WO2020062445A1 - 防治nitm的药物组合物及其医药用途 - Google Patents

防治nitm的药物组合物及其医药用途 Download PDF

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Publication number
WO2020062445A1
WO2020062445A1 PCT/CN2018/113969 CN2018113969W WO2020062445A1 WO 2020062445 A1 WO2020062445 A1 WO 2020062445A1 CN 2018113969 W CN2018113969 W CN 2018113969W WO 2020062445 A1 WO2020062445 A1 WO 2020062445A1
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Prior art keywords
pharmaceutical composition
pharmaceutically acceptable
atropine
myopia
acceptable salt
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PCT/CN2018/113969
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English (en)
French (fr)
Inventor
刘继东
王宁利
郭雷
杨强
高坤
李林蔚
顾红
孙洋
付乐
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沈阳兴齐眼药股份有限公司
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Application filed by 沈阳兴齐眼药股份有限公司 filed Critical 沈阳兴齐眼药股份有限公司
Priority to JP2021516570A priority Critical patent/JP7359204B2/ja
Priority to CN201880098058.0A priority patent/CN112789043A/zh
Priority to EP18934879.0A priority patent/EP3858353B1/en
Priority to US17/279,555 priority patent/US20210259961A1/en
Publication of WO2020062445A1 publication Critical patent/WO2020062445A1/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
    • A61K31/33—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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/08—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
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia

Definitions

  • the invention belongs to the field of medicine and relates to a pharmaceutical composition for preventing and controlling NITM and its medical use.
  • the pharmaceutical composition is an ophthalmic pharmaceutical composition such as an ophthalmic preparation.
  • Myopia refers to the fact that parallel light rays from a distance are focused in front of the retinal photosensitive layer without using the adjustment function. In short, when the eye is at rest, parallel light rays are focused in front of the retina. How far the refractive error deviates from 0D is considered myopia, and there is no international standard for this. It is more practical to take -0.25D or 0.50D (see "Myopia,” edited by Hu Xingning, People's Medical Publishing House, the first edition in June 2009, page 3).
  • myopia there are also myopia divided into pseudomyopia, true myopia and pathological myopia (see “Blue Book of Myopia Prevention and Control and Blind Prevention Model 2015”, edited by Li Jianjun, People's Medical Publishing House, February 2016, first edition, Pages 8-9), or divide myopia into false myopia, true myopia, and mixed myopia (see “Ophthalmic Flex Optics”, Xu Guangdi, editor, Military Medical Science Press, 1st edition, June 2005, 71 -72 pages; “Eye Optics”, edited by Wang Yuliang, Li Kai, People's Military Medical Publishing House, 1st edition, August 2008, pp. 399-401 "Classification of myopic eyes”).
  • Pseudo-myopia also known as accommodative myopia or functional myopia, refers to myopia in the normal state, using a palliative medicine (1% atropine eye drops, three times a day for three consecutive days; Or once a day, for seven days in a row), myopia disappears, appearing as emmetropia or hyperopia; after the effect of regulating paralytic drugs disappears, it quickly returns to myopia.
  • pseudomyopia accounts for about 5% -10% of adolescent myopia, which is mainly seen in myopia with a course of less than one year and refractive power below -1.00D.
  • pseudomyopia is the primary stage of the occurrence and development of myopia (see Myopia Ophthalmology, edited by Hu Xuning and others, People's Medical Publishing House, June 2009, first edition, page 28; Chinese Medical Association Eye Scientific Division Eye Flexion Group "Definition and Classification Standards of True and False Myopia").
  • NITM Near work induced transient myopia
  • NITM is a short-term, temporary far point that appears to the eye after a short period of close work, because the lens cannot quickly and effectively reduce its refractive power. Recently, it is a phenomenon known as regulation hysteresis involving the interaction of the sympathetic nerve and parasympathetic nervous system.
  • NITM refers to the change in refractive power (equivalent spherical lens: spherical lens + 1/2 cylindrical lens) after close-up work, and its size is The difference between the refractive power after close work and the refractive power before close work (see Lin Zhong et al., Research status of short-term myopia induced by close work, Chinese Journal of Ophthalmology, July 2012, Vol. 48, No. No. 7, p. 657).
