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WO2025067471A1 - 一种α-肾上腺素受体激动剂眼用组合物及其用途 - Google Patents

一种α-肾上腺素受体激动剂眼用组合物及其用途 Download PDF

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Publication number
WO2025067471A1
WO2025067471A1 PCT/CN2024/121882 CN2024121882W WO2025067471A1 WO 2025067471 A1 WO2025067471 A1 WO 2025067471A1 CN 2024121882 W CN2024121882 W CN 2024121882W WO 2025067471 A1 WO2025067471 A1 WO 2025067471A1
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Prior art keywords
receptor agonist
ophthalmic composition
eye
composition according
myopia
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PCT/CN2024/121882
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English (en)
French (fr)
Inventor
王琦芳
马琳
郭树华
周文超
庞亮
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Suzhou Pro Heal Pharmaceuticals Technology Co Ltd
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Suzhou Pro Heal Pharmaceuticals Technology Co Ltd
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Publication of WO2025067471A1 publication Critical patent/WO2025067471A1/zh
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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61P27/06—Antiglaucoma agents or miotics
    • 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 disclosure belongs to the field of biomedicine technology, and specifically, relates to an ⁇ -adrenaline receptor agonist ophthalmic composition and uses thereof.
  • Preservatives also known as antibacterial agents or preservatives, are chemical drugs that can inhibit the growth and reproduction of microorganisms.
  • preservatives themselves can cause damage to the ocular surface, and long-term use may lead to dry eyes, corneal and conjunctival epithelial damage, etc. Therefore, single-dose ophthalmic preparations without preservatives are a new direction in the development of ophthalmic drugs.
  • Adrenergic receptor agonists are a class of compounds with chemical structures and pharmacological actions similar to those of adrenaline. They bind to adrenaline receptors and stimulate them, producing adrenaline-like effects. They are also called adrenaline mimetics and are all amine compounds. According to their selectivity for different adrenaline receptor subtypes, they are divided into three categories: ⁇ -adrenaline receptor agonists, ⁇ -adrenaline receptor agonists, and ⁇ , ⁇ -adrenaline receptor agonists. There are many types of ophthalmic preparations of ⁇ -adrenaline receptor agonists on the market, but most of them contain preservatives.
  • M cholinergic receptor agonists bind to cholinergic receptors and produce effects similar to those of acetylcholine.
  • the representative drug is pilocarpine, also known as pilocarpine.
  • pilocarpine As early as 1959, 0.5% to 2% pilocarpine eye drops were used to treat glaucoma. It was the first FDA-approved drug for the treatment of glaucoma, but it has significant side effects, such as eye stinging and burning, conjunctival congestion, superficial keratitis, retinal detachment, headaches caused by ciliary spasm, and long-term use may cause lens opacity, so new first-line treatment drugs continue to be developed.
  • the purpose of the present invention is to provide an ophthalmic preparation with simple formula, long-term use, good stability, high patient compliance, few side effects, easy use and multiple functions.
  • the present disclosure provides the use of an ⁇ -adrenergic receptor agonist and an M cholinergic receptor agonist in combination for preparing a medicament for preventing, improving, alleviating or treating an eye disease.
  • the ophthalmic composition provided by the present disclosure comprises an ⁇ -adrenergic receptor agonist and an M-cholinergic receptor agonist, the mixture of which synergistically increases the efficacy of the drug, can meet the needs of different patients for improving near vision and distance vision, and has a longer retention time of up to 10 hours.
  • the ophthalmic composition provided by the present disclosure can also quickly eliminate conjunctival congestion and visual fatigue, and has a good therapeutic effect on the prevention and treatment of eye diseases such as presbyopia, ocular hypertension, dry eye, myopia, hyperopia, strabismus, astigmatism, photophobia or glaucoma.
  • eye diseases such as presbyopia, ocular hypertension, dry eye, myopia, hyperopia, strabismus, astigmatism, photophobia or glaucoma.
  • the ophthalmic composition provided by the present disclosure does not contain other excipients such as preservatives, buffers, chelating agents and excipients, thereby reducing the irritation to the eyes caused by the excipients, having high safety, few side effects, and being suitable for long-term use.
  • the synergistic therapeutic effect of the ⁇ -adrenergic receptor agonist and the M cholinergic receptor agonist in the ophthalmic composition provided by the present disclosure on hyperopia treatment and myopia relief is significantly better than that of a single ⁇ -adrenergic receptor agonist and a single M cholinergic receptor agonist.
  • the synergistic therapeutic effect of the combination on myopia relief is also better than that of the combined preparation of atropine and cevimeline.
  • Figure 1 is a diagram of the finished product of formulation 11.
  • FIG2 is a comparison of the eye irritation of single prescription formulations 7 and 9 and formulations 10-11 before and after administration.
  • FIG3 is a comparison of the eye irritation of compound preparation formulas 1-3 and 5 before and after administration.
  • FIG4 is a graph showing the effects of formulations 4, 9 and 11 on the near vision of the subjects.
  • the term “about” or “approximately” means within plus or minus 10% of a given value or range. Where an integer is required, the term means within plus or minus 10% of a given value or range, rounded up or down to the nearest integer.
  • the articles “a” and “an” refer to one or more than one (ie, at least one) of the grammatical object to which the article refers.
  • an element means one element or more than one element.
  • administering when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refers to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid.
  • administering can refer to, for example, treatment, pharmacokinetics, diagnosis, research, and experimental procedures.
  • Treatment of cells includes contact of an agent with a cell, and contact of an agent with a fluid, wherein the fluid is in contact with the cell.
  • administering also mean in vitro and ex vivo treatment of, for example, a cell, by an agent, a diagnosis, a combination composition, or by another cell.
  • Treatment when applied to humans, veterinary medicine, or research subjects, refers to therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.
  • the term "prevent, improve, alleviate or treat” refers to the medical management of patients for the purpose of curing, improving, stabilizing or preventing diseases, pathological conditions or conditions.
  • the term includes active therapy, i.e., treatment specifically for the purpose of improving diseases, pathological conditions or conditions, and also includes etiological treatment, i.e., treatment for the purpose of removing the cause of the relevant diseases, pathological conditions or conditions.
  • the term also includes palliative treatment, i.e., treatment designed to relieve symptoms rather than cure diseases, pathological conditions or conditions; the term also includes preventive treatment, i.e., treatment for the purpose of minimizing or partially or completely inhibiting the development of relevant diseases, pathological conditions or conditions; and supportive treatment, i.e., treatment for supplementing another specific therapy for the purpose of improving relevant diseases, pathological conditions or conditions.
  • the "prevent, improve, alleviate or treat” refers to reducing the severity of the symptoms of eye conditions that adversely affect visual acuity.
  • the ophthalmic preparations or ophthalmic compositions described herein can be used to improve or treat myopia or hyperopia symptoms, and patients can visually focus on objects at close distances and objects at long distances by using the preparations.
  • the term "subject" is used to describe an animal, human or non-human to whom an ophthalmic formulation or ophthalmic composition or method according to the present invention is provided for treatment.
  • Human and veterinary applications are contemplated by the present disclosure.
  • the term includes, but is not limited to, birds, reptiles, amphibians, and mammals, such as humans, other primates, pigs, rodents, such as mice and rats, rabbits, guinea pigs, hamsters, horses, cattle, cats, dogs, sheep, chickens, and goats.
  • the subject is a human, chicken, or mouse.
  • the subject is a human. Both pediatric and adult subjects are included.
  • a subject described herein can be an adult subject (e.g., 18 years or older, 21 years or older, 25 years or older, 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, 60 years or older, 65 years or older, 70 years or older, 75 years or older, 80 years or older, 85 years or older, 90 years or older, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 18, 20, 21, 24, 25, 27, 28, 30, 33, 35, 37, 39, 40, 42, 44, 45, 48, 50, 52, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104 or more years).
  • adult subject e.g., 18 years or older, 21 years or older, 25 years or older, 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, 60 years or older, 65 years or older, 70 years or older, 75 years or older, 80 years
  • the term "effective amount” refers to an amount sufficient to obtain the desired therapeutic and/or preventive effect, such as an amount that causes prevention or alleviation of symptoms associated with ophthalmic disorders.
  • the amount of the composition administered to the subject will depend on the type and severity of the disease and the nature of the individual, such as normal health, age, sex, weight, ethnicity, degree of myopia, rate of myopia progression, and tolerance to drugs. The amount also depends on the degree, severity, and type of the disease, as well as the treatment regimen formulated by a professional (such as a physician). Professional technicians will be able to determine the appropriate dosage based on these and other factors.
  • the ophthalmic composition can also be administered in combination with one or more other therapeutic compound biopharmaceuticals and therapeutic molecules (such as polypeptides).
  • ⁇ -adrenergic receptor agonists and M cholinergic receptor agonists or ophthalmic compositions containing them can be administered to subjects with one or more symptoms or signs of ophthalmic disorders.
  • a "therapeutically effective amount" refers to the average level of the physiological effects that minimize the reduction of ophthalmic disorders, preferably the average level of the physiological effects that minimize the progression of myopia.
  • formulation As used herein, the terms “formulation,” “ophthalmic 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,” “ophthalmic composition,” and “composition” may be used to refer to a mixture of one or more active agents (active ingredients) with a carrier or other excipient.
