## represents p ⁇ 0.01.
  • Myopia is the most common refractive error, which refers to a refractive state in which the focus falls in front of the retina after the parallel light is refracted by the refractive system of the eye in a relaxed state of accommodation.
  • myopia There are four common types of myopia: (1) according to the size of the refraction, it can be divided into mild (low) myopia, moderate myopia and high (severe) myopia; (2) according to whether the refractive component is abnormal, it can be divided into refractive Optical myopia and axial myopia; (3) According to whether there are pathological changes, it can be divided into pathological myopia and simple myopia; (4) According to the classification of causes, it can be divided into primary myopia and concurrent/secondary myopia Shortsighted.
  • myopia caused by lens lesions.
  • the mismatch of refractive components also includes that the vitreous cavity is too large, which causes the position of the retina to move backward, causing the imaging focus of distant objects to fall in front of the retina, which is manifested as a negative diopter.
  • diopter is generally accepted as the only indicator for identifying all types of myopia, measuring their severity and evaluating the effect of myopia treatment.
  • spectacles are the main way to correct myopia in children and adolescents.
  • Adult patients can use laser surgery to correct myopia.
  • myopia can be corrected in most cases with glasses, contact lenses, or refractive surgery, it cannot slow its progression. Any type of myopia that progresses to high myopia is a particularly dangerous vision problem because of the high risk of retinal, choroidal, and scleral complications. Therefore, myopia correction cannot be simply understood as myopia treatment.
  • the clinical treatment of myopia is mainly reflected in the inhibition or slowdown of the progression of myopia, involving two methods, optical and pharmacological.
  • Orthokeratology can delay the progression of myopia in children and adolescents, but the effect of this treatment method varies greatly between individuals and requires close assistance from professional optometrists (Jinhai Huang, Ophthalmology. 2016 Apr; 123(4): 697-708. ); pharmacological options for myopia control are very limited (Tatiana V Tkatchenko, Trends Pharmacol Sci. 2019 Nov;40(11):833-852.), such as atropine eye drops, although many studies have shown efficacy in treating myopia , but it was clinically observed that the degree of myopia rebounded after drug withdrawal, and the use process was accompanied by more serious side effects such as mydriasis and photophobia (Prema Ganesan, Expert Rev Ophthalmol.
  • Bendazac Lysine (BDL) or benzylic acid has analgesic and antipruritic, anti-cell necrosis, choleretic and therapeutic effects on dyslipidemia.
  • Benzyl lysine is clinically used to treat cataracts by preventing lens protein degeneration.
  • benzylic acid or benzylic acid can treat, prevent or slow down myopia and its related symptoms, and it is shown that these compounds can effectively control, inhibit, delay or slow down myopia.
  • Progress, and finally used to prepare preparations or pharmaceutical compositions for the prevention and treatment of myopia, and such compounds have the advantages of high drug safety and few adverse reactions.
  • the present application provides benzylic acid or benzylic acid, or an optical isomer or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or Use of its metabolites, or analogs or derivatives thereof, or crystalline compounds thereof, or a combination of these substances, characterized in that the use is one of the following or at least two of them are satisfied simultaneously:
  • the match can maintain emmetropia or try to maintain emmetropia
  • benzylic acid or benzylic acid or an optical isomer or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a Metabolites, or analogs or derivatives thereof, or crystalline compounds thereof, or a combination of these substances as the sole active ingredient or the main active ingredient.
  • the only active ingredient or the main active ingredient is more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or 100% of the total active ingredient, and the percentage is by mass ratio or molar ratio.
  • these substances or combinations thereof and the one or more other drugs are formulated or designed for sequential administration, or simultaneous administration, or sequential administration, or alternating administration, or interval administration The form of administration, or the form of administration alone.
  • the abnormal development of the eyeball associated with refractive error is an individual's infancy (eg, 2-28 years in humans), primarily induced by environmental factors or primarily caused by human factors (eg, prolonged close reading, frequent electronic use Screens, persistent nearsightedness, lack of chance for farsightedness, improper use of refractive glasses, drug side effects, obesity, trauma, poor learning environment, lack of outdoor exercise), while genetic factors are secondary, concomitant, synergistic, or all
  • the abnormal development of the refractive index is completely independent of genetic factors, and its main feature is that the focus of parallel light falls in front of the retina after passing through the refractive system of the eye in a relaxed state of accommodation.
  • the benzylic acid or benzylic acid analogs or derivatives thereof are one of the following compounds (a)-(c):
  • R 1 is H, P (protium, Protium), D (deuterium, Deuterium), T (tritium, Tritium), p-CH 3 , mF, m-Cl, or p-Cl
  • R 2 is H, P (Protium, Protium), D (Deuterium, Deuterium), T (Tritium, Tritium), K or Na;
  • R 1 is H, P (protium, Protium), D (deuterium, Deuterium), T (tritium, Tritium), p-CH 3 , mF, m-Cl, or p-Cl;
  • R 2 is H, P (Protium, Protium), D (Deuterium, Deuterium), T (Tritium, Tritium), K or Na.
  • systemic administration eg, oral, intravenous infusion
  • topical administration eg, eye drops, intravitreal injection, skin ointment or ointment application, preferably, 3% skin ointment or ophthalmic ointment
  • parenteral such as mucosal, transdermal, microneedle
  • non-invasive such as ophthalmic ointment applied to the cornea or squeezed into the lower eyelid and stretched
  • non-invasive delivery methods eg, ophthalmic spray
  • the modes of administration eg, eye drops, oral administration
  • formulations for topical administration include, but are not limited to, aqueous, oily, or suspension formulations, which may incorporate pharmacologically and/or physiologically active ingredients, such as mydriatic components, Decongestion components, eye muscle (such as ciliary muscle) regulating components, anti-inflammatory components, astringent components, antihistamine components, anti-allergic components, hepatoprotectives (avoid or reduce liver toxicity ) components, blood-retinal barrier enhancing components (making compounds more difficult to penetrate through this physiological barrier), local anesthetic components, glaucoma treatment components, cataract treatment components, and the like.
  • pharmacologically and/or physiologically active ingredients such as mydriatic components, Decongestion components, eye muscle (such as ciliary muscle) regulating components, anti-inflammatory components, astringent components, antihistamine components, anti-allergic components, hepatoprotectives (avoid or reduce liver toxicity ) components, blood-retinal barrier enhancing components (making compounds more difficult to
  • the concentration or proportion of these substances or their combination in the pharmaceutical composition, preparation or device is at least not less than 0.01%, preferably 0.01% to 0.8%, preferably 0.05% to 0.5%, more Preferably, it is 0.1%; or the concentration or proportion of these substances or their combination is lower than 0.01%, and the percentage is expressed as mass/volume concentration (ratio) or mass ratio or mole (number) ratio, preferably, the The concentration is the use concentration or the storage concentration.
  • the concentration of these substances or combinations thereof is, for example, 0.01%-0.05%, 0.05%-0.1%, 0.1%-0.5%, and the percentage is expressed as mass/volume concentration (ratio), preferably, the The stated concentration is the use concentration or the storage concentration.
  • the pharmaceutical composition or preparation can be injection, tablet, lyophilized powder for injection, capsule, effervescent tablet, chewable tablet, buccal tablet, granule, ointment, syrup, oral liquid, Aerosols, nasal drops, external preparations, oral preparations, etc.; preferably ophthalmic dosage forms, including but not limited to eye drops (eye drops), eye ointments, eye sprays, implants, eye gels, Eye patches, ophthalmic microspheres, ophthalmic sustained-release preparations, periocular injections or intraocular injections; can also be free solutions, oil-water mixtures, suspensions (agents), liniments, lotions, creams, drops , powder, spray, ointment, patch, paste, pill, suppository or emulsion.
  • the myopic individual or the individual who is prone to myopia is a human, which can be a child, a teenager, a middle-aged person or an elderly person, preferably a group of 3 to 26 years old, more preferably a group of 6 to 18 years old; or an adult , or a minor, preferably a group of people whose eyes (eyeballs) are still in the growth and development stage; or a school-age group, preferably a group of students in grades 1 to 12.
  • myopia is refractive myopia or axial myopia; congenital myopia (myopia at birth or before school age), early-onset myopia (under 14 years of age), late-onset myopia (16-18 years of age) , late-onset myopia (after adulthood); low-grade myopia (mild myopia), moderate myopia, high myopia (severe myopia); pseudo-myopia, true myopia, half-true (mixed) myopia; children and/or Or juvenile myopia (preferably the age of the crowd is 3-26 years old, more preferably the age of the crowd is 6-18 years old), juvenile myopia, juvenile myopia, adult myopia, elderly myopia; simple myopia, pathological myopia; axial myopia Simple myopia, simple axial myopia; axial myopia in children and/or adolescents (preferably the age group is 3-26 years old, more preferably the age group is 6-18 years old); school-aged and preschool-aged population axial myopia; primary sexual myopia, secondary myopia; primary myopia in children and/or adolescents (
  • the aforementioned myopia includes or does not include myopia or myopic symptoms due to lens lesions.
  • myopia-related symptoms or signs include complications of myopia, such as complications of high myopia, floaters, glaucoma, posterior staphyloma, retinal detachment, retinal tear, amblyopia, macular hemorrhage, choroidal neoplasia Vascular, choroidal atrophy, macular degeneration or macular degeneration, visual field defect, progressive or sudden decrease in vision (especially near vision), eye soreness and/or pain, night blindness, astigmatism, anisometropia, blindness, vitreous liquefaction , vitreous opacity, strabismus, frequent blinking, frequent eye rubbing, anisometropia, blurred vision when looking at distant objects, need to squint or partially close eyelids to see distant objects clearly, headache due to eye fatigue, trouble seeing while driving Especially at night (nocturnal myopia), retinal atrophy (bleeds and tears), subretinal neovascularization, and ocular atrophy.
  • the pharmaceutical composition, formulation or device further comprises medical preparations or drugs, including but not limited to myopia treatment drugs (such as atropine, dibazole, pirenzepine, muscarinic antagonists) Agents, 7-Methylxanthine (7MX), Ampicillin, Indolamine, Timolol Maleate, Epinephrine, Pirenzepine, Pyrazine, Piramphenic, Pirenzepine, Pirenzepine, Methylphenidate amines, chloramphenicol, acetylcholinesterase inhibitors, dopamine agonists, gamma-aminobutyric acid, naloxone, glucagon, retinoic acid, etc.), M receptor blockers (such as M3 receptor blockers) blocker or antagonist or inhibitor), polyunsaturated fatty acids (such as DHA, EPA), salidroside, formononetin, prazosin, homatropine, anisod
  • the pharmaceutical composition, formulation or device further comprises a medicinal preparation or medicament comprising benzylic acid or various salt forms thereof, or benzylic acid or various salt forms thereof .
  • benzdalic acid or its various salt forms is ultimately formed with benzylic acid, or benzyl lysine, or its optical isomer or its racemate, or its solvent compounds, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, or analogs or derivatives thereof, or combinations of crystalline compounds thereof;
  • the medical formulation or drug can also be administered concurrently with the pharmaceutical composition, formulation or device, such as simultaneous or sequential administration during a specific administration (treatment) process, administration on the same day, administration in the same week, Administration in the same month, administration in the same year; or alternating administration at intervals, such as alternating administration at 4-hour intervals, alternating administration at 12-hour intervals, alternating administration every other day, alternating administration every other week, alternating administration every other month, alternating administration every other year Dosing.
  • a specific administration (treatment) process administration on the same day, administration in the same week, Administration in the same month, administration in the same year
  • alternating administration at intervals such as alternating administration at 4-hour intervals, alternating administration at 12-hour intervals, alternating administration every other day, alternating administration every other week, alternating administration every other month, alternating administration every other year Dosing.
  • the one or more other drugs include, but are not limited to, myopia treatment drugs (eg, atropine, dibazole, pirenzepine, muscarinic antagonists, 7-methylxanthine (7MX), piren zepine, ampicillin, indopamine, timolol maleate, epinephrine, pyrazine, piramphene, piramphene, pirenzepine, methylamine, chlorazolamide, acetylcholinesterase inhibitor, dopamine agonist agents, gamma-aminobutyric acid, naloxone, glucagon, retinoic acid, etc.), M receptor blockers (such as M3 receptor blockers or antagonists or inhibitors), polyunsaturated fatty acids (such as DHA, EPA), salidroside, formononetin, prazosin, homatropine, anisodamine (racemic), tropicamide,
  • the one or more other drugs may also include benzylic acid or various salt forms thereof, or benzylic acid lysine or various salt forms thereof.
  • benzylic acid or its various salt forms can finally be combined with benzylic acid, or its optical isomer or its racemate, or Its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analog or its derivative, or its crystalline compound is used in combination; or these substances of the present application are combined with these
  • “benzdalysine or its various salt forms” can finally be used with benzylic acid, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable form. Salts, or prodrugs thereof, or metabolites thereof, or analogs or derivatives thereof, or crystalline compounds thereof are used in combination.
  • the combined use is that the one or more other drugs are administered concurrently, such as simultaneous or sequential administration, same day administration, same week administration, same month administration during a particular administration (treatment) Drugs, administered in the same year; or alternate administration at intervals, such as alternate administration at 4-hour intervals, alternate administration at 12-hour intervals, alternate administration every other day, alternate administration every other week, alternate administration every other month, and alternate administration every other year.
  • concurrently such as simultaneous or sequential administration, same day administration, same week administration, same month administration during a particular administration (treatment) Drugs, administered in the same year; or alternate administration at intervals, such as alternate administration at 4-hour intervals, alternate administration at 12-hour intervals, alternate administration every other day, alternate administration every other week, alternate administration every other month, and alternate administration every other year.
  • the preparation can also be oral products or cosmetics such as health products, food, dietary supplements, nutritional products, drinks; wherein, the cosmetics can be free solutions, oil-water mixtures, suspensions (agents), One or a combination of liniments, lotions, sprays, creams, drops, granules, ointments, pastes, pills, suppositories, emulsions, and patches.
  • cosmetics can be free solutions, oil-water mixtures, suspensions (agents), One or a combination of liniments, lotions, sprays, creams, drops, granules, ointments, pastes, pills, suppositories, emulsions, and patches.
  • the device is an instrument, device, consumable, system, medical device, healthcare product, or product that alters the appearance of the eye, such as contact lenses, eyeglasses, that can release a drug or have a drug delivery function or potential drug delivery capability , intraocular lens, suture, OK lens cleaning (maintenance) system, eye patch, eye patch, beauty contact lens, micro-needle, eye spray system, eye massager (myopia massager), eye fumigation device, eye watch Drug delivery device, intraocular drug delivery device, fundus drug delivery device, implanted pump, wearable device, acupressure device, eye relaxation device, myopia treatment device or a combination of medicine and equipment for myopia prevention and control.
  • the device may be referred to as an ophthalmic device.
  • variable may be equal to any integer value within the numerical range, including the endpoints of the range.
  • variable may 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 may be 0.0, 0.1, 0.01, 0.001, or any other real value for an inherently continuous variable .
  • the terms "individual” and “subject” include humans as well as non-human animals, including, for example, farm animals such as sheep, pigs, cattle and horses; pet animals such as dogs and cats; laboratory animals such as mice, Rats and non-human primates.
  • the mammal is a human.
  • administering includes any route by which the compound is introduced or administered to the subject to perform its intended function.
  • administering can be carried out by any suitable route, including but not limited to oral, intraocular, intranasal, parenteral (by intravenous, intramuscular, intraperitoneal or subcutaneous) or topical administration.
  • administering includes self-administration and administration by others.
  • single use means that only one mode of administration is used in each stage of the entire drug process, and the mode of administration can be changed in different stages of the drug process (but there is no alternation).
  • select one for use means that the entire administration process is limited to only one route of administration and will not change.
  • amino acid as used herein includes naturally occurring amino acids and synthetic amino acids as well as amino acid analogs and amino acid mimetics that act in a similar manner to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code and those that have been modified later, such as hydroxy(yl)proline, gamma-carboxyglutamic acid, and O-phosphoserine.
  • Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, e.g., alpha-carbon, carboxyl, amino and R groups bound to hydrogen, such as For homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium.
  • Such analogs have modified R groups (eg, norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
  • Amino acid mimetics refer to chemical compounds that have structures that differ from the general chemical structure of amino acids, but that act in a manner similar to naturally occurring amino acids. Amino acids may be referred to herein by commonly known three-letter symbols or one-letter symbols as suggested by the IUPAC-IUB Biochemical Nomenclature Committee.
  • the term "effective amount” refers to an amount sufficient to achieve the desired therapeutic and/or prophylactic effect, eg, to cause prevention or alleviation of a disorder associated with an ophthalmic disorder.
  • the amount of the composition administered to a subject will depend on the type and severity of the disease and the nature of the individual, such as general health, age, sex, weight, ethnicity, degree of myopia, rate of myopia progression and tolerance to drugs. The amount will also depend on the degree, severity and type of disease, as well as the treatment regimen prescribed by a professional (eg, a physician). A skilled artisan will be able to determine the appropriate dosage based on these and other factors.
  • the pharmaceutical composition may also be administered in combination with one or more other therapeutic compounds, biopharmaceuticals, and therapeutic molecules (e.g., polypeptides).
  • benzylic acid, a benzylic acid compound, or a pharmaceutical composition containing the same can be administered to a subject having one or more symptoms or symptoms of an ophthalmic disorder.
  • a "therapeutically effective amount" of benidalysine refers to an average level that minimizes the physiological effects of ophthalmic disorders, preferably minimizes the physiological effects of myopia progression.
  • formulation As used herein, the terms “formulation,” “pharmaceutical composition,” and “composition” are used interchangeably and may refer to a mixture of two or more compounds, elements, or molecules. In some aspects, the terms “formulation,” “pharmaceutical composition,” and “composition” may be used to refer to one or more active agents (active ingredients) in admixture with a carrier or other excipient. Compositions can take almost any physical form, including solids, liquids (eg, solutions), or gases.
  • an injectable dosage form can include one or more formulations or compositions provided in a form for administration to a subject.
  • an injectable dosage form can be a formulation or composition prepared in a manner suitable for administration by injection.
  • pharmaceutically acceptable means approved by regulatory authorities such as CFDA (China), EMEA (Europe) and/or FDA (US) and/or any other national regulatory authorities for use in animals, preferably humans .
  • an "ophthalmologically acceptable carrier” is an ophthalmologically acceptable solvent, suspension or vehicle for the delivery of a pharmaceutical composition to the eye of a subject.
  • the carrier can be solid or liquid.
  • the carrier is "ophthalmologically acceptable” in the sense that the carrier is suitable for administration to the eye without causing any major adverse reaction.
  • spontaneous refers to the administration of at least two active ingredients by the same or different routes (eg, oral and eye drops) and at the same or substantially the same time during therapeutic administration; or at the same time or substantially the same time to administer and perform the procedure; or to administer and administer the therapeutic device at or substantially the same time.
  • routes eg, oral and eye drops
  • the term “individually” refers to the administration of therapy, limited to one mode or one substance at the same or substantially the same time, eg, the administration of only one active ingredient.
  • quential refers to therapeutic administration when at least two active ingredients are administered at different times, by the same or different routes of administration. More specifically, “sequential application” refers to the administration of one of the active ingredients completely before the administration of the other active ingredients begins. Thus, one active ingredient may be administered seconds, minutes, hours or days before the other active ingredients are administered.
  • the terms “treating,” “controlling,” “inhibiting,” “delaying,” “reducing,” “preventing,” “preventing,” or “alleviating” as used herein refer to both therapeutic treatments and preventive or preventive measures, Among other things, the aim is to prevent or slow (reduce) the target condition or disorder, or even eliminate or reverse it.
  • a subject after receiving a therapeutic amount of a benzdalysine compound or a pharmaceutical composition containing the same according to the methods described herein, a subject exhibits observable and/or observable symptoms of one or more symptoms and symptoms of an ophthalmic disorder Either the measured avoidance, reduction and disappearance, or the slowing down of disease progression, the subject's ophthalmic disorder is successfully treated.
  • “Treatment” of myopia or myopia-related symptoms reduces, inhibits, prevents, prevents and/or reverses, eg, at least about 5%, at least about 10%, or at least about 20% compared to the level of .
  • 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%).
  • propensity to develop myopia can refer to the situation in which the diopter level has decreased but has not yet become negative; it can also be predicted or considered by authoritative institutions or professional physicians to be susceptible to myopia or high-risk groups.
  • Optid composition or “ophthalmic preparation” or “ophthalmic preparation” refers to an ophthalmic composition, or an ophthalmic pharmaceutical composition, or an ophthalmic pharmaceutical product; or for the prevention and/or treatment of ocular diseases, vision protection ,
  • the pharmaceutical part of a drug, preparation, cosmetic, nutraceutical, combination or device for maintaining, improving, avoiding, slowing or reversing vision impairment.
  • “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, steridonic acid, eicosatetraenoic acid, or a combination thereof.
  • Analog refers to a structural derivative of a parent compound (such as benzylic acid or benzylic acid as referred to herein) that differs from the parent compound by only one element (including isotopes).
  • derivatives of a compound as used herein includes any molecule that is functionally and/or structurally related to the compound, such as an acid, amide, ester, ether, acetylated variant, hydroxylated variant, or alkyl group of the compound Li (C 1 -C 6 ) variants, halides, deuterated compounds, and the like.
  • the derivative should have a Tanimoto similarity index with the parent drug 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.
  • Tanimoto similarity index can be calculated by software available online such as Small Molecule Subgraph Detector (http://www.ebi.ac.uk/thornton-srv/software/SMSD/).
  • Preferred derivatives should be related both structurally and functionally to the parent compound, i.e. they should also retain at least part of the activity of the parent drug, such as benzdalai described in ref.
  • Synthesis and biological evaluations of novel bendazac lysine analogues as potent anticataract agents Amino acid derivatives or analogs Bioorganic & Medicinal Chemistry Letters, 20, 2115-2118, 2010), more preferably they should have a modulating effect on refractive development.
  • derivatives also include metabolites of a drug, eg, molecules that result from (biochemical) modification or processing of the drug after administration to an organism, usually by a specialized catalytic system, and which exhibit or retain the drug biological activity. Metabolites have been disclosed to be responsible for most of the therapeutic effects of the parent drug.
  • metabolite refers to a modification that retains at least part of the activity of the parent drug, preferably inhibits aldose reductase (AR) activity or has a therapeutic, preventive or slowing effect on myopia and related symptoms.
  • AR aldose reductase
  • terapéuticaally acceptable salt means a salt or zwitterionic form of the compounds disclosed herein, which 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 compound in the appropriate free base form 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, caproate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate , maleate, malonate, DL-mandelate, mesitylene sulfonate, mesylate, naphthalene sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, paraben acid salt, pectate, persulfate, 3-pheny
  • basic groups in the compounds disclosed herein can be quaternized with the following: methyl, ethyl, propyl, and butyl chloride, bromide, and iodide; dimethyl sulfate, diethyl ester, dibutyl sulfate esters and dipentyl esters; decyl, lauryl, myristyl and steryl chlorides, bromides and iodides; and benzyl and phenethyl bromides.