  • the inventors After intensive research and creative labor, the inventors have surprisingly found that low-concentration atropine can effectively treat NITM, and the therapeutic effect is in a dose-pharmacological relationship (0.001% -0.2%).
  • the inventors have further found that the use of borate systems has a better therapeutic effect than phosphate buffer systems, and the use of polyols to regulate permeability is better than the use of inorganic salts such as sodium chloride, especially when only boric acid is used in the system to adjust the pH and osmotic pressure , The effect is the best.
  • the pharmaceutical composition or ophthalmic preparation of the present invention may further contain a tackifier used in a conventional ophthalmic preparation, preferably hydroxypropyl cellulose, and the pharmaceutical composition or ophthalmic preparation may or may not contain a bacteriostatic agent.
  • One aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising 0.001% to 0.2% of atropine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients;
  • the pH of the pharmaceutical composition is 4.0-6.5;
  • the pharmaceutical composition comprises 0.05% to 5% of a pH adjusting agent, and the pH adjusting agent is selected from any one of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, citrate, boric acid, and borate. One or more.
  • the pH adjusting agent can be used or added in a solid form, and can also be used or added in the form of a buffer / buffer system (eg, a phosphate buffer, a citrate buffer, a borate buffer, etc.).
  • a buffer / buffer system eg, a phosphate buffer, a citrate buffer, a borate buffer, etc.
  • sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, citrate, boric acid and / or borate may also have other functions or effects.
  • the pharmaceutical composition is an ophthalmic preparation, such as an ophthalmic liquid preparation (such as an eye drop, an eye wash, or an intraocular injection solution), an ophthalmic semi-solid preparation (E.g., eye ointment, ophthalmic cream, or ophthalmic gel) or ophthalmic solid preparation (e.g., eye mask, eye pill, or intraocular insert); optionally, the ophthalmic liquid formulation may be in a solid form Packaging, prepare a separate solvent, prepare a solution or suspension just before use.
  • an ophthalmic liquid preparation such as an eye drop, an eye wash, or an intraocular injection solution
  • an ophthalmic semi-solid preparation E.g., eye ointment, ophthalmic cream, or ophthalmic gel
  • ophthalmic solid preparation e.g., eye mask, eye pill, or intraocular insert
  • the ophthalmic liquid formulation may be in a solid form Packaging, prepare a separate solvent, prepare a solution or suspension just before use.
  • the pharmaceutical composition wherein the concentration or content of the atropine or a pharmaceutically acceptable salt thereof is 0.001% to 0.1%, preferably 0.005% to 0.05%, more It is preferably 0.005% to 0.02%, further preferably 0.005% to 0.015% or 0.008% to 0.012%, such as 0.008%, 0.009%, 0.010%, 0.011%, or 0.012%, and particularly preferably 0.01%; preferably, said The pharmaceutically acceptable salt of atropine is atropine sulfate.
  • the pharmaceutical composition wherein the pH of the pharmaceutical composition is 4.0-6.0, preferably 4.5-6.0, more preferably 4.5-5.5, such as 4.5- 5.0, 5.5-5.5, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4 or 5.5.
  • the pharmaceutical composition wherein,
  • the content of the pH adjusting agent is 0.5% to 5%, more preferably 1% to 3%, even more preferably 1.5% to 2.5%, 1.5% to 2.0%, 1.5% to 2.25%, or 1.75% to 2.25%.
  • the citrate is sodium citrate, and / or the borate is sodium tetraborate.
  • the pharmaceutical composition wherein the pharmaceutical composition comprises 0.5% -3%, 1% -3%, 1.5% -2.5%, 1.5% -2.25% , 1.5% -2.0%, 1.75% -2.25%, or 1.75% -2% of boric acid, such as 1.5%, 1.6%, 1.7%, 1.75%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.25 %, 2.3%, 2.4% or 2.5%.
  • the pharmaceutical composition wherein the pharmaceutical composition further comprises any one or more selected from the following 1) to 5) (for example, any (2, 3, 4 or 5):
  • a thickener is selected from one or more of hypromellose, sodium carboxymethyl cellulose, and sodium hyaluronate; preferably, the content of the thickener is 0.01 5% -5%, preferably 0.5-3%, more preferably 0.5% -1.5%, such as 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4 % Or 1.5%; particularly preferred is 0.8% to 1.2%.