  • a composition may take almost any physical form, including solid, liquid (e.g., solution), or gas.
  • the term "pharmaceutically acceptable” means approved for use in animals, preferably humans, by regulatory authorities such as CFDA (China), EMEA (Europe) and/or FDA (US) and/or any other national regulatory authorities.
  • myopia refers to the convergence of parallel light rays in front of the retina after passing through the eye's refractive system in a relaxed state of accommodation. According to the cause of refraction, it is divided into refractive myopia and axial myopia, and their clinical manifestations are blurred vision at a distance and good vision at a close distance. In the early stages of myopia, there is often fluctuation in long-distance vision. Since there is no or little accommodation when looking at close objects, the convergence function is correspondingly weakened, which can easily cause exotropia or exotropia.
  • Myopia-related symptoms also include poor night vision, floaters, photopsia, etc., and fundus changes of varying degrees may occur, myopic arc plates, macular hemorrhage or formation of subretinal neovascularization, irregular shaped white atrophic spots, or circular black spots with pigmentation (Fuchs spots), lattice degeneration and cystic degeneration of the retina periphery, vitreous liquefaction, opacity and posterior vitreous detachment at a young age, and the risk of retinal holes and detachment is higher than that of normal people.
  • hyperopia refers to a refractive state in which a parallel beam of light is refracted by the relaxed eyeball and imaged behind the retina. Hyperopia occurs when the refractive power of the eyeball is insufficient or the axial length of the eyeball is insufficient. Its optical focus is behind the retina, so the image formed on the retina is blurred.
  • the eye irritation reaction score standard refers to the "Technical Guidelines for Drug Irritation, Allergy and Hemolysis Studies", which can be seen in Table 1.
  • the present disclosure provides an ophthalmic composition comprising an ⁇ -adrenergic receptor agonist and an M cholinergic receptor agonist.
  • the ophthalmic composition further comprises a pH adjuster, an osmotic pressure adjuster, and water.
  • the ophthalmic composition does not contain other auxiliary materials such as preservatives, buffers, complexing agents and excipients.
  • the alpha-adrenergic receptor agonist is selected from norepinephrine, metaraminol, phenylephrine, methoxamine, oxymetazoline, naphazoline, xylometazoline, apraclonidine, dexmedetomidine, brimonidine, dopamine, ephedrine, pseudoephedrine, mephentermine, or at least one of the derivatives of the foregoing compounds.
  • the ⁇ -adrenaline receptor agonist is selected from at least one of oxymetazoline, naphazoline, xylometazoline, dexmedetomidine, brimonidine, or derivatives of the foregoing compounds.
  • the alpha-adrenergic receptor agonist is selected from at least one of oxymetazoline, naphazoline, brimonidine, or a derivative of the foregoing compounds.
  • the alpha-adrenergic receptor agonist is brimonidine or a derivative thereof.
  • the alpha-adrenergic receptor agonist is brimonidine tartrate.
  • the M cholinergic receptor agonist is selected from at least one of acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, aceclidine, cevimeline, xanomeline, and sabcomeline.
  • the M cholinergic receptor agonist is selected from at least one of carbachol, pilocarpine, aceclidine, cevimeline, or xanomeline.
  • the M cholinergic receptor agonist is selected from at least one of pilocarpine, aceclidine, or cevimeline.
  • the M cholinergic receptor agonist is cevimeline.
  • the pH adjuster is selected from one or more of hydrochloric acid, boric acid, phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium bicarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide.
  • the pH adjuster is selected from one or more of hydrochloric acid, boric acid, citric acid, sodium hydroxide, and potassium hydroxide.
  • the pH adjuster is selected from hydrochloric acid and/or sodium hydroxide.
  • the ⁇ -adrenergic receptor agonist in the composition is brimonidine tartrate, and the mass ratio of the brimonidine tartrate is 0.001%-0.5% (w/w); in some embodiments, the ⁇ -adrenergic receptor agonist in the composition is brimonidine tartrate, and the mass ratio of the brimonidine tartrate is 0.001%-0.4% (w/w), for example, it can be 0.001%-0.01% (w/w), 0.01%-0.05% (w/w), 0.05%-0.2% (w/w), 0.2%-0.3% (w/w) or 0.3%- 0.4% (w/w); in some embodiments, the ⁇ -adrenergic receptor agonist in the composition is brimonidine tartrate, and the mass ratio of the brimonidine tartrate is 0.05%-0.4% (w/w); in some preferred embodiments, the ⁇ -adrenergic receptor agonist in the composition is brimonidine tartrate, and the mass ratio of the brimonidine
  • the M cholinergic receptor agonist in the composition is cevimeline, and the mass ratio of the M cholinergic receptor agonist is 0.1%-10% (w/w), for example, it can be 0.1%-0.5% (w/w), 0.5%-1% (w/w), 1%-2% (w/w), 2%-4% (w/w), 4%-8% (w/w) or 8%-10% (w/w); in some preferred embodiments, the M cholinergic receptor agonist in the composition is cevimeline, and the mass ratio of the M cholinergic receptor agonist is 1%-4.5% (w/w); in some preferred embodiments, the M cholinergic receptor agonist in the composition is cevimeline, and the mass ratio of the M cholinergic receptor agonist is 1.25%-4.5% (w/w); in some preferred embodiments, the M cholinergic receptor agonist in the composition is cevimeline, and the mass ratio of the M cholinergic receptor agonist is 1.25%-4.5% (w/w); in
  • the pH regulator in the composition is hydrochloric acid and/or sodium hydroxide, and the mass ratio of the hydrochloric acid and/or sodium hydroxide is 0.001%-0.5% (w/w), for example, 0.001%-0.002% (w/w), 0.002%-0.001% (w/w), 0.001%-0.1% (w/w), 0.1%-0.2% (w/w), 0.2%-0.4% (w/w) or 0.2%-0.5% (w/w); in some preferred embodiments, the combination In some preferred embodiments, the pH regulator in the composition is hydrochloric acid and/or sodium hydroxide, and the mass ratio of the hydrochloric acid and/or sodium hydroxide is 0.001%-0.2% (w/w); in some preferred embodiments, the pH regulator in the composition is hydrochloric acid and/or sodium hydroxide, and the mass ratio of the hydrochloric acid and/or sodium hydroxide is 0.001%-0.1% (w/w); in some preferred embodiments, the pH regulator in the composition is
  • the osmotic pressure regulator in the composition is sodium chloride, and the mass ratio of the sodium chloride is 0-0.9% (w/w), for example, it can be: 0%-0.001% (w/w), 0.001%-0.01% (w/w), 0.01%-0.1% (w/w), 0.1%-0.3% (w/w), 0.3%-0.5% (w/w) or 0.5%-0.9% (w/w); in some preferred embodiments, the mass ratio of the osmotic pressure regulator in the composition is 0%-0.8% (w/w); in some preferred embodiments, the mass ratio of the osmotic pressure regulator in the composition is 0%-0.7% (w/w); in some preferred embodiments, the mass ratio of the osmotic pressure regulator in the composition is 0%-0.6% (w/w).
  • the present disclosure provides a method for preparing the aforementioned ophthalmic composition, comprising the following steps:
  • the ophthalmic composition preparation was obtained by filtering and sterilizing through a microporous filter membrane (one 0.45 ⁇ m hydrophilic PES filter membrane and two 0.22 ⁇ m hydrophilic PES filter membranes).
  • the ophthalmic composition can be prepared into any dosage form of ophthalmic preparations, including eye drops, eye gels, eye ointments, eye patches, eye masks, eye washes, or intraocular injections.
  • the preparation method is: the ⁇ -adrenergic receptor agonist and a small amount of water for injection are mixed and stirred to dissolve for standby use, and the M cholinergic receptor agonist and a small amount of water for injection are mixed and stirred to dissolve for standby use.
  • the preparation method further comprises filtering and sterilizing through a microporous filter membrane, and aseptically filling the finished product by Blow/Fill/Seal under the sterile protection of a Class A air shower.
  • the present disclosure provides the use of an ⁇ -adrenergic receptor agonist and an M cholinergic receptor agonist in combination for preparing a medicament for preventing, improving, alleviating or treating an eye disease.
  • the present disclosure provides a use of the aforementioned ophthalmic composition in the preparation of a medicament for preventing, improving, alleviating or treating eye diseases.
  • the ophthalmic composition further comprises a pharmaceutically acceptable carrier and/or excipient. These substances are used to help the stability of the formulation or to help improve the activity or its biological effectiveness, or in the case of an eye drop experiment, to efficiently transport the drug to the posterior segment of the eye.
  • a pharmaceutically acceptable carrier and/or excipient are used to help the stability of the formulation or to help improve the activity or its biological effectiveness, or in the case of an eye drop experiment, to efficiently transport the drug to the posterior segment of the eye.
  • the preparation that can be used in such an ophthalmic composition can be in the form of its original compound itself, or optionally in the form of its pharmaceutically acceptable salt.
  • the ophthalmic composition thus formulated can select any appropriate method known to those skilled in the art to administer the drug as needed.
  • the suitable dosage of the ophthalmic composition can be prescribed in a variety of ways according to factors such as the formulation method, administration mode, patient's age, weight, sex, morbidity, diet, administration time, administration route, excretion rate and reaction sensitivity.