  • Myopia means that in the relaxed state of accommodation, parallel rays of light are collected in front of the retina after passing through the eye's refractive system. Divided into refractive myopia and axial myopia according to the cause of refraction, their clinical manifestations are blurred vision at distance and good near vision. In the early stage of myopia, long-distance vision often fluctuates. Because no or less adjustment is needed when looking at near, the gathering function is correspondingly weakened, which is easy to cause exophoria or exotropia.
  • Symptoms related to myopia also include poor night vision, floaters, flashes, etc., and can occur with varying degrees of fundus changes, myopia arc plate, macular hemorrhage or the formation of subretinal neovascular tumors, irregularly shaped white can occur Atrophic spots, or pigmented round black spots (Fuchs spots), lattice degeneration and cystoid degeneration around the retina, vitreous liquefaction, opacity and posterior vitreous detachment at a younger age, retinal holes and detachment occur.
  • Myopia can be a serious condition that debilitates the eye.
  • a potential disadvantage (risk) of myopia is that the eyeball elongates slightly, causing the lens of the eye to focus light from distant objects slightly in front of the retina. For this reason, myopia is often referred to as shortened vision or near vision. In severe cases, this elongation of the eyeball can stretch and thin certain inner parts of the eye, which can increase the risk of retinal detachment, cataracts, glaucoma, blindness, and more. Therefore, farsightedness is much more severe than mere shortening of vision.
  • Myopia is an axial elongation of the eye that affects most people.
  • the onset of myopia is usually during primary school age and progresses until the growth of the eye is complete.
  • corrective lenses are available, the development of myopia can lead to increased visual defects.
  • the present disclosure recognizes the importance of pharmaceutical compositions and therapies for treating, preventing, controlling, controlling, inhibiting, slowing, slowing, delaying, reducing, delaying and/or alleviating the onset and progression of myopia, particularly through Pharmaceutical compositions that facilitate administration or practice, reduce potential side effects and provide therapeutic benefits or combinations thereof, devices containing or delivering the pharmaceutical compositions, and methods of their use.
  • myopia Various causes of myopia have been discussed and studied, such as genetic predisposition, prolonged book work or screen time, and insufficient exposure to bright light. Regardless of the underlying cause of myopia in a given situation, which may be one or more of the causes listed above, the elongated eyeball associated with myopia can be debilitating in all people affected by this condition. Because the eyes grow during childhood and school age, myopia usually occurs in school-age children and adolescents and can persist with these individuals throughout their lives. Therefore, aggressive pharmacological interventions in individuals, such as school-age children and adolescents, can improve the quality of life of these individuals in their youth and for the remainder of their lives.
  • a "myopia” or “myopia-prone individual” is a child, adolescent, middle-aged or elderly, preferably 3 to 26 years old, more preferably 6 to 18 years old; or a minor, preferably ocular (eyeball) people who are still in the growth and development stage; or school-age people, preferably students in grades one to twelfth.
  • myopia include refractive myopia or axial myopia; congenital myopia (myopia at 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 (preferable population age 3-26 age, more preferably the age group is 6-18 years old), juvenile myopia, adult myopia, elderly myopia; simple myopia, pathological myopia; axial simple myopia, simple axial myopia; children and/or Axial myopia in adolescents (preferably in the age group of 3-26 years, more preferably in the age group of 6-18 years); Axial myopia in school-age and pre-school age groups; Primary myopia, secondary myopia; Children and/or adolescents with primary myopia Ongoing myopia (preferably in the age group of 3-26 years, more preferably in the age group of
  • Axial myopia means that the anterior and posterior diameter of the eyeball is too long (the axial length of the eye does not match other refractive components because it exceeds the normal range), while the refractive power (the refractive performance of other refractive components of the eye such as the cornea and lens) is basically normal. range of myopia.
  • Refractive myopia refers to myopia in which the axial length is basically within the normal range, but is mainly caused by changes in the refractive properties of the refractive components.
  • Phathological myopia also known as degenerative myopia, is a degenerative disease of the fundus. Patients with myopia usually have higher refractive power (generally greater than 600 degrees), significantly impaired visual function, and worse distance vision. In addition, abnormal vision, light perception, contrast perception, etc. are also common, often accompanied by poor night vision (night blindness), floaters, floating objects, and flashes. This type of myopia is characterized by obvious pathological changes, including retinal pigment epithelium thinning and atrophy, choroidal neovascularization and retinal detachment, macular degeneration and other symptoms in the patient's eye fundus, which can lead to blindness.
  • “Simple myopia” refers to myopia that usually occurs at school age, and gradually stabilizes with the cessation of development. The degree of myopia is below 600 degrees, and the fundus generally has no obvious pathological changes. The progressive development of this type of myopia can be corrected to normal with appropriate lenses, and other visual function indicators are mostly normal.
  • Primary myopia specifically refers to a type of myopia whose cause and mechanism cannot be determined using existing diagnostic techniques. In the process of its occurrence and development, there are non-transient functional-structural changes specific to myopia, including congenital myopia and acquired simple myopia.
  • Complicated/secondary myopia refers to temporary myopia (such as toxic myopia, drug-induced myopia, traumatic myopia, diabetic Myopia and primary cataract myopia), etc., this type of myopia is characterized by many clear precipitating factors and repeated visual fluctuations. This type of myopia is often more common in the elderly population.
  • Axial simple myopia sometimes referred to as simple axial myopia, is a type of simple myopia characterized by simple myopia in which the imaging focus is in front of the retina due to axial lengthening and/or increased depth of the vitreous cavity.
  • This type of myopia the refractive tissue of the eye (such as corneal curvature), is basically normal, and it is the most common type of myopia in children and adolescents, mostly in people aged 2 to 30.
  • Progressive myopia refers to a type of myopia in which the dioptric power continues to decrease over time or with the age of the individual, which, if left untreated, will generally eventually develop into high myopia.
  • Moderate myopia usually refers to myopia between 300 degrees and 600 degrees.
  • “Curvature myopia” is myopia caused solely by the increased curvature of the cornea or lens.
  • “Exponential myopia” is mainly caused by the increase of refractive power caused by the increase of aqueous humor and lens refractive index, which belongs to refractive myopia.
  • Adjustment tension myopia because the eyeball's near-load is too heavy, the ciliary muscle is over-adjusted, and there is myopia caused by adjustment tension or adjustment spasm.
  • Myopia caused by lens disease refers to changes in lens structural parameters or internal structure due to lens protein degeneration, accompanied by changes in some of its physical properties such as thickness, hardness, and refractive index, which in turn cause parallel light to accumulate in the retina after passing through the diseased lens. A type of myopia before.
  • Distance vision is also known as uncorrected distance vision. Medically, it refers to facing the eye chart at a horizontal distance of 5 meters, normally opening eyes and looking straight ahead, without wearing glasses and any auxiliary equipment that can increase vision (such as frame glasses, contact lenses, visual acuity measured with contact lenses, pinhole lenses, etc.).
  • 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, macula Degeneration or macular degeneration, visual field defect, progressive or sudden decrease in vision (especially near vision), eye soreness and/or pain, night blindness, astigmatism, anisometropia, blindness, vitreous liquefaction, vitreous opacity, strabismus, Frequent blinking, frequent eye rubbing, anisometropia, blurred vision when looking at distant objects, need to squint or partially close the eyelids to see distant objects clearly, headache due to eye strain, trouble seeing when driving, especially at night (night myopia), retinal atrophy (bleeds and tears), subretinal neovascularization, and ocular atrophy.
  • Abnormal development of the eyeball is the abnormal development of the size of the eyeball in children and adolescents (such as 3-26 years old), which is mainly characterized by an excessively long axial length, which causes the parallel light to pass through the normal refractive system of the eye and the imaging focus is located in front of the retina ; or developmental abnormalities that are primarily induced by environmental factors or are primarily caused by human factors (eg, prolonged close reading, frequent use of electronic screens, persistent nearsightedness, lack of hyperopia opportunities, inappropriate use of refractive glasses), and genetic factors Are secondary factors, concomitant factors, synergistic factors, or that the abnormal development is completely independent of genetic factors.
  • Derivatives of benzylic acid or benzylic acid lysine include optical isomers or their racemates or their metabolites (such as 5-hydroxybendazac), etc., and may specifically include, but are not limited to, Hong Shen et al. (Bioorganic & Medicinal Chemistry Those listed in Letters, 20, 2115-2118, 2010).
  • Commercially available eye drops containing benzyl lysine can be used (such as H20063847), or a technique well-known to those skilled in the art can be used to prepare benzyl lysine and its derivatives.
  • An exemplary preparation The method comprises the following steps: in the first synthesis, phenylhydrazine is used as a starting material, and ⁇ -benzylphenylhydrazine is prepared by benzylation reaction with benzyl chloride.
  • the second step of synthesis is to use ⁇ -benzyl phenylhydrazine and urea to form a ring under high temperature conditions to obtain 3-hydroxy-1-benzyl indazole.
  • the third step of synthesis is to use 3-hydroxy-1-benzyl indazole and chloroacetic acid to undergo carboxymethylation to obtain benzylic acid, namely ⁇ -[(1-benzyl-1H-indazole-3- base) oxy]acetic acid.
  • the fourth step of synthesis is the salt formation reaction between benzylic acid and L-lysine in tetrahydrofuran, and then recrystallization in ethanol to obtain the final product benzylic acid-lysine.
  • R 1 is H, P (protium, Protium), D (deuterium, Deuterium), T (tritium, Tritium), p-CH 3 , mF, m-Cl, or p-Cl
  • R 2 is H, P (Protium, Protium), D (Deuterium, Deuterium), T (Tritium, Tritium), K or Na;
  • R 1 is H, P (protium, Protium), D (deuterium, Deuterium), T (tritium, Tritium), p-CH 3 , mF, m-Cl, or p-Cl
  • R 2 is H, P (Protium, Protium), D (Deuterium, Deuterium), T (Tritium, Tritium), K or Na;
  • R 1 is H, P (protium, Protium), D (deuterium, Deuterium), T (tritium, Tritium), p-CH 3 , mF, m-Cl, or p-Cl;
  • R 2 is H, P (Protium, Protium), D (Deuterium, Deuterium), T (Tritium, Tritium), K or Na.
  • Preparation refers to oral products or cosmetics such as health products, food, dietary supplements, nutritional products, drinks, etc.; wherein, the cosmetics can be free solutions, oil-water mixtures, suspensions (agents), liniments, lotions, One or a combination of sprays, creams, drops, granules, ointments, pastes, pills, suppositories, emulsions, and patches.
  • a “device” is an instrument, device, consumable, system, medical device, healthcare product, or product that alters the appearance of the eye, such as contact lenses, glasses, intraocular lenses, Suture thread, OK lens cleaning (maintenance) system, eye patch, eye patch, color contact lens, microneedle, eye spray system, eye massager (myopia massager), eye fumigation device, ocular surface drug delivery device, Intraocular drug delivery device, fundus drug delivery device, implanted pump, wearable device or combination of medicine and equipment for myopia prevention and control.
  • the only active ingredient or the main active ingredient refers to the addition of benzylic acid or benzylic acid, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable Except for the salts, or their prodrugs, or their metabolites, or their analogs or derivatives, or their crystalline compounds, or a combination of these substances, without or with only a small amount of other Active substances for the treatment of myopia.
  • the content of its analogs or derivatives, its crystalline compounds, or the combination of these substances accounts for more than 50%, more than 60%, more than 70%, more than 80%, more than 90% of the total active ingredients , or 100%, the percentage is mass ratio or molar ratio; or benzylic acid or benzylic acid, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable
  • the salt, or its prodrug, or its metabolite, or its analogs (analogues) or derivatives (derivatives), or its crystalline compound, or a combination of these substances contributes more than 50% to the efficacy of the treatment of myopia during the medication process. % or more, 60% or more, 70% or more, 80% or more, 90% or more, or
  • composition therapy is a widely used and powerful strategy in medicine to achieve synergistic therapeutic effects, reduce dose and toxicity, and minimize or delay the induction of resistance (Chou TC., "Drug combination studies and their synergy” quantification using the Chou-Talalay method,” Cancer Res. (2010) 70:440-6).
  • the present disclosure identifies compounds for the treatment, prevention or mitigation of myopia and its associated symptoms, such as benzyl lysine, to enhance myopia (degree) reduction or myopia (progress) slowing effect while avoiding or minimizing Adverse side effects, such as those observed with atropine therapy.
  • the pharmaceutical composition of the present application has significantly better technical effects than atropine in the treatment, prevention or alleviation of myopia and related symptoms.
  • benzylic acid and benzylic acid can significantly slow down the process of diopter change in form deprivation guinea pigs and negative lens-induced guinea pig myopia models, and can significantly inhibit axial lengthening. Based on this, it can be confirmed that The compounds in the form of benzylic acid and salts thereof have the effect of treating, preventing or controlling the progression of myopia in animals, especially humans, such as school-age children, adolescents or young adults.
  • the present application provides a method for treating or preventing myopia and related symptoms in a subject, comprising administering to the subject a therapeutically effective amount of benzylic acid, benzylic acid and/or their therapeutically acceptable salts and its derivatives.
  • the benzylic acid or benzylic acid lysine is administered alone, preferably, the benzylic acid and/or benzylic acid lysine are administered simultaneously or sequentially with other drugs, preferably the benzylic acid and/or benzylic acid are administered /or benzdalysine is administered in the form of a pharmaceutical composition
  • the pharmaceutical composition is prepared as an ophthalmic preparation, preferably, the ophthalmic preparation further comprises a pharmaceutically acceptable carrier, preferably, the The carrier is an ophthalmically acceptable carrier.
  • the present application also provides a technique and method for inhibiting the progression of axial myopia by inhibiting the elongation of the axial length of the eye, comprising administering to a subject a therapeutically effective amount of benzylic acid, benzylic acid and/or their treatment Acceptable salts and derivatives thereof.
  • the benzylic acid or benzylic acid lysine is administered alone, preferably, the benzylic acid and/or benzylic acid lysine are administered simultaneously or sequentially with other drugs, preferably the benzylic acid and/or benzylic acid are administered /or benzdalysine is administered in the form of a pharmaceutical composition, preferably, the pharmaceutical composition is prepared as an ophthalmic preparation, preferably, the ophthalmic preparation further comprises a pharmaceutically acceptable carrier, preferably, the The carrier is an ophthalmically acceptable carrier.
  • the present application also provides a technique and method for reducing myopia power, comprising administering to a subject a therapeutically effective amount of benzylic acid, benzylic acid and/or their therapeutically acceptable salts and derivatives thereof.
  • the benzylic acid or benzylic acid lysine is administered alone, preferably, the benzylic acid and/or benzylic acid lysine are administered simultaneously or sequentially with other drugs, preferably the benzylic acid and/or benzylic acid are administered /or benzdalysine is administered in the form of a pharmaceutical composition, preferably, the pharmaceutical composition is prepared as an ophthalmic preparation, preferably, the ophthalmic preparation further comprises a pharmaceutically acceptable carrier, preferably, the The carrier is an ophthalmically acceptable carrier.
  • the present application also provides a hyperopia improving agent for myopic individuals, which can improve the distance vision of myopic individuals by reducing the distance between the ocular imaging focus of a distant object and the retina.
  • the hyperopia improving agent contains benzylic acid, benzylic acid and/or their therapeutically acceptable salts and derivatives thereof.
  • the above-mentioned myopic individual is refractive myopia.
  • the above-mentioned myopic individual is axial myopia.
  • the present application also relates to pharmaceutical compositions or methods of treating, preventing or managing myopia and its associated symptoms in individuals such as toddlers, school children, adolescents or young adults.
  • the treatment object of the technical solution of the present application is an adolescent with an age range of 6-28 years old, preferably 6-18 years old, and most preferably 12-18 years old.
  • the treatment subject of the technical solution of the present application is an adult.
  • treating, preventing or managing myopia and its associated symptoms can include administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition or dosage form.
  • the pharmaceutical composition comprises a therapeutically effective amount of a benzylic acid compound or a salt thereof and derivatives thereof, such as protium, deuterium, tritium substituted.
  • the pharmaceutical composition contains benzylic acid or a therapeutically acceptable salt thereof (eg, benzylic acid lysine) or a derivative thereof At least one of the substances; or, the pharmaceutical composition contains benzylic acid or a therapeutically acceptable salt or derivative thereof; preferably, both benzylic acid and benzylic acid are included; preferably Preferably, it contains both benida lysine and benida dibasic calcium phosphate; preferably, it contains benida dibasic calcium phosphate; preferably, it also contains a pharmaceutically acceptable carrier; preferably, wherein the device is delivered in a sustained release manner the pharmaceutical composition.
  • benzylic acid or a therapeutically acceptable salt thereof eg, benzylic acid lysine
  • the pharmaceutical composition contains benzylic acid or a therapeutically acceptable salt or derivative thereof; preferably, both benzylic acid and benzylic acid are included; preferably Preferably, it contains both benida lysine and ben
  • the subject (patient) is treated for a period of time between about 0.5 months and 20 years, such as at least 6 months, at least 1 A period of at least 2 years, at least 3 years, at least 5 years, at least 9 years, or at least 13 years.
  • the pharmaceutical 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 pharmaceutical composition is an aqueous composition
  • the aqueous composition has an osmotic pressure close to or consistent with the tear phase; or the pharmaceutical composition is an ophthalmic composition (such as an ophthalmic topical composition) or an ophthalmic preparation, preferably, the ophthalmic preparation is an ophthalmic aqueous preparation , ophthalmic gel preparation, ophthalmic emulsion, ophthalmic liposome, ophthalmic ointment (preferably, the ophthalmic ointment is ophthalmic ointment, preferably, the ophthalmic ointment contains petrolatum or liquid paraffin); or the drug
  • the compositions are eye drop formulations, eye spray formulations, topical formulations, nanoparticulate suspensions, or nanodiscs, sustained release formulations or subconjunctival depots
  • a pharmaceutical composition as disclosed herein may be an ophthalmic aqueous formulation, such as in the form of eye drops.
  • an ophthalmic aqueous formulation as described herein can be packaged in an eye drop bottle and administered as drops.
  • the ophthalmic aqueous formulation can be administered as a single administration (ie, a single dose), which can include one, two, three, or more drops instilled into a patient's eye.
  • one dose of an ophthalmic aqueous formulation described herein is one drop of the aqueous composition from the eye drop bottle.
  • a pharmaceutical composition as disclosed herein can be an ophthalmic gel formulation.
  • the ophthalmic gel formulation can be packaged in an eye drop bottle and administered as drops.
  • the ophthalmic gel formulation can be administered as a single administration (ie, a single dose), which can include one, two, three, or more drops instilled into a patient's eye.
  • one dose of an ophthalmic gel described herein is one drop of the gel composition from the eye drop bottle.
  • a pharmaceutical composition as disclosed herein can be an ophthalmic ointment formulation.
  • the ophthalmic ointment formulation may be packaged in a tube or other squeezable container having a dispensing spout through which the ointment strip will be delivered.
  • an ophthalmic ointment formulation can be administered as a single administration (ie, a single dose), which can include one or more strips into a patient's eye.
  • one dose of ophthalmic ointment is a strip of ointment composition dispensed through the orifice of a dispensing tube.
  • the pharmaceutical composition is an ophthalmic pharmaceutical composition contained within a contact lens blister pack.
  • the pharmaceutical composition is administered by a non-invasive route of administration.
  • a pharmaceutical 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 device is preferably an ophthalmic device such as It can be understood to mean an object placed on or present in the eye.
  • the device may provide optical correction.
  • Devices include, but are not limited to, color lenses, contact lenses, ocular inserts, cornealonlays, cornealinlays, nanowafers, liposomes, nanoparticles, punctalonlays ) or a hydrogel matrix with microfluid reservoirs.
  • the pharmaceutical composition is a sustained release formulation contained within a device.
  • the pharmaceutical composition is contained within the device.
  • the pharmaceutical composition is an ophthalmic composition and the ophthalmic composition is contained within a device.
  • the device needs to contain the pharmaceutical composition or be capable of delivering the pharmaceutical composition to the corresponding target tissue for myopia treatment.
  • the device delivers the pharmaceutical composition in a sustained release manner.
  • the pharmaceutical composition is formulated 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 (eye), 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 composition for the treatment of axial myopia or refractive myopia.
  • the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of individuals (patients) diagnosed with anterior myopia (or at risk of developing myopia or predisposed to developing myopia).
  • the pharmaceutical composition is substantially uniformly distributed throughout the device.
  • the device is contained within a contact lens blister pack.
  • the pharmaceutical composition is submerged within the device within the contact lens blister pack.
  • a cell, organ or tissue with a compound such as benzylic acid or benzylic acid lysine can be done using any method known to those skilled in the art. Suitable methods include in vitro, ex vivo or in vivo methods. In vivo methods typically involve administering the benzylic acid or/and benzylic acid compounds of the present application, or a pharmaceutical composition containing the same, to a mammal, preferably a human. When used in vivo for therapy, the benzylic acid or/and the benzylic acid 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). The dosage and dosing regimen will depend on the degree of the ophthalmic disorder in the subject, the subject, and the subject's medical history.
  • the compounds disclosed herein may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003).
  • a prodrug of a compound described herein is a modified form of the compound that is susceptible to chemical changes under physiological conditions to yield the compound.
  • prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be gradually converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical agent. Prodrugs are often useful because in some cases they may be easier to administer than the compound or parent drug.
  • prodrug are bioavailable by oral administration, whereas the parent drug is not.
  • the prodrug may also be more soluble in the pharmaceutical composition than the parent drug.
  • Many prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • a non-limiting example of a prodrug is a compound that is administered as an ester ("prodrug") but then metabolically hydrolyzed to a carboxylic acid (the active entity).
  • the compounds disclosed herein can exist as therapeutically acceptable salts, including acid addition salts.
  • Suitable salts include those formed with organic and inorganic acids. Such acid addition salts are generally pharmaceutically acceptable; base addition salts may also be formed and are pharmaceutically acceptable.
  • base addition salts may also be formed and are pharmaceutically acceptable.
  • Base additions can be prepared 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 during the final isolation and purification of the compound.
  • 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 during the final isolation and purification of the compound.
  • a salt such as a hydroxide, carbonate or bicarbonate of a metal cation
  • the cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium and aluminum and 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, dicyclohexylamine Benzylamine, N,N-dibenzylphenethylamine, 1-diphenylhydroxymethylamine and N,N'-dibenzylethylenediamine.
  • Other representative organic amines suitable for forming 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 ingredients.
  • the carrier must be "acceptable” in the sense that it is compatible with the other ingredients of the formulation and not injurious to its recipient. Appropriate formulations depend on the chosen route of administration. Any of the well-known techniques, carriers and excipients that are suitable and understood in the art can be used; see, for example, Remington's Pharmaceutical Sciences.
  • compositions disclosed herein may be produced in any manner known in the art, eg, by means of conventional mixing, dissolving, granulating, dragee-coating, attrition, emulsifying, encapsulating, entrapping, or compression processes.
  • Formulations include suitable oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual, ocular , intranasal and intraocular) formulations, 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. Typically, these methods include bringing into association a compound of the present application, or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient”), with the carrier which constitutes one or more accessory ingredients step.
