WO2021247635A1 - Methods and compositions for preventing and treating myopia with levocabastine, a selective histamine h1-receptor antagonist, and derivatives thereof - Google Patents

Methods and compositions for preventing and treating myopia with levocabastine, a selective histamine h1-receptor antagonist, and derivatives thereof Download PDF

Info

Publication number
WO2021247635A1
WO2021247635A1 PCT/US2021/035344 US2021035344W WO2021247635A1 WO 2021247635 A1 WO2021247635 A1 WO 2021247635A1 US 2021035344 W US2021035344 W US 2021035344W WO 2021247635 A1 WO2021247635 A1 WO 2021247635A1
Authority
WO
WIPO (PCT)
Prior art keywords
myopia
subject
composition
years
age
Prior art date
Application number
PCT/US2021/035344
Other languages
English (en)
French (fr)
Inventor
Andrei V. Tkatchenko
Tatiana V. TKATCHENKO
Original Assignee
The Trustees Of Columbia University In The City Of New York
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Trustees Of Columbia University In The City Of New York filed Critical The Trustees Of Columbia University In The City Of New York
Priority to CN202180049465.4A priority Critical patent/CN115835905A/zh
Priority to EP21816939.9A priority patent/EP4157453A4/en
Priority to KR1020227046225A priority patent/KR20230051130A/ko
Priority to JP2022574559A priority patent/JP2023529374A/ja
Priority to CA3181292A priority patent/CA3181292A1/en
Priority to IL298796A priority patent/IL298796A/en
Publication of WO2021247635A1 publication Critical patent/WO2021247635A1/en
Priority to US18/073,181 priority patent/US20230138414A1/en