  • a skilled doctor can usually easily determine the prescription and the dosage that is effective for the desired treatment or prevention.
  • the therapeutically effective amount and specific treatment regimen for a certain subject may be affected by many factors, including the pharmacodynamic activity of the drug used, the age, weight, general condition, sex, diet, administration time, disease susceptibility, disease progression and the judgment of the treating physician, etc.
  • the administration mode, dosage form and dosage of the drug are affected by many factors such as the patient's age, weight, sex, morbidity, diet, administration time, excretion rate and reaction sensitivity. Therefore, the administration mode, dosage form and dosage of the ophthalmic preparation or ophthalmic composition described in the present invention are not limited to the administration mode, dosage form and dosage described in the embodiments of the present invention.
  • the eye diseases include conjunctival congestion caused by environmental factors, infection or inflammation, visual fatigue caused by long-term close-up use of the eyes, and presbyopia, ocular hypertension, dry eye, myopia, hyperopia, strabismus, astigmatism, photophobia or glaucoma.
  • the environmental stimuli include irritating smoke, wind and sand, ultraviolet radiation and long-term topical medication.
  • Visual fatigue includes dry eyes, soreness and pain, blurred vision, and even symptoms such as decreased vision and dizziness.
  • the present disclosure provides a method for preventing, improving, alleviating or treating an eye disease, comprising administering an effective amount of the aforementioned ophthalmic drug to an affected eye of a subject.
  • the subject refers to any animal, including humans and non-human animals.
  • Non-human animals include all vertebrates, for example, mammals, such as non-human primates (particularly higher primates), sheep, dogs, rodents (e.g., mice or rats), guinea pigs, goats, pigs, cats, rabbits, cattle, and any livestock or pets; and non-mammals, such as chickens, amphibians, reptiles, etc.
  • the subject is preferably a human.
  • the ophthalmic preparation provided by the present disclosure is applied to one or both eyes of a patient showing symptoms of an ocular disease to improve the symptoms of the ocular disease.
  • the application of the ophthalmic preparation provided by the present invention can fully improve the patient's near visual acuity.
  • administering the ophthalmic preparation provided by the present invention can enable the patient to focus on objects at a distance around the normal reading distance without using corrective lenses or corrective eye surgery.
  • administering the ophthalmic preparation provided by the present invention can alleviate presbyopia-related symptoms, including making near visual acuity possible without using corrective lenses or glasses.
  • the application of the ophthalmic preparation provided by the present invention can fully improve the patient's long-distance visual acuity.
  • administering the ophthalmic preparation provided by the present invention can enable the patient to focus on objects at a distance around the normal reading distance without using corrective lenses or corrective eye surgery.
  • administering the ophthalmic preparation provided by the present invention can alleviate myopia-related symptoms, including making long-distance visual acuity possible without using corrective lenses or glasses.
  • an ophthalmic composition provided by the present disclosure is administered to a patient to improve the patient's ability to focus on near and distant objects after the patient has undergone corrective surgery to treat an eye condition (e.g., including corrective eye surgery to treat cataracts).
  • the present disclosure provides the aforementioned composition, which is used to treat a patient's hyperopia while also alleviating the patient's myopia symptoms.
  • the relieving the patient's myopia symptoms is improving the patient's distance vision.
  • the present disclosure provides a method for preventing, improving, alleviating or treating an eye disease, comprising administering an effective amount of an ⁇ -adrenergic receptor agonist and an M cholinergic receptor agonist, or the aforementioned ophthalmic composition to a subject in need thereof.
  • the eye disease is selected from one or more of conjunctival hyperemia, visual fatigue, presbyopia, ocular hypertension, dry eye, myopia, hyperopia, strabismus, astigmatism, photophobia, or glaucoma.
  • the present disclosure provides an ⁇ -adrenergic receptor agonist and an M cholinergic receptor agonist in combination or the aforementioned ophthalmic composition for preventing, improving, alleviating or treating ocular diseases;
  • the eye disease is selected from one or more of conjunctival hyperemia, visual fatigue, presbyopia, ocular hypertension, dry eye, myopia, hyperopia, strabismus, astigmatism, photophobia, or glaucoma.
  • Example 1 Preparation method of ophthalmic composition preparation
  • the ophthalmic composition preparation was obtained by filtering and sterilizing through a microporous filter membrane (one 0.45 ⁇ m hydrophilic PES filter membrane and two 0.22 ⁇ m hydrophilic PES filter membranes).
  • the component concentrations in the prepared formulations are shown in Table 3.
  • formulas 1-11 can form stable and uniform solutions.
  • the finished product of formula 11 is shown in Figure 1.
  • the properties of other formulations are similar to those of formula 11, all of which are clear and transparent solutions.
  • Formulas 4, 5, 6 and 11 were placed at high temperature of 40°C for 1 month, and their pH, osmotic pressure molar concentration, purity or content did not change significantly.
  • the stability results are shown in Table 4.
  • Subject information The subjects are a male, about 60 years old, with mild presbyopia, and a female, about 45 years old, with myopia. Both subjects are in good health, can comply with the requirements during the trial, can undergo various examinations as specified in the trial protocol, and can report subjective symptoms. The subjects understand the purpose of the trial, the nature of the trial drugs, the possible risks of the trial, and their own rights and interests and voluntarily participate in this trial. When the same subject undergoes different groups of formulations, there is at least a two-day interval between the first group of formulations and the second group of formulations.
  • the subjects Before using formulation 3, the subjects had scattered or diffuse corneal opacity, while the cornea was clear after using formulation 3.
  • the compound preparation is more comfortable than the single prescription preparation. There is no irritation, itching, redness, swelling, dryness, increased eye secretions or other discomfort during the whole process.
  • the compound preparation can improve eye comfort, eliminate eye fatigue, and improve the clarity of vision.
  • the subject is a female, about 45 years old, myopic, in good health, able to comply with all requirements during the trial, able to undergo various examinations as specified in the trial protocol, and able to report subjective symptoms; the subject understands the purpose of the trial, the nature of the trial drugs, the possible risks of the trial, and her own rights and interests and voluntarily participates in this trial.
  • the tester uses a benchmark for testing vision to point to the sight mark on the vision chart, and requires the subject to say or use gestures to indicate the direction of the gap of the sight mark under the premise of tightly covering one of the left and right eyes, and test line by line to find the best recognition line for the testee, so as to test the specific vision of the left and right eyes respectively.
  • the test results are shown in Figure 4.
  • single prescription formulation 9 (0.2% brimonidine tartrate eye drops) did not improve the near vision ability of the subjects; after using single prescription formulation 11 (2.25% cevimeline eye drops) and compound formulation 4 (0.1% brimonidine tartrate and 4% cevimeline compound eye drops), the subjects had no irritation, no itching, no redness, no dryness, no increased eye secretions and other discomfort during the test, and could eliminate eye fatigue, improve the clarity of vision, and improve the near vision in a short time by 0.3, and then continue to maintain the near vision until the end of observation (8h); compound formulation 4 can improve the near vision by 0.3 within 15min, which is better than single prescription formulation 11. From the analysis of the results, it can be concluded that the mixture of brimonidine tartrate and cevimeline synergistically increases the efficacy of the drug and prolongs the duration of action.
  • Subject information The subject is a male, about 60 years old, with both presbyopia and myopia, in good health, able to comply with all requirements during the trial, able to undergo various examinations as specified in the trial protocol, and able to report subjective symptoms; the subject understands the purpose of the trial, the nature of the trial drugs, the possible risks of the trial, and his own rights and interests and voluntarily participates in this trial. Before using the compound preparation formula 6, the subject had symptoms of eye fatigue and mild congestion of the conjunctiva.
  • the method for determining myopia is the same as that of Example 3, and the method for testing hyperopia is tested by using the national standard logarithmic visual acuity test chart, with a distance of 5m as the standard, and the test is performed in a well-lit environment, and the best visual acuity is 1.0.
  • the tester uses a pole for testing vision, points to the sight mark of the vision chart, and requires the subject to say or use gestures to indicate the direction of the gap of the sight mark under the premise of strictly covering one of the left and right eyes, and detects line by line to find the best recognition line for the testee, thereby testing the specific vision of the left and right eyes respectively.
  • the test results are shown in Figure 5.
  • the subjects can quickly eliminate the symptoms of conjunctival congestion, and the whole process is free of irritation, itching, redness, swelling, dryness, and other discomforts such as increased eye secretions, and can eliminate eye fatigue and improve the clarity of vision.
  • the subjects' short-term (10min) near vision can be improved by 0.1 (scored as 1.0), and the near vision can be improved by 0.3 for 15min, and then the near vision is maintained until the end of observation (10h); the long-distance vision is also improved, and the long-distance vision can be improved by 0.2 for 20min, and then the long-distance vision is maintained until the end of observation (10h).
  • the compound eye drops of brimonidine tartrate and cevimeline can not only improve near vision, but also improve long-distance vision.
  • the ophthalmic composition of the present invention can improve the clarity of vision of patients with refractive errors, and has a long action time and good safety.