  • an osmotic pressure regulator for example, any one or more selected from glycerol, mannitol, propylene glycol, sodium chloride, and potassium chloride;
  • a preservative for example, any one or more selected from benzalkonium chloride, paraben antibacterial agents, and polyquaternium salts;
  • a stabilizer for example, any one or more selected from the group consisting of disodium edetate and calcium sodium edetate;
  • the pharmaceutical composition is free of preservatives, and / or free of stabilizers.
  • the pharmaceutical composition is water in addition to the active ingredient (atropine and / or a pharmaceutically acceptable salt thereof, such as atropine sulfate) and excipients.
  • the pharmaceutical composition wherein the ingredients and content of the pharmaceutical composition is selected from any one of the following groups (1) to (8):
  • composition of the present invention can be prepared by technical means known to those skilled in the art.
  • Another aspect of the invention relates to the use of atropine or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing atropine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention of NITM (short-term myopia induced by close-range work) ;
  • the pharmaceutically acceptable salt is atropine sulfate
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients;
  • the pharmaceutical composition is the pharmaceutical composition according to any one of the present invention.
  • the use wherein the medicament is an ophthalmic preparation, preferably an eye drop.
  • the use wherein the eye drops are administered once or every other day, 1-2 drops each time; preferably, the eye drops are dropped on the conjunctiva Inside the capsule.
  • the use, wherein the subject of the eye drops is a close-sighted person or a near-sighted person;
  • the near-sighted person is a myopia patient or a non-myopia patient;
  • the myopia-susceptible person is a person aged 6-18 years.
  • kit product which includes a drug and a product description
  • the medicine is atropine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing atropine or a pharmaceutically acceptable salt thereof;
  • the pharmaceutically acceptable salt is atropine sulfate
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients;
  • the pharmaceutical composition is the pharmaceutical composition according to any one of the present invention.
  • the medicament is an ophthalmic preparation, preferably an eye drop.
  • the kit product wherein the product description records that the eye drops are administered once or every other day, 1-2 drops each time;
  • the product description further states that the eye drops are dropped into the conjunctival sac.
  • the kit product wherein the product description records that the subject of the eye drops is a myopia patient or a non-myopia patient;
  • the product description states that the subject of the eye drops is a close eye user
  • the product description records that the subject of the eye drops is a near-sighted patient or a non-myopia patient with near-sighted eyes;
  • the product description states that the subject of the eye drops is a person who is susceptible to myopia
  • the product description records that the subject of the eye drops is a person from 6 to 18 years old, such as a 6-18 year old myopia patient or a 6-18 year old non-myopia patient.
  • Yet another aspect of the present invention relates to atropine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing atropine or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of NITM (short-term myopia induced by close-range work);
  • the pharmaceutically acceptable salt is atropine sulfate
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients;
  • the pharmaceutical composition is the pharmaceutical composition according to any one of the present invention.
  • the pharmaceutical composition is an ophthalmic preparation, preferably an eye drop.
  • the near-sighted person is a myopia patient or a non-myopia patient;
  • the myopia-susceptible person is a person aged 6-18 years.
  • Yet another aspect of the present invention relates to a method for treating and / or preventing NITM, comprising the step of administering an effective amount of a drug to a subject in need, wherein the drug is atropine or a pharmaceutically acceptable salt thereof, or A pharmaceutical composition containing atropine or a pharmaceutically acceptable salt thereof;
  • the pharmaceutically acceptable salt is atropine sulfate
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients;
  • the pharmaceutical composition is the pharmaceutical composition according to any one of the present invention.
  • the pharmaceutical composition is an ophthalmic preparation, preferably an eye drop.
  • the method for treating and / or preventing NITM wherein the eye drops are administered once or every other day, 1-2 drops each time; preferably given before bedtime medicine;
  • the eye drops are dropped into the conjunctival sac.