Links

Classifications

    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • 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
    • A61K9/0051—Ocular inserts, ocular implants
    • 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 disclosure relates to methods and compositions for preventing and/or treating an ocular disease.
  • the disclosure relates to preventing and/or treating myopia with systemic or topical administration of levocabastine hydrochloride, which is a selective histamine HI -receptor antagonist, and derivatives thereof.
  • Myopia (nearsightedness) is the most common ocular disorder in the world.
  • the prevalence of myopia in the U.S. has increased from 25% to 48% in the last 40 years. 1, 2 In parts of Asia, more than 80% of the population are affected by myopia. 3
  • the worldwide prevalence of myopia is predicted to increase from 25% in 2020 to 50% by 2050. 4
  • Myopia often leads to serious pathological complications such as chorioretinal atrophy, retinoschisis, retinal tears, retinal detachment, and myopic macular degeneration, which often lead to blindness. 5, 6 It also represents a major risk factor for a number of other serious ocular diseases such as cataracts and glaucoma, which also often lead to vision impairment and vision loss. 7, 8 Because of the increasing prevalence, myopia is rapidly becoming one of the leading causes of vision loss, and the World Health Organization designated myopia as one of five priority health conditions. 5, 9
  • the eye is able to respond to myopiagenic optical defocus even if the optic nerve was severed, 39 demonstrating that the signaling cascade regulating refractive eye development is located within the eye itself and does not require a feedback from the brain.
  • Myopia seems to progress the most during a susceptible period between ages 6-16 and then begins to slow down. 40, 41 In previous generations, myopic progression was assumed to end at around age 20. However, that has changed since more students have entered graduate school followed by jobs requiring 8 hours of sustained computer work. 42 This conjecture was recently studied in a cohort of post university graduates with a mean age of 35. 43 Myopia was found to progress in approximately 10% of the cohort who spent a lot of time in front of computers. Those subjects who did not spend time in front of computers did not progress as much.
  • Spectacles with bifocal lenses were the first to be used to control myopia progression.
  • the multi-center COMET study which was designed to determine if bifocals could slow the progression of myopia as compared to a single vision spectacle lenses demonstrated that bifocals slowed the progression of myopia by 20% in the first year; however, the effect was significantly reduced in years 2-4 47
  • Atropine a nonselective muscarinic antagonist
  • Atropine is an alkaloid produced by Atropa belladonna, which has been traditionally used in ophthalmic practice as a mydriatic and cycloplegic drug.
  • Atropine for the treatment of Myopia 1 revealed that the 1% atropine eye drops retard the progression of myopia by approximately 76% over the 2-year treatment period.
  • 7-methylxanthine (7-MX) a nonselective adenosine receptor antagonist, is a natural metabolite of caffeine and theobromine, two alkaloids produced by several plant species and major constituents of cacao, coffee, and tea.
  • the first indication that 7-MX might be a potential medication for myopia control came from an observation that 7-MX causes thickening of the sclera and an increase in the diameter of the scleral collagen fibrils, 62 i.e., it causes changes in the sclera opposite to those observed in myopic eyes.
  • Several other compounds have been suggested to suppress myopia to various degrees.
  • the muscarinic receptor antagonists pirenzepine and himbacine were shown to inhibit the development of experimental myopia in tree shrews, rhesus monkeys, and chickens. 67, 68 While pirenzepine was found to suppress the progression of myopia in children by 40%, clinical trials were eventually discontinued due to serious side effects.
  • GABAB and GABAc receptor antagonists such as (l,2,5,6-tetrahydropyridin-4yl) methylphosphinic acid (TPMPA), CGP46381, and (3-aminocyclopentanyl) butylphosphinic acid (3-ACPBPA) were shown to suppress myopia development in chickens and guinea pigs.
  • TPMPA l,2,5,6-tetrahydropyridin-4yl
  • CGP46381 CGP46381
  • 3-ACPBPA 3-aminocyclopentanyl butylphosphinic acid
  • apomorphine a dopamine receptor agonist
  • a dopamine receptor agonist was found to inhibit myopia development in several animal models, such as chicken, mouse and non-human primates, 75, 76 and an intraocular-pressure-lowering drug latanoprost was found to reduce progression of myopia in guinea pigs.
  • a recent drug screen in a mouse model of myopia identified crocetin, a natural carotenoid found in the crocus flowers and Gardenia jasminoides fruits, as a potential anti-myopia agent. 78
  • the disclosure provides a method for preventing and/or treating myopia in a subject in need thereof by suppressing ocular signaling pathways underlying the development of myopia using an oral composition, extended drug release formulations or compositions, extended drug delivery by contact lenses, or eye drops comprising a drug compound or agent identified using pharmacogenomic pipeline for anti-myopia drug development.