  • Subject information The subjects are a male, about 60 years old, who is both presbyopic and myopic, and a female, about 45 years old, who is myopic. They are in good health, can comply with all requirements during the trial, can undergo various examinations as specified in the trial protocol, and can report subjective symptoms. The subjects understand the purpose of the trial, the nature of the trial drugs, the possible risks of the trial, and their own rights and interests and voluntarily participate in this trial. When the same subject undergoes different groups of formulations, there will be at least two days between the first group of formulations and the second group of formulations.
  • Determination of long-distance vision It is mainly tested by using the national standard logarithmic vision test chart to check the patient's long-distance vision, with a distance of 5m as the standard and the test performed in sufficient light. The best visual acuity is 1.0.
  • the tester points to the sight mark on the vision chart with a vision test pole, and requires the subject to say or use gestures to indicate the direction of the gap in the sight mark while tightly covering one of the left or right eyes.
  • the test is carried out line by line to find the best recognition line for the testee, so as to test the specific vision of the left and right eyes respectively.
  • the applicant further prepared a formula 12 ophthalmic composition containing 0.05wt% atropine + 2.25wt% cevimeline, and a formula 13 ophthalmic composition containing 0.15wt% brimonidine tartrate + 2.25wt% cevimeline.
  • the specific preparation process can refer to Example 1.
  • the ophthalmic compositions of formulas 12 and 13 can both improve long-distance vision.
  • the ophthalmic composition of formula 13 can improve long-distance vision by 0.3 at 20 minutes, while the ophthalmic composition of formula 12 containing atropine can only improve long-distance vision by 0.1. From the analysis of the results, it can be concluded that the combination of brimonidine tartrate and cevimeline can improve long-distance vision, and the onset time is fast, and the long-distance vision is improved more; the compound eye drops of atropine and cevimeline have a slightly slower onset than the same concentration of cevimeline eye drops, and the long-distance vision is improved less.

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Abstract

涉及一种α-肾上腺素受体激动剂眼用组合物及其用途，其包含α-肾上腺素受体激动剂和M胆碱受体激动剂。提供的眼用组合物可满足不同患者提高近距视力和远距视力的需求，并且具有较长的保持时间，达到10h。此外，提供的组合物还能快速消除结膜充血，消除视疲劳，对预防及治疗老花眼、高眼压症、干眼症、近视、远视、斜视、散光、畏光或青光眼等眼部疾病有很好的疗效。

Description

一种α-肾上腺素受体激动剂眼用组合物及其用途 技术领域
本公开属于生物医药技术领域，具体地，本公开涉及一种α-肾上腺素受体激动剂眼用组合物及其用途。
背景技术
随着现代科技的发展，人们对电子产品的依赖度提高，无论是儿童，成年人还是老年人的学习和生活都离不开电子产品。电子产品对眼睛的危害也日益显现出来，包括眼睛红血丝、眼睛疲劳、视物模糊、眼睛干涩发痒、害怕阳光以及视力下降等。这些危害对个人的学习和生活都会造成一定程度的影响，长期以往就会导致视力受损，影响个人的生活质量。另外，随着近视人群的年龄增大，有些患者存在着单眼近视和另一只眼远视的情况。
目前市面上在售的以及临床在研的眼用制剂，为了防止在开封后重复使用过程中被微生物污染，超过九成眼用制剂中都含有防腐剂，为多剂量包装，可以多次重复使用。防腐剂又称为抑菌剂或保存剂，是能够抑制微生物生长与繁殖的化学药品。但防腐剂本身会造成眼表损伤，长期使用可能会导致出现干眼症、角膜、结膜上皮损伤等。因此，不含防腐剂的单剂量眼用制剂是目前眼科用药发展的新方向。
肾上腺素受体激动剂是一类化学结构及药理作用和肾上腺素相似的化合物，与肾上腺素受体结合并激动受体，产生肾上腺素样作用，又称为拟肾上腺素，均为胺类化合物。按其对不同肾上腺素受体亚型的选择性而分为三大类：α肾上腺素受体激动剂、β肾上腺素受体激动剂和α、β肾上腺素受体激动剂。已上市的α-肾上腺素受体激动剂的眼用制剂有多种，但大多含防腐剂。
M胆碱受体激动剂与胆碱受体结合，产生与乙酰胆碱类似的作用，代表药物为毛果芸香碱，又名匹鲁卡品。早在1959年，0.5％～2％毛果芸香碱滴眼液就已经被用于到青光眼的治疗，是FDA批准的第一个用于青光眼治疗的药物，但其有较大的副作用，如眼睛刺痛和烧灼感、结膜充血、浅表角膜炎、视网膜脱离、睫状体痉挛而产生头痛、长期使用可能会出现晶状体混浊等，因此继续发新的一线治疗药物。近年来，陆陆续续有报道将M胆碱受体激动剂应用于预防及治疗老花眼病症中。2021年10月，首个FDA批准上市的治疗老花眼的Vuity(NDA 214028)就是通过缩瞳来改善近距离视力的，其活性成分为1.25％的毛果芸香碱(WO2019209955)。Eyenovia Inc通过“微矩阵药膜(MicroLine)”技术(WO2020180793)将相对高浓度的毛果芸香碱递送至眼睛，从而达到治疗老花眼的目的。Orasis Pharmaceuticals开发的一种含有低浓度(0.4％)的毛果芸香碱和专有载体的老花眼药物(WO2018033792)。以上这些已上市和临床在研的老花眼药物，为了提高药物的稳定性，采用了复杂的制剂配方。
因此，市场上急需一款配方简单、能够长期使用、稳定性好、患者依从性高、副作用小、使用便捷且具有多重功效的眼用制剂。
发明内容
为了解决现有技术中存在的问题，本公开的目的在于提供一种配方简单、能够长期使用、稳定性好、患者依从性高、副作用小、使用便捷且具有多重功效的眼用制剂。
为了实现上述目的，本公开采用以下具体方案：
在一方面，本公开提供了一种眼用组合物，其包含α-肾上腺素受体激动剂和M胆碱受体激动剂。