  • active ingredient a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof
  • 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,
  • Formulations of the compounds disclosed herein suitable for oral administration can be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined quantity of the active ingredient; as powders or granules; as in aqueous liquids or non- Solutions or suspensions in aqueous liquids; or provided as oil-in-water emulsions or water-in-oil emulsions.
  • the active ingredient can also be presented as a bolus, syrup, electuary or paste.
  • compositions that 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 lubricant, 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.
  • Tablets may optionally be coated or scored and may be formulated so as to provide sustained or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for 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.
  • stabilizers may be added.
  • Dragee cores are provided with a suitable coating.
  • concentrated sugar solutions can 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 for oral pharmaceutical formulations such as capsules and tablets include, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugars, microcrystalline cellulose (MCC), powdered cellulose, corn starch, pregelatinized starch, dextrate, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate , magnesium carbonate, magnesium oxide, poloxamers (such as polyethylene oxide) and hydroxypropyl methylcellulose.
  • the filler may have complexed solvent molecules, as in the case where the lactose used is lactose monohydrate.
  • disintegrants used in oral pharmaceutical formulations include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, poly Vidone, crospovidone (polyvinylpolypyrrolidone), methylcellulose, microcrystalline cellulose, powdered cellulose, low-substituted hydroxypropylcellulose, 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 palmitate stearate, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, benzene Sodium formate, sodium lauryl sulfate, sodium stearoyl fumarate, stearic acid, talc and zinc stearate.
  • glidants include, but are not limited to, silicon dioxide (SiO2), talc cornstarch, and poloxamers. Poloxamers (or available from BASF Corporation) are A-B-A block copolymers wherein 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, acacia, alginic acid, carbomer, sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oils, hydroxyethyl cellulose , hydroxypropyl cellulose, hydroxypropyl methyl cellulose, copolyvidone (copolyvidone), methyl cellulose, liquid glucose, maltodextrin, polymethacrylate, povidone, pregelatinized starch, algae sodium, starch, sucrose, tragacanth and corn gluten.
  • acacia alginic acid, carbomer, sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oils, hydroxyethyl cellulose , hydroxypropyl cellulose, hydroxypropyl methyl cellulose, copolyvidone (copolyvidone), methyl cellulose, liquid glucose, maltodextrin,
  • the compounds can 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 may be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, e.g., physiological Saline or sterile pyrogen-free water.
  • a sterile liquid carrier e.g., physiological Saline or sterile pyrogen-free water.
  • Extemporaneous injection solutions and suspensions may 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, in particular a syringe.
  • the pharmaceutical composition is administered by intraocular injection, more preferably by intravitreal injection into the vitreous.
  • Formulations for parenteral administration include: aqueous and non-aqueous (oily) sterile injectable solutions of the active compound, which may contain antioxidants, buffers, bacteriostatic agents and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending 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 sodium carboxymethyl cellulose, sorbitol, or dextran.
  • 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 enable the preparation of highly concentrated solutions.
  • the compounds can also be formulated for storage.
  • Such depot formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, troches, lozenges or gels formulated in conventional manner.
  • Such compositions may contain the active ingredient in a flavored base such as sucrose and acacia or tragacanth.
  • the compounds can also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycols or other glycerides.
  • Certain compounds disclosed herein can be administered topically, ie, by non-systemic administration. This includes administering the compounds disclosed herein to the eye, epidermis, outside of the oral cavity, ear and/or nose so that the compound does not appreciably enter the bloodstream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • the active ingredient for topical application may comprise, for example, 0.001% to 10% w/w (by weight) of the formulation.
  • the active ingredient may comprise up to 10% w/w. In other embodiments, it may comprise less than 5% w/w.
  • the active ingredient may comprise from 2% w/w to 5% w/w. In other embodiments, it may comprise 0.1% to 2% w/w of the formulation, preferably 0.1% to 0.5% w/w. In certain embodiments, it may comprise 0.01% w/w, 0.05% w/w, 0.1% w/w, 0.25% w/w, 0.5% w/w of the formulation.
  • the active ingredient for topical administration may comprise, for example, 0.001% w/v to 10% w/v (on a weight/volume basis, in g/100ml) of the formulation.
  • the active ingredient may comprise up to 10% w/v. In other embodiments, it may comprise less than 5% w/v.
  • the active ingredient may comprise from 0.2% w/v to 0.5% w/v. In other embodiments, it may comprise 0.1% w/v to 2% w/v, preferably 0.1%-0.5% w/v of the formulation. In certain embodiments, it may comprise 0.01% w/v, 0.05% w/v, 0.1% w/v, 0.25% w/v, 0.5% w/v of the formulation.
  • formulations in aqueous solution or suspension for topical application to the eye or ear are in the form of drops.
  • Formulations in aqueous solution or suspension for topical administration to the nose are in the form of drops, sprays or aerosols.
  • aqueous generally means an aqueous formulation wherein the formulation contains >50%, more preferably >75% and especially >90% water by weight.
  • These drops may be delivered in single-dose ampoules, which may preferably be sterile, thus enabling the need for bacteriostatic components of the formulation.
  • the drops may be delivered from a multi-dose vial, which may preferably include a device for withdrawing any preservative therefrom upon delivery of the formulation, such devices being known in the art.
  • Solution and suspension formulations can be administered nasally using a nebulizer.
  • Intranasal delivery of solutions, suspensions, or dry powders can also be facilitated by propellant-based aerosol systems, including, but not limited to, hydrofluoroalkane-based propellants.
  • the active pharmaceutical ingredient may be delivered in the form of a dry powder.
  • the formulations of the present application are administered twice a day.
  • the formulations can also be formulated for administration at any frequency of administration, including once a week, once every 5 days, once every 3 days, once every 2 days, once 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 may vary from a single administration to a regimen extending over months or years.
  • 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 lozenges in a base such as gelatin and glycerol or sucrose and acacia.
  • the base contains the active ingredient in lozenges.
  • the compounds are 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 present application may take the form of dry powder compositions, 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 recited herein below, or an appropriate fraction thereof, of the active ingredient.
  • formulations may include other agents conventional in the art for the type of formulation in question, eg, formulations suitable for oral or intranasal administration may include flavoring agents.
  • Compounds may be administered orally or via injection at doses of 0.01 to 300 mg/kg per day.
  • the dosage range for adults is generally 0.1 mg to 50 mg/day.
  • Tablets or other presentation forms provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dose or doses, for example 0.05 mg to 100 mg, Usually about 1 mg to 50 mg, preferably 5 mg.
  • the compounds can be administered in various ways, such as orally, topically, or by injection.
  • the precise amount of compound administered to a patient is the responsibility of the attending physician.
  • the specific dosage level for any particular patient will depend on 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.
  • the efficacy of one of the compounds described herein can be enhanced by the administration of an adjuvant (ie, the adjuvant may have only minimal therapeutic benefit by itself, but when combined with another therapeutic agent, may have minimal effect on the patient's overall therapeutic benefit is enhanced).
  • the benefit experienced by a patient can be enhanced by administering one of the compounds described herein with another therapeutic agent that also has a therapeutic benefit (which also includes a treatment regimen).
  • the therapeutic benefit may be enhanced by also providing the patient with another myopia treatment agent, such as atropine.
  • another myopia treatment agent such as atropine.
  • the total benefit experienced by the patient may simply be the addition of the two therapeutic agents, or the patient may experience synergistic benefit.
  • compositions in dry or liquid form can be provided as single-dose or multi-dose pharmaceutical compositions.
  • the liquid or dry pharmaceutical composition is provided in a single dose, which means that the container in which it is provided contains one dose of the drug.
  • the liquid or dry pharmaceutical composition is a multi-dose pharmaceutical composition, which means that the container in which it is provided contains more than one therapeutic dose, ie, the multi-dose composition contains at least 2 doses.
  • Such multiple dose compositions may be administered to different patients in need thereof, or may be administered to a single patient wherein the remaining doses are stored until needed after application of the first dose.
  • the pharmaceutical composition is in a container.
  • Containers for liquid or dry pharmaceutical compositions are, for example, syringes, vials, vials with stoppers and seals, 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 the dual chamber syringe and the reconstitution solution is provided in the second chamber of the dual chamber syringe.
  • the dry composition is reconstituted prior to application to a patient in need thereof.
  • Reconstitution can be carried out in the container in which the dry composition is provided, such as in vials, syringes, dual chamber syringes, ampoules and cartridges.
  • Reconstitution is performed by adding a predetermined amount of reconstitution solution to the dry composition.
  • Solutions for reconstitution are sterile liquids such as water or buffers, which may contain other additives such as preservatives and/or antimicrobials such as benzyl alcohol and cresol.
  • the reconstitution solution is sterile water.
  • the pharmaceutical composition of the present application can be administered in the form of an ophthalmic preparation, and the ophthalmic preparation of the present application comprises an ophthalmically acceptable carrier.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the concentration of the drugs can be selected to be an effective and suitable amount of each drug.
  • the formulations and methods of the present application have been used in any subject who may 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 present application provides a device containing a pharmaceutical composition comprising benzylic acid or a therapeutically acceptable salt thereof (such as benzylic acid lysine) or a derivative thereof, preferably wherein The device delivers the pharmaceutical composition in a sustained release manner.
  • the devices deliver the pharmaceutical compositions in a sustained release, preferably circadian rhythm.
  • the pharmaceutical compositions are formulated as ophthalmic compositions, eg, as ophthalmic compositions for the treatment of an ophthalmic disorder or condition.
  • the pharmaceutical compositions are formulated as ophthalmic compositions for the treatment of anterior myopia, myopia or myopia progression.
  • the pharmaceutical compositions are formulated as ophthalmic compositions for the treatment of high, moderate, or low myopia.
  • the pharmaceutical compositions are formulated for use in patients diagnosed with anterior myopia (or at risk for or prone to myopia) Therapeutic ophthalmic composition.
  • the pharmaceutical compositions are ophthalmically administered to the patient's eye, preferably the eye is myopic.
  • the pharmaceutical compositions are administered topically.
  • the pharmaceutical compositions are ophthalmically administered to a patient's eye via a device.
  • the pharmaceutical compositions are administered 1, 2, 3, 4 or 5 times per day.
  • Therapeutic drug dosage, toxicity, and efficacy of treatment can be determined by standard pharmaceutical procedures in experimental animals, eg, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose that is therapeutically effective in the 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD50/ED50.
  • Compounds that exhibit high therapeutic indices are preferred. Although compounds with toxic side effects can be used, consideration should be given to designing a delivery system or a suitable mode of administration that can target such compounds to the corresponding tissue or focal site, in order to reduce exposure to unrelated cells or tissues. possible damage is minimized and thus side effects are reduced.
  • Data obtained from animal studies can be used in formulating a range of dosages for use in humans. Depending on the type of formulation employed and the route of administration utilized, the dosage may vary within, and sometimes outside, this range.
  • a series of different doses can be formulated in animal models to obtain indicators including minimum effective concentration, circulating blood concentration range after single and multiple doses, and drug exposure. Such results can be used to more accurately help determine useful doses in humans through body surface area conversion.
  • treating a subject with a therapeutically effective amount of a therapeutic composition described herein can include a single treatment or a series of treatments.
  • Use of the methods of the present application controls, slows, reduces, delays and/or slows the progression of myopia in a treated patient within the following ranges relative to no treatment: between about 5-95%, between about 5-90%, Between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50%, between about 5-40%, between about 5-30%, about 5 -20%, between about 10-100%, between about 20-90%, between about 30-90%, between about 40-90%, between about 50-90%, or between about 75-90% between.
  • Use of the pharmaceutical composition, device or method of treatment limits the magnitude of the negative diopter in the administered subject's eye to about 1.0-6.0D, 1.0-5.0D, 1.0-4.0D, 1.0-3.0D, 1.0-2.0D, less than 6.0 D. Less than 5.0D, less than 4.0D, less than 3.0D, less than 2.0D, and less than 1.0D.
  • application of the methods of the present application halts or reverses myopia progression in a treated patient.
  • These patients have high myopia, moderate myopia, or low myopia; or the patients are anterior myopia (or are at risk of developing myopia).
  • axial (or longitudinal) growth of the eye of a treated patient is prevented, controlled, slowed, retarded, delayed and/or slowed using the methods of the present application.
  • application of the methods of the present application controls, slows, reduces, delays and/or slows the progression of myopia in a patient diagnosed with or at risk of developing myopia, improves the patient's eye (e.g., myopia) eye, anterior myopia, or eye at risk of developing myopia) and/or reduced choroidal thickness (ChT) in said patient's eye (eg, myopic eye, premyopia, or eye at risk of developing myopia) The axial (or longitudinal) growth rate.
  • myopia e.g., myopia
  • ChoT choroidal thickness
  • the axial (or longitudinal) growth of the eye of a treated patient is controlled, slowed, reduced, delayed, and/or slowed by between about 5-95%, about 5% relative to untreated, using the methods of the present application. -90%, about 5-80%, about 5-70%, about 5-60%, about 5-50%, about 5-40%, about 5-30 %, between about 5-20%, between about 10-100%, between about 20-90%, between about 30-90%, between about 40-90%, between about 50-90% Occasionally between about 75-90%.
  • application of the methods of the present application results in a smaller increase in pupil size or no pupil dilation occurs relative to atropine monotherapy.
  • oral preparations are solid preparations such as tablets, capsules, granules and powder preparations, and liquid preparations such as syrups and beverage preparations; optional (a): In solid preparations, excipients can be formulated Agents, lubricants, binders, disintegrating agents, etc., preferably, preservatives, antioxidants, colorants and sweeteners can be formulated, more preferably, additives are used; optional (b): in liquid preparations Including solvents, dissolving aids, suspending agents and isotonic agents, preferably, mixed reagents, buffers, pain relievers, etc., more preferably, additives such as preservatives, antioxidants, colorants, sweeteners, etc. are used.
  • the drug can be injection, tablet, lyophilized powder, capsule, effervescent tablet, chewable tablet, buccal tablet, granule, ointment, syrup, oral liquid, aerosol, Nasal drops, topical preparations, oral preparations, etc.; preferably ophthalmic dosage forms, including but not limited to eye drops (eye drops), eye ointments, eye sprays, implants, eye gels, eye patches, eye drops Microspheres, ophthalmic sustained-release preparations, periocular injections, intraocular injections; can also be free solutions, oil-water mixtures, suspensions (agents), liniments, lotions, creams, drops, granules, sprays agents, ointments, patches, pastes, pills, suppositories, emulsions.
  • the "ophthalmic formulation or drug" and the pharmaceutical composition or formulation of the present application are administered concurrently, such as simultaneous or sequential administration during a specific administration (treatment), administration on the same day, administration in the same week , Administration in the same month, administration in the same year; or alternating administration at intervals, such as alternating administration at 4-hour intervals, alternating administration at 12-hour intervals, alternating administration every other day, alternating administration every other week, alternating administration every other month, alternating administration every other year Alternate dosing.
  • Benzyl lysine preparations include two types of ready-made medicines that have been commercialized and pharmaceutical compositions formulated by the inventors using only the benzylic lysine compound as an effective pharmaceutical ingredient.
  • Benzyl lysine medicine BDL(S)
  • BDL(S) Benzyl lysine medicine
  • the dosage form is directly used for local administration in the eyes of guinea pig myopia model
  • Benzyl lysine compound purchased from MedChemExpress.
  • the benida lysine compound powder was directly and completely dissolved in 0.9% physiological saline to prepare a 5 mg/ml (11.669 mM) preparation (BDL).
  • BDL 5 mg/ml (11.669 mM) preparation
  • the overall appearance of the preparation is clear, transparent, uniform and free of suspending substances visible to the naked eye.
  • it is directly applied locally to the eyes or diluted with 0.9% normal saline before use according to the dosage requirements.
  • benzylic acid The preparations of benzylic acid include two types of directly purchased commercialized medicines and those prepared by the inventors simply using benzylic acid compounds.
  • the commercially available patent medicine is 3% benzylic acid ointment, which was purchased by the inventor from Iwaki Pharmaceutical Co., Ltd., Japan; the benzylic acid compound was purchased from MedChemExpress.
  • the benzylic acid was completely dissolved in DMSO to prepare a 330 mg/ml (1166.9 mM) stock solution, and stored at -20 degrees.
  • Lysine was purchased from MedChemExpress, fully soluble in 0.9% saline, and formulated to be tested at 1.7 mg/ml (11.669 mM).
  • M-hydroxy-methylaniline was purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd. Completely dissolve hydroxy-methylaniline in 0.9% saline to prepare a 250mM stock solution, and store at -20 degrees. It was diluted with 0.9% normal saline before the experiment started, and the final concentration of hydroxy-methylaniline preparation used in the examples was 5 mM. All formulation operations were performed in a dark room.
  • Sorbinil purchased from MedChemExpress. Sorbinil powder was dissolved in DMSO to prepare a 4.8 mg/ml (20 mM) stock solution, and stored at -20 degrees. It was diluted with 0.9% physiological saline before the experiment, and the final concentration of the Sorbinil preparation used in the examples was 24 ⁇ g/ml (100 ⁇ M), and all operations were carried out in a dark room.
  • the aldose reductase inhibitor Zopolrestat was purchased from MedChemExpress. Zopolrestat powder was dissolved in DMSO to prepare 84mg/ml (1M) mother solution, and stored at -20 degrees. Diluted with physiological saline before the experiment, the final concentration of the Zopolrestat preparation used in the examples was 420 ⁇ g/ml (1 mM), and all operations were carried out in a dark room.
  • Atropine powder was purchased from Stanford Chemicals, and was completely dissolved in 0.9% normal saline to prepare 1 mg/ml, that is, a 0.1% preparation (positive control). All operations were performed in a dark room.
  • compositions are formulated and stored according to routine laboratory methods and standards.
  • the preparation process of all preparations may use conventional physical and chemical solubilization means such as heating, stirring, pH adjustment, etc., and no compound precipitation occurs before all preparations are administered.
  • the form deprivation and lens-induced guinea pig myopia model is a classic and recognized myopia animal model in the art, which can be used to evaluate the efficacy and safety of myopia treatment drugs, and its construction method is well known to those skilled in the art.
  • the guinea pig Form deprivation myopia (FDM) and lens induced myopia (LIM) models, drug administration and data analysis were operated and performed in accordance with the published literature in the inventor's laboratory [1-4] ] .
  • the examples of the present application use healthy guinea pigs (ie, no underlying diseases, such as hypertension, hyperglycemia, eye diseases or abnormalities, etc.), and both males and females are used.
  • the animal experiments in this application have been reviewed by the Ethics Committee of Experimental Animals of Wenzhou Medical University.
  • the form deprivation and lens-induced guinea pig myopia model used in Example 3 below is constructed as follows:
  • the myopia model adopts monocular form deprivation (FD) and lens-induced (LI) modeling methods.
  • Form deprivation uses a special light transmittance of 1%, which does not fall off by itself.
  • the eye mask completely covers the animal's right eye, and the other eye (left eye) is obtained. normal vision.
  • Lens induction A -4D lens was used to fix the animal's right anterior eye, and the left eye obtained normal vision. Clean the lenses twice a day to prevent blurring. Administer daily from 9:00-9:30 am.
  • the animals in the control group and the experimental group took off their eyecups or lenses under the red light, respectively, and were injected with 0.1ml of solvent control or 5mg/mL of the test drug or positive control under the conjunctiva around the right eyeball. After the injection, the animals were determined. The administration was successful without trauma, and the eyecups and lenses were restored immediately, and the administration of each animal was controlled within about 10 seconds. Dosing was started on the day of modeling, and the animals with form deprivation were given once a day for 2 weeks, and the lens-induced animals were given once a day for 1 week.
  • mice in the same model drug effect experiment were measured in the same time period, and the first measurement time was 3 weeks old.
  • the above-mentioned animals were tested for diopter and axial parameters before the experiment, 1 week of experiment and 2 weeks of experiment (FD only).
  • the measurement of the diopter was carried out by the eccentricinfraredphotoretinoscope (EIR) built in our laboratory, and the average value was taken as the final result for each eye.
  • the axial parameters of guinea pigs were measured using the A-ultrasound probe in the CinemascanA/B ultrasonic diagnostic apparatus (QuantelMedical, Aviso, France). /s, lens 1723.3m/s, vitreous 1540m/s.
  • the detection contents include anterior chamber depth (ACD), lens thickness (LT), vitrous chamber depth (VCD) and axial length (AL).
  • ACD anterior chamber depth
  • LT lens thickness
  • VCD vitrous chamber depth
  • AL axial length
  • Embodiment 3 the in vivo therapeutic effect experiment of benzyl lysine
  • the experimental animals were 3-week-old tricolor guinea pigs and were divided into two groups: form deprivation group (FD) and lens induction group (LI).
  • the form deprivation group was divided into three groups: the negative control group was injected with 100 microliters of normal saline around the eye of the model, the experimental group was injected with the same volume of benzydal lysine 0.5 mg every day, and the positive control group was injected Mold eyes were given 100 ⁇ l of 0.1% atropine.
  • the lens induction group was divided into two groups: the negative control group was injected with 100 microliters of normal saline around the eye of the model every day, and the experimental group was injected with the same volume of benidalysine 0.5 mg into the eye of the model every day. Before the first dosing, 1 week after dosing and 2 weeks after dosing (FD only), binocular refractive, vitreous cavity and axial parameters of all tested animals were detected, respectively.
  • the normal saline injection group induced myopia -4.42 ⁇ 0.95D, while the benzylic lysine injection group induced myopia -3.49 ⁇ 1.15D after one week of administration, compared with the normal saline group, which inhibited 21.0% of myopia (figure 1). It can be seen that, compared with the normal saline group, the benidalysine administration group significantly inhibited the negative diopter of the guinea pigs with lens-induced myopia. Acid inhibition.
  • benzylic lysine can significantly slow down the negative process of the diopter of myopic individuals, and at the same time can significantly inhibit the lengthening of the eye axis. Prevention and control, especially in the treatment, prevention or improvement of refractive myopia or axial myopia and its related symptoms.
  • the above-mentioned experimental results of the present application prove that benzydal lysine has good preventive, slowing and therapeutic effects on myopia in humans, especially in children and adolescents.
  • Example 4 Commercial Benzyl lysine eye drops (0.5%, BDL(S)) inhibit the progression of myopia
  • Form deprivation (FD) or lens-induced (LI) myopia modeling was performed on guinea pigs at 8:00 a.m. on the first day of the experiment.
  • the form deprivation myopia model adopts the face mask method.
  • the headgear is made by the inventor using a 10-inch milky white non-toxic latex balloon.
  • the guinea pig model individual covers the headgear (experimental eye) for the right eye, and does not cover the headgear (contralateral eye) for the left eye.
  • the lens-induced myopia model used -4D lens the lens was purchased from Wenzhou Xinshijie Technology Co., Ltd., and the specific parameters were: center power -4D, base arc 16mm, diameter 11.8mm.
  • the lens was fixed on the right anterior eye of the guinea pig (experimental eye), and the left eye was left untreated (contralateral eye).
  • FD and LI induction continued throughout the cycle of benidalysine potency experiments, with only brief removal of headgear or lenses during administration or ocular testing (eg, diopter testing).
  • the diopter and axial parameters of the test animals were detected at 1 week and 2 weeks. All data collection and processing methods were the same as those published by the inventor's laboratory [4] , and the statistical basis was the same. The difference between the experimental eye and the contralateral eye of the subject.