  • one embodiment is a method of preventing and/or treating myopia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising an active drug compound identified using pharmacogenomic pipeline for anti-myopia drug development.
  • the active drug compound is a selective histamine HI -receptor antagonist levocabastine hydrochloride having the structure: or a derivative thereof.
  • the disclosure provides methods for preventing and/or treating myopia by administering to a subject a therapeutically effective amount of levocabastine hydrochloride or a derivative thereof, in a form of oral composition, extended drug release formulation or composition, extended drug delivery by contact lenses, or eye drops during a susceptible period for myopia development.
  • the disclosure provides methods for preventing and/or treating myopia by administering to a subject a repeating dose of a therapeutically effective amount of a levocabastine hydrochloride or a derivative thereof, in a form of oral composition, extended drug release formulation or composition, extended drug delivery by contact lenses, or eye drops during a susceptible period for myopia development.
  • the active drug compound is a selective histamine HI -receptor antagonist.
  • the selective histamine HI -receptor antagonist includes but is not limited to azelastine, alcaftadine, antazoline, carbinoxamine, epinastine, olopatadine, and ketotifen, and derivatives thereof.
  • the disclosure provides methods for preventing and/or treating myopia by administering to a subject a therapeutically effective amount of a selective histamine HI -receptor antagonist, in a form of oral composition, extended drug release formulation or composition, extended drug delivery by contact lenses, or eye drops during a susceptible period for myopia development.
  • the disclosure provides methods for preventing and/or treating myopia by administering to a subject a repeating dose of a therapeutically effective amount of a selective histamine HI -receptor antagonist, in a form of oral composition, extended drug release formulation or composition, extended drug delivery by contact lenses, or eye drops during a susceptible period for myopia development.
  • the composition is administered to the subject once a day. In some embodiments, the composition is administered once a week. In some embodiments, the composition is administered twice a week. In some embodiments, the composition is administered three times a week. In some embodiments, the composition is administered to the subject continuously or intermittently for about 5 years to about 10 years.
  • the subject is a young adult, i.e., under 30 years of age. In some embodiments, the subject is a child, i.e., under the age of 18. In some embodiments, the subject is about 4 years of age to about 30 years of age. In some embodiments, the subject is about 6 years of age to about 20 years of age. In some embodiments, the subject is about 8 years of age to about 15 years of age. In some embodiments, the subject is about 10 years of age to about 12 years of age.
  • the subject has myopia. In some embodiments, the subject is at risk for myopia. In some embodiments, the subject is susceptible to myopia.
  • the subject is monitored for suppression of myopia and the therapeutically effective amount and/or frequency of administration of the drug compound is adjusted depending on the degree of suppression. Suppression of myopia may be monitored using methods known in the art.
  • kits comprising compositions and agents for practicing the disclosed methods.
  • Fig. 1A shows a mouse induced to have myopia with -25 D lenses.
  • Fig. IB is a graph show the statistically significant myopic shift in refraction observed in the eyes of the mice treated with -25 D lenses for 21 days.
  • Fig. 1C shows that the lens-induced myopia in mice is due to a statistically significant increase in the vitreous chamber depth, as in human myopia.
  • Fig. ID shows the power simulations demonstrating the relationship between statistical power and a number of animals for induced myopia experiments.
  • ACD anterior chamber depth
  • CRC corneal radius of curvature
  • LT lens thickness
  • VCD vitreous chamber depth
  • OD right (myopic) eye
  • OS left (control) eye.
  • Error bars SD. P, significance value.
  • Fig. 2 shows that systemic administration of 5 mg/kg levocabastine hydrochloride completely suppresses development of myopia in mice with experimentally induced myopia.
  • myopia or “myopic” shall mean eye disease condition in which the posterior segment of the eye is too large for the optical power of the eye and the focal point is located in front of the retina; thus, producing blurred distant vision.
  • hyperopia or “hyperopic” shall mean eye condition in which the posterior segment of the eye is too small for the optical power of the eye and the focal point is located behind the retina; thus, producing blurred near vision.
  • negative lens shall mean a lens which shifts focal point of the eye towards the back of the eye; thus, rendering the eye hyperopic.
  • genetic network shall mean a network of interconnected genes which regulate a physiological or biological process.
  • the term “differentially expressed” shall mean changes in gene expression level induced by environmental factors, changes in genetic background, or other internal or external insult or influence.