  • the method for treating and / or preventing NITM wherein the subject of the eye drops is a myopia patient or a non-myopia patient;
  • the subject of the eye drops is a close eye user
  • the subject of the eye drops is a near-sighted patient or a non-myopia patient with near-sighted eyes;
  • the subject of the eye drops is a person who is susceptible to myopia, such as a person aged 6-18 years;
  • the myopia-susceptible person is a myopia patient or a non-myopia patient.
  • the actual dosage and cycle of administration can be determined according to the subject's own physical condition or in accordance with a doctor's order. Usually, it can be administered in a short or long term, such as 1 month, 2 months, 3 months, 4 Month, 5 months, 6 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years or more.
  • the term "close-eye person” refers to a person who has a short distance between the eye and the gaze target and maintains constant gaze for a period of time.
  • a period of time means at least 30 minutes, at least 45 minutes , At least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 4 hours or more.
  • continuous gaze refers to uninterrupted gaze; in some cases, one, two, or three breaks may be allowed, but each break time does not exceed 5 seconds, preferably not more than 3 seconds or not.
  • close-eye users include, but are not limited to, elementary and middle school students, office white-collar workers, people engaged in video games or video, etc .
  • fixation targets include, but are not limited to, electronic display devices (mobile phone display, computer display, electronic reading) Device, etc.), books, test papers, etc.
  • the near-sighted person includes a myopia patient and a non-myopia patient.
  • myopia-susceptible person includes a person who is susceptible to myopia but has not yet suffered from myopia, or a person who has suffered from myopia and is liable to further aggravate the degree of myopia.
  • people (children, adolescents) between the ages of 6 and 18 are susceptible to myopia because their eyes and optic nerve system are not fully developed, or because they are under pressure to study, or are exposed to video games or videos more frequently.
  • the myopia-susceptible persons include myopia patients and non-myopia patients, and are preferably myopia patients or non-myopia patients aged 6-18 years.
  • the concentration of the atropine or a pharmaceutically acceptable salt thereof refers to the mass-volume percentage concentration.
  • the atropine or a pharmaceutically acceptable salt thereof refers to the mass / volume (g / ml) percentage content.
  • the content of a certain auxiliary material refers to the mass / volume (g / ml) percentage content unless otherwise specified.
  • the mass / volume percentage refers to the number of grams of the solute contained in a volume of one hundred milliliters.
  • the relative density of the liquid preparation involved in the present invention is about 1.0. Therefore, in the actual preparation process, it can be calculated as one hundred grams per hundred milliliters. Therefore, the mass / volume (g / ml) percentage can also be approximately the mass / mass (g / g) percentage.
  • the effect of using boric acid and / or borate to adjust the pH value and / or adjust the osmotic pressure is very good, which is superior to other pH adjusting agents and / or osmotic pressure adjusting agents;
  • boric acid and / or borate can enhance the effect of treating and / or preventing NITM
  • Atropine or a pharmaceutically acceptable salt thereof for example, atropine sulfate
  • a pharmaceutical composition containing atropine or a pharmaceutically acceptable salt thereof for example, atropine sulfate
  • a 0.01% atropine sulfate eye drop was prepared in 0.9% physiological saline, and the pH was adjusted to 6.0 with hydrochloric acid. For test group administration.
  • the initial NITM value after administration was reduced by more than or equal to 0.20D compared to the initial NITM at baseline to determine that the case was effective.
  • Effective rate number of effective cases / number of medications ⁇ 100%.
  • the NITM at baseline refers to the NITM value before drug administration, that is, day 0, and the initial NITM at baseline is the difference between the average refractive power of the eye within 10 s after close-up work and the refractive power before close-up work.
  • the measurement method of NITM at baseline is consistent with the measurement method of NITM at each time point after the following administration.
  • NITM measurement Comprehensive optometry (non-ciliary muscle paralysis), according to the optometry results, wear full correction glasses to correct far vision to the best vision, and obtain the equivalent spherical power. Rest for 10 minutes in a completely dark room to relax any adjustments that may be present. Then use an infrared autorefractor (WAM-5500 from Japan Seiko Co., Ltd.), fix the 5m distance vision target with both eyes, measure the distance diopter of the right eye, and record the data. Then began to work at close range. Close-range work uses binocular reading. The reading content is simplified Chinese 12pt font, the reading distance is 35-40cm, and the reading time is 1h.