  • the individual solvent (negative control) or drug (benzdalysine) in the lens-induced group was administered from 9 to 10 am on the day of modeling. The volume was 100 ⁇ l, and it was administered once a day for 1 week.
  • the diopter and axial parameters of all subjects were detected, and all data collection and processing methods were referred to the form deprivation group.
  • test drug (0.5% benzdalysine eye drops, approved by Chinese medicine H20063847
  • solvent control negative control group
  • Example 3 The results show that: it is consistent with the conclusion of Example 3.
  • the changes of the diopter and axial parameters of the animals in the negative control group were in line with the expectations of the myopia model, and the positive control drug atropine showed its expected efficacy in the experiment, which proves that the two myopia models in this experiment were successfully established and can be used for the test drugs. Efficacy evaluation.
  • Benzyl lysine eye drops commercially available in China can significantly inhibit and slow down the progression (development) of myopia in the form deprivation myopia model and the negative lens-induced myopia model, that is, the process of myopic individuals becoming negative in refractive index is affected by Benzyl lysine
  • the eye drops were successfully delayed and effectively controlled, and even in individual animals in the benzdalysine treatment group, the inventor found that the progression of myopia was almost completely terminated by the test drug.
  • the treatment effect of 0.5% benzyl lysine eye drops on myopia is better than that of 0.1% atropine eye drops at 1 week of medication, but there is no statistical difference between the two;
  • the therapeutic effect of 0.5% benzyl lysine eye drops on myopia is similar to that of 0.1% atropine eye drops, and the difference in efficacy between the two is very significant compared with the negative control group.
  • benzyl lysine also effectively prevented the aggravation of myopia.
  • the negative speed of the diopter in the drug intervention group was significantly slower than that in the control group, and there was a significant difference in the diopter between the two at the end of the experiment.
  • the commercialized benida lysine eye drops can be used for the treatment of myopia (eye), especially to control the rate of progression of the disease, so as to reduce the complications and risk of blindness caused by high myopia, especially in children and adolescent stage interventions.
  • Example 5 The dose-response relationship experiment of different concentrations of benzylic acid myopia treatment (0.01%, 0.05%, 0.1% and 0.5%)
  • FD + saline group negative control
  • FD + 0.01% benzyl lysine FD + 0.05% benzyl lysine
  • FD + 0.1% benzyl Dalysine FD+0.5% benzalkonium lysine
  • experimental group refers to the administration of 0.5% benzalkonium lysine to FDM model individuals
  • FD+0.1% atropine positive control
  • Form deprivation (FD) myopia modeling was performed on guinea pigs at 8:00 a.m. on the first day of the experiment.
  • the form deprivation myopia model adopts the face mask method.
  • the headgear is made by the inventor using a 10-inch milky white non-toxic latex balloon.
  • the guinea pig model individual covers the headgear (experimental eye) for the right eye, and does not cover the headgear (contralateral eye) for the left eye.
  • FD induction continued throughout the duration of the benzydal lysine potency test, with only brief removal of the headgear during administration or ocular testing (eg, diopter testing).
  • the position of the headgear was checked at 8:00 am, 12:00 noon, 7:00 pm every day after the start of the drug effect experiment and before administration, and the individuals whose headgear fell off more than 3 times were eliminated. From the day of modeling, the corresponding solvent (negative control) or drug was administered to the experimental eyes of the FDM model between 9 and 10 am. The administration method was subconjunctival injection. Dosing for 2 weeks. At the beginning of the drug efficacy experiment of this model, the diopter and eye axis parameters of the test animals were detected at the beginning of the experiment, and all the data collection and processing methods were the same as those published by the inventor's laboratory [4] , and the statistical basis was the same. The difference between the experimental eye and the contralateral eye of the subject. All the above pharmacodynamic experiments were repeated at least three times, and the benzylic acid lysine preparation was prepared by the inventor using physiological saline.
  • the myopia inhibition rate (calculated as: (drug group diopter - solvent group diopter)/solvent group diopter) with diopter as an index also increased correspondingly, indicating that bendalysine
  • the benidalysine preparation prepared by the inventor using only normal saline is consistent with the efficacy of the commercially available benidalysine, that is, 0.5% bendalysine has the same effect on 1 week of medication.
  • the therapeutic effect of myopia is better than that of 0.1% atropine, but there is no statistical difference between atropine and benzdalysine; the treatment effect of 0.5% benzdalysine on myopia is better than that of 0.1% atropine eye drops after 2 weeks of treatment Similarly, the efficacy of the two groups was significantly different compared with the negative control group. This shows that benzylic acid as the main active ingredient or the only active ingredient can play a role in the treatment and prevention of myopia. Statistically, the 0.05% and 0.1% two groups of benzdalysine preparations also showed a significant therapeutic effect on myopia (effectively inhibited the negative process of diopter), and the low concentration group of 0.01% benzdalysine was on the diopter index 1.
  • the weekly test was similar to the negative control group, and the 2-week test was slightly stronger than the negative control group but not statistically different.
  • 0.05%, 0.1% and 0.5% of three concentrations of benzyl lysine also inhibited the increase of vitreous cavity depth (VCD) and the prolongation of axial length (AL) in myopic individuals.
  • VCD vitreous cavity depth
  • A axial length
  • benzyl lysine can effectively inhibit the posterior segment of the eye (vitreous cavity depth and axial length of the subject) ) and can effectively control, inhibit, delay or slow down the (continuous) negative process of myopic individuals or individuals with a tendency to develop myopia.
  • the use of benidalysine alone can prevent and treat myopia (eye)
  • or benandalysine can be used to prepare a preparation or a pharmaceutical composition
  • the preparation or pharmaceutical composition can be used for Myopia (eye) prevention and treatment.
  • the concentration of benzyl lysine in the above preparation or pharmaceutical composition is not less than 0.01%, and can be 0.05%-1% of benzyl lysine.
  • the concentration of benidalysine eye drops is a reasonable formula for clinical myopia prevention and control, that is, the concentration of benidalysine in the preparation or pharmaceutical composition is preferably 0.1% to 0.25%.
  • the way to achieve or improve the myopia prevention and control effect of benidalysine for myopic people or people with myopia tendency also includes increasing bendalysine Ocular bioavailability, increase the frequency of drug administration, use in combination with other myopia treatment drugs and optimize the formulation of benidalysine preparations, etc.
  • the above-mentioned benidalysine preparation or pharmaceutical composition can effectively reduce (inhibit) the prolongation of the axial length of the myopic or myopic-prone individual and effectively reduce (inhibit) the increase in the depth of the vitreous cavity of the myopic or myopic-prone individual;
  • the The benidalysine preparation or pharmaceutical composition can treat (prevent and control) myopia, especially for people aged 6 to 18 years old.
  • 3-week-old tricolor guinea pigs were tested for diopter (infrared eccentric photorefractometer) and axial (A-ultrasound) after excluding individuals with obvious eye diseases or abnormalities.
  • Staggered no more than 2D animals were randomly divided into the following 4 groups: form deprivation (FD) + solvent control (NS) group, FD + 0.5% benzyl lysine eye drops (BDL(S)) group, lens induced (LI)+solvent control (NS) group, LI+0.5% benzyl lysine (BDL(S)) group.
  • Form deprivation (FD) or lens-induced (LI) myopia modeling was performed on guinea pigs at 8:00 a.m. on the first day of the experiment.
  • the form deprivation myopia model adopts the face mask method.
  • the headgear is made by the inventor using a 10-inch milky white non-toxic latex balloon.
  • the guinea pig model individual covers the headgear (experimental eye) for the right eye, and does not cover the headgear (contralateral eye) for the left eye.
  • the lens-induced myopia model used -4D lens the lens was purchased from Wenzhou Xinshijie Technology Co., Ltd., and the specific parameters were: center power -4D, base arc 16mm, diameter 11.8mm.
  • the lens was fixed on the right anterior eye of the guinea pig (experimental eye), and the left eye was left untreated (contralateral eye).
  • FD and LI induction continued throughout the cycle of benidalysine potency experiments with brief removal of headgear or lenses during dosing or choroidal thickness measurements only.
  • the corresponding solvent or drug was given to the experimental eye of the FDM model between 9 and 10 am every day.
  • the method of administration was subconjunctival injection next to the experimental eye. .
  • the lens-induced myopia model individuals in the lens-induced group were given solvent (negative control) or drug (benzdalysine) at 9-10 am on the day of modeling, and the administration method was subconjunctival injection next to the eye of the experimental eye. , the injection volume was 100 ⁇ l, and the drug was administered once a day for 1 week.
  • the above two models of myopia were detected by Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany) at 30-60min after the last administration. All data collection and processing methods were the same as those published by the inventor's laboratory.
  • the same [4] the statistical basis is the difference between the experimental eye and the contralateral eye of the same individual subject, and the statistical method is the independent sample T test. All the above efficacy experiments were repeated at least twice, and the test drug (0.5% benzdalysine eye drops) and the solvent control (negative control group) were produced and provided by the same commercial benzdalysine eye drops manufacturer to the inventor.
  • the mean value of the choroidal thickness difference between the experimental eye and the contralateral eye was -17.51 ⁇ m, while the mean value of the choroidal thickness difference between the experimental eye and the contralateral eye of the myopic individual after benzdalysine intervention was -9.20 ⁇ m , indicating that the choroidal thickness of the experimental eye approaches the level of the choroidal thickness of the normal eye in the same individual after drug intervention (the difference between the two decreases);
  • the mean value of the choroidal thickness difference between the experimental eye and the contralateral eye is - 23.38 ⁇ m, while the mean difference of choroidal thickness between the experimental eye and the contralateral eye of myopic individuals after benzdalysine intervention was -6.31 ⁇ m, and the choroidal thickness of the experimental eye in individual animals even completely recovered to the normal eye level after administration (see Figure 5).
  • Corneal curvature (RCC), anterior chamber depth (ACD) and lens thickness (LT) indices were also not affected by the test drug.
  • benzylic lysine can significantly inhibit the decrease of choroidal thickness and slow down the thinning trend of choroidal thickness in myopic individuals or individuals with myopia tendency.
  • benzylic lysine increases the choroidal thickness of the myopic individual, it will move the retina to the lens, and eventually the distance between the imaging focus of the myopic eye and the retina is shortened or even coincident with the two.
  • the distance between the imaging focus and the retina is the degree of myopia.
  • benzylic acid can shorten the distance between the two or inhibit the increase of the distance between the two, which itself is reducing the degree of myopia.
  • this myopia treatment (prevention and control) effect embodied by benzyl lysine in this application is not limited to axial myopia, refractive myopia, pathological myopia, simple myopia, pseudomyopia or true myopia, It has nothing to do with the age, gender, degree of myopia, speed of myopia progression, ethnicity, and age at the onset of myopia, that is, benzydal lysine has therapeutic and preventive effects on all types of myopia.
  • Example 7 Therapeutic effect of benzylic acid ointment for eye administration with benzylic acid eye drops (non-invasive administration or non-invasive administration)
  • 3-week-old tricolor guinea pigs were tested for diopter (infrared eccentric photorefractometer) and axial (A-ultrasound) after excluding individuals with obvious eye diseases or abnormalities.
  • Animals with a difference of no more than 2D were randomly divided into three groups: FD+saline group, FD+0.5% benzyl lysine eye drops (self-prepared), FD+0.1% atropine.
  • the guinea pigs were subjected to form deprivation, using the mask method, with the right eye covered (experimental eye) and the left eye not covered (contralateral eye).
  • FD induction continued throughout the duration of the benzydal lysine potency test, with only brief removal of the headgear during administration or ocular testing (eg, diopter testing).
  • the position of the headgear was checked at 8:00 am, 12:00 noon, 7:00 pm every day after the start of the drug effect experiment and before administration, and the individuals whose headgear fell off more than 3 times were eliminated. From the day of modeling, the corresponding solvent or drug was administered to the experimental eyes at 9-10 am, and the eye drops were directly administered.
  • the second eye-drop administration was performed at 2:30-3:30 pm, that is, twice a day, each time
  • the dosing volume was 25 ⁇ l, and the drug was administered continuously for 2 weeks.
  • the actual effective therapeutic dose of the drug obtained by each eye was lower than that of the eye of the same volume.
  • the dose of the peribulbar injection, and the total volume of eye drops administered to the test animals every day is also smaller than the injection volume of Example 5. Therefore, in this example, regardless of whether the benida lysine eye drops or 0.1% atropine, the drug effect of the eye drops directly administered by eye drops is inferior to the therapeutic effect of peribulbar injection on myopia.
  • Atropine eye drops are used for the current clinical trial concentration.
  • this concentration of atropine did not observe any therapeutic effect on the guinea pig myopia model, whether it is the refractive index or the ocular axis parameter index, which may be related to the short time that the eye drops stay on the surface of the eyeball after the eye drops are administered to the animals.
  • the risk-benefit ratio of benida lysine for the treatment of myopia is better than that of atropine (for example, the use of benida lysine during the day will not appear in myopia treatment at the same time similar to atropine dilation of pupils) photophobia), especially suitable for the treatment of myopia in children and adolescents and the prevention and control of myopia in school-aged people.
  • the specific experimental process is as follows: apply benzylic acid ointment on the corneal surface and periocular skin of the test eye (experimental eye) of the guinea pig form deprivation myopia model described in this application, and manually and quickly close the eyelids 10 times, but because the ointment cannot quickly Absorption and eye mask coverage and normal blinking of animals, the inventors found that there is also a certain amount of benzylic acid ointment left on the inner surface of the eye mask during the next application.
  • the dose of benzylic acid ointment is 18mg ⁇ 2mg each time.
  • the deprived eyes are administered at 9-10 am every day, and the second administration is at 2:30-3:30 pm, that is, twice a day. , for 2 consecutive weeks.
  • the diopter and eye axis parameters of the test animals were detected at the beginning of the experiment, and all the data collection and processing methods were the same as those published by the inventor's laboratory [4] , and the statistical basis was the same. The difference between the experimental eye and the contralateral eye of the subject.
  • the myopia suppression rate of 3% benzylic acid ointment for 1 week and 2 weeks was 17.7% and 25.9%, respectively, and the therapeutic effect was inferior to 0.5% benzylic acid lysine or 0.1% atropine in the same batch, but much better than the same batch Subform deprivation myopia model untreated group.
  • the possible reason is that the modeling mask affects the ocular absorption of benzylic acid in the ointment, or because the dosage form is mainly aimed at the human skin route of administration, it is not a reasonable formulation for the drug bioavailability of benzylic acid in the eyes of guinea pigs.
  • benzylic acid (ointment) still has an effective prevention and control effect on myopia.
  • the increase in the depth of the vitreous cavity and the prolongation of the axial length of the myopic individuals can be obtained after application.
  • the mean vitreous cavity depth prolongation in the myopia treatment group with benzylic acid ointment was 0.09 mm and the mean axial length prolongation was 0.09 mm, and the corresponding indicators in the same batch of myopia unintervention group were 0.13 mm and 0.12 mm (see Figure 6).
  • the axial lengthening of myopic individuals is mainly caused by the increase in the depth of the vitreous cavity, and benzylic acid can simultaneously reduce the increase in the depth of the vitreous cavity and the lengthening of the axial length of the myopic individuals.
  • No obvious ocular abnormalities were found in animals after administration of benzylic acid, and the pupils, corneal curvature, anterior chamber and lens-related indicators of the subjects were not affected by the drug (see Figure 7).
  • benzylic acid and its salt forms can also effectively treat and prevent myopia when other non-invasive (non-invasive) administration methods are used, and delay the development of short-sighted individuals or patients.
  • Individuals with myopia tendencies tend to have a negative process of refraction.
  • direct eye drop administration of benzylic acid lysine eye drops or eye administration of benzylic acid eye ointment is used to treat myopia, so as to inhibit the prolongation of the ocular axis and reduce the depth of the vitreous cavity of myopic individuals or individuals with myopia tendency.
  • Example 8 Effects of simple lysine and simple benzylic acid eye drops on myopia
  • 3-week-old tricolor guinea pigs were tested for diopter (infrared eccentric photorefractometer) and axial (A-ultrasound) after excluding individuals with obvious eye diseases or abnormalities.
  • Staggered no more than 2D animals were randomly divided into 5 groups: FD + saline group (NS), FD + lysine (L-lysine), FD + 0.5% benzyl lysine (BDL), FD + DMSO (for benzyl The solvent control group, vehicle), and FD+bendazac (experimental group, refer to the administration of benzylic acid to FDM model individuals, bendazac).
  • the guinea pigs were subjected to form deprivation, using the mask method, with the right eye covered (experimental eye) and the left eye not covered (contralateral eye).
  • FD induction continued throughout the duration of the efficacy experiment, with only brief removal of the headgear during drug administration or ocular testing (eg, diopter testing).
  • the position of the headgear was checked at 8:00 am, 12:00 noon, 7:00 pm every day after the start of the drug effect experiment and before administration, and the individuals whose headgear fell off more than 3 times were eliminated.
  • the myopia inhibition rate of pure benzylic acid was 33.4% and 30.1% at 1 week and 2 weeks.
  • benzylic acid is the key and only part of the drug effect of benzylic acid in the treatment of myopia, which can effectively inhibit and slow down the negative process of myopic individual's diopter.
  • benzylic acid can also significantly inhibit the axial extension and slow down the increase of the depth of the vitreous cavity of myopic individuals after administration, and there is a statistical difference with the negative control group, and its effect is equimolar with the same batch.
  • the benzyl lysine experimental group was similar (see Figure 9).
  • benzylic acid and benzylic acid lysine in inhibiting choroidal thickness reduction in myopic or myopic-prone individuals showed consistent efficacy in terms of efficacy, and benzylic acid significantly inhibited choroidal thickness reduction in myopic or myopic-prone individuals and Slow down the thinning trend of its choroidal thickness.
  • benzylic acid and its corresponding compounds in any of its salt forms are effective in the treatment of myopia by inhibiting axial elongation and slowing the increase in the depth of the vitreous cavity.
  • Myopia tends to be a process in which an individual's diopter becomes negative.
  • benzylic acid and its pharmaceutically acceptable salts can effectively increase the thickness of the choroid and reduce the degree of myopia.
  • the dosage form of above-mentioned benzylic acid and its pharmaceutically acceptable salt (such as benzylic acid lysine) in the treatment and prevention of myopia can be eye drops, eye ointment, eye spray, eye injection and Ophthalmic gels; devices, formulations or pharmaceutical compositions containing such compounds (drugs) can be used to control myopia progression.
  • benzylic acid and its pharmaceutically acceptable salt such as benzylic acid lysine
  • Embodiment 9 The therapeutic effect of Sorbinil and Zopolrestat on guinea pig form deprivation myopia model
  • 3-week-old tricolor guinea pigs were tested for diopter (infrared eccentric photorefractometer) and axial (A-ultrasound) after excluding individuals with obvious eye diseases or abnormalities.
  • Animals with no more than 2D variance were randomly divided into 3 groups: FD+DMSO, FD+Sorbinil, FD+Zopolrestat.
  • IC 50 of zopolrestat 3.1 nM
  • IC 50 of sorbinil 3.14 ⁇ 0.02 ⁇ M
  • the final concentration of Zopolrestat preparation actually used in the inventor’s experiment is 1 mM
  • the final concentration of Sorbinil preparation is 100 ⁇ M.
  • the guinea pigs were modeled with form deprivation myopia.
  • the form deprivation myopia model adopts the face mask method.
  • the head cover is made by the inventor using a 10-inch milky white non-toxic latex balloon.
  • the right eye of the guinea pig model is covered with the head cover (experimental eye), and the left eye is not covered with the head cover (contralateral eye).
  • FD induction continued throughout the duration of the benzydal lysine potency test, with only brief removal of the headgear during administration or ocular testing (eg, diopter testing).
  • the position of the headgear was checked at 8:00 am, 12:00 noon, 7:00 pm every day after the start of the drug effect experiment and before administration, and the individuals whose headgear fell off more than 3 times were eliminated. From 9-10 am on the day of modeling, the corresponding solvent or drug was administered to the experimental eyes of the FDM model. The frequency of administration was once a day, and the administration method was subconjunctival injection. At the beginning of the drug efficacy experiment of this model, the diopter and eye axis parameters of the test animals were detected at the beginning of the experiment, and all the data collection and processing methods were the same as those published by the inventor's laboratory [4] , and the statistical basis was the same. The difference between the experimental eye and the contralateral eye of the subject. All the above efficacy experiments were repeated at least 3 times, and the test drug and solvent control (negative control group) in this example were prepared by the inventors themselves.
  • Example 10 The therapeutic effect of m-hydroxy-methylaniline on guinea pig form deprivation myopia model
  • the guinea pig form deprivation myopia model described in this application was used to evaluate the efficacy of the drug. All individuals were tested for diopter and axial length. Hydroxymethylaniline (compound A) and FD + 0.1% atropine (positive control). At 8:00 am on the first day of the experiment, the guinea pigs were subjected to form deprivation, using the mask method, with the right eye covered (experimental eye) and the left eye not covered (contralateral eye). From 9-10 am on the day of modeling, the solvent or drug in the corresponding group of experimental eyes was administered by subconjunctival injection in the parabulbar, and the injection volume was 100 ⁇ l, once a day for 1 week. The diopter and axial parameters were detected at the beginning and after the end of the drug effect experiment. All data collection and processing methods were the same as other embodiments of this application, and the statistical basis was the difference between the experimental eye and the contralateral eye of the same subject.
  • the changes in diopter and axial parameters of the animals in the negative control group in this experiment were in line with the expectations of the myopia model, and the positive control drug atropine showed its expected efficacy in the experiment. Drug efficacy evaluation.
  • the experimental results are shown in Fig. 15. Neither the negative diopter nor the increase in the depth of the vitreous cavity or the axial length of the eye were inhibited after the administration of m-hydroxymethylaniline. It shows that m-hydroxymethylaniline has no preventive or therapeutic effect on myopia. After the administration of m-hydroxymethylaniline, the axial parameters and refraction of the subjects did not show statistical differences with the negative control group. No slowing effect.
  • Atropine showed normal myopia treatment effect, but all the tested animals in this group had mydriasis, and the anterior chamber depth and lens thickness were not affected after the drug intervention (Fig. 15).
  • the experimental results prove that not all compounds (drugs) with cataract treatment effects can be used to treat myopia; not all compounds with antioxidant activity or can reduce BLOA (Biological Liquid Oxidant Activity) have myopia prevention and control Efficacy.