在另一方面，本公开提供了α-肾上腺素受体激动剂和M胆碱受体激动剂联合在制备用于预防、改善、减轻或治疗眼部疾病的药物中的应用。
在另一方面，本公开提供了一种利用前述眼用组合物在制备用于预防、改善、减轻或治疗眼部疾病的药物中的应用。
本公开至少具有以下有益效果：
(1)本公开提供的眼用组合物包含α-肾上腺素受体激动剂和M胆碱受体激动剂，两者混合协同增加了药物的疗效，可满足不同患者提高近距视力和远距视力的需求，并且具有较长的保持时间，达到10h。
(2)本公开提供的眼用组合物还能快速消除结膜充血，消除视疲劳，对预防及治疗老花眼、高眼压症、干眼症、近视、远视、斜视、散光、畏光或青光眼等眼部疾病有很好的疗效。
(3)本公开提供的眼用组合物中不含防腐剂、缓冲剂、络合剂和赋型剂等其他辅料，减少了由于辅料对眼部产生的刺激作用，安全性高、副作用少，适合长期使用。
(3)本公开提供的眼用组合物中α-肾上腺素受体激动剂和M胆碱受体激动剂对远视治疗和近视缓解的协同治效果明显优于单个的α-肾上腺素受体激动剂和单个的M胆碱受体激动剂。该组合对近视缓解的协同治疗效果同样优于阿托品和西维美林的组合制剂。
附图说明
图1为配方11的制剂成品图。
图2为单处方制剂配方7和9以及配方10-11给药前后的眼部刺激性对比图。
图3为复方制剂配方1-3和5给药前后的眼部刺激性对比图。
图4为制剂配方4、9和11对受试者近距视力的影响图。
图5为制剂配方6对受试者近距视力和远距视力的影响图。
具体实施方式
I.术语
为了更容易理解本公开，以下具体定义了某些技术和科学术语。除显而易见在本文件中的它处另有明确定义，否则本文使用的所有其它技术和科学术语都具有本公开所属领域的一般技术人员通常理解的含义。
如本文使用的和除非另作说明，术语“约”或“大约”是指在给定值或范围的加或减10％之内。在需要整数的情况下，该术语是指在给定值或范围的加或减10％之内、向上或向下舍入到最接近的整数。
在本文的描述中，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。
在本文的描述中，涉及到“一些实施例”、“一些实施方式”或“一些实施方案”，其描述了所有可能实施例的子集，但是可以理解，“一些实施例”可以是所有可能实施例的相同子集或不同子集，并且可以在不冲突的情况下相互结合。
如本文使用的和除非另作说明，术语“包含”，“包括”，“具有”，“含有”，包括其语法上的等同形式，通常应当理解为开放式且非限制性的，例如，不排除其他未列举的要素或步骤。
本文使用的冠词“一”和“一种”是指该冠词所指的一个或一个以上(即至少一个)的语法对象。举例来说，“一种元件”表示一个元件或一个以上的元件。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。
“施用”、“给予”和“处理”当应用于动物、人、实验受试者、细胞、组织、器官或生物流体时，是指外源性药物、治疗剂、诊断剂或组合物与动物、人、受试者、细胞、组织、器官或生物流体的接触。“施用”、“给予”和“处理”可以指例如治疗、药物代谢动力学、诊断、研究和实验方法。细胞的处理包括试剂与细胞的接触，以及试剂与流体的接触，其中所述流体与细胞接触。“施用”、“给予”和“处理”还意指通过试剂、诊断、结合组合物或通过另一种细胞体外和离体处理例如细胞。“处理”当应用于人、兽医学或研究受试者时，是指治疗处理、预防或预防性措施，研究和诊断应用。
整个说明书和权利要求书中使用的术语“基本上由……组成”或其变形表示包括所有所述元件或元件组，并且任选包括与所述元件类似或不同性质的其它元件，所述其它元件非显著改变指定给药方案、方法或组合物的基本性质或新性质。
如本文所用，术语“预防、改善、减轻或治疗”，是指以治愈、改善、稳定或预防疾病、病理状态或病症为目的对患者进行的医学管理。该术语包括积极疗法，即专门以改善疾病、病理状态或病症为目的的治疗，并且还包括病因治疗，即以除去相关疾病、病理状态或病症的病因为目的的治疗。此外，该术语还包括姑息治疗，即设计用于缓解症状而非治愈疾病、病理状态或病症的治疗；该术语还包括预防性治疗，即以最大程度降低或者部分或完全抑制相关疾病、病理状态或病症的发展为目的的治疗；以及支持性治疗，即用于补充另一种以改善相关疾病、病理状态或病症为目的的特定疗法的治疗。在本发明的具体实施方式中，所述“预防、改善、减轻或治疗”是指减轻不利地影响视敏度的眼睛病况的症状的严重性，具体而言，本文中描述眼用制剂或眼用组合物能用于改善或治疗近视或远视症状，患者通过使用该制剂，能够在视觉上聚焦于近距离处物体和远距离处物体。
如本文所用，术语“受试者”，以描述向其提供根据本发明所述的眼用制剂或眼用组合物或方法的治疗的动物、人类或非人类。本公开预期了人类和兽医学应用。该术语包括(但不限于)：鸟类、爬行动物、两栖动物和哺乳动物，例如人类、其他灵长类动物、猪、啮齿动物，例如小鼠和大鼠、兔、豚鼠、仓鼠、马、牛、猫、狗、绵羊、鸡和山羊。在一些实施方案中，所述受试者是人、鸡或小鼠。在优选的实施方案中，所述受试者是人类。儿科和成人受试者均包括在内。例如，在本文中描述的受试者可以是成人受试者(例如，18岁或更大、21岁或更大、25岁或更大、30岁或更大、35岁或更大、40岁或更大、45岁或更大、50岁或更大、60岁或更大、65岁或更大、70岁或更大、75岁或更大、80岁或更大、85岁或更大、90岁或更大或2、3、4、5、6、7、8、9、10、12、13、14、15、16、18、20、21、24、25、27、28、30、33、35、37、39、40、42、44、45、48、50、52、55、60、65、70、75、80、85、90、95、96、97、98、99、100、101、102、103、104或更多岁)。
如本文所用，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。所述眼用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，α-肾上腺素受体激动剂和M胆碱受体激动剂或含有其的眼用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，“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。
如本文所用，术语“制剂”、“眼用组合物”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”、“眼用组合物”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。
如本文所用，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，“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。
如本文所用，“远视”指平行光束经过调节放松的眼球折射后成像于视网膜之后的一种屈光状态，当眼球的屈光力不足或其眼轴长度不足时就产生远视。其光学焦点在视网膜之后，因而在视网膜上所形成的像是模糊不清的。
如本文所用，眼刺激反应分值标准参照《药物刺激性、过敏性和溶血性研究技术指导原则》，具体可见表1。
表1.眼刺激反应分值标准

如本文所用，眼刺激评价标准见表2。
表2.眼刺激性评价标准
II.具体实施方案详述
在一方面，本公开提供了一种眼用组合物，其包含α-肾上腺素受体激动剂和M胆碱受体激动剂。
在一些实施方案中，所述眼用组合物还包含pH调节剂、渗透压调节剂和水。
在一些实施方案中，所述眼用组合物中不含有防腐剂、缓冲剂、络合剂和赋型剂等其他辅料。
在一些实施方案中，所述α-肾上腺素受体激动剂选自去甲肾上腺素、间羟胺、去氧肾上腺素、甲氧明、羟甲唑啉、萘甲唑啉、赛洛唑啉、阿可乐定、右美托咪定、溴莫尼定、多巴胺、麻黄碱、伪麻黄碱、美芬丁胺或前述化合物衍生物中的至少一种。
在一些实施方案中，所述α-肾上腺素受体激动剂选自羟甲唑啉、萘甲唑啉、赛洛唑啉、右美托咪定、溴莫尼定或前述化合物衍生物中的至少一种。
在一些实施方案中，所述α-肾上腺素受体激动剂选自羟甲唑啉、萘甲唑啉、溴莫尼定或前述化合物衍生物中的至少一种。
在一些实施方案中，所述α-肾上腺素受体激动剂为溴莫尼定或其衍生物。
在一些实施方案中，所述α-肾上腺素受体激动剂为酒石酸溴莫尼定。
在一些实施方案中，所述M胆碱受体激动剂选自乙酰胆碱、醋甲胆碱、卡巴胆碱、氯贝胆碱、毛果芸香碱、醋克立定、西维美林、呫诺美林、沙可美林中的至少一种。
在一些实施方案中，所述M胆碱受体激动剂选自卡巴胆碱、毛果芸香碱、醋克立定、西维美林或呫诺美林中的至少一种。
在一些实施方案中，所述M胆碱受体激动剂选自毛果芸香碱、醋克立定或西维美林中的至少一种。
在一些实施方案中，所述M胆碱受体激动剂为西维美林。
在一些实施方案中，所述pH调节剂选自盐酸、硼酸、磷酸、磷酸二氢钠、磷酸氢二钠、柠檬酸、柠檬酸钠、酒石酸、酒石酸钠、碳酸氢钠、碳酸钠、氢氧化钠和氢氧化钾中的一种或多种。
在一些实施方案中，所述pH调节剂选自盐酸、硼酸、柠檬酸、氢氧化钠、氢氧化钾中的一种或多种。
在一些实施方案中，所述pH调节剂选自盐酸和/或氢氧化钠。