  • WAM-5500 infrared autorefractor
  • NITM is the difference between the refractive power within 10s after close work and the refractive power before close work (Table 1).
  • NITM decay time It refers to the time it takes for the initial NITM to decrease to zero (the decay time reflects how fast the eye works to return to daily levels after temporary myopia caused by short-term work. Unit: seconds).
  • Diopter diopters nearsightedness, farsightedness, myopia in the present invention
  • lenticular diopters astigmatism
  • equivalent spherical diopter power spherical diopter power + 1/2 cylindrical diopter power.
  • the inventors unexpectedly found that 0.01% atropine has a therapeutic effect on temporary myopia caused by short-distance work in a short period of time, and the initial NITM value and decay time of the control group and the test group after 1 month of administration All had significant differences (one-way analysis of variance).
  • the effective rate of drug administration basically reached a steady state (greater than 80.00%) after 90 days of administration. Starting from 30 days, the effective rate of the experimental group compared with the control group was statistically different ( ⁇ 2 inspection).
  • a 0.9% physiological saline was used to prepare atropine sulfate eye drops at concentrations of 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.1%, and 0.2%, and the pH was adjusted to 5.5 with hydrochloric acid, respectively.
  • test group administration For test group administration.
  • the selected eye diopters ranged from -0.50DS to -5.00DS, astigmatism ⁇ -1.0DC; initial NITM value ⁇ -0.25D; intraocular pressure was normal, not exceeding 21mmHg. Randomly divided into 8 groups, 15 cases in each group.
  • test groups were instilled with 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.1%, 0.2% atropine sulfate eye drops formulated with 0.9% physiological saline, and the control group was administered 0.9% saline; They were administered once a day, one drop per eye each time, and dropped into the conjunctival sac at 9 o'clock the night before bedtime, and the medication was continued for 2 weeks.
  • the NITM test was performed at 7 o'clock on the 0th, 7th, and 14th days, and the measured initial NITM value, NITM decay time, and pupil diameter were recorded.
  • Participants should focus their attention on the text, and keep the text clear, not to be distracted in the middle. After completing short-distance work, the subjects quickly (within 2 s) gazed at the hyperopia target. And measure the long-distance diopter of the right eye wearing full correction glasses.
  • the therapeutic effect is judged by combining the initial NITM value and the NITM decay time, and a statistical difference is effective. Specifically, the initial NITM value is mainly used, and the decay time is supplemented. Differences in initial NITM values are sufficient. One-way analysis of variance was used for statistics. P ⁇ 0.05 was considered statistically significant.
  • a 0.9% sodium chloride solution was used to prepare 0.01% atropine sulfate eye drops, and the pH was adjusted to 4.0, 4.5, 5.0, 5.5, 6.0, and 6.5 with hydrochloric acid, respectively.
  • a total of 105 6-18 year old myopia patients were selected.
  • the selected eye diopters ranged from -0.50DS to -5.00DS, astigmatism ⁇ -1.0DC; initial NITM value ⁇ -0.25D; intraocular pressure was normal, not exceeding 21mmHg.
  • the atropine solution pH 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, respectively
  • the atropine solution prepared in the 6 experimental groups was dropped, and 0.9% physiological saline was dropped in the control group; each group was administered once a day, each time One drop per eye, before dripping into the conjunctival sac, for 2 weeks.
  • NITM tests were performed on days 0, 7, and 14 and the measured initial NITM values and NITM decay time were recorded.
  • Participants should focus their attention on the text, and keep the text clear, not to be distracted in the middle. After completing short-distance work, the subjects quickly (within 2 s) gazed at the hyperopia target. And measure the long-distance diopter of the right eye wearing full correction glasses.