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Abstract

本申请涉及用于预防和/或治疗近视的方法和药物组合物。本申请的药物组合物或方法能够有效防控近视，并且安全无明显副作用，具有良好的临床应用前景。

Description

用于治疗近视的方法和药物组合物 技术领域
本申请涉及用于治疗、预防或控制近视及其相关症状的方法及药物。
背景技术
公元前350年，亚里士多德首次使用“近视”一词(Paulus T V M de Jong，Br J Ophthalmol.2018 Aug；102(8):1021-102)指代一种屈光不正现象，目前近视已经是全球最严重的公共卫生问题之一。早期的文献指出2010年全球近视患病人数接近18.4亿，占当时世界总人口的27％，其中高度近视人群1.7亿，占2.8％，特别是东亚地区，如中国、日本、韩国和新加坡，近视患病率接近50％，远高于澳洲、欧洲和美洲。预计到2050年，近视的全球患病率将高达50％以上(Brien A Holden，Ophthalmology.2016 May；123(5):1036-42)。我国6至18岁儿童和青少年近视的发病率尤其严重。2016年，一项57904例样本的流行病学调查显示，我国华北、华东、华南、西南和西北地区抽取的6个省市的中小学生近视患病率为55.7％，其中6～8岁组、10～12岁组、13～15岁组和16～18岁组近视患病率分别为35.8％、58.9％、73.4％和81.2％(周佳,马迎华,马军etal.中国6省市中小学生近视流行现状及其影响因素分析.中华流行病学杂志2016；37:29-34.)。流行病学数据显示，全球近视和高度近视患病率不断攀升，社会、生活和环境因素的显著变化是影响近视患病率不断攀升、近视低龄化、重度化的重要原因之一(Susan Vitale，Arch Ophthalmol.2009 Dec；127(12):1632-9)，这种趋势短时期内不会发生明显改善。
近视的危害很多。除引起远距视物模糊外，近视尤其是高度近视还可能引起青光眼、白内障、视网膜脱落、视网膜撕裂、后巩膜葡萄肿、黄斑出血或近视黄斑病变、脉络膜新生血管化等严重并发症，损害视力相关的生活质量，增加视力相关工作难度导致视力损害，甚至致盲(Chen-Wei Pan，Ophthalmic Physiol Opt.2012 Jan；32(1):3-16.和Seang-Mei Saw，Ophthalmic Physiol Opt.2005 Sep；25(5):381-91.)。
发明内容
鉴于上述技术问题，本申请提供一种苄达赖氨酸或苄达酸、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、或其类似物或其衍生物、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至少两项：
(a)用于预防和/或治疗近视及其相关症状；
(b)用于延缓、减弱或治疗与屈光不正相关的眼球的异常发育；
(c)用于使个体在不借助或更换镜片(如近视框架眼镜或OK镜)或不依靠其它视力矫正手段(如屈光手术)的条件下获得更清晰的远视力；
(d)用于控制、抑制、延缓或减缓近视个体或有近视发生倾向个体的屈光度(持续)变负进程(速度)；
(e)用于联合手术(如屈光矫正手术、近视角膜激光手术、晶状体手术)或其它视力矫正手段(如角膜接触镜)来预防和/或治疗近视及其相关症状；
(f)用于与一种或多种其他药物联合使用来预防和/或治疗近视及近视相关症状；
(g)用于减少视网膜和晶状体之间距离，优选的是在近视个体中或有近视倾向个体中减少视网膜和晶状体之间距离；
(h)用于减小近视度数、或治疗近视眼、或近视眼治疗、或控制近视进展、或近视矫正、或缓解近视、或青少年近视预防；
(i)用于抑制或治疗晶状体病变导致的近视；
(j)用于制备药物组合物、制剂或装置，所述药物组合物、制剂或装置以实现上述(a)至(i)中的至少一项用途。
在一些实施方式中，苄达赖氨酸或苄达酸、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、或其类似物或其衍生物、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。
在一些实施方式中，唯一活性成分或主要活性成分是其含量占全部活性成分的50％以上、60％以上、70％以上、80％以上、90％以上、或100％，所述百分比为质量比或摩尔比。
在一些实施方式中，这些物质或其组合与所述一种或多种其他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，与屈光不正相关的眼球的异常发育是个体幼年阶段(如人类2-28岁)，主要由环境因素诱发或者主要是人为因素导致(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)，而遗传因素是次要因素、伴随因素、协同因素、或者所述异常发育完全与遗传因素无关的屈光发育异常，其主要特征是在调节放松状态下，平行光线通过眼的屈光系统屈折后焦点落在视网膜之前。
在一些实施方式中，采用全身给药(如口服、静脉滴注)、或局部给药(如滴眼、玻璃体内注射、皮肤油膏或软膏涂抹)、或肠胃外给药(如通过粘膜给药、透皮给药、微针给药)的方式、或非侵入给药方式(如将眼药膏涂抹于角膜或挤入下眼睑拉伸形成的囊内)、或无创给药方式(如利用眼用喷剂给药)。
在一些实施方式中，皮肤油膏或软膏涂抹采用3％皮肤油膏或眼用软膏涂抹。
在一些实施方式中，将上述给药方式(如滴眼、口服)同时使用、或联合使用、或交替使用、或间隔使用、或单独使用、或选择其一使用。
在一些实施方式中，局部给药使用的制剂包括但不限于水性剂、油性剂或悬浮液剂，该制剂可以加入具有药理活性和/或生理活性的成分，这样的成分例如扩瞳组分、充血去除组分、眼肌(如睫状肌)调节组分、抗炎剂组分、收敛剂组分、抗组胺剂组分、抗过敏剂组分、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)、维生素、氨基酸、抗菌剂组分、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、青光眼治疗组分、白内障治疗组分等。
在一些实施方式中，这些物质或其组合在所述药物组合物、制剂或装置中的浓度或占比至少不小于0.01％，优选为0.01％至0.8％，优选为0.05％至0.5％，更优选为0.1％；或者所述这些物质或其组合的浓度或占比低于0.01％，所述百分比表示为质量/体积浓度(比)或质量比或摩尔(数)比。
在一些实施方式中，药物组合物或制剂可以为注射液、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、眼周注射剂或眼内注射剂；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、栓剂或乳剂。
在一些实施方式中，近视个体或有近视发生倾向个体为人，可以是儿童、青少年、中年人或老年人，优选为3至26岁人群，更优选为6至18岁人群；或为成年人、或为未成年人，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。
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、半真半假(混合)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、青少年近视、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)；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、位置性近视、弯曲性近视；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、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、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、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。
在一些实施方式中，药物组合物、制剂或装置中还包含医用制剂或药物，所述医用制剂或药物包括但不限于近视治疗药物(如阿托品、地巴唑、哌仑西平、毒蕈碱拮抗剂、7-甲基黄嘌呤(7MX)、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、维甲酸等)、M受体阻断剂(如针对M3受体的阻断剂或拮抗剂或抑制剂)、苄达酸或其各种盐形式、苄达赖氨酸或其各种盐形式、多不饱和脂肪酸(如DHA、EPA)、红景天苷、芒柄花黄素、哌唑嗪、后马托品、山莨菪碱(消旋)、托吡卡胺、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)、非选择性腺苷酸拮抗剂、扩血管药物、扩瞳药、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、抗过敏药物、抗炎药物、护肝类药物、眼科疾病的治疗性组分、局部眼用麻醉药、或眼科用制剂。
在一些实施方式中，一种或多种其他药物包括但不限于近视治疗药物(如阿托品、地巴唑、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、维甲酸等)、M受体阻断剂(如针对M3受体的阻断剂或拮抗剂或抑制剂)、苄达酸或其各种盐形式、苄达赖氨酸或其各种盐形式、多不饱和脂肪酸(如DHA、EPA)、红景天苷、芒柄花黄素、哌唑嗪、后马托品、山莨菪碱(消旋)、托吡卡胺、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)、非选择性腺苷酸拮抗剂、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、抗过敏药物、抗炎药物、护肝类药物、眼科疾病的治疗性组分、局部眼用麻醉药、扩瞳药、或眼科用制剂或药物。
在一些实施方式中，制剂还可以为保健品、食品、膳食补充剂、营养品、饮品等口服制品或化妆品；其中，所述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(近视按摩仪)、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。
附图说明
图1：苄达赖氨酸控制近视进展。
图2：苄达赖氨酸滴眼液治疗的安全性。
图3：不同浓度的苄达赖氨酸滴眼液防控近视。
图4：不同浓度苄达赖氨酸治疗的安全性。
图5：苄达赖氨酸增加近视个体的脉络膜厚度。
图6：苄达赖氨酸滴眼液滴眼给药和苄达酸药膏眼部涂抹给药的治疗效果。
图7：苄达赖氨酸滴眼液滴眼给药和苄达酸药膏眼部涂抹给药的安全性。
其中，图1-5中，*苄达赖氨酸(苄达酸)给药组与阴性对照组统计差异。#阿托品给药组与阴性对照组统计差异。*代表p<0.05，**代表p<0.01,***代表p<0.001，#代表p<0.05，##代表p<0.01，###代表p<0.001。图6和图7中，*苄达赖氨酸滴眼液与生理盐水组差异，#阿托品给药组与生理盐水组统计差异，$苄达酸药膏与生理盐水组差异。*代表p<0.05，***代表p<0.001，#代表p<0.05，##代表p<0.01，$代表p<0.05。
图8：单纯赖氨酸不能治疗近视，#BDL与生理盐水溶剂组差异，#代表p<0.05，##代表p<0.01，###代表p<0.001。
图9：单纯苄达酸眼药水具备与苄达赖氨酸眼药水一致的近视治疗作用。其中，#BDL与生理盐水溶剂组差异，*bendazac与vehicle溶剂组差异。*代表p<0.05，***代表p<0.001，##代表p<0.01，###代表p<0.001。
图10：单纯苄达酸治疗的安全性。
图11：单纯的赖氨酸治疗的安全性。
图12：苄达酸抑制近视个体的脉络膜厚度变小，*代表p<0.05。
图13：Sorbinil和Zopolrestat不能治疗近视。
图14：醛糖还原酶抑制剂给药的安全性评价。
图15：间羟基甲基苯胺不能治疗近视。#阿托品给药组与阴性对照组统计差异，##代表p<0.01。
具体实施方式
下面将结合附图对本申请技术方案的实施例进行详细的描述。以下实施例仅用于更加清楚地说明本申请的技术方案，因此只作为示例，而不能以此来限制本申请的保护范围。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
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。常见的近视分类有四种：(1)根据屈光度大小，可分为轻度(低度)近视、中度近视及高度(重度)近视；(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)根据成因分类，可分为原发性近视和并发性/继发性近视。不论是哪类近视的发生和发展，屈光系统(即屈光介质，包括角膜、晶状体和玻璃体等)各成分之间的不匹配是近视形成和决定其严重程度的关键。以屈光性近视为例，在其它屈光成分正常的前提下，如果个体的角膜曲率异常，平行光线通过该角膜后的焦点将偏离视网膜上原有位置，进而引起屈光度的变化，常见为圆锥角膜导致的近视；再如某些病变造成晶状体屈光指数改变，也会直接影响平行光线在视网膜的投射位置，这种情况下，如果平行光线的焦点落于视网膜前方，则称晶状体病变导致的近视；屈光成分不匹配的情况还包括玻璃体腔过大导致视网膜位置后移，造成远处物体眼内成像焦点落在视网膜前方，表现为屈光度变负。可见，上述近视分类方法在实际临床中还会根据具体情况做进一步的细分。但是，屈光度被公认为是判定所有近视类型、衡量其严重程度和评价近视治疗效果的唯一指标。根据《控制近视进展药物临床研究技术指导原则》和学界一致观点认为，儿童和青少年(尤其是6-18岁)最为常见的近视类型是轴性单纯性近视(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.)，眼轴延长的主要部位在眼球的后极部。与人类近视表现一致，目前已发现哺乳类动物(如树鼠，绒猴，豚鼠)长时间的实验性近视眼模型中也出现眼轴延长、巩膜变薄及巩膜胶原纤维变细现象(Neville A McBrien，Prog Retin Eye Res.2003 May；22(3):307-38.)。在实际药物临床前开发阶段，研究者们几乎都使用形觉剥夺(form-deprivation，FD)或镜片诱导(lens induced，LI)两种经典近视疾病模型来评估近视防控的药效(D A Goss，Am J Optom Physiol Opt.1981 Oct；58(10):859-69.和Hao Wu，Proc Natl Acad Sci U S A.2018Jul 24；115(30):E7091-E7100.和Sen Zhang，Invest Ophthalmol Vis Sci.2019 Jul 1；60(8):3074-3083.)，而对这两种近视模型同时具有治疗和防控效果的化合物被认为最具有成药可能。
近视的发病机制仍未完全清楚。目前认为环境因素是近视多发的主要诱因，影响近视患病率和严重程度，而遗传引起的近视病例相对比较少见。环境因素包括调节过度、周边视网膜远视性离焦、采光照明(光照异常)、形觉剥夺等，其诱发近视的具体机制可能是视网膜辨识诱导近视的视近视觉信息后，这些信号经脉络膜传递到巩膜，导致巩膜细胞外基质成分发生改变，最终引发屈光度下降直至屈光度变负，形成近视。这也可以简单概括为光学离焦触发了离焦特异性信号，从而调控眼的屈光发育(Wen-Yi Wang，Biomed Pharmacother.2021 Jan；133:111092.和Tatiana V Tkatchenko，Trends Pharmacol Sci.2019Nov；40(11):833-852.和David Troilo，Invest Ophthalmol Vis Sci.2019 Feb 28；60(3):M31-M88.)。在正常发育的个体中，眼睛的大小也会随身体其它部位一起生长。人类出生至幼年阶段跟其它哺乳动物一致，都表现出远视。在此后的生长阶段随着眼球中各屈光成分的进一步发育和眼轴适度延长，平行光线的成像焦点与视网膜二者位置重叠(即焦点落在视网膜上)，转为正视。这个发育过程中如果出现长时间持续的视近视觉信息，则会出现包括眼轴过度延长等一系列屈光成分不匹配的病症，导致平行光线的成像焦点落于视网膜前方，形成近视。因此，如何保证眼球发育过程中各屈光成分相互匹配，阻止眼球过度生长，是近视防控的关键。以往的研究发现近视个体中屈光发育异常与巩膜重塑、结缔组织合成减少所导致的巩膜组织流失以及第一型胶原蛋白(COL1)的降解增加有关，多巴胺、胰岛素、一氧化氮或参与其中。
目前框架眼镜是矫正儿童和青少年近视的主要方式，成年患者可采用激光手术矫正近视。虽然近视大多数情况下可借由眼镜、隐形眼镜或者屈光手术矫正，但却无法延缓其进展。任何一类近视一旦发展为高度近视将是特别危险的视力问题，因为有视网膜、脉络膜和巩膜并发症的高度风险。因此，近视矫正不能简单理解为近视治疗。临床上近视治疗主要体现为抑制或减缓近视进展，涉及的方法有光学和药理学两种。角膜塑型镜可延缓儿童和青少年近视进展，但这种治疗手段个体之间效果差异大，且需要专业视光医生密切辅助(Jinhai Huang，Ophthalmology.2016 Apr；123(4):697-708.)；近视控制的药理学选择是十分有限的(Tatiana V Tkatchenko，Trends Pharmacol Sci.2019 Nov；40(11):833-852.)，例如阿托品滴眼液虽然在很多研究中表现出近视治疗效果，但临床观察到停药后近视程度反弹、使用过程伴随扩瞳和畏光等较严重的副作用(Prema Ganesan，Expert Rev Ophthalmol.2010 Dec 1；5(6):759-787.)，且其在中国并未被国家药品监督管理局批准使用；7-甲基黄嘌呤是另外一个在研的控制近视的药物，其安全性和有效性还需更多的数据支持(Klaus Trier，J Ocul Biol Dis Infor.2008 Dec；1(2-4):85-93.和Tatiana V Tkatchenko，Trends Pharmacol Sci.2019 Nov；40(11):833-852.)。因此，目前尚缺乏疗效和安全性明确的用于控制近视进展的药物，该疾病领域存在着未被满足的临床需求。
已知苄达赖氨酸(Bendazac Lysine,BDL)或苄达酸有镇痛止痒、抗细胞坏死、利胆和治疗血脂异常的作用。临床上苄达赖氨酸通过防止晶状体蛋白变性来治疗白内障。
发明人通过研究出乎意料地发现，苄达酸或苄达赖氨酸可以对近视及其相关症状有治疗、预防或减缓的作用，表现为该类化合物可以有效控制、抑制、延缓或减缓近视进展，最终用于制备预防和治疗近视的制剂或药物组合物，并且该类化合物具有用药安全性高、不良反应 少等优势。
鉴于上述发现，本申请提供苄达赖氨酸或苄达酸、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、或其类似物或其衍生物、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至少两项：
(a)用于预防和/或治疗近视及其相关症状；
(b)用于抑制、减缓近视个体或有近视发生倾向个体的眼轴延长和/或其眼玻璃体腔长度(深度)增加；
(c)用于增加近视个体或有近视发生倾向个体的脉络膜厚度和/或抑制其脉络膜厚度的减少；
(d)用于延缓、减弱或治疗与屈光不正相关的眼球的异常发育；
(e)用于使个体在不借助或更换镜片(如近视框架眼镜或OK镜)或不依靠其它视力矫正手段(如屈光手术)的条件下获得更清晰的远视力；
(f)用于控制、抑制、延缓或减缓近视个体或有近视发生倾向个体的屈光度(持续)变负进程(速度)；
(g)用于联合手术(如屈光矫正手术、近视角膜激光手术、晶状体手术)或其它视力矫正手段(如角膜接触镜)来预防和/或治疗近视及其相关症状；
(h)用于与一种或多种其他药物联合使用来预防和/或治疗近视及近视相关症状；
(i)用于减少视网膜和晶状体之间距离，优选的是在近视个体中或有近视倾向个体中减少视网膜和晶状体之间距离；
(j)用于减小近视度数、或治疗近视眼、或近视眼治疗、或控制近视进展、或近视矫正、或缓解近视、或青少年近视预防；
(k)用于抑制或治疗晶状体病变导致的近视；
(l)用于在眼球处于发育阶段个体中维持屈光度稳定，特别是控制眼轴延长速度以保持其跟屈光介质之间的匹配，优选地，所述匹配可以保持正视或尽量保持正视；
(m)用于在眼球处于发育阶段个体中维持屈光度稳定，特别是控制眼轴延长速度以保持其跟屈光介质之间的匹配，优选地，所述匹配可以避免近视发生或抑制近视度数增加；
(n)用于制备药物组合物、制剂或装置，所述药物组合物、制剂或装置以实现上述(a)至(m)中的至少一项用途。
在一些实施方式中，苄达赖氨酸或苄达酸、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、或其类似物或其衍生物、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。
在一些实施方式中，唯一活性成分或主要活性成分是其含量占全部活性成分的50％以上、60％以上、70％以上、80％以上、90％以上、或100％，所述百分比为质量比或摩尔比。
在一些实施方式中，这些物质或其组合与所述一种或多种其他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，屈光不正相关的眼球的异常发育是个体幼年阶段(如人类2-28岁)，主要由环境因素诱发或者主要是人为因素导致(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)，而遗传因素是次要因素、伴随因素、协同因素、或者所述异常发育完全与遗传因素无关的屈光发育异常，其主要特征是在调节放松状态下，平行光线通过眼的屈光系统屈折后焦点落在视网膜之前。
在一些实施方式中，苄达赖氨酸或苄达酸的类似物(analogues)或其衍生物(derivatives)为下列化合物(a)-(c)之一：
(a)
Figure PCTCN2022090230-appb-000001
其中，R 1为H、P(氕，Protium)、D(氘，Deuterium)、T(氚，Tritium)、p-CH 3、m-F、m-Cl、或p-Cl；R 2为H、P(氕，Protium)、D(氘，Deuterium)、T(氚，Tritium)、K或Na；
(b)
Figure PCTCN2022090230-appb-000002
其中，R 1为H、P(氕，Protium)、D(氘，Deuterium)、T(氚，Tritium)、p-CH 3、m-F、m-Cl、或p-Cl；R 2为H、P(氕，Protium)、D(氘，Deuterium)、T(氚，Tritium)、K或Na；
(c)
Figure PCTCN2022090230-appb-000003
其中，R 1为H、P(氕，Protium)、D(氘，Deuterium)、T(氚，Tritium)、p-CH 3、m-F、m-Cl、或p-Cl；R 2为H、P(氕，Protium)、D(氘，Deuterium)、T(氚，Tritium)、K或Na。
在一些实施方式中，采用全身给药(如口服、静脉滴注)、或局部给药(如滴眼、玻璃体内注射、皮肤油膏或软膏涂抹，优选的，3％皮肤油膏或眼用软膏涂抹)、或肠胃外给药(如通过粘膜给药、透皮给药、微针给药)的方式、或非侵入给药方式(如将眼药膏涂抹于角膜或挤入下眼睑拉伸形成的囊内)、或无创给药方式(如利用眼用喷剂给药)。
在一些实施方式中，给药方式(如滴眼、口服)同时使用、或联合使用、或交替使用、或间隔使用、或单独使用、或选择其一使用。
在一些实施方式中，局部给药使用的制剂包括但不限于水性剂、油性剂或悬浮液剂，该制剂可以加入具有药理活性和/或生理活性的成分，这样的成分例如扩瞳组分、充血去除组分、眼肌(如睫状肌)调节组分、抗炎剂组分、收敛剂组分、抗组胺剂组分、抗过敏剂组分、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)、局部麻醉剂组分、青光眼治疗组分、白内障治疗组分等。
在一些实施方式中，这些物质或其组合在所述药物组合物、制剂或装置中的浓度或占比至少不小于0.01％，优选为0.01％至0.8％，优选为0.05％至0.5％，更优选为0.1％；或者所述这些物质或其组合的浓度或占比低于0.01％，所述百分比表示为质量/体积浓度(比)或质量比或摩尔(数)比，优选地，所述浓度为使用浓度或储存浓度。
在一些实施方式中，这些物质或其组合的浓度例如为0.01％-0.05％，0.05％-0.1％，0.1％-0.5％，所述百分比表示为质量/体积浓度(比)，优选地，所述浓度为使用浓度或储存浓度。
在一些实施方式中，药物组合物或制剂可以为注射液、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、眼周注射剂或眼内注射剂；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、栓剂或乳剂。
在一些实施方式中，近视个体或有近视发生倾向个体为人，可以是儿童、青少年、中年人或老年人，优选为3至26岁人群，更优选为6至18岁人群；或为成年人、或为未成年人，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。
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、半真半假(混合)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、青少年近视、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)；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、位置性近视、弯曲性近视；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、环境因素主导的近视。
在一些实施方式中，前述的近视包括或不包括晶状体病变导致的近视或近视症状。
在一些实施方式中，近视相关症状或体征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、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。
在一些实施方式中，药物组合物、制剂或装置中还包含医用制剂或药物，所述医用制剂或药物包括但不限于近视治疗药物(如阿托品、地巴唑、哌仑西平、毒蕈碱拮抗剂、7-甲基黄嘌呤(7MX)、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、维甲酸等)、M受体阻断剂(如针对M3受体的阻断剂或拮抗剂或抑制剂)、多不饱和脂肪酸(如DHA、EPA)、红景天苷、芒柄花黄素、哌唑嗪、后马托品、山莨菪碱(消旋)、托吡卡胺、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)、非选择性腺苷酸拮抗剂、扩血管药物、扩瞳药、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、抗过敏药物、抗炎药物、护肝类药物、眼科疾病的治疗性组分、局部眼用麻醉药、或眼科用制剂。
在一些实施方式中，药物组合物、制剂或装置中还包含医用制剂或药物，所述医用制剂或药物包括苄达酸或其各种盐形式、或者苄达赖氨酸或其各种盐形式。这意味着，在这些药物组合物、制剂或装置中最终形成“苄达酸或其各种盐形式”与苄达赖氨酸、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、或其类似物或其衍生物、或其晶体型化合物的组合形式；或者这些药物组合物、制剂或装置中最终形 成“苄达赖氨酸或其各种盐形式”与苄达酸、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、或其类似物或其衍生物、或其晶体型化合物的组合形式。
在一些实施方式中，医用制剂或药物也可以和所述药物组合物、制剂或装置同期给药，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。