在一些实施方案中，所述组合物中α-肾上腺素受体激动剂为酒石酸溴莫尼定，所述酒石酸溴莫尼定的质量比为0.001％-0.5％(w/w)；在一些实施方案中，所述组合物种α-肾上腺素受体激动剂为酒石酸溴莫尼定，所述酒石酸溴莫尼定的质量比为0.001％-0.4％(w/w)，例如可以为0.001％-0.01％(w/w)、0.01％-0.05％(w/w)、0.05％-0.2％(w/w)、0.2％-0.3％(w/w)或0.3％-0.4％(w/w)；在一些实施方案中，所述组合物中α-肾上腺素受体激动剂为酒石酸溴莫尼定，所述酒石酸溴莫尼定的质量比为0.05％-0.4％(w/w)；在一些优选的实施方案中，所述组合物中α-肾上腺素受体激动剂为酒石酸溴莫尼定，所述酒石酸溴莫尼定的质量比为0.1％-0.3％(w/w)；在一些优选的实施方案中，所述组合物中α-肾上腺素受体激动剂为酒石酸溴莫尼定，所述酒石酸溴莫尼定的质量比为0.1％-0.2％(w/w)。
在一些实施方案中，所述组合物中M胆碱受体激动剂为西维美林，所述M胆碱受体激动剂的质量比为0.1％-10％(w/w)，例如可以为0.1％-0.5％(w/w)、0.5％-1％(w/w)、1％-2％(w/w)、2％-4％(w/w)、4％-8％(w/w)或8％-10％(w/w)；在一些优选的实施方案中，所述组合物中M胆碱受体激动剂为西维美林，所述M胆碱受体激动剂的质量比为1％-4.5％(w/w)；在一些优选的实施方案中，所述组合物中M胆碱受体激动剂为西维美林，所述M胆碱受体激动剂的质量比为1.25％-4.5％(w/w)；在一些优选地实施方案中，所述组合物中M胆碱受体激动剂为西维美林，所述M胆碱受体激动剂的质量比为1.25％-4％(w/w)。
在一些实施方案中，所述组合物中pH调节剂为盐酸和/或氢氧化钠，所述盐酸和/或氢氧化钠的质量比为0.001％-0.5％(w/w)，例如可以为0.001％-0.002％(w/w)、0.002％-0.001％(w/w)、0.001％-0.1％(w/w)、0.1％-0.2％(w/w)、0.2％-0.4％(w/w)或0.2％-0.5％(w/w)；在一些优选的实施方案中，所述组合物中pH调节剂为盐酸和/或氢氧化钠，所述盐酸和/或氢氧化钠的质量比为0.001％-0.2％(w/w)；在一些优选的实施方案中，所述组合物中pH调节剂为盐酸和/或氢氧化钠，所述盐酸和/或氢氧化钠的质量比为0.001％-0.1％(w/w)；在一些优选地实施方案中，所述组合物中pH调节剂为盐酸和/或氢氧化钠，所述盐酸和/或氢氧化钠的质量比为0.002％-0.05％(w/w)。
在一些实施方案中，所述组合物中渗透压调节剂为氯化钠，所述氯化钠的质量比为0-0.9％(w/w)，例如可以为：0％-0.001％(w/w)、0.001％-0.01％(w/w)、0.01％-0.1％(w/w)、0.1％-0.3％(w/w)、0.3％-0.5％(w/w)或0.5％-0.9％(w/w)；在一些优选的实施方案中，所述组合物中渗透压调节剂的质量比为0％-0.8％(w/w)；在一些优选的实施方案中，所述组合物中渗透压调节剂的质量比为0％-0.7％(w/w)；在一些优选的实施方案中，所述组合物中渗透压调节剂的质量比为0％-0.6％(w/w)。
在另一方面，本公开提供了一种前述眼用组合物的制备方法，包括以下步骤：
1.主药溶解
(1)α-肾上腺素受体激动剂的溶解：边搅拌注射用水边加入处方量的α-肾上腺素受体激动剂，搅拌至完全溶解，备用；
(2)M胆碱受体激动剂的溶解：边搅拌注射用水边加入处方量的M胆碱受体激动剂，搅拌至完全溶解，备用；
2.制剂配制
在配液罐中加入注射用水，并将处方量的氯化钠加入至配液罐中并搅拌溶解，分别加入处方量的α-肾上腺素受体激动剂溶液和处方量的M胆碱受体激动剂溶液，搅拌混匀；
3.调节pH
调节pH前先测量pH值，然后再加入0.5mol/L的NaOH溶液或者0.1mol/L的HCl溶液，将pH值调节至pH内控标准6.0～7.0，药液pH优选6.6；
4.定容
使用注射用水定容至处方量；
5.过滤
经微孔滤膜(一道0.45μm亲水PES滤膜及两道0.22μm亲水PES滤膜)过滤除菌，即得眼用组合物制剂。
在一些实施方案中，所述眼用组合物可以制作成眼用制剂的任何剂型，包括滴眼剂、眼凝胶剂、眼膏剂、眼贴剂、眼膜剂、洗眼剂或眼内注射剂。
在一些实施方案中，所述眼用组合物为的剂型为滴眼剂时，该制备方法为：将所述的α-肾上腺素受体激动剂和少量注射用水混合并搅拌溶解备用，将所述的M胆碱受体激动剂和少量注射用水混合并搅拌溶解备用。在配液灌中加入适量的注射用水，将所述的渗透压调节剂按需要的量加入至配液罐中并搅拌溶解，然后将α-肾上腺素受体激动剂溶液和M胆碱受体激动剂溶液加入至配液罐中，混匀后取样检测药液pH，根据药液pH值，不断加入pH调节剂调节药液pH内控标准；之后使用注射用水定容至处方量，并搅拌，后经微孔滤膜过滤除菌，即得α-肾上腺素受体激动剂滴眼液。
在一些实施方案中，所述制备方法还包括经微孔滤膜过滤、除菌，在A级风淋的无菌保护下进行吹灌封(Blow/Fill/Seal)无菌灌装成品。
在另一方面，本公开提供了α-肾上腺素受体激动剂和M胆碱受体激动剂联合在制备用于预防、改善、减轻或治疗眼部疾病的药物中的应用。
在另一方面，本公开提供了一种利用前述眼用组合物在制备用于预防、改善、减轻或治疗眼部疾病的药物中的应用。
在一些实施方案中，所述眼用组合物还包含药学上课接受的载体和/或辅料。这些物质根据需要用于帮助配方的稳定性或有助于提高活性或它的生物有效性或在滴眼实验的情况下能够将药物高效运送至眼后段，在这种眼用组合物中可以使用的制剂可以是其原始化合物本身的形式，或任选地使用其药物学可接受的盐的形式，如此配制的眼用组合物根据需要可选择本领域技术人员已知的任何适当的方式将药物进行给药。
在一些实施方案中，所述眼用组合物的适合的给药剂量根据制剂化方法、给药方式、患者的年龄、体重、性别、病态、饮食、给药时间、给药途径、排泄速度及反应灵敏性之类的因素而可以进行多种处方，熟练的医生通常能够容易地决定处方及处方对所希望的治疗或预防有效的给药剂量。针对某一对象(如哺乳动物：人)的治疗有效量和具体治疗方案可受诸多因素的影响，包括所用药物的药效活性、给药对象的年龄、体重、一般情况、性别、饮食、给药时间、疾病易感性、疾病进程以及收治医师的判断等，此外，本领域技术人员清楚药物的给药方式、给药剂型、给药剂量受患者的年龄、体重、性别、病态、饮食、给药时间、排泄速度及反应灵敏性等众多因素的影响，因此，本发明中所述的眼用制剂或眼用组合物的给药方式、给药剂型、给药剂量并不局限于本发明实施例中所述的给药方式、给药剂型、给药剂量。
在一些实施方案中，所述眼部疾病包括由环境因素刺激、感染或炎症引起的结膜充血、长时间近距离用眼产生的视疲劳，以及老花眼、高眼压症、干眼症、近视、远视、斜视、散光、畏光或青光眼。其中，所述环境刺激包括刺激性烟雾、风沙、紫外线辐射和长期局部用药等。视疲劳包括眼睛干涩、酸胀疼痛、视物模糊，甚至视力下降、头晕等症状。
在另一方面，本公开提供了一种预防、改善、减轻或治疗眼部疾病的方法，所述方法包括将有效量的前述眼用祝贺吴施用于受试者的患眼。
在一些实施方案中，所述受试者是指任何动物，还指人类和非人类的动物。非人类的动物包括所有脊椎动物，例如，哺乳动物，如非人灵长类动物(特别是高等灵长类动物)、绵羊、狗、啮齿类动物(例如：小鼠或大鼠)、豚鼠、山羊、猪、猫、兔、牛、和任何家畜或宠物；以及非哺乳动物，如鸡，两栖类，爬行动物等。在本发明的具体实施方式中，所述受试者优选为人。
在一些实施方案中，将本公开提供的眼用制剂施用至表现出眼部疾病症状的患者的一只眼睛或两只眼睛以改善其眼部疾病症状。在一些实施方案中，不依赖于其他治疗方法，施用本发明提供的眼用制剂可以充分地改善患者的近距离视敏度。例如，给予本发明提供的眼用制剂可以使得患者能够聚焦在正常阅读距离周围的距离处的物体上而不使用矫正透镜或矫正性眼部手术。对于在老花眼的早期阶段的患者，给予本发明提供的眼用制剂可以减轻老花眼相关症状，包括使得近距离视敏度成为可能而不使用矫正透镜或眼镜。在一些实施方案中，不依赖于其他治疗方法，施用本发明提供的眼用制剂可以充分地改善患者的远距离视敏度。例如，给予本发明提供的眼用制剂可以使得患者能够聚焦在正常阅读距离周围的距离处的物体上而不使用矫正透镜或矫正性眼部手术。对于在近视眼的早期阶段的患者，给予本发明提供的眼用制剂可以减轻近视眼相关症状，包括使得远距离视敏度成为可能而不使用矫正透镜或眼镜。
在一些实施方案中，在患者已经进行了针对治疗眼部病况的矫正性手术(例如，包括针对治疗白内障的矫正性眼部手术)之后，将本公开提供的眼用组合物给予至患者以改善患者聚焦在附近和远距离物体上的能力。
在一方面，本公开提供了前述组合物，其用于治疗患者远视的同时还能缓解患者近视症状。
在一些实施方案中，所述缓解患者近视症状为提高患者的远距视力。
在一方面，本公开提供了一种预防、改善、减轻或治疗眼部疾病的方法，其包括向有需要的受试者施用有效量的α-肾上腺素受体激动剂和M胆碱受体激动剂，或前述的眼用组合物。
在一些实施方案中，所述眼部疾病选自结膜充血、视疲劳、老花眼、高眼压症、干眼症、近视、远视、斜视、散光、畏光或青光眼中的一种或多种。
在一方面，本公开提供了α-肾上腺素受体激动剂和M胆碱受体激动剂联合或前述的眼用组合物，其用于预防、改善、减轻或治疗眼部疾病；