  • Example 4-8 Effect of different prescriptions of atropine sulfate eye drops on NITM (1)
  • Example 4 Example 5
  • Example 6 Example 7
  • Example 8 Atropine sulfate 0.005g 0.010g 0.020g 0.010g 0.020g Hypromellose —— ———— 1.000g 1.000g Sodium dihydrogen phosphate 0.250g 0.250g 0.250g 0.250g 0.250g 0.250g Disodium phosphate 0.0025g 0.0025g 0.0025g 0.0025g 0.0025g 0.0025g Edetate disodium 0.010g 0.010g 0.010g 0.010g 0.010g 0.010g Sodium chloride 0.76g 0.76g 0.76g 0.76g Benzalkonium chloride 0.010g 0.010g 0.010g 0.010g 0.010g Water for injection 100ml 100ml 100ml 100ml 100ml 100ml 100ml 100ml 100ml 100ml
  • the preparation method is as follows:
  • the selected eye diopters ranged from -0.50DS to -5.00DS, astigmatism ⁇ -1.0DC; initial NITM value ⁇ -0.25D; intraocular pressure was normal, not exceeding 21mmHg.
  • Randomly divided into 6 groups 15 cases in each group.
  • Atropine eye drops (prepared in Examples 4 to 8) were dropped in the five test groups, and 0.9% physiological saline was used in the control group. Each group was administered once a day, one drop per eye each time. In the conjunctival sac, medication was continued for 2 weeks.
  • NITM tests were performed on days 0, 7, and 14 and the initial NITM value and decay time were recorded.
  • Example 9-13 Effect of different prescriptions of atropine sulfate eye drops on NITM (2)
  • Example 9 Example 10
  • Example 11 Example 12
  • Example 13 Atropine sulfate 0.010g 0.020g 0.010g 0.020g 0.010g Hypromellose 1.000g 1.000g 1.000g 1.000g Propylene glycol 0.300g 0.300g —— ———— Sodium chloride —— —— 0.135g 0.135g —— Boric acid 1.750g 1.750g 1.750g 2.0g Edetate disodium 0.010g 0.010g 0.010g 0.010g 0.010g 0.010g Benzalkonium chloride 0.010g —— —— 0.010g —— Water for injection 100ml 100ml 100ml 100ml 100ml 100ml 100ml 100ml 100ml 100ml 100ml 100ml 100ml
  • the selected eye diopters ranged from -0.50DS to -5.00DS, astigmatism ⁇ -1.0DC; initial NITM value ⁇ -0.25D; intraocular pressure was normal, not exceeding 21mmHg.
  • Randomly divided into 6 groups 15 cases in each group.
  • Atropine eye drops (prepared in Examples 9-13) were dropped in the five test groups, and 0.9% physiological saline was used in the control group. Each group was administered once a day, one drop per eye each time. In the conjunctival sac, medication was continued for 2 weeks.
  • NITM tests were performed on days 0, 7, and 14. The initial NITM value, decay time, and pupil diameter before the NITM test were recorded.
  • Participants should focus their attention on the text, and keep the text clear, not to be distracted in the middle. After completing short-distance work, the subjects quickly (within 2 s) gazed at the hyperopia target. And measure the long-distance diopter of the right eye wearing full correction glasses.
  • borate buffer salt system can not only improve the treatment effect of NITM, but also have low mydriatic side effects, especially when boric acid is used alone (Example 13).
  • Example 14-18 The effect of different prescriptions of atropine sulfate eye drops on NITM (3)
  • the selected eye diopters ranged from -0.50DS to -5.00DS, astigmatism ⁇ -1.0DC; initial NITM value ⁇ -0.25D; intraocular pressure was normal, not exceeding 21mmHg.
  • Randomly divided into 6 groups 15 cases in each group.
  • Atropine eye drops (prepared in Examples 14-18) were dropped in the five test groups, and 0.9% physiological saline was used in the control group. Each group was administered once a day, one drop per eye each time. In the conjunctival sac, medication was continued for 2 weeks.
  • NITM tests were performed on days 0, 7, and 14 and the initial NITM value and decay time were recorded.
  • Participants should focus their attention on the text, and keep the text clear, not to be distracted in the middle. After completing short-distance work, the subjects quickly (within 2 s) gazed at the hyperopia target. The distance diopter of the right eye wearing full correction glasses was measured again, and the initial NITM was recorded.
  • results show that the pharmaceutical composition of the present invention can effectively treat and / or prevent NITM in patients with myopia.
  • the results also show that the effect of the pharmaceutical composition prepared in Examples 14-17 is close, and the effect of the pharmaceutical composition of Example 18 is relatively poor, so the preferred pH is 6.0 or less.