在一些实施方式中，一种或多种其他药物包括但不限于近视治疗药物(如阿托品、地巴唑、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、维甲酸等)、M受体阻断剂(如针对M3受体的阻断剂或拮抗剂或抑制剂)、多不饱和脂肪酸(如DHA、EPA)、红景天苷、芒柄花黄素、哌唑嗪、后马托品、山莨菪碱(消旋)、托吡卡胺、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)、非选择性腺苷酸拮抗剂、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、抗过敏药物、抗炎药物、护肝类药物、眼科疾病的治疗性组分、局部眼用麻醉药、扩瞳药、或眼科用制剂或药物。
在一些实施方式中，一种或多种其他药物也可以包括苄达酸或其各种盐形式、或者苄达赖氨酸或其各种盐形式。这意味着，本申请的这些物质与这些药物联合使用时最终可以采用“苄达酸或其各种盐形式”与苄达赖氨酸、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、或其类似物或其衍生物、或其晶体型化合物联合使用的形式；或者本申请的这些物质与这些药物联合使用时最终可以采用“苄达赖氨酸或其各种盐形式”与苄达酸、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、或其类似物或其衍生物、或其晶体型化合物联合使用的形式。
在一些实施方式中，联合使用是所述一种或多种其他药物被同期给药，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。
在一些实施方式中，制剂还可以为保健品、食品、膳食补充剂、营养品、饮品等口服制品或化妆品；其中，所述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(近视按摩仪)、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，装置可称为眼科装置。
术语和定义
除非另有定义，本文所使用的所有的技术和科学术语与属于本申请的技术领域的技术人员通常理解的含义相同；本文中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本申请；本申请的说明书和权利要求书及上述附图说明中的术语“包括”和“具有”以及它们的任何变形，意图在于覆盖不排他的包含。
在本文中提及“一种或多种”表示存在该要素的至少一个；可以存在多个这样的要素，除非另有明确具体的限定。
在本申请的描述中，术语“和/或”仅仅是一种描述关联对象的关联关系，表示可以存在三 种关系，例如A和/或B，可以表示：单独存在A，同时存在A和B，单独存在B这三种情况。另外，本文中字符“/”，一般表示前后关联对象是一种“或”的关系。
在本文中提及“实施例”或“实施例方式”意味着，结合实施例(或“实施例方式”)描述的特定特征、结构或特性可以包含在本申请的至少一个实施例(或“实施例方式”)中。在说明书中的各个位置出现该短语并不一定均是指相同的实施例(或“实施例方式”)，也不是与其它实施例(或“实施例方式”)互斥的独立的或备选的实施例(或“实施例方式”)。本领域技术人员显式地和隐式地理解的是，本文所描述的实施例(或“实施例方式”)可以与其它实施例(或“实施例方式”)相结合。
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/其/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“或者/或”指“和/或”的“包括性”涵义，而不是“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。
术语“个体”、“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、大鼠和非人灵长类。在优选的实施方式中，所述哺乳动物是人。
本文中使用的将化合物、制剂、受试品或药物“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”，包括但不限于口服、眼内、鼻内、肠胃外(通过静脉内、肌内、腹腔内或皮下)或者局部给药。“给药”包括自己给药和由其他人给药。
本文的给药方式中，“单独使用”代表整个用药过程每个阶段仅使用一种给药方式，而用药过程不同阶段可以变换给药方式(但不存在交替)。
本文的给药方式中，“选择其一使用”代表整个用药过程仅仅限于一种给药途径，不会改变。
本文中使用的术语“氨基酸”包括天然存在的氨基酸和合成的氨基酸以及氨基酸类似物和以类似于天然存在的氨基酸的形式作用的氨基酸模拟物。天然存在的氨基酸是通过遗传密码编码的氨基酸以及后来被改性的那些氨基酸，比如羟(基)脯氨酸、γ-羧基谷氨酸和O-磷酸丝氨酸。氨基酸类似物指的是具有和天然存在的氨基酸相同的基本化学结构的化合物，例如，所述的基本化学结构即结合至氢的α-碳、羧基、氨基和R基，所述氨基酸类似物比如为高丝氨酸、正亮氨酸、蛋氨酸亚砜、蛋氨酸甲基锍。这样的类似物具有改性的R基(例如正亮氨酸)或改性的肽主链，但保持与天然存在的氨基酸相同的基本化学结构。氨基酸模拟物指的是具有与氨基酸的通用化学结构不同的结构、但以类似于天然存在的氨基酸的方式作用的化学化合物。本文中按照IUPAC-IUB生化命名委员会建议的通常已知的三字母符号或者一字母符号可指代氨基酸。
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、民族、近视程度、近视进展速度和对药物的耐受力。所述量还取决于疾病的程度、严重性和类型，以及专业人员(如医师)制定的治疗方案。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。所述药 物组合物还可结合一种或多种其他的治疗化合物、生物药和治疗性分子(如多肽)来给药。在本文描述的方法中，苄达酸、苄达赖氨酸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，苄达赖氨酸的“治疗有效量”是指最小程度地减轻眼科病症的生理作用的平均水平，优选为最小程度地控制近视进展的生理作用的平均水平。
本文中使用的术语“制剂”、“药物组合物”和“组合物”可互换使用并可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”、“药物组合物”和“组合物”可用于指一种或多种活性剂(活性成分)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。
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、优选人的。
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。
本文中使用的术语“同时”是指治疗给药时，通过相同或不同的途径(如口服和滴眼)且在同一时间或基本上在同一时间将至少两种活性成分给药；或者在同一时间或基本上在同一时间给药和进行手术；或者在同一时间或基本上在同一时间给药和施用治疗装置。
本文中使用的术语“单独”是指治疗给药时，在同一时间或者基本上相同的时间仅局限于一种方式或一种物质，如仅将一种有效成分给药。
本文中使用的术语“顺序”是指治疗给药指时，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，可在将其它的活性成分给药之前的若干秒、若干分钟、若干小时或若干天之前，将一种活性成分给药。
本文中使用的术语“治疗”、“控制”、“抑制”、“延缓”、“减少”、“防控”、“预防”、或“减缓”指的是治疗处理措施和预防或防止措施，其中，目的是防止或减缓(减轻)目标病症或失调，甚至将其消除或逆转。例如在接受了根据本文所述的方法的治疗量的苄达赖氨酸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/或测定到的避免、减少和消失，或者是病情进展的减缓，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。例如在一些实施方式中“治疗”并不需要100％消除或防止近视或近视症状。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、个体或标本中)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减轻、抑制、阻止、预防和/或逆转了例如至少约5％、至少约10％或至少约20％。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％)。
文中使用的术语“近视发生倾向(个体)”，可以是已经发生屈光度水平下降，但尚未变为负值的情况；也可以是由权威机构或专业医师预测或认为的近视易感体质或高危人群；还可以是有近视家族病史的个体；还可以包括接受较多视近视觉信息却缺乏视远机会的个体情况；还可以指近视发生(患病)率或一旦近视后其严重程度不低于平均水平的情形；还可以指服药后其不良反应或接受的手术术后风险包含屈光度下降的情形；还可以指如果不使用药物或其他近视治疗(防控)手段进行干预，该个体就会出现近视或其屈光度会降为0以下的情况。
“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、药械组合或装置的药学部分。
“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。
“类似物”指母体化合物(如本申请提及的苄达酸或苄达赖氨酸)的结构衍生物，其与母体化合物相比只有一个元素(包括同位素)不同。
本文中使用的术语化合物的“衍生物”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(C 1-C 6)变体、卤代物、氘代物等。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，例如参考文献Synthesis and biological evaluations of novel bendazac lysine analogues as potent anticataract agents中描述的苄达赖氨酸衍生物或类似物(Bioorganic&Medicinal Chemistry Letters,20,2115-2118,2010)，更优选它们应针对屈光发育有调节作用。而且，“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。代谢物已被公开为负责母体药物的大部分治疗作用。
本文所用的“代谢物”是指保留母体药物的至少部分活性、优选针对醛糖还原酶(Aldose Reductase，AR)活性具有抑制作用或对于近视及相关症状具有治疗、预防或减缓其进展作用的改性或加工的药物。
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、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)。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。
本申请提到“这些物质”是指苄达赖氨酸或苄达酸、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、或其类似物(analogues)或衍生物(derivatives)、其晶体型化合物。
“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。按屈光原因分为屈光性近视和轴性近视，它们的临床表现均为远距离视物模糊，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。近视相关症状还包括夜间视力差、飞蚊症、闪光感等，并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，具有上述临床症状者称为病理性近视。
近视可能是严重使眼睛虚弱的疾病。近视的潜在缺陷(风险)是眼球稍微拉长，导致眼晶状体将来自远物的光线聚焦在视网膜稍前方。因此，近视通常被称为视力缩短或视力靠近。在严重的情况下，眼球的这种拉长会拉伸并变薄眼睛的某些内部部分，这会增加视网膜脱离、白内障、青光眼、失明等的风险。因此，近视远比单纯的视力缩短严重得多。
近视存在眼的轴向伸长，影响大部分人群。近视发病通常在小学年龄期间，并且发展直至眼的生长完成。尽管可以使用校正镜片，但是近视的发展仍可以导致视觉缺陷增加。本申请公开认识到用于治疗、预防、防控、控制、抑制、减缓、减慢、延缓、降低、延迟和/或减轻近视的发生和发展的药物组合物和疗法的重要性，特别是通过方便施用或实施，降低潜在副作用和提供治疗益处或其组合的药物组合物、含有或递送所述药物组合物的装置和它们的使用方法。
学界已经讨论和研究了多种近视的原因，例如基因易感性、延长的书本工作或屏幕时间、暴露在明亮的光线下不足等。不管在给定的情况中近视的潜在原因是什么，其可能是上述列举的原因中的一种或多种，对于受这种症状影响的所有人与近视相关的拉长的眼球都会虚弱。因为眼睛在童年和学龄期成长，近视通常发生在学龄儿童和青少年并且可以与这些个体保持一生。因此，对个体的积极用药干预治疗，例如学龄儿童和青少年，可以改善这些个体年轻时和剩下的生命中的生活质量。
“近视个体”或“有近视倾向个体”为儿童、青少年、中年人或老年人，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。
在本文中，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申请中“近视”或“近视眼”所表达的含义。
“近视”的具体类型有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)；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。
“轴性近视”指眼球前后径过长(眼轴长度因超出正常范围造成其与其它屈光成分不匹配)，而屈光力(角膜和晶状体等眼其他屈光成分的屈光性能)基本在正常范围的近视。
“屈光性近视”指轴长基本在正常范围内，而主要由于屈光成分的屈光性能发生改变所导致的近视。
“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(一般大于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。这类近视其特征为发生明显病理改变，包括患者眼底出现视网膜色素上皮变薄及萎缩、脉络膜新生血管和视网膜脱离、黄斑变性等症状，严重可致盲。
“单纯性近视”是指多在学龄期发病，随发育停止而渐趋稳定，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，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。
“原发性近视”特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非一时性的功能-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(如角膜曲率)基本正常，是儿童及青少年最常见的近视类型，多发于2至30岁人群。
“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。
“中度近视”通常指300度以上600度以下的近视。
“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。
“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。
“晶状体病变导致的近视”是指由于晶状体蛋白变性引发晶状体结构参数或内部构造发生变化，伴随其一些物理性质如厚度、硬度、折射率发生改变，进而引发平行光线经该病变晶状体后聚集在视网膜之前的一类近视。
“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。
“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、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。
“眼球的异常发育”是儿童及青少年阶段(如3-26岁)眼球的大小发育异常，其主要特征是眼轴长度过长，导致平行光线通过眼部正常屈光系统后成像焦点位于视网膜前方；或者是主要由环境因素诱发的、或者主要是人为因素导致的发育异常(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)，而遗传因素是次要因素、伴随因素、协同因素、或者所述异常发育完全与遗传因素无关。
“苄达赖氨酸”，化学名为L-赖氨酸(1-苄基-1H-吲哒唑-3-氧基)乙酸盐，分子式：C 6H 14N 2O 2·C 16H 14N 2O 3，分子量：428.49，结构式如下：
Figure PCTCN2022090230-appb-000004
“苄达酸”，结构式如下：
Figure PCTCN2022090230-appb-000005
“苄达酸或苄达赖氨酸的衍生物”包括光学异构体或其外消旋体或其代谢产物(如5-hydroxybendazac)等，具体还可以包括但不限于Hong Shen等(Bioorganic&Medicinal Chemistry Letters,20,2115-2118,2010)列举的那些。可以采用商品化的含有苄达赖氨酸的滴眼液(如国药准字H20063847)，也可以采用本领域技术人员熟知的工艺来制备苄达赖氨酸及其衍生物，一个示例性的制备方法包括以下步骤：第一步合成是以苯肼为起始原料,与氯化苄经苄基化反应，制得α-苄基苯肼。第二步合成是用α-苄基苯肼与尿素在高温条件下反应成环，制得3-羟基-1-苄基吲哒唑。第三步合成是用3-羟基-1-苄基吲哒唑与氯乙酸经过羧甲基化反应，制得苄达酸即α-[(1-苄基-1H-吲哒唑-3-基)氧]乙酸。第四步合成是苄达酸与L-赖氨酸在四氢呋喃中进行成盐反应,然后在乙醇中重结晶,得到终产物苄达赖氨酸。
“苄达赖氨酸或苄达酸的类似物(analogues)或其衍生物(derivatives)”，例如(a)-(c)：
(a)
Figure PCTCN2022090230-appb-000006
其中，R 1为H、P(氕，Protium)、D(氘，Deuterium)、T(氚，Tritium)、p-CH 3、m-F、m-Cl、或p-Cl；R 2为H、P(氕，Protium)、D(氘，Deuterium)、T(氚，Tritium)、K或Na；
(b)
Figure PCTCN2022090230-appb-000007
其中，R 1为H、P(氕，Protium)、D(氘，Deuterium)、T(氚，Tritium)、p-CH 3、m-F、m-Cl、或p-Cl；R 2为H、P(氕，Protium)、D(氘，Deuterium)、T(氚，Tritium)、K或Na；
(c)
Figure PCTCN2022090230-appb-000008
其中，R 1为H、P(氕，Protium)、D(氘，Deuterium)、T(氚，Tritium)、p-CH 3、m-F、m-Cl、或p-Cl；R 2为H、P(氕，Protium)、D(氘，Deuterium)、T(氚，Tritium)、K或Na。
“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；其中，所述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。
“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(近视按摩仪)、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、可穿戴设备或用于近视防控的药械组合。
本申请提到“唯一活性成分或主要活性成分”是指除了苄达赖氨酸或苄达酸、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、或其类似物(analogues)或衍生物(derivatives)、或其晶体型化合物、或这些物质的组合之外，不含或仅含少量的其他的治疗近视的活性物质。例如，苄达赖氨酸或苄达酸、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、或其类似物(analogues)或衍生物(derivatives)、或其晶体型化合物、或这些物质的组合的含量占全部活性成分的50％以上、60％以上、70％以上、80％以上、90％以上、或100％，所述百分比为质量比或摩尔比；或苄达赖氨酸或苄达酸、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、或其类似物(analogues)或衍生物(derivatives)、或其晶体型化合物、或这些物质的组合在用药过程中对近视治疗药效贡献在50％以上、60％以上、70％以上、80％以上、90％以上、或100％。
药物组合物疗法是医学中广泛使用且强大的策略，其目的在于实现协同治疗效果、降低剂量和毒性以及最大程度减小或延迟耐药性的诱导(Chou TC.，“Drug combination studies and their synergy quantification using the Chou-Talalay method，”Cancer Res.(2010)70：440-6)。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，如苄达赖氨酸，以提高近视(度数)减低或近视(进程)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，除了对屈光度指标的改善外，实验中没有观察到畏光、瞳孔扩张等不良反应。在实验中，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，进一步基于苄达赖氨酸或苄达酸已有的临床应用基础，可认为在将其用 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。
经过实验，我们出人意料地发现，苄达酸及苄达赖氨酸可显著减缓形觉剥夺豚鼠和负镜诱导豚鼠近视模型的屈光度变负进程，并且可以显著抑制眼轴延长，基于此，可证实苄达酸及其盐形式化合物对于动物体尤其是人类，如学龄儿童、青少年或年轻的成年人的近视具有治疗、防止或控制近视进展的效果。
本申请提供了一种治疗或预防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苄达酸、苄达赖氨酸和/或它们治疗上可接受的盐及其衍生物。优选地，所述苄达酸或苄达赖氨酸单独施用，优选地，所述苄达酸和/或苄达赖氨酸与其他药物同时或顺序施用，优选地，所述苄达酸和/或苄达赖氨酸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。
本申请同时提供了一种通过抑制眼轴长度的伸长来抑制轴向近视进展的技术和方法，包括向受试者施用治疗有效量的苄达酸、苄达赖氨酸和/或它们治疗上可接受的盐及其衍生物。优选地，所述苄达酸或苄达赖氨酸单独施用，优选地，所述苄达酸和/或苄达赖氨酸与其他药物同时或顺序施用，优选地，所述苄达酸和/或苄达赖氨酸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。
本申请同时提供了一种减少近视度数的技术和方法，包括向受试者施用治疗有效量的苄达酸、苄达赖氨酸和/或它们治疗上可接受的盐及其衍生物。优选地，所述苄达酸或苄达赖氨酸单独施用，优选地，所述苄达酸和/或苄达赖氨酸与其他药物同时或顺序施用，优选地，所述苄达酸和/或苄达赖氨酸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。
本申请同时提供一种近视个体远视提高剂，其能够通过减小远处物体眼部成像焦点与视网膜之间的距离来改善近视个体的远视力。该远视提高剂含有苄达酸、苄达赖氨酸和/或它们治疗上可接受的盐及其衍生物。优选的，上述近视个体为屈光性近视。优选的，上述近视个体为轴性近视。
本申请也涉及在个体例如幼儿、学龄儿童、青少年或年轻的成年人中治疗、预防或控制近视及其相关症状的药物组合物或方法。在一些实施方式中，本申请的技术方案的治疗对象为青少年，年龄范围6-28岁，优选6-18岁，最优选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。在一些实例中，治疗、预防或控制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。
在一种实施方式中，药物组合物包含治疗有效量的苄达酸化合物或其盐及其衍生物，如氕，氘，氚取代物。
在其它实施方式中，对于任何一个或多个药物组合物、装置或治疗方法，其中所述药物组合物含有苄达酸或其治疗上可接受的盐(如苄达赖氨酸)或其衍生物中的至少一种物质；或者，所述药物组合物包含苄达赖氨酸或其治疗上可接受的盐或其衍生物；优选地，同时含有苄达酸和苄达赖氨酸；优选地，同时含有苄达赖氨酸和苄达磷酸氢钙；优选地，含有苄达磷酸氢钙；优选地，还包含药学上可接受的载体；优选地，其中所述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、装置或治疗方法的某些实施方式中，将所述治疗对象(患者)治疗约0.5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9年或者至少13年的一段时间。
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、装置或治疗方法，其中所述药物组合物是水性组合物，优选地，所述水性组合物具有跟泪液相近或一致的渗透压；或者所述药物组合物是眼科组合物(如眼 科局部组合物)或眼科制剂，优选地，所述眼科制剂为眼科水性制剂、眼科凝胶制剂、眼科乳剂、眼科脂质体、眼科软膏剂(优选地，所述眼科软膏剂为眼药膏，优选地，所述眼科软膏剂中含有凡士林或液体石蜡)；或者所述药物组合物是滴眼剂制剂、眼喷雾制剂、局部制剂、纳米颗粒混悬剂、或纳米圆片、缓释制剂或结膜下储库等。
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，如以滴眼剂的形式。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。
在其它实施方式中，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，药物组合物是通过无创给药途径施用的。
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、装置或治疗方法，其中所述装置优选是眼科装置，例如其可以理解为表示置于眼上或存在于眼中的物体。所述装置可以提供光学修正。装置包括(但不限于)美瞳、隐形眼镜、眼插入物、角膜覆盖物(cornealonlay)、角膜镶嵌物(cornealinlay)、纳米圆片(nanowafers)、脂质体、纳米颗粒、泪点塞(punctalonlay)或具有微流体储库(microfluidreservoirs)的水凝胶基质。
在其它实施方式中，药物组合物是包含在装置内的缓释制剂。
在其它实施方式中，药物组合物包含在装置内。
在其它实施方式中，药物组合物是眼科组合物并且所述眼科组合物包含在装置内。
在其它实施方式中，装置需含有药物组合物或能够递送药物组合物到达近视治疗相应靶点组织。
在其它实施方式中，装置以缓释方式递送所述药物组合物。
在其它实施方式中，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，将所述药物组合物配制为用于前近视、近视(眼)或近视发展治疗的眼科组合物。
在其它实施方式中，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。
在其它实施方式中，将所述药物组合物配制为用于轴性近视或屈光性近视治疗的眼科组合物。