在一些实施方案中，所述眼部疾病选自结膜充血、视疲劳、老花眼、高眼压症、干眼症、近视、远视、斜视、散光、畏光或青光眼中的一种或多种。
实施例
通过参考在此给出的一些具体实施例可获得对本公开的进一步的理解，这些实施例仅用于说明本公开，其无意于对本公开的范围做出任何限制。显然，可以对本公开作出多种改动和变化而不脱离本公开的实质，因此，这些改动和变化同样在本申请要求保护的范围内。
实施例1.眼用组合物制剂的制备方法
1.主药溶解
(1)α-肾上腺素受体激动剂的溶解：边搅拌注射用水边加入处方量的α-肾上腺素受体激动剂，搅拌至完全溶解，备用；
(2)M胆碱受体激动剂的溶解：边搅拌注射用水边加入处方量的M胆碱受体激动剂，搅拌至完全溶解，备用；
2.制剂配制
在配液罐中加入注射用水，并将处方量的氯化钠加入至配液罐中并搅拌溶解，分别加入处方量的α-肾上腺素受体激动剂溶液和处方量的M胆碱受体激动剂溶液，搅拌混匀；
3.调节pH
调节pH前先测量pH值，然后再加入0.5mol/L的NaOH溶液或者0.1mol/L的HCl溶液，将pH值调节至pH内控标准6.0～7.0，药液pH优选6.6；
4.定容
使用注射用水定容至处方量；
5.过滤
经微孔滤膜(一道0.45μm亲水PES滤膜及两道0.22μm亲水PES滤膜)过滤除菌，即得眼用组合物制剂。制备得到的各配方制剂中的组分浓度见表3。
表3.各配方组合物制剂的组分浓度

*注：给与受试者的眼用制剂都是现配现用。
经观察，配方1-11均能形成稳定、均一的溶液。其中，配方11的制剂成品图见图1，其他制剂配方性状与配方11类似，均为澄清透明溶液。配方4、5、6和11在高温40℃条件下放置1个月，其pH、渗透压摩尔浓度与纯度或含量均未发生显著变化，其稳定性结果见表4。
表4.配方4、5、6和11的稳定性结果
实施例2.不同配方制剂的眼部刺激实验
受试者信息：受试者为一名男性，约60岁，其眼部状况轻微老视，和一名女性，约45岁，近视患者。两位受试者的健康状态良好，能遵守试验期间的各项要求，可按照试验方案中的规定进行各项检查，能够报告主观症状。受试者了解了试验目的、试验用药品的性质试验的可能风险及自己的权益自愿参加本试验。同一受试者在进行不同组配方时，接受第一组配方试验与第二组配方试验之间至少间隔两天。
取单处方制剂配方7-11的溶液，各一滴，滴入受试者的下结膜穹窿后，提醒受试者稍微把下眼睑往外提，闭眼，然后压住内眦部位，同时可以转动眼球，保持一分钟，分别记录给药前和给药后5分钟的眼部刺激性情况。根据《药物刺激性、过敏性和溶血性研究技术指导原则》计算分值(即表1)，并根据表2判断刺激性程度，具体试验结果见表5，对应的部分配方实验后受试者眼部情况见图2，配方8试验后受试者眼部无刺激，受试者眼部情况可参照配方7的实验照片。
表5.单处方制剂眼刺激性评分
从表5和图2的实验结果可知，单处方制剂配方7(0.002％萘甲唑啉滴眼液)、制剂配方8(0.025％盐酸羟甲唑啉滴眼液)和制剂配方9(0.2％酒石酸溴莫尼定眼液)使用前后，受试者眼睛无明显结膜充血加重或减轻的情况。根据实际观测和受试者描述，整个过程基本无刺激或不适之感。在受试者使用了单处方制剂配方10(1.25％硝酸毛果芸香碱眼液)和制剂配方11(2.25％西维美林眼液)后，眼睛出现轻微的结膜充血情况，其中，使用制剂配方11的症状较制剂配方10的轻。继续观察，受试者眼部症状10min后基本能够恢复正常，整个过程基本无刺激或不适之感。另取复方制剂配方1-5的溶液，各一滴，滴入受试者的下结膜穹窿后，提醒受试者稍微把下眼睑往外提，闭眼，然后压住内眦部位，同时可以转动眼球，保持一分钟，分别记录给药前和给药后5分钟的眼部刺激性情况。根据表1计算分值，并根据表2判断刺激性程度，具体试验结果见表6，对应的部分配方实验后受试者眼部情况见图3，配方4试验后受试者眼部无刺激，受试者眼部情况可参照配方3的实验照片。
表6.复方制剂眼刺激性评分

从表6和图3的实验结果可知，受试者在使用复方眼用制剂配方1(0.002％萘甲唑啉和2.25％西维美林的复方滴眼液)前，有轻微的结膜充血症状，在使用复方眼用制剂配方1后，结膜充血症状快速消失；受试者在使用制剂配方2(0.025％盐酸羟甲唑啉和1.25％硝酸毛果芸香碱的复方滴眼液)、制剂配方3(0.1％酒石酸溴莫尼定和2％西维美林的复方滴眼液)、制剂配方4(0.1％酒石酸溴莫尼定和4％西维美林的复方滴眼液)、制剂配方5(0.15％酒石酸溴莫尼定和4％西维美林的复方滴眼液)和制剂配方6(0.2％酒石酸溴莫尼定和4％西维美林的复方滴眼液)后，受试者眼睛未出现结膜充血症状。其中受试者在使用制剂配方3前，角膜散在或弥漫性混浊，而使用制剂配方3后角膜清晰。根据实际观测和受试者描述，复方制剂的舒适度优于单处方制剂，整个过程无刺激、无瘙痒、无红肿、无干涩以及眼分泌物增多等其他不适之感，复方制剂能够提高眼部的舒适度，消除眼疲劳，提高视物的清晰度。
实施例3.不同配方制剂对近视患者的影响
制剂配方4、9和11受试者信息：受试者为一名女性，约45岁，近视患者，健康状态良好，能遵守试验期间的各项要求，可按照试验方案中的规定进行各项检查，能够报告主观症状；受试者了解了试验目的、试验用药品的性质试验的可能风险及自己的权益自愿参加本试验。同一受试者在进行不同组配方时，接受第一组配方试验与第二组配方试验之间至少间隔两天。
取制剂配方4、9和11溶液各一滴，滴入受试者的下结膜穹窿后，稍微把下眼睑往外提，闭眼，然后压住内眦部位，同时可以转动眼球，保持一分钟，观察给药前和给药后的眼部刺激性情况，并记录给药前和给药后5分钟、10分钟、15分钟、20分钟、30分钟、1小时、1.5小时、2小时、3小时、5小时、7小时、8小时的近距视力情况。其中，通过使用国家标准近用视力检查表来检查受试者的近视力，以30cm距离为标准，在光线充足的情况下进行测试，最好视力表现为0.8。测试时，检测者用检测视力的标杆，指着视力表的视标，要求受试者在严密遮盖左右眼其中之一的前提下，说出或者用手势表示视标的缺口方向，逐行检测，找出被检验者最佳辨认行，从而分别测试左右眼的具体视力。测试结果见图4。
由图4可知，使用单处方制剂配方9(0.2％酒石酸溴莫尼定滴眼液)，并未提高受试者的视近能力；使用单处方制剂配方11(2.25％西维美林眼液)和复方制剂配方4(0.1％酒石酸溴莫尼定和4％西维美林的复方滴眼液)后，受试者受试过程无刺激、无瘙痒、无红肿、无干涩以及眼分泌物增多等其他不适之感，并且可以消除眼疲劳，提高视物的清晰度，短时间内的近距视力可以提高0.3，之后继续维持近距视力至观察结束(8h)；复方制剂配方4在15min内近距视力即可以提高0.3，优于单处方制剂配方11。由此结果分析得出，酒石酸溴莫尼定与西维美林两者混合协同增加了药物的疗效，并且延长作用时间。
实施例4.配方制剂6对患者近视和远视的影响
受试者信息：受试者为一名男性，约60岁，既老视又近视患者，健康状态良好，能遵守试验期间的各项要求，可按照试验方案中的规定进行各项检查，能够报告主观症状；受试者了解了试验目的、试验用药品的性质试验的可能风险及自己的权益自愿参加本试验。受试者在使用了复方制剂配方6前，用眼疲劳，结膜有轻微充血症状。
取制剂配方6溶液，滴一滴在受试者下结膜穹窿后，提醒受试者稍微把下眼睑往外提，闭眼，然后压住内眦部位，同时可以转动眼球，保持一分钟，观察给药前和给药后的眼部刺激性情况，并记录给药前和给药后5分钟、10分钟、15分钟、20分钟、30分钟、1小时、1.5小时、2小时、3小时、5小时、7小时、8小时、10小时的近距和远距视力情况。近视视力的测定方法同实施例3，远视视力测试方法通过使用国家标准对数视力检查表检测，以5m距离为标准，在光线充足的情况下进行测试，最好视力表现为1.0。测试时，检测者用检测视力的标杆，指着视力表的视标，要求受试者在严密遮盖左右眼其中之一的前提下，说出或者用手势表示视标的缺口方向，逐行检测，找出被检验者最佳辨认行，从而分别测试左右眼的具体视力。测试结果见图5。
由图5和实际观测结果可知，在使用了复方制剂配方6(0.2％酒石酸溴莫尼定和4％西维美林的复方滴眼液)后，受试者可以快速消除结膜充血症状，整个过程无刺激、无瘙痒、无红肿、无干涩以及眼分泌物增多等其他不适之感，并且可以消除眼疲劳，提高视物的清晰度。受试者短时间(10min)的近距视力可以提高0.1(按1.0计分)，15min的近距视力可以提高0.3，之后继续维持近距视力至观察结束(10h)；远距视力也得到了提高，20min的远距视力可以提高0.2，之后继续维持远距力至观察结束(10h)。
综上，酒石酸溴莫尼定和西维美林的复方滴眼液不仅可以提高近距视力，并且可以提高远距视力。另一方面可以说明本发明的眼用组合物可以提高屈光不正患者视物的清晰度，并且作用时间长，安全性好。
对比例1
受试者信息：受试者为一名男性，约60岁，既老视又近视的患者和一名女性，约45岁，近视患者，健康状态良好，能遵守试验期间的各项要求，可按照试验方案中的规定进行各项检查，能够报告主观症状；受试者了解了试验目的、试验用药品的性质试验的可能风险及自己的权益自愿参加本试验。同一受试者在进行不同组配方时，接受第一组配方试验与第二组配方试验之间至少间隔两天。