  • NITM Intraocular pressure
  • the initial NITM value is ⁇ -0.20D; the intraocular pressure is normal and does not exceed 21mmHg.
  • Atropine eye drops (prepared in Examples 14-18) were dropped in the five test groups, and 0.9% physiological saline was used in the control group. Each group was administered once a day, one drop per eye each time. In the conjunctival sac, medication was continued for 2 weeks.
  • NITM tests were performed on days 0, 7, and 14 and the initial NITM value and decay time were recorded.
  • Participants should focus their attention on the text, and keep the text clear, not to be distracted in the middle. After completing short-distance work, the subjects quickly (within 2 s) gazed at the hyperopia target. The distance diopter of the right eye wearing full correction glasses was measured again, and the initial NITM was recorded.
  • results show that the pharmaceutical composition of the present invention can effectively treat and / or prevent NITM in subjects with normal vision.
  • the results also show that the effect of the pharmaceutical composition prepared in Examples 14-17 is close, and the effect of the pharmaceutical composition of Example 18 is relatively poor, so the preferred pH is 6.0 or less.

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Abstract

本发明属于医药领域，涉及一种防治NITM的药物组合物及其医药用途。具体地，所述药物组合物为眼用药物组合物例如眼用制剂。具体地，本发明涉及一种药物组合物，其包含0.001％－0.2％的阿托品或其可药用盐，以及一种或多种药学上可接受的辅料；其中，所述药物组合物的pH值为4.0－6.5；所述药物组合物包含0.5％－5％的pH调节剂，所述pH调节剂选自磷酸二氢钠、磷酸氢二钠、枸橼酸、枸橼酸盐、硼酸和硼酸盐中的任意一种或多种。本发明的药物组合物能够有效地治疗和/或预防NITM，具有良好的应用前景。

Description

防治NITM的药物组合物及其医药用途 技术领域
本发明属于医药领域，涉及一种防治NITM的药物组合物及其医药用途。具体地，所述药物组合物为眼用药物组合物例如眼用制剂。
背景技术
近视是指在不使用调节功能的状态下，远处来的平行光线在视网膜感光层前方聚焦，简言之，眼在休息状态下，平行光线在视网膜前方聚焦。屈光偏离0D多远才算是近视，国际上对此还没有统一的标准。以-0.25D或0.50D为准较为实际(请参见《近视眼学》，胡诞宁等主编，人民卫生出版社，2009年6月第一版，第3页)。
中化医学会眼科学分会眼屈光学组在1985年制订了《真、假性近视定义与分类标准》，将近视分为假性近视、真性近视和半真性近视三大类(请参见《近视眼学》，胡诞宁等主编，人民卫生出版社，2009年6月第一版，第25－26页)。此外还有将近视分为假性近视、真性近视和病理性近视(请参见《近视眼防控与防盲模式蓝皮书2015》，李建军主编，人民卫生出版社，2016年2月第1版，第8－9页)，或者将近视分为假性近视、真性近视和混合性近视(请参见《眼科屈光学》，徐广第主编，军事医学科学出版社，2005年6月第1版，第71-72页；《眼视光学》，王育良、李凯主编，人民军医出版社，2008年8月第1版，第399-401页“近视眼的分类”)。
假性近视又称调节性近视(accommodative myopia)或功能性近视(functional myopia)，指在常态下为近视，使用调节麻痹药(1％阿托品眼药滴眼剂，每日三次，连续三天；或每日一次，连续七天)后近视消失，呈现为正视或远视；在调节麻痹药作用消失后又很快恢复为近视。在我国，假性近视约占5％-10％的青少年近视，主要见于病程在一年以内，屈光度在-1.00D以下的近视。一般认为，假性近视是近视发生、发展的初级阶段(请参见《近视眼学》，胡诞宁等主编，人民卫生出版社，2009年6月第一版，第28页；中华医学会眼科学分会眼屈光学组《真、假性近视定义与分类标准》)。
近距工作诱导的短暂性近视(Nearwork Induced Transient Myopia,NITM)为一段时间近距工作后，由于晶状体不能快速有效地减少自身屈光力而表现出的幅度较