在其它实施方式中，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或者是有近视发生倾向)的个体(患者)的治疗的眼科组合物。
在其它实施方式中，药物组合物基本均一地分布在整个装置中。
在其它实施方式中，装置包含在隐形眼镜泡罩包装内。
在其它实施方式中，药物组合物浸没在隐形眼镜泡罩包装内的装置内。
可以使用本领域的技术人员所知的任何方法来将细胞、器官或组织与苄达酸或苄达赖氨酸等化合物接触。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 的苄达酸或/和苄达赖氨酸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，苄达酸或/和苄达赖氨酸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，如在Hydrolysis in Drug and Prodrug Metabolism：Chemistry，Biochemistry，and Enzymology(Testa，Bernard and Mayer，Joachim M.Wiley-VHCA，Zurich，Switzerland 2003)中所述。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该化合物的化合物的修改形式。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，前药可逐渐转化成化合物。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，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；也可以形成碱加成盐，并且是药学上可接受的。为了更全面地讨论盐的制备和选择，请参考Pharmaceutical Salts：Properties，Selection，and Use(Stahl，P.Heinrich.Wiley-VCHA，Zurich，Switzerland，2002)。
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。载体必须是“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。
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、糖浆剂、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。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)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(SiO2)、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：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。
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。
本文公开的某些化合物可局部施用，即通过非全身性施用。这包括将本文公开的化合物施于眼、表皮、口腔的外部，耳和/或鼻里，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。
用于局部施用的活性成分可占制剂的例如0.001％至10％w/w(按重量计)。在某些实施方案中，活性成分可占多达10％w/w。在其它实施方案中，其可占不到5％w/w。在某些实施方案中，活性成分可占2％w/w至5％w/w。在其它实施方案中，其可占制剂的0.1％至2％w/w，优选为0.1％-0.5％w/w。在某些实施方案中，其可占制剂的0.01％w/w、0.05％w/w、0.1％w/w、0.25％w/w、0.5％w/w。
一些实施方式中，用于局部施用的活性成分可占制剂的例如0.001％w/v至10％w/v(按重量/体积计，单位：g/100ml)。在某些实施方案中，活性成分可占多达10％w/v。在其它实施方案中，其可占不到5％w/v。在某些实施方案中，活性成分可占0.2％w/v至0.5％w/v。在其它实施方案中，其可占制剂的0.1％w/v至2％w/v，优选为0.1％-0.5％w/v。在某些实施方案中，其可占制剂的0.01％w/v、0.05％w/v、0.1％w/v、0.25％w/v、0.5％w/v。
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＞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安瓿递送，所述安瓿可优选为无菌的，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。或者可以干粉剂的形式递送活性药物成分。
在特定的实施方案中，本申请的制剂每天施用2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1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。
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下面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，例如适合口服或鼻内施用的制剂可包括调味剂。
可以按每天0.01至300mg/kg的剂量口服或经由注射施用化合物。成人的剂量范围一般是0.1mg至50mg/天。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0.05mg至100mg、通常大约1mg至50mg，优选是5mg。
可以按各种方式施用化合物，例如口服施用、局部施用或通过注射施用。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肝脏损伤，则可能适当的是施用护肝药与初始的治疗剂相组合。或仅作为例子，可通过施用佐剂而使本文所述的化合物之一的疗效得到加强(即佐剂本身可能仅具有最小的治疗益处，但与另一种治疗剂组合时，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(如阿托品)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，例如在小瓶、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”。
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将有所不同，这取决于受治疗的宿主和具体的施用方式。
本申请药物组合物的活性物质含量。药物混合时，药物的浓度可以选择各药物的有效的适合量。
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。
在另一个方面，本申请提供了含有药物组合物的装置，所述药物组合物包含苄达酸或其治疗上可接受的盐(如苄达赖氨酸)或其衍生物，优选地，其中所述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、装置或治疗方法的某些实施方式中，所述装置以缓释方式递送所述药物组合物，优选地，所述缓释存在昼夜节律性。
在本文所公开的药物组合物、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、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、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、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或者是有近视发生倾向)的患者的治疗的眼科组合物。
在本文所公开的药物组合物、装置或治疗方法的某些实施方式中，将所述药物组合物眼科施用于所述患者的眼，优选地，所述眼为近视眼。
在本文所公开的药物组合物、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、装置或治疗方法的某些实施方式中，通过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、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。
可以通过试验动物中的标准药学过程来确定治疗性药物的用量、毒性和治疗效率，例如，用于确定LD50(总数50％的致命剂量)和ED50(总数50％中有效治疗的剂量)。毒性和治疗效果之间的剂量比是治疗指数，且其可以表示为比率LD50/ED50。表现出高治疗指数的化合物是优选的。尽管具有毒性副作用的化合物可以使用，但应当考虑设计传递系统或合适的给药方式，该传递系统或给药方式可将这样的化合物靶向相应组织或病灶位置，以将对无关的细胞或组织的可能损伤最小化，且由此降低副作用。
从动物研究获取的数据可以用在配制人类中使用的剂量范围中。根据使用的制剂类型和利用的给药途径，剂量可以在该范围内变化，有时也可以超出该范围。可以在动物模型中制定一系列不同的剂量来获得包括最低起效浓度、单次给药和多次给药后的循环血药浓度范围、药物暴露量等指标。这样的结果通过体表面积换算可以用来更准确地帮助确定人类中的有用剂量。
本领域技术人员将认识到，某些因素可以影响有效地治疗一对象的剂量和时间，包括但不限于疾病或失调的严重程度、该对象是否完全配合治疗、先前的治疗、健康情况和/或对象的年龄以及存在的其它疾病。而且，利用本文描述的治疗有效量的治疗组合物来治疗一对象可以包括单次治疗或一系列治疗。
应用本申请的方法将受治疗患者的近视发展控制、减缓、降低、延迟和/或减慢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。
药物组合物、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。
一些实施例中，应用本申请的方法中止或逆转了受治疗患者中的近视发展。这些患者患有高度近视、中度近视或低度近视；或者患者是前近视(或者具有发展为近视的风险)。
一些实施例中，应用本申请的方法预防、控制、减缓、延缓、延迟和/或减慢了受治疗患者眼的轴向(或纵向)生长。
一些实施例中，应用本申请的方法控制、减缓、降低、延迟和/或减慢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(choroidal thickness，ChT)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。
一些实施例中，应用本申请的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/或减慢了约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。
一些实施例中，应用本申请的方法相对于阿托品单一疗法导致了较小的瞳孔尺寸增加或没有扩瞳现象发生。
在一些实施方式中，口服的制剂为固体制剂如片剂、胶囊、颗粒剂和粉末制剂，以及液体制剂如糖浆剂和饮料制剂；可选的(a)：在固体制剂中，可以配制赋形剂、润滑剂、粘合剂、崩解剂等，优选的，可以配制防腐剂、抗氧化剂、着色剂和甜味剂，更优选的，使用添加剂；可选的(b)：在液体制剂中包括溶剂、溶解助剂、悬浮剂和等渗剂，优选的，可以混合试剂、缓冲剂、无痛剂等，更优选的，使用添加剂如防腐剂、抗氧化剂、着色剂、甜味剂等。
在一些实施方式中，药物可以为注射液、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。
在一些实施方式中，“眼科用制剂或药物”与本申请的药物组合物或制剂被同期给药，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。
下文将详细地描述本申请的特定实施例。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。
实施例1主要试剂或制剂(药物组合物)的配制方法和来源
苄达赖氨酸制剂包括已经商品化的成药和仅使用苄达赖氨酸化合物作为有效药学成分由发明人自行配制的药物组合物两类。苄达赖氨酸成药(BDL(S))，即中国国内市售0.5％苄达赖氨酸滴眼液(国药准字H20063847)，该剂型制剂直接用于豚鼠近视模型眼部局部给药；苄达赖氨酸化合物，购自MedChemExpress。在不添加其它药学辅料或其它化合物的条件下，苄达赖氨酸化合物粉剂直接完全溶解于0.9％生理盐水中配制成5mg/ml(11.669mM)制剂(BDL)。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，对受试个体给药时直接眼部局部施用或使用前按剂量要求用0.9％生理盐水作相应稀释后再施药。
苄达酸制剂包括直接购买已经商品化的成药和发明人单纯使用苄达酸化合物自行配制两类。其中，市售成药为3％苄达酸药膏，发明人购自日本岩城制药株式会社；苄达酸化合物购自MedChemExpress。将苄达酸完全溶解于DMSO配置330mg/ml(1166.9mM)母液，-20度保存。实验开始前以母液：PEG300：Tween80：0.9％生理盐水＝1:45:5:49的比例进行工作液的制备，苄达酸制剂终浓度为3.3mg/ml(11.669mM)。所有制备操作均在暗室中进行。
赖氨酸购自MedChemExpress，可完全溶解于0.9％生理盐水，配制成1.7mg/ml(11.669mM)的受试制剂。
M-hydroxy-methylaniline购自上海毕得医药科技股份有限公司。将hydroxy-methylaniline完全溶解于0.9％生理盐水配置成250mM的母液，-20度保存。实验开始前用0.9％生理盐水稀释，实施例中使用的hydroxy-methylaniline制剂终浓度为5mM。所有配制操作均在暗室中进行。
醛糖还原酶抑制剂(Aldose Reductase Inhibitor，ARI)Sorbinil，购自MedChemExpress。将Sorbinil粉剂溶解于DMSO配置成4.8mg/ml(20mM)母液，-20度保存。实验开始前以 0.9％生理盐水进行稀释，实施例中使用的Sorbinil制剂终浓度24μg/ml(100μM)，所有操作均在暗室中进行。
醛糖还原酶抑制剂Zopolrestat，购自MedChemExpress。将Zopolrestat粉剂溶解于DMSO配置成84mg/ml(1M)母液，-20度保存。实验开始前以生理盐水进行稀释，实施例中使用的Zopolrestat制剂终浓度420μg/ml(1mM)，所有操作均在暗室中进行。
阿托品粉剂购自Stanford Chemicals，用0.9％生理盐水完全溶解后配置成1mg/ml，即0.1％的制剂(阳性对照)。所有操作均在暗室中进行。
其它未提及制剂或药物组合物均按照实验室常规方法及标准进行配制和储存。所有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，所有制剂给药前均无化合物析出情况出现。
实施例2动物模型的构建及实验方法
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。豚鼠形觉剥夺近视模型(Form deprivation myopia，FDM)和镜片诱导近视模型(lens induced myopia，LIM)造模、给药及数据分析均按照发明人所在实验室已经发表文献操作及执行 [1-4]。本申请的实施例采用健康豚鼠(即没有基础疾病，如高血压、高血糖、眼部疾病或异常等)，且雌雄均用。本申请动物实验已通过温州医科大学实验动物伦理委员会审议。以下实施例3所使用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，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。镜片诱导使用-4D镜片固定于动物右眼前，左眼获得正常的视觉。每天两次清洁镜片防止镜片模糊。每日上午9:00-9:30给药。给药时，对照组及实验组动物分别在红光下取下眼罩或镜片，并给以右眼球周结膜下注射0.1ml的溶剂对照或5mg/mL受试药物或阳性对照，注射后确定动物给药成功无创伤并立即复原眼罩和镜片，每只动物给药过程控制在10秒左右。造模当天开始给药，形觉剥夺动物每天给药1次连续给药2周，镜片诱导动物每天给药1次连续给药1周。
动物分组
1、形觉剥夺组：
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＝11。
形觉剥夺加药物注射组：单眼佩戴眼罩并给佩戴眼注射苄达赖氨酸(0.5mg/天)2周，样本量＝14。
形觉剥夺加阳性对照组：单眼佩戴眼罩并给佩戴眼注射0.1％阿托品2周，样本量＝12。
2、镜片诱导组：
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＝14。
镜片诱导加药物注射组：单眼佩戴-4D镜片并给佩戴眼注射苄达赖氨酸(0.5mg/天)1周，样本量＝14。
动物眼球参数测量
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。分别对上述动物在实验前、实验1周和实验2周(仅FD)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。检测内容包括前房深度(anteriorchamberdepth，ACD)，晶体厚度(lensthickness，LT)，玻璃体 腔深度(vitrouschamberdepth，VCD)和眼轴长度(axiallength，AL)。检测前2分钟左右用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。
实施例3、苄达赖氨酸的体内治疗效果实验
实验动物为3周龄三色豚鼠，分为两大组：形觉剥夺组(FD)和镜片诱导组(LI)。形觉剥夺组分为三个小组：阴性对照组每天造模眼球旁注射生理盐水100微升，实验组每天给以造模眼球旁注射相同体积苄达赖氨酸0.5mg，阳性对照组每天造模眼给以0.1％阿托品100微升。镜片诱导组分为两个小组：阴性对照组每天造模眼球旁注射生理盐水100微升，实验组每天给以造模眼球旁注射相同体积苄达赖氨酸0.5mg。第一次给药前、给药1周和给药2周(仅FD)分别进行所有受试动物双眼屈光、玻璃腔体和眼轴参数检测。
实验结果：
FD组给药一周后，生理盐水注射组诱导近视-3.75±1.76D，两周后诱导近视-6.17±1.52D，而苄达赖氨酸注射组给药一周后诱导近视为-2.15±1.09D，对比生理盐水组抑制了42.6％的近视，而此时0.1％阿托品诱导的近视为-2.98±1.54D，近视抑制率为20.5％；苄达赖氨酸给药两周后诱导近视为-3.46D，对比生理盐水组抑制了43.9％的近视，0.1％阿托品诱导的近视为-3.93D，近视抑制率为36.4％。与此对应的玻璃体腔深度和眼轴长度的延长均受到苄达赖氨酸的抑制(见图1)。总之，相较于生理盐水组，苄达赖氨酸给药组明显抑制形觉剥夺性近视的豚鼠的屈光度变负、玻璃体腔深度延长以及眼轴长度延长。
LI组给药一周后，生理盐水注射组诱导近视-4.42±0.95D，而苄达赖氨酸注射组给药一周后诱导近视为-3.49±1.15D，对比生理盐水组抑制了21.0％的近视(图1)。可以看出，相较于生理盐水组，苄达赖氨酸给药组明显抑制镜片诱导性近视的豚鼠的屈光度变负，同时，玻璃体腔深度和眼轴长度的延长也均受到苄达赖氨酸的抑制。
另外，所有苄达赖氨酸治疗组动物在整个实验周期中未观察到眼部异常情况及未观察到个体出现毒性反应，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受试药物影响(见图2)。
以上实验表明，苄达赖氨酸可以显著减缓近视个体屈光度变负进程，同时可以显著抑制其眼轴延长，能够显著改善形觉剥夺和镜片诱导豚鼠的近视相关症状，提示其可应用于近视的防控，尤其是应用于屈光性近视或轴性近视及其相关症状的治疗、防止或改善。本申请的上述实验结果证明苄达赖氨酸对人类尤其是儿童和青少年近视有很好的预防、减缓及治疗作用。
实施例4、商品苄达赖氨酸滴眼液(0.5％，BDL(S))抑制近视进展
健康的3周龄三色豚鼠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5组：形觉剥夺(FD)+溶剂对照(NS)组、FD+0.5％苄达赖氨酸滴眼液(BDL(S))组、FD+0.1％阿托品、镜片诱导(LI)+溶剂对照(NS)组、LI+0.5％苄达赖氨酸(BDL(S))组。实验第一天上午8点开始给豚鼠进行形觉剥夺(FD)或镜片诱导(LI)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)。镜片诱导近视模型使用-4D镜片，镜片购自温州欣视界科技有限公司，具体参数为：中心度数-4D，基弧16mm，直径11.8mm。所述镜片固定于豚鼠右眼前(实验眼)，左眼不作处理(对侧眼)。FD和LI诱导在整个苄达赖氨酸药效实验周期中持续进行，仅给药或眼部检测(如屈光度检测)时短暂取下头套或镜片。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或擦拭镜片，淘汰头套或者镜片脱落3次以上的个体。造模当日开始每日上午9-10点间给予FDM模型实验眼对应的溶剂或药物，给药方式是球旁结膜下注射，注射体积为100μl，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 [4]，统计依 据为同一受试个体实验眼和对侧眼的差值。对于镜片诱导近视模型，造模当日开始每日上午9-10点给予镜片诱导组个体溶剂(阴性对照)或药物(苄达赖氨酸)，给药方式为眼部球旁结膜下注射，注射体积为100μl，每日给药1次连续给药1周。实验开始和结束时检测所有受试动物屈光度和眼轴参数，所有数据收集及处理方式参照形觉剥夺组。以上所有药效实验至少重复2次，本实施例受试药物(0.5％苄达赖氨酸滴眼液，国药准字H20063847)及溶剂对照(阴性对照组)由同一商品化苄达赖氨酸滴眼液制造商生产并提供给发明人。
结果显示：与实施例3的结论一致。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两个近视模型造模成功，可用于受试药物药效评价。中国境内市售0.5％苄达赖氨酸滴眼液可显著抑制和减缓形觉剥夺近视模型和负镜诱导近视模型的近视进展(发展)，即近视个体屈光度变负进程被苄达赖氨酸滴眼液成功延缓和有效控制，甚至在苄达赖氨酸治疗组个别动物中发明人发现其近视进程几近被受试药物完全终止。就FDM组屈光度指标而言，用药1周时0.5％苄达赖氨酸滴眼液对近视的治疗效果好于0.1％阿托品滴眼液，但二者之间没有统计学差异；用药2周时0.5％苄达赖氨酸滴眼液对近视的治疗效果与0.1％阿托品滴眼液相近，二者药效相较阴性对照组均差异极显著。在LIM组中苄达赖氨酸同样有效阻止了近视程度的加重，药物干预组动物的屈光度变负速度明显慢于对照组，且实验结束时二者屈光度存在显著性差异，苄达赖氨酸同样有效治疗了负镜诱导所致的近视。具体结果是在相同的近视视觉信息输入条件下(都是-4D)，相同检测时间点(给药1周)药物干预组屈光度大于溶剂组(都为负值，阴性对照组屈光度均值已经达到-4D，药物干预组还没有)，说明苄达赖氨酸可以有效控制近视进展。同时，上述两个近视研究经典疾病模型被苄达赖氨酸治疗后动物的玻璃体腔深度(VCD)的增加和眼轴长度(AL)的延长也得到相应的有效抑制(与阴性对照组存在统计学差异)，并且形觉剥夺实验中两个检测时间点的上述相应指标市售苄达赖氨酸组都优于阿托品组。另外，所有苄达赖氨酸治疗组动物在整个实验周期中未观察到眼部异常情况及未观察到个体出现毒性反应，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受试药物影响。阳性对照组阿托品给药后动物出现瞳孔扩大。
综上，在没有发生明显药物不良反应的前提下，商品苄达赖氨酸滴眼液可以有效防控和治疗哺乳动物(包括人)近视，尤其是可以减缓和控制近视程度加深，能够显著改善近视疾病模型的相关症状，表现为苄达赖氨酸有效减少(抑制)近视或有近视倾向个体眼轴长度延长和苄达赖氨酸有效减少(抑制)其玻璃体腔深度增加，提示其可应用于近视的防控，无论是应用于屈光性近视或轴性近视及其相关症状的治疗、防止或改善。因此，商品化的苄达赖氨酸滴眼液可以用于近视(眼)治疗，特别是能够控制其病情进展速度，以减轻高度近视所带来的并发症及致盲风险，尤其是在儿童和青少年阶段进行干预治疗。
实施例5、苄达赖氨酸近视治疗之不同浓度量效关系实验(0.01％、0.05％、0.1％和0.5％)
健康的3周龄三色豚鼠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6组：FD+生理盐水组(阴性对照)、FD+0.01％苄达赖氨酸、FD+0.05％苄达赖氨酸、FD+0.1％苄达赖氨酸、FD+0.5％苄达赖氨酸(实验组，指对FDM模型个体施用0.5％苄达赖氨酸)、FD+0.1％阿托品(阳性对照)。为了更加直观，作图时，将百分数对应换算成了毫克单位。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诱导在整个苄达赖氨酸药效实验周期中持续进行，仅给药或眼部检测(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模型实验眼对应的溶剂(阴性对照)或药物，给药方式是球旁结膜下注射，注射体积为100μl，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，所有数据收集与处理方式均与 发明人所在实验室已经发表文献相同 [4]，统计依据为同一受试个体实验眼和对侧眼的差值。以上所有药效实验至少重复三次，所述苄达赖氨酸制剂为发明人使用生理盐水自行配制。
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，可用于苄达赖氨酸药效评价。与阴性对照组相比，苄达赖氨酸(除0.9％生理盐水作为溶剂外不含其它药学辅料)呈剂量依赖性减缓受试个体近视程度的加深。随着苄达赖氨酸给药剂量的提高，以屈光度为指标的近视抑制率(计算公式为：(药物组屈光度-溶剂组屈光度)/溶剂组屈光度)也相应提高，说明苄达赖氨酸给药越多，近视(眼)防控效果越好。就屈光度指标而言，发明人仅使用生理盐水自行配制的苄达赖氨酸制剂与苄达赖氨酸市售成药表现出的药效一致，即用药1周时0.5％苄达赖氨酸对近视的治疗效果好于0.1％阿托品，但阿托品和苄达赖氨酸二者之间没有统计学差异；用药2周时0.5％苄达赖氨酸对近视的治疗效果与0.1％阿托品滴眼液相仿，二者药效相较阴性对照组均差异极显著。这说明苄达赖氨酸作为主要活性成分或者唯一活性成分可以对近视起到治疗和防控作用。统计学上，0.05％和0.1％两组苄达赖氨酸制剂也表现出对近视的显著治疗效果(有效抑制屈光度变负进程)，低浓度组0.01％苄达赖氨酸在屈光度指标上1周检测时与阴性对照组相似，2周检测时略强于阴性对照组但没有统计学差异。0.05％、0.1％和0.5％三个浓度的苄达赖氨酸对近视个体玻璃体腔深度(VCD)的增加和眼轴长度(AL)的延长也有相应的抑制。其中，除最低浓度的0.01％苄达赖氨酸实验组外，其它更高浓度的苄达赖氨酸和阿托品一样，都可以有效抑制受试个体眼部后节(玻璃体腔深度和眼轴长度)的延长且都可以有效控制、抑制、延缓或减缓近视个体或有近视发生倾向个体的屈光度(持续)变负进程，与溶剂组相比，上述抑制效果存在显著性差异或二者间差异极显著(见图3)。给药期间所有浓度的苄达赖氨酸实验组未观察到动物眼部刺激现象和任何眼部异常现象，前房深度、晶体厚度和瞳孔等相关指标未受苄达赖氨酸给药影响，阳性对照阿托品组所有动物观察到给药后瞳孔放大且与溶剂组存在统计学差异(见图4)，这与临床试验报道的该药物不良反应一致。