  • experimentally induced myopia is used here to describe myopia induced in animal models by experimental manipulations, such as the application of negative lenses over the eye.
  • whole-genome gene expression profiling refers to a method of analyzing differential gene expression at the level of the entire genome; thus, providing information about expression of all genes encoded by the genome.
  • gene-based genome-wide association study refers to a genetic study which analyzes statistical associations between genetic variations in the genome and a disease at the level of specific genes, found previously to be involved in a disease process by other experimental approaches such as whole-genome gene expression profiling.
  • positive optical defocus shall mean the condition when focal point of the eye is located in front of the retina.
  • negative optical defocus shall mean the condition when focal point of the eye is located behind the retina.
  • the term “derivative” refers to structural analog of a compound that is derived from a compound by a chemical reaction.
  • a structural analog is a compound having a structure similar to that of another compound but differing from it in respect to a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced with other atoms, groups, or substructures.
  • a structural analog can also differ from another compound in one or more atoms, functional groups, or substructures, which are added to or subtracted from another compound.
  • a structural analog can be imagined to be formed by those skilled in art, at least theoretically, from the other compound.
  • the term “subject” as used in this application means a human subject. In some embodiments of the present invention, the “subject” has myopia, is at risk for myopia or is susceptible to myopia.
  • treat refers to a means to slow down, relieve, ameliorate or alleviate at least one of the symptoms of the disease, or reverse the disease after its onset.
  • prevent refers to acting prior to overt disease onset, to prevent the disease from developing or minimize the extent of the disease or slow its course of development.
  • the term “in need thereof’ would be a subject known to be, or suspected of, suffering from myopia.
  • a subject in need of treatment would be one that has already developed the disease or condition.
  • a subject in need of prevention would be one with risk factors of the disease or condition.
  • agent means a substance that produces or is capable of producing an effect and would include, but is not limited to, chemicals, pharmaceuticals, biologies, small organic molecules, antibodies, nucleic acids, peptides, and proteins.
  • terapéuticaally effective amount is used herein to mean an amount sufficient to cause an improvement in a clinically significant condition in the subject, or delays or minimizes or mitigates one or more symptoms associated with the disease, or results in a desired beneficial change of physiology in the subject.
  • a total of 138 drug compounds with anti-myopic potential were identified. Using the gene pathways and z-scores, these drug compounds were assigned to top 10, top 20, top 40, top 80, and low priority categories based on their predicted potential to suppress myopia and known or predicted side effects. These drug compounds were then tested on a mouse model of myopia (Example 1).
  • the disclosure provides in some aspects methods of preventing and/or treating myopia comprising administering to a subject in need thereof a therapeutically effective amount of levocabastine hydrochloride or a derivative thereof.
  • the levocabastine hydrochloride or derivative is administered systemically. In certain embodiments, the levocabastine hydrochloride or derivative is administered orally. In certain embodiments, the levocabastine hydrochloride or derivative is administered locally. In some embodiments, the levocabastine hydrochloride or derivative is administered directly to or into the eye. In some embodiments, the levocabastine hydrochloride or derivative is administered via injection. In other embodiments, the levocabastine hydrochloride or derivative is administered as extended drug release formulations or compositions, extended drug delivery by contact lenses, or eye drops.
  • the levocabastine hydrochloride is used directly as the active ingredient in the drug.
  • the levocabastine hydrochloride can be chemically modified to improve its efficacy, reduce side effects, improve penetration through ocular tissues, increase stability, or improve bioavailability.
  • the levocabastine hydrochloride (or its derivative) is a sole component of the drug.
  • the methods and compositions described herein comprise the use of pharmaceutical formulations comprising the levocabastine hydrochloride (or its derivative).
  • pharmaceutical formulation refers to preparations, which include the levocabastine hydrochloride (or its derivative) and additional ingredients, such as other drugs capable of suppressing myopia or excipients (vehicles, additives, preservatives, buffers), which can reasonably be administered to a subject to improve the efficacy of the active ingredient(s) or increase stability of the active ingredient(s).
  • a formulation is stable if the active ingredient(s) essentially retain their physical properties, and/or chemical properties, and/or biological activity at room temperature (15-30° C) for at least a week, or at 2-8° C for 3 months to 1 year.