远距视力的测定：主要是通过使用国家标准对数视力检查表来检查患者的远距视力，以5m距离为标准，在光线充足的情况下进行测试，最好视力表现为1.0。测试时，检测者用检测视力的标杆，指着视力表的视标，要求受试者在严密遮盖左右眼其中之一的前提下，说出或者用手势表示视标的缺口方向，逐行检测，找出被检验者最佳辨认行，从而分别测试左右眼的具体视力。
为了进一步验证酒石酸溴莫尼定和西维美林组合制剂的协同作用，申请人进一步配制了包含0.05wt％阿托品+2.25wt％西维美林的配方12眼用组合物，和包含0.15wt％酒石酸溴莫尼定+2.25wt％西维美林的配方13眼用组合物，其具体配制过程可参照实施例1。
取配方12和配方13的眼用制剂各一滴，滴入受试者下结膜穹窿后，稍微把下眼睑往外提，闭眼，然后压住内眦部位，同时可以转动眼球，保持1分钟，记录给药前和给药后5分钟、10分钟、15分钟、20分钟的远距视力情况，结果见下表7。
表7.远距视力测试结果
从表7可知，配方12和13的眼用组合物均可以提高远距视力。其中配方13的眼用组合物在20min时，远距视力即可提高0.3，而此时包含阿托品的配方12眼用组合物仅能提高0.1的远距视力。由此结果分析得出，酒石酸溴莫尼定和西维美林的组合可以提高远距视力，且起效时间快，远距视力提高较多；阿托品和西维美林的复方滴眼液相对于同浓度的西维美林滴眼液，起效略慢，远距视力提高较少。
综上，进一步验证了酒石酸溴莫尼定和西维美林的眼用组合物的协同作用。
以上所述，仅为本发明的实施例，并非对本发明任何形式上和实质上的限制，应当指出，对于本技术领域的普通技术人员，在不脱离本发明方法的前提下，还将可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。凡熟悉本专业的技术人员，在不脱离本发明的精神和范围的情况下，当可利用以上所揭示的技术内容而做出的些许更动、修饰与演变的等同变化，均为本发明的等效实施例；同时，凡依据本发明的实质技术对上述实施例所作的任何等同变化的更动、修饰与演变，均仍属于本发明的技术方案的范围内。

Claims (15)

  1. 一种眼用组合物，其包含α-肾上腺素受体激动剂和M胆碱受体激动剂。
  2. 权利要求1所述的眼用组合物，其特征在于，所述眼用组合物还包含pH调节剂、渗透压调节剂和水。
  3. 权利要求1所述的眼用组合物，其特征在于，所述α-肾上腺素受体激动剂选自去甲肾上腺素、间羟胺、去氧肾上腺素、甲氧明、羟甲唑啉、萘甲唑啉、赛洛唑啉、阿可乐定、右美托咪定、溴莫尼定、多巴胺、麻黄碱、伪麻黄碱、美芬丁胺或前述化合物衍生物中的至少一种；
    优选地，所述α-肾上腺素受体激动剂为溴莫尼定；
    优选地，所述α-肾上腺素受体激动剂为酒石酸溴莫尼定。
  4. 权利要求1所述的眼用组合物，其特征在于，所述M胆碱受体激动剂选自乙酰胆碱、醋甲胆碱、卡巴胆碱、氯贝胆碱、毛果芸香碱、醋克立定、西维美林、呫诺美林、沙可美林中的至少一种；
    优选地，所述M胆碱受体激动剂为西维美林。
  5. 权利要求2所述的眼用组合物，其特征在于，所述pH调节剂选自盐酸、硼酸、磷酸、磷酸二氢钠、磷酸氢二钠、柠檬酸、柠檬酸钠、酒石酸、酒石酸钠、碳酸氢钠、碳酸钠、氢氧化钠和氢氧化钾中的一种或多种；
    优选地，所述pH调节剂为盐酸和/或氢氧化钠。
  6. 权利要求1-5任一项所述的眼用组合物，其特征在于，所述α-肾上腺素受体激动剂为酒石酸溴莫尼定，所述酒石酸溴莫尼定的质量比为0.001％-0.5％(w/w)，优选为0.001％-0.4％(w/w)，进一步优选为0.1％-0.3％(w/w)，进一步优选为0.1％-0.2％(w/w)。
  7. 权利要求1-6任一项所述的眼用组合物，其特征在于，所述M胆碱受体激动剂为西维美林，所述M胆碱受体激动剂的质量比为0.1％-10％(w/w)，进一步优选为1％-4.5％(w/w)，进一步优选为1.25％-4.5％(w/w)，进一步优选为1.25％-4％(w/w)。
  8. 权利要求1-7任一项所述的眼用组合物，其特征在于，所述pH调节剂为盐酸和/或氢氧化钠，所述盐酸和/或氢氧化钠的质量比为0.001％-0.5％(w/w)，进一步优选为0.001％-0.2％(w/w)，进一步优选为0.001％-0.1％(w/w)，进一步优选为0.002％-0.05％(w/w)。
  9. 权利要求1-8任一项所述的眼用组合物，其特征在于，所述渗透压调节剂为氯化钠，所述氯化钠的质量比为0-0.9％(w/w)，进一步优选为0％-0.8％(w/w)，进一步优选为0％-0.7％(w/w)，进一步优选为0％-0.6％(w/w)。
  10. α-肾上腺素受体激动剂和M胆碱受体激动剂联合在制备用于预防、改善、减轻或治疗眼部疾病的药物中的应用。
  11. 权利要求1-9任一项所述的眼用组合物在制备用于预防、改善、减轻或治疗眼部疾病的药物中的应用；
    优选地，所述药物还包含药学上可接受的载体和/或辅料。
  12. 权利要求10或11所述的应用，所述眼部疾病选自结膜充血、视疲劳、老花眼、高眼压症、干眼症、近视、远视、斜视、散光、畏光或青光眼中的一种或多种。
  13. 权利要求1-9任一项所述的眼用组合物，其用于治疗患者远视的同时还能缓解患者近视症状；
    优选地，所述缓解患者近视症状为提高患者的远距视力。
  14. 一种预防、改善、减轻或治疗眼部疾病的方法，其包括向有需要的受试者施用有效量的α-肾上腺素受体激动剂和M胆碱受体激动剂，或权利要求1-9任一项所述的眼用组合物；
    优选地，所述眼部疾病选自结膜充血、视疲劳、老花眼、高眼压症、干眼症、近视、远视、斜视、散光、畏光或青光眼中的一种或多种。
  15. α-肾上腺素受体激动剂和M胆碱受体激动剂联合或权利要求1-9任一项所述的眼用组合物，其用于预防、改善、减轻或治疗眼部疾病；
    优选地，所述眼部疾病选自结膜充血、视疲劳、老花眼、高眼压症、干眼症、近视、远视、斜视、散光、畏光或青光眼中的一种或多种。
PCT/CN2024/121882 2023-09-28 2024-09-27 一种α-肾上腺素受体激动剂眼用组合物及其用途 Pending WO2025067471A1 (zh)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105792815A (zh) * 2013-08-28 2016-07-20 远视眼治疗有限责任公司 用于治疗远视眼的组合物和方法
CN107847492A (zh) * 2015-06-18 2018-03-27 远视眼治疗有限责任公司 用于改善远视力和治疗眼睛屈光不正的组合物
CN113226300A (zh) * 2018-08-08 2021-08-06 盛元医药广州有限公司 治疗老花眼的组合物和方法
CN113518620A (zh) * 2018-10-10 2021-10-19 乐恩姿医药 用于治疗老花眼的组合物和方法
US20220105090A1 (en) * 2013-08-28 2022-04-07 Lenz Therapeutics, Inc. Compositions and methods for the treatment of eye conditions
CN114588156A (zh) * 2022-04-22 2022-06-07 温州医科大学附属眼视光医院 一种眼用制剂及其在治疗老花眼中的应用
WO2023114347A1 (en) * 2021-12-16 2023-06-22 Lenz Therapeutics, Inc. Compositions and methods for the treatment of eye conditions

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105792815A (zh) * 2013-08-28 2016-07-20 远视眼治疗有限责任公司 用于治疗远视眼的组合物和方法
US20220105090A1 (en) * 2013-08-28 2022-04-07 Lenz Therapeutics, Inc. Compositions and methods for the treatment of eye conditions
CN107847492A (zh) * 2015-06-18 2018-03-27 远视眼治疗有限责任公司 用于改善远视力和治疗眼睛屈光不正的组合物
CN113226300A (zh) * 2018-08-08 2021-08-06 盛元医药广州有限公司 治疗老花眼的组合物和方法
CN113518620A (zh) * 2018-10-10 2021-10-19 乐恩姿医药 用于治疗老花眼的组合物和方法
WO2023114347A1 (en) * 2021-12-16 2023-06-22 Lenz Therapeutics, Inc. Compositions and methods for the treatment of eye conditions
CN114588156A (zh) * 2022-04-22 2022-06-07 温州医科大学附属眼视光医院 一种眼用制剂及其在治疗老花眼中的应用

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