本实施例结果证明：单纯使用苄达赖氨酸就可防控和治疗近视(眼)，或者苄达赖氨酸可以用于制备制剂或药物组合物，所述制剂或药物组合物可以用于近视(眼)防控和治疗。优选的，上述制剂或药物组合物中苄达赖氨酸浓度不低于0.01％，可以是0.05％-1％的苄达赖氨酸。综合考虑FDA(Food and Drug Administration)认为的苄达酸可能造成人体严重肝脏毒性和近视治疗药物应长期持续用药以及监管部门就儿科用药安全性的专门要求三方面，发明人认为0.1％-0.25％浓度的苄达赖氨酸滴眼液是临床近视防控使用的合理配方，即制剂或药物组合物中苄达赖氨酸浓度优选为0.1％至0.25％。同时，除了在制备苄达赖氨酸制剂时提高其浓度外，就近视人群或有近视倾向人群针对苄达赖氨酸来达到或提高其近视防控效果的方式还包括增加苄达赖氨酸眼部生物利用率、增加药物给药频次、与其它近视治疗药物联合使用和优化苄达赖氨酸制剂配方等。总之，以上所述苄达赖氨酸制剂或药物组合物能够有效减少(抑制)近视或有近视倾向个体眼轴长度延长和有效减少(抑制)近视或有近视倾向个体玻璃体腔深度增加；所述苄达赖氨酸制剂或药物组合物能够治疗(防控)近视，尤其针对6至18岁人群近视治疗。
实施例6、苄达赖氨酸能够显著增加脉络膜厚度
(一)苄达赖氨酸有效抑制FDM和LIM豚鼠模型的脉络膜厚度变小
3周龄三色豚鼠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4组：形觉剥夺(FD)+溶剂对照(NS)组、FD+0.5％苄达赖氨酸滴眼液(BDL(S))组、镜片诱导(LI)+溶剂对照(NS)组、LI+0.5％苄达赖氨酸(BDL(S))组。实验第一天上午8点开始给豚鼠进行形觉剥夺(FD)或镜片诱导(LI)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)。镜片诱导近视模型使用-4D镜片， 镜片购自温州欣视界科技有限公司，具体参数为：中心度数-4D，基弧16mm，直径11.8mm。所述镜片固定于豚鼠右眼前(实验眼)，左眼不作处理(对侧眼)。FD和LI诱导在整个苄达赖氨酸药效实验周期中持续进行，仅给药或脉络膜厚度检测时短暂取下头套或镜片。药效实验开始后的每日早6点、中午12点、晚6点及给药前检查头套位置或擦拭镜片，淘汰头套或者镜片脱落3次以上的个体。造模当日开始每日上午9-10点间给予FDM模型实验眼对应的溶剂或药物，给药方式是实验眼球旁结膜下注射，注射体积为100μl，每日给药1次连续给药2周。对于镜片诱导近视模型，造模当日开始每日上午9-10点给予镜片诱导组个体溶剂(阴性对照)或药物(苄达赖氨酸)，给药方式为实验眼眼部球旁结膜下注射，注射体积为100μl，每日给药1次连续给药1周。上述两种近视模型在最后一次给药后30-60min时使用Spectralis HRA+OCT(Heidelberg Engineering,Heidelberg,Germany)检测所有眼脉络膜厚度，所有数据收集与处理方式均与发明人所在实验室已经发表文献相同 [4]，统计依据为同一受试个体实验眼和对侧眼的差值，统计方法为独立样本T检验。以上所有药效实验至少重复二次，受试药物(0.5％苄达赖氨酸滴眼液)及溶剂对照(阴性对照组)由同一商品化苄达赖氨酸滴眼液制造商生产并提供给发明人。
结果显示：无论FDM还是LIM模型，相较溶剂对照组苄达赖氨酸都能够有效增加FDM和LIM模型中豚鼠的脉络膜厚度，并且二者间存在统计学差异(LIM模型溶剂对照组和药物组差异极显著)，具体药效表现形式是FDM和LIM模型溶剂组豚鼠实验眼均出现脉络膜厚度变小，而苄达赖氨酸可抑制近视眼脉络膜厚度变小。其中，在FDM模型中，实验眼与对侧眼的脉络膜厚度差值均值是-17.51微米，而苄达赖氨酸干预后近视个体实验眼与对侧眼的脉络膜厚度差值均值是-9.20微米，表明实验眼的脉络膜厚度在药物干预后向同一个体中正常眼的脉络膜厚度水平靠近(二者差值减小)；在LIM模型中，实验眼与对侧眼的脉络膜厚度差值均值是-23.38微米，而苄达赖氨酸干预后近视个体实验眼与对侧眼的脉络膜厚度差值均值是-6.31微米，个别动物中实验眼脉络膜厚度在给药后甚至完全恢复至正常眼水平(见图5)。角膜曲率(RCC)、前房深度(ACD)和晶体厚度(LT)指标亦没有受到受试药物影响。综上，苄达赖氨酸可以显著抑制近视个体或有近视倾向个体脉络膜厚度变小及减缓其脉络膜厚度变薄趋势。
在近视个体中，平行光线通过调节放松的眼的屈光系统屈折后，焦点落在视网膜之前。当苄达赖氨酸增加该近视个体脉络膜厚度，则会使视网膜向晶状体方向移动，最终导致近视眼成像焦点与视网膜之间的距离缩短甚至二者恰好吻合。成像焦点与视网膜之间的距离，就是近视的度数，苄达赖氨酸在近视个体中可以缩短二者距离或抑制二者距离的增大，本身就是在减少近视度数。对近视个体给与苄达赖氨酸会导致用药眼获得清晰度更佳的远视力和其近视屈光状态被有效减少(近视被治疗，减少近视度数)，包括其远视力提升。因此，本申请中苄达赖氨酸体现出的这种近视治疗(防控)效果不仅仅限于轴性近视、屈光性近视、病理性近视、单纯性近视、假性近视或是真性近视，也与用药对象年龄、性别、近视程度、近视进展速度、民族和近视出现年龄等因素无关，即苄达赖氨酸对所有近视类型都有治疗和防控作用。
实施例7、使用苄达赖氨酸滴眼液滴眼给药和苄达酸药膏眼部涂抹给药的治疗效果(非侵入给药方式或无创给药方式)
3周龄三色豚鼠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，随机分成三组：FD+生理盐水组、FD+0.5％苄达赖氨酸滴眼液(自行配制)、FD+0.1％阿托品。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)。FD诱导在整个苄达赖氨酸药效实验周期中持续进行，仅给药或眼部检测(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点给予实验眼对应的溶剂或药物，直接滴眼，下午2:30-3:30进行第二次滴眼给药，即一天两次给药，每次给 药体积为25μl，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，所有数据收集与处理方式均与发明人所在实验室已经发表文献相同 [4]，统计依据为同一受试个体实验眼和对侧眼的差值。以上所有药效实验至少重复两次。
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5的注射给药体积。因此，本实施例中不论苄达赖氨酸滴眼液还是0.1％的阿托品，滴眼液直接滴眼给药的药效都差于球周注射给药对近视的治疗效果。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，可用于苄达赖氨酸药效评价。眼轴参数方面，相较生理盐水溶剂组，苄达赖氨酸和0.1％阿托品都可以显著抑制形觉剥夺近视模型眼轴延长(存在统计学差异)，二者就近视个体眼轴长度增加和玻璃体腔深度变大都表现出几乎相同的抑制作用；苄达赖氨酸滴眼1周和2周近视抑制率与0.1％阿托品滴眼组相比药效接近(分别为35.5％VS.28.1％和33.9％VS.36.9％，且二者药效均与阴性对照溶剂组存在统计学差异)(见图6)，但阿托品组给药期间出现瞳孔扩张不良反应而苄达赖氨酸组未见明显眼部异常。无论是阿托品还是苄达赖氨酸近视干预，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，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，苄达赖氨酸对近视个体治疗的用药风险收益比都优于阿托品(如白天使用苄达赖氨酸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。
对于受试药物药膏剂型，本实施例没有设置对照组，因为所使用的3％苄达酸药膏为日本国内市售商品，发明人无法获得该产品相对应的不含苄达酸的制剂，含相同辅料的阿托品药膏由于同样原因也排除在外。然而，就苄达酸该剂型对近视治疗的药效评估，发明人依然可以参考本申请同为非侵入给药实验中的相同批次相同模型对照组指标。具体实验过程为：将苄达酸药膏涂抹于本申请所描述的豚鼠形觉剥夺近视模型受试眼(实验眼)角膜表面及眼周皮肤，并手动快速闭合眼睑10次，但由于药膏不能快速吸收及眼罩覆盖和动物正常眨眼，发明人发现在下一次施药时眼罩内面也有一定的苄达酸药膏残留。苄达酸药膏每次给药剂量为18mg±2mg，造模当天开始每天上午9-10点对剥夺眼施药，下午2:30-3:30第二次给药，即一天两次给药，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，所有数据收集与处理方式均与发明人所在实验室已经发表文献相同 [4]，统计依据为同一受试个体实验眼和对侧眼的差值。
3％的苄达酸药膏给药1周和2周近视抑制率分别为17.7％和25.9％，治疗效果逊于同批次0.5％苄达赖氨酸或0.1％阿托品，但远好于同批次形觉剥夺近视模型未治疗组。可能的原因是造模遮蔽物影响药膏中苄达酸的眼部吸收，或者是由于该剂型主要针对人皮肤给药途径，因而对豚鼠眼部的苄达酸药物生物利用度不是合理配方。但是，苄达酸(药膏)依然对近视表现出有效的防控作用，除了可以抑制近视个体屈光度变负进程外，近视个体的玻璃体腔深度的增加和眼轴长度的延长在施药后都得到相应的抑制，具体为给药2周时苄达酸药膏近视治疗组玻璃体腔深度延长均值为0.09mm和眼轴长度延长均值为0.09mm，同批次近视未干预组相应指标为0.13mm和0.12mm(见图6)。可见，近视个体的眼轴延长主要是玻璃体腔深度的增加导致，苄达酸可以同时减小近视个体玻璃体腔深度的增加和眼轴长度的延长。苄达酸给药后动物未见明显眼部异常，受试个体的瞳孔、角膜曲率、前房和晶体相关指标也没有受到药物影响(见图7)。
综上，除了眼部注射给药方式外，利用其它非侵入(无创)给药方式时苄达酸及其盐形 式(如赖氨酸盐)同样可以有效治疗和防控近视，延缓近视个体或有近视倾向个体屈光度变负进程。具体为，利用苄达赖氨酸滴眼液直接滴眼给药或苄达酸眼药膏眼部给药来治疗近视，抑制近视个体或有近视倾向个体眼轴延长和减少其玻璃体腔深度增加。
实施例8、单纯赖氨酸和单纯苄达酸眼药水对近视的作用
3周龄三色豚鼠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5组：FD+生理盐水组(NS)、FD+赖氨酸(L-lysine)、FD+0.5％苄达赖氨酸(BDL)、FD+DMSO(针对苄达酸设置的溶剂对照组,vehicle)、FD+苄达酸(实验组，指对FDM模型个体施用苄达酸,bendazac)。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)。FD诱导在整个药效实验周期中持续进行，仅给药或眼部检测(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，每日一次连续给药2周。药效实验开始时、实验1周和2周时检测屈光度和眼轴参数，所有数据收集与处理方式均与发明人所在实验室已经发表文献相同 [4]，统计依据为同一受试个体实验眼和对侧眼的差值。以上所有药效实验至少重复三次，所述药物制剂均为发明人自行配制。
实验结果显示，无论是生理盐水还是DMSO溶剂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0.5％苄达赖氨酸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，可用于苄达酸和赖氨酸的药效评价。单纯使用与0.5％苄达赖氨酸相同摩尔的赖氨酸对近视的进展不论是屈光度变负还是玻璃体腔深度和眼轴长度延长都没有抑制作用。给药过程中1周和2周时的屈光度指标，赖氨酸干预组的近视度数甚至高于生理盐水组，而相同摩尔的苄达赖氨酸却都可以有效抑制施药个体屈光度变负进程且与生理盐水组存在统计学差异(见图8)。因此，赖氨酸不具有任何近视治疗或防控的药效，苄达赖氨酸发挥其近视治疗的药效与其分子中赖氨酸成分无直接因果关系，任何一种苄达酸药学上可接受的盐都可以用于近视治疗和预防。
单纯的苄达酸与其DMSO溶剂对照组相比1周和2周近视抑制率为33.4％和30.1％，其近视治疗效果与同批次等摩尔苄达赖氨酸阳性对照组一致，并且二者与各自对应的阴性对照都存在统计学差异，证明苄达酸才是苄达赖氨酸分子在近视治疗中发挥药效的关键和唯一部分，其可以有效抑制和减缓近视个体屈光度变负进程。与DMSO溶剂组相比，苄达酸给药后也可以显著抑制近视个体的眼轴延长和减缓其玻璃腔体深度增加，且与阴性对照组存在统计学差异，其效果与同批次等摩尔的苄达赖氨酸实验组相似(见图9)。
苄达赖氨酸、苄达酸或赖氨酸给药后动物未见明显眼部异常，受试个体的瞳孔、角膜曲率、前房深度和晶体厚度相关指标也没有受到药物影响(见图10-11)。
上述实验中，苄达酸及其对应溶剂阴性对照按照本申请所述方案在给药2周时检测脉络膜厚度，结果显示单纯使用苄达酸(眼药水形式)可以抑制近视眼脉络膜厚度减少，近视个体实验眼与对侧眼的脉络膜厚度差值均值是-18.82微米，而苄达酸干预后近视个体实验眼和对侧眼的脉络膜均值差值是-8.47微米，苄达酸药物组和DMSO溶剂组二者间存在统计学差异(见图12)。因此，苄达酸和苄达赖氨酸抑制近视个体或有近视倾向个体的脉络膜厚度减少表现出药效方面的一致性，苄达酸可以显著抑制近视个体或有近视倾向个体脉络膜厚度变小及减缓其脉络膜厚度变薄趋势。
上述结果证明：苄达酸及其任何一种盐形式的对应化合物(如苄达赖氨酸)均可以有效治疗近视，其通过抑制眼轴延长和减缓玻璃腔体深度增加来延缓近视个体或有近视倾向个体屈光度变负的进程。同时，苄达酸及其药学上可接受的盐(如苄达赖氨酸)都可以有效增加脉络膜厚度，减小近视度数。上述苄达酸及其药学上可接受的盐(如苄达赖氨酸)在近视治疗及预防中的剂型可以是滴眼液，也可以是眼药膏、眼用喷剂、眼用注射液和眼用凝胶；含有该类化合物(药物)的装置、制剂或药物组合物都可以用于控制近视进展。
实施例9、Sorbinil和Zopolrestat对豚鼠形觉剥夺近视模型治疗效果
3周龄三色豚鼠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，随机分成3组：FD+DMSO、FD+Sorbinil、FD+Zopolrestat。根据化合物数据库信息，zopolrestat的IC 50＝3.1nM，sorbinil的IC 50＝3.14±0.02μM，发明人实验中实际使用的Zopolrestat制剂终浓度为1mM，Sorbinil制剂终浓度为100μM。实验第一天上午8点给豚鼠进行形觉剥夺近视造模。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，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诱导在整个苄达赖氨酸药效实验周期中持续进行，仅给药或眼部检测(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。造模当日开始每天上午9-10点给予FDM模型实验眼对应的溶剂或药物，给药频率为每日一次，给药方式为球旁结膜下注射，注射体积为100μl，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，所有数据收集与处理方式均与发明人所在实验室已经发表文献相同 [4]，统计依据为同一受试个体实验眼和对侧眼的差值。以上所有药效实验至少重复执行3次，本实施例受试药物及溶剂对照(阴性对照组)都由发明人自行配制。
结果表明，Sorbinil和Zopolrestat给药后没有近视治疗作用，无法控制近视进展。这两个醛糖还原酶抑制剂不能抑制FD诱导的屈光度变负进程和减缓近视个体眼轴延长的进展。在整个实验周期中每个检测时间点Sorbinil和Zopolrestat这两个药物无论是屈光度指标还是眼轴参数指标与溶剂组相比都没有显著性差异(图13)。此外，Sorbinil和Zopolrestat给药后对受试个体的角膜曲率、前房深度和晶体厚度相关指标也没有影响(见图14)。综上，醛糖还原酶不是近视治疗药物的开发靶点，不是所有的醛糖还原酶抑制剂都具备近视防控的药效。
实施例10、间羟基甲基苯胺(m-hydroxy-methylaniline)对豚鼠形觉剥夺近视模型治疗效果
利用本申请所描述的豚鼠形觉剥夺近视模型评估药效，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：FD+0.9％生理盐水(NS)、FD+间羟基甲基苯胺(化合物A)和FD+0.1％阿托品(阳性对照)。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，给药方式为球旁结膜下注射，注射体积为100μl，每日1次连续给药1周。药效实验开始时和结束后检测屈光度和眼轴参数，所有数据收集及处理方式均与本申请其它实施例相同，统计依据为同一受试个体实验眼和对侧眼的差值。
本次实验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。实验结果如图15所示，间羟基甲基苯胺给药后不论是屈光度变负还是玻腔深度或眼轴长度的增加都没有被抑制。说明间羟基甲基苯胺没有近视预防或治疗作用。间羟基甲基苯胺给药后受试个体的眼轴参数和屈光度都没有表现出与阴性对照组的统计学差异，该药物对近视个体的眼轴延长没有抑制作用，其对玻璃体腔深度增加也没有减缓作用。本实施例中阿托品表现出正常的近视治疗效果，但该组所有受试动物均出现瞳孔扩大，前房深度和晶状体厚度在给药干预后亦没有受到影响(图15)。综上，实验结果证明：并不是所有具备白内障治疗效果的化合物(药物)都可以用于治疗近视；并不是所有具备抗氧化活性或可以降低BLOA(Biological Liquid Oxidant Activity)的化合物都拥有近视防控药效。
最后应说明的是：以上各实施例仅用以说明本申请的技术方案，而非对其限制；尽管参照前述各实施例对本申请进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本申请各实施例技术方案的范围，其均应涵盖在本申请的权利要求和说明书的范围当中。尤其是，只要不存在结构冲突，各个 实施例中所提到的各项技术特征均可以任意方式组合起来。本申请并不局限于文中公开的特定实施例，而是包括落入权利要求的范围内的所有技术方案。
参考文献：
1Lu F,Zhou X,Zhao H,et al.Axial myopia induced by a monocularly-deprived facemask in guinea pigs:A non-invasive and effective model.Exp Eye Res 2006；82:628-636.
2Lu F,Zhou X,Jiang L,et al.Axial myopia induced by hyperopic defocus in guinea pigs:A detailed assessment on susceptibility and recovery.Exp Eye Res 2009；89:101-108.
3Wu H,Chen W,Zhao F,et al.Scleral hypoxia is a target for myopia control.Proc Natl Acad Sci U S A 2018；115:E7091-E7100.
4Pan M,Zhao F,Xie B,et al.Dietary omega-3polyunsaturated fatty acids are protective for myopia.Proc Natl Acad Sci U S A 2021；118.

Claims (18)

  1. 苄达赖氨酸或苄达酸、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、或其类似物或其衍生物、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至少两项：
    (a)用于预防和/或治疗近视及其相关症状；
    (b)用于延缓、减弱或治疗与屈光不正相关的眼球的异常发育；
    (c)用于使个体在不借助或更换镜片(如近视框架眼镜或OK镜)或不依靠其它视力矫正手段(如屈光手术)的条件下获得更清晰的远视力；
    (d)用于控制、抑制、延缓或减缓近视个体或有近视发生倾向个体的屈光度(持续)变负进程(速度)；
    (e)用于联合手术(如屈光矫正手术、近视角膜激光手术、晶状体手术)或其它视力矫正手段(如角膜接触镜)来预防和/或治疗近视及其相关症状；
    (f)用于与一种或多种其他药物联合使用来预防和/或治疗近视及近视相关症状；
    (g)用于减少视网膜和晶状体之间距离，优选的是在近视个体中或有近视倾向个体中减少视网膜和晶状体之间距离；
    (h)用于减小近视度数、或治疗近视眼、或近视眼治疗、或控制近视进展、或近视矫正、或缓解近视、或青少年近视预防；
    (i)用于抑制或治疗晶状体病变导致的近视；
    (j)用于制备药物组合物、制剂或装置，所述药物组合物、制剂或装置以实现上述(a)至(i)中的至少一项用途。
  2. 如前述权利要求所述的用途，其特征在于，所述苄达赖氨酸或苄达酸、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、或其类似物或其衍生物、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。
  3. 如权利要求2所述的用途，其特征在于，所述唯一活性成分或主要活性成分是其含量占全部活性成分的50％以上、60％以上、70％以上、80％以上、90％以上、或100％，所述百分比为质量比或摩尔比。
  4. 如前述权利要求之一所述的用途，所述这些物质或其组合与所述一种或多种其他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。
  5. 如前述权利要求之一所述的用途，其特征在于，所述与屈光不正相关的眼球的异常发育是个体幼年阶段(如人类2-28岁)，主要由环境因素诱发或者主要是人为因素导致(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)，而遗传因素是次要因素、伴随因素、协同因素、或者所述异常发育完全与遗传因素无关的屈光发育异常，其主要特征是在调节放松状态下，平行光线通过眼的屈光系统屈折后焦点落在视网膜之前。
  6. 如前述权利要求之一所述的用途，采用全身给药(如口服、静脉滴注)、或局部给药(如滴眼、玻璃体内注射、皮肤油膏或软膏涂抹)、或肠胃外给药(如通过粘膜给药、透皮给药、微针给药)的方式、或非侵入给药方式(如将眼药膏涂抹于角膜或挤入下眼睑拉伸形成的囊内)、或无创给药方式(如利用眼用喷剂给药)。
  7. 如权利要求6所述的用途，所述皮肤油膏或软膏涂抹为采用3％皮肤油膏或眼用软膏涂抹，所述百分比(％)表示为质量/体积浓度(比)或质量比或摩尔(数)比。
  8. 如前述权利要求之一所述的用途，将所述给药方式(如滴眼、口服)同时使用、或联合使用、或交替使用、或间隔使用、或单独使用、或选择其一使用。
  9. 如前述权利要求之一所述的用途，所述局部给药使用的制剂包括但不限于水性剂、油性剂或悬浮液剂，该制剂可以加入具有药理活性和/或生理活性的成分，这样的成分例如扩瞳组分、充血去除组分、眼肌(如睫状肌)调节组分、抗炎剂组分、收敛剂组分、抗组胺剂组分、抗过敏剂组分、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)、维生素、氨基酸、抗菌剂组分、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、青光眼治疗组分、白内障治疗组分等。
  10. 如前述权利要求之一所述的用途，所述这些物质或其组合在所述药物组合物、制剂或装置中的浓度或占比至少不小于0.01％，优选为0.01％至0.8％，优选为0.05％至0.5％，更优选为0.1％；或者所述这些物质或其组合的浓度或占比低于0.01％，所述百分比表示为质量/体积浓度(比)或质量比或摩尔(数)比。
  11. 如前述权利要求之一所述的用途，所述药物组合物或制剂可以为注射液、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、眼周注射剂或眼内注射剂；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、栓剂或乳剂。
  12. 如前述权利要求之一所述的用途，所述近视个体或有近视发生倾向个体为人，可以是儿童、青少年、中年人或老年人，优选为3至26岁人群，更优选为6至18岁人群；或为成年人、或为未成年人，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。
  13. 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、半真半假(混合)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、青少年近视、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)；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、位置性近视、弯曲性近视；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、环境因素主导的近视。
  14. 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、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、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。
  15. 如前述权利要求之一所述的用途，所述药物组合物、制剂或装置中还包含医用制剂或药 物，所述医用制剂或药物包括但不限于近视治疗药物(如阿托品、地巴唑、哌仑西平、毒蕈碱拮抗剂、7-甲基黄嘌呤(7MX)、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、维甲酸等)、M受体阻断剂(如针对M3受体的阻断剂或拮抗剂或抑制剂)、苄达酸或其各种盐形式、苄达赖氨酸或其各种盐形式、多不饱和脂肪酸(如DHA、EPA)、红景天苷、芒柄花黄素、哌唑嗪、后马托品、山莨菪碱(消旋)、托吡卡胺、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)、非选择性腺苷酸拮抗剂、扩血管药物、扩瞳药、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、抗过敏药物、抗炎药物、护肝类药物、眼科疾病的治疗性组分、局部眼用麻醉药、或眼科用制剂。
  16. 如前述权利要求之一所述的用途，所述一种或多种其他药物包括但不限于近视治疗药物(如阿托品、地巴唑、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、维甲酸等)、M受体阻断剂(如针对M3受体的阻断剂或拮抗剂或抑制剂)、苄达酸或其各种盐形式、苄达赖氨酸或其各种盐形式、多不饱和脂肪酸(如DHA、EPA)、红景天苷、芒柄花黄素、哌唑嗪、后马托品、山莨菪碱(消旋)、托吡卡胺、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)、非选择性腺苷酸拮抗剂、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、抗过敏药物、抗炎药物、护肝类药物、眼科疾病的治疗性组分、局部眼用麻醉药、扩瞳药、或眼科用制剂或药物。
  17. 如前述权利要求之一所述的用途，其特征在于，所述制剂还可以为保健品、食品、膳食补充剂、营养品、饮品等口服制品或化妆品；其中，所述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。
  18. 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(近视按摩仪)、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。
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