  • Levocabastine hydrochloride (or its derivative) is considered to retain its physical properties in a pharmaceutical formulation if it meets defined specifications for degradation, and/or aggregation, and/or precipitation upon visual examination of color and/or clarity, or as measured by light scattering or other suitable art recognized methods.
  • Levocabastine hydrochloride (or its derivative) is considered to retain its chemical stability in a pharmaceutical formulation if the active ingredient content within about 90% of the amount at the time the pharmaceutical formulation was prepared.
  • Some types of chemical degradation include oxidation and hydrolysis, which can be evaluated, for example, by LC- MS/MS-based methods.
  • Levocabastine hydrochloride (or its derivative) is considered to retain its biological stability in a pharmaceutical formulation if the active ingredient at a given time is within about 90% of the biological activity exhibited at the time the pharmaceutical formulation was prepared as determined by in vivo testing, for example.
  • the therapeutically effective dose of the levocabastine hydrochloride is the amount sufficient to at least partially prevent and/or treat myopia.
  • a therapeutically effective dose is sufficient if it can produce even an incremental change in the symptoms or conditions associated with the disease.
  • the therapeutically effective dose does not have to completely cure the disease or completely eliminate symptoms.
  • the therapeutically effective dose can significantly slow the progression of myopia in a subject suffering from the disease.
  • the dose and frequency of drug administration effective for this use will depend on the severity of the disease (i.e., low progressing versus high progressing myopia), type of myopia (i.e., syndromic myopia versus common myopia), subject age, body mass of the subject, and route of administration among other factors.
  • the dose and frequency of the drug administration can be adjusted using well understood and commonly used state of art in optometric and ophthalmologic practices.
  • the levocabastine hydrochloride described herein can be co-administered with other agents including additional agents for the prevention and/or treatment of myopia.
  • the co administration of agents can be by any administration described herein.
  • the additional agent can be in the same composition as the levocabastine hydrochloride.
  • the additional agent can be in a separate composition from the levocabastine hydrochloride.
  • the administration of more than one composition can be simultaneous, concurrently or sequentially.
  • the disclosure further provides in some aspects methods of preventing and/or treating myopia comprising administering to a subject in need thereof a therapeutically effective amount of a selective histamine HI -receptor antagonist.
  • the selective histamine HI -receptor antagonist includes but is not limited to azelastine, alcaftadine, antazoline, carbinoxamine, epinastine, olopatadine, ketotifen, or derivatives thereof.
  • the selective histamine HI -receptor antagonist is administered systemically. In certain embodiments, the selective histamine HI -receptor antagonist is administered orally. In certain embodiments, the selective histamine Hl-receptor antagonist is administered locally. In some embodiments, the selective histamine Hl-receptor antagonist is administered directly to or into the eye. In some embodiments, the selective histamine Hl- receptor antagonist is administered via injection. In other embodiments, the selective histamine Hl-receptor antagonist is administered as extended drug release formulations or compositions, extended drug delivery by contact lenses, or eye drops.
  • the selective histamine Hl-receptor antagonist is used directly as the active ingredient in the drug.
  • the selective histamine Hl-receptor antagonist can be chemically modified to improve its efficacy, reduce side effects, improve penetration through ocular tissues, increase stability, or improve bioavailability.
  • the selective histamine Hl-receptor antagonist is a sole component of the drug.
  • the methods and compositions described herein comprise the use of pharmaceutical formulations comprising the selective histamine Hl- receptor antagonist.
  • pharmaceutical formulation refers to preparations, which include the selective histamine Hl-receptor antagonist and additional ingredients, such as other drugs capable of suppressing myopia or excipients (vehicles, additives, preservatives, buffers), which can reasonably be administered to a subject to improve the efficacy of the active ingredient(s) or increase stability of the active ingredient(s).
  • a formulation is stable if the active ingredient(s) essentially retain their physical properties, and/or chemical properties, and/or biological activity at room temperature (15-30° C) for at least a week, or at 2-8° C for 3 months to 1 year.
  • the selective histamine HI -receptor antagonist is considered to retain its physical properties in a pharmaceutical formulation if it meets defined specifications for degradation, and/or aggregation, and/or precipitation upon visual examination of color and/or clarity, or as measured by light scattering or other suitable art recognized methods.
  • the selective histamine HI -receptor antagonist is considered to retain its chemical stability in a pharmaceutical formulation if the active ingredient content within about 90% of the amount at the time the pharmaceutical formulation was prepared.
  • Some types of chemical degradation include oxidation and hydrolysis, which can be evaluated, for example, by LC- MS/MS-based methods.
  • the selective histamine HI -receptor antagonist is considered to retain its biological stability in a pharmaceutical formulation if the active ingredient at a given time is within about 90% of the biological activity exhibited at the time the pharmaceutical formulation was prepared as determined by in vivo testing, for example.
  • the therapeutically effective dose of the selective histamine HI -receptor antagonist is the amount sufficient to at least partially prevent and/or treat myopia.
  • a therapeutically effective dose is sufficient if it can produce even an incremental change in the symptoms or conditions associated with the disease.
  • the therapeutically effective dose does not have to completely cure the disease or completely eliminate symptoms.
  • the therapeutically effective dose can significantly slow the progression of myopia in a subject suffering from the disease.
  • the dose and frequency of drug administration effective for this use will depend on the severity of the disease (i.e., low progressing versus high progressing myopia), type of myopia (i.e., syndromic myopia versus common myopia), subject age, body mass of the subject, and route of administration among other factors.
  • the dose and frequency of the drug administration can be adjusted using well understood and commonly used state of art in optometric and ophthalmologic practices.
  • the selective histamine HI -receptor antagonist described herein can be co administered with other agents including additional agents for the suppression, prevention and/or treatment of myopia.
  • the co-administration of agents can be by any administration described herein.
  • the additional agent can be in the same composition as the selective histamine HI -receptor antagonist.
  • the additional agent can be in a separate composition from the selective histamine HI -receptor antagonist.
  • the administration of more than one composition can be simultaneous, concurrently or sequentially.
  • Oral compositions of the drug can be in a form of capsules, tablets, powders, granules, solutions, syrups, suspensions (in non-aqueous or aqueous liquids), or emulsions.
  • Tablets or hard gelatin capsules may comprise lactose, starch or derivatives thereof, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, stearic acid or salts thereof.
  • Soft gelatin capsules may comprise vegetable oils, waxes, fats, semi-solid, or liquid polyols. Solutions and syrups may comprise water, polyols, and sugars.
  • An active agent intended for oral administration may be coated with or admixed with a material that delays disintegration and/or absorption of the active agent in the gastrointestinal tract. Thus, the sustained release may be achieved over many hours and if necessary, the active agent can be protected from degradation within the stomach.
  • Pharmaceutical compositions for oral administration may be formulated to facilitate release of an active agent at a particular gastrointestinal location due to specific pH or enzymatic conditions.
  • compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Extended drug release formulations or compositions can be in a form of a nanosponge, patch, gel or other device capable of gradual release of the drug over extended period of time, which is injected in the anterior or posterior segment of the eye or administered or applied to the anterior or posterior surfaces of the eye.
  • Extended drug delivery by contact lenses can be in a form of piano contact lens, single vision corrective contact lens, or multi-focal contact lens, in which either internal surface of the lens is coated with the drug, or the entire volume of the lens is loaded with the drug.
  • Eye drops can be in a form of traditional eye drops well-known and commonly used by those skilled in the art, or in a form of a micro-dosing device which delivers a strictly controlled amount of the drug to the eye.
  • the composition is administered to the subject once a day. In some embodiments, the composition is administered once a week. In some embodiments, the composition is administered twice a week. In some embodiments, the composition is administered three times a week. In some embodiments, the composition is administered to the subject continuously or intermittently for about 5 years to about 10 years.
  • the composition is administered more than once.
  • Treatment using the present methods and compositions can continue as long as needed.
  • the efficacy of the treatment in a subject with myopia is evaluated every 3-6 months and the dose and/or frequency of drug administration is adjusted depending on the degree of myopia suppression.
  • the treatment is discontinued once the subject does not exhibit any further progression of myopia, which can be evaluated by temporarily discontinuing the treatment and measuring changes in refractive error over 1-6 months using well understood state of art in optometric and ophthalmologic practices.
  • the subject is a child, i.e., under 18 years of age. In some embodiments, the subject is a young adult, i.e., under 30 years of age. In some embodiments, the subject is about 4 years of age to about 30 years of age. In some embodiments, the subject is about 6 years of age to about 20 years of age. In some embodiments, the subject is about 8 years of age to about 15 years of age. In some embodiments, the subject is about 10 years of age to about 12 years of age.
  • the subject has myopia. In some embodiments, the subject is at risk for myopia. In some embodiments, the subject is susceptible to myopia.
  • Risk factors for myopia can include but are not limited to having one or more parents with myopia.
  • kits for practicing the disclosed methods are also within the scope of the present disclosure.
  • the kit can comprise instructions for use in any of the methods described herein.
  • the included instructions can comprise a description of administration of the agents to a subject to achieve the intended activity in a subject.
  • the kit may further comprise a description of selecting a subject suitable for treatment based on identifying whether the subject is in need of the treatment.
  • the instructions relating to the use of the drugs described herein generally include information as to dosage, dosing schedule, and route of administration for the intended treatment.
  • the containers may be unit doses, bulk packages ( e.g ., multi-dose packages) or sub unit doses.
  • Instructions supplied in the kits of the disclosure are typically written instructions on a label or package insert.
  • the label or package insert indicates that the pharmaceutical compositions are used for treating, delaying the onset, and/or alleviating a disease or disorder in a subject.
  • kits provided herein are in suitable packaging.
  • suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, and the like. Kits optionally may provide additional components such as buffers and interpretive information.
  • the kit comprises a container and a label or package insert(s) on or associated with the container.
  • the disclosure provides articles of manufacture comprising contents of the kits described above.
  • Example 1 Myopia can be induced in mammals using negative spectacle lenses
  • High- resolution MRI revealed enlargement of the eye and the vitreous chamber in the treated eyes.
  • the diameter of lens-treated eyes was on average 65 + 8 pm larger ( P ⁇ 0.0001; Fig. 1C), and the vitreous chamber depth in the lens-treated eyes was 61 + 4 pm longer ( P ⁇ 0.0001; Fig. ID), than that of the control fellow eyes.
  • No significant interocular differences were observed in the anterior chamber depth, corneal radius of curvature and crystalline lens thickness (Fig. ID), suggesting that changes induced in the mouse eyes treated with negative lenses, are primarily confined to the posterior segment of the eye, similar to human myopia.
  • Statistical power analysis revealed that differences as small as 0.5 diopters in refractive error between the eyes can be identified with 90% statistical power with the sample size of 22 mice.
  • Levocabastine hydrochloride was identified as one of the top 10 drug candidates using the pharmacogenomic pipeline for anti-myopic drug development. It was discovered that systemic oral administration of levocabastine hydrochloride inhibited myopia by >100%.
  • the experimental group of B6 mice was raised with -25 D lenses over right eye (as described in Example 1) on a diet supplemented with 5 mg/kg of levocabastine hydrochloride for 3 weeks, while the control group of B6 mice with -25 D lenses over right eye was raised on a regular non-medicated diet.
  • Trier K Olsen EB, Kobayashi T, Ribel-Madsen SM. Biochemical and ultrastructural changes in rabbit sclera after treatment with 7-methylxanthine, theobromine, acetazolamide, or 1, -ornithine. Br J Ophthalmol 1999;83:1370-1375.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/US2021/035344 2020-06-02 2021-06-02 Methods and compositions for preventing and treating myopia with levocabastine, a selective histamine h1-receptor antagonist, and derivatives thereof WO2021247635A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CN202180049465.4A CN115835905A (zh) 2020-06-02 2021-06-02 用于用选择性组胺h1-受体拮抗剂左卡巴斯汀及其衍生物预防和治疗近视的方法和组合物
EP21816939.9A EP4157453A4 (en) 2020-06-02 2021-06-02 METHODS AND COMPOSITIONS FOR PREVENTING AND TREATING MYOPIA WITH LEVOCABASTINE, A SELECTIVE HISTAMINE H1 RECEPTOR ANTAGONIST, AND DERIVATIVES THEREOF
KR1020227046225A KR20230051130A (ko) 2020-06-02 2021-06-02 선택적 히스타민 h1-수용체 길항제인 레보카바스틴 및 이의 유도체를 이용한 근시의 예방 및 치료를 위한 방법 및 조성물
JP2022574559A JP2023529374A (ja) 2020-06-02 2021-06-02 レボカバスチン、選択的ヒスタミンｈ１受容体アンタゴニスト、及びその誘導体を用いて近視を予防及び治療するための方法及び組成物
CA3181292A CA3181292A1 (en) 2020-06-02 2021-06-02 Methods and compositions for preventing and treating myopia with levocabastine, a selective histamine h1-receptor antagonist, and derivatives thereof
IL298796A IL298796A (en) 2020-06-02 2021-06-02 Methods and preparations for the prevention and treatment of myopia (myopia) with levocevastine, a selective antagonist of the H1-histamine receptor, and its derivatives
US18/073,181 US20230138414A1 (en) 2020-06-02 2022-12-01 Methods and compositions for preventing and treating myopia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063033291P 2020-06-02 2020-06-02
US63/033,291 2020-06-02

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US18/073,181 Continuation-In-Part US20230138414A1 (en) 2020-06-02 2022-12-01 Methods and compositions for preventing and treating myopia

Publications (1)

Publication Number Publication Date
WO2021247635A1 true WO2021247635A1 (en) 2021-12-09

Family

ID=78829881

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/035344 WO2021247635A1 (en) 2020-06-02 2021-06-02 Methods and compositions for preventing and treating myopia with levocabastine, a selective histamine h1-receptor antagonist, and derivatives thereof

Country Status (7)

Country Link
EP (1) EP4157453A4 (ko)
JP (1) JP2023529374A (ko)
KR (1) KR20230051130A (ko)
CN (1) CN115835905A (ko)
CA (1) CA3181292A1 (ko)
IL (1) IL298796A (ko)
WO (1) WO2021247635A1 (ko)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116270442A (zh) * 2021-12-21 2023-06-23 浙江瑞瞳生物科技有限公司 一种用于矫正近距离视力的眼用制剂

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110306661A1 (en) * 2009-02-20 2011-12-15 Senju Pharmaceutical Co., Ltd. Hydrogel contact lens for sustained drug release and drug release method using hydrogel contact lens for sustained drug release
US20140036225A1 (en) * 2012-07-31 2014-02-06 Khaled Chehab Lens incorporating myopia control optics and muscarinic agents
WO2017219080A1 (en) * 2016-06-21 2017-12-28 The University Of Newcastle Treatment for myopia
US20200138801A1 (en) * 2017-02-21 2020-05-07 Singapore Health Services Pte Ltd Composition and method for preventing or delaying onset of myopia comprising atropine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITUB20160876A1 (it) * 2016-02-19 2017-08-19 Dambrosio Enzo Maria Combinazione di un agente antiallergico con un antagonista muscarinico e/o un agonista dopaminergico per l'uso in prevenzione/ arresto di miopia assiale nell’uomo
AU2018371787A1 (en) * 2017-11-21 2020-11-05 Sydnexis, Inc. Ophthalmic composition and delivery device thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110306661A1 (en) * 2009-02-20 2011-12-15 Senju Pharmaceutical Co., Ltd. Hydrogel contact lens for sustained drug release and drug release method using hydrogel contact lens for sustained drug release
US20140036225A1 (en) * 2012-07-31 2014-02-06 Khaled Chehab Lens incorporating myopia control optics and muscarinic agents
WO2017219080A1 (en) * 2016-06-21 2017-12-28 The University Of Newcastle Treatment for myopia
US20200138801A1 (en) * 2017-02-21 2020-05-07 Singapore Health Services Pte Ltd Composition and method for preventing or delaying onset of myopia comprising atropine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4157453A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116270442A (zh) * 2021-12-21 2023-06-23 浙江瑞瞳生物科技有限公司 一种用于矫正近距离视力的眼用制剂

Also Published As

Publication number Publication date
IL298796A (en) 2023-02-01
CA3181292A1 (en) 2021-12-09
EP4157453A1 (en) 2023-04-05
JP2023529374A (ja) 2023-07-10
CN115835905A (zh) 2023-03-21
KR20230051130A (ko) 2023-04-17
EP4157453A4 (en) 2024-06-19

Similar Documents

Publication Publication Date Title
Upadhyay et al. Biological mechanisms of atropine control of myopia
Pineles et al. Atropine for the prevention of myopia progression in children: a report by the American Academy of Ophthalmology
Mak et al. Epidemiology of myopia and prevention of myopia progression in children in East Asia: a review
Wu et al. Epidemiology of myopia
Pugazhendhi et al. Pathogenesis and prevention of worsening axial elongation in pathological myopia
Russo et al. Myopia onset and progression: can it be prevented?
Tkatchenko et al. Pharmacogenomic approach to antimyopia drug development: pathways lead the way
EP4157453A1 (en) Methods and compositions for preventing and treating myopia with levocabastine, a selective histamine h1-receptor antagonist, and derivatives thereof
US20230138414A1 (en) Methods and compositions for preventing and treating myopia
WO2021252717A1 (en) Methods and compositions for preventing and treating myopia with berberine, a berberidaceaen alkaloid, and derivatives thereof
WO2021252719A1 (en) Methods and compositions for preventing and treating myopia with s-methyl-l-thiocitrulline, a selective neuronal nitric oxide synthase (nnos) inhibitor, and derivatives thereof
EP4164605A1 (en) Methods and compositions for preventing and treating myopia with fingolimod, a sphingosine-1-phosphate receptor modulator, and derivatives thereof
WO2021252628A1 (en) Methods and compositions for preventing and treating myopia with trichostatin a, a histone deacetylase (hdac) inhibitor, and derivatives thereof
WO2021252626A1 (en) METHODS AND COMPOSITIONS FOR PREVENTING AND TREATING MYOPIA WITH FENOTEROL HYDROBROMIDE, A β2- ADRENERGIC RECEPTOR AGONIST, AND DERIVATIVES THEREOF
Garcia et al. Prevention of myopia progression using orthokeratology

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21816939

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022574559

Country of ref document: JP

Kind code of ref document: A

Ref document number: 3181292

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021816939

Country of ref document: EP

Effective date: 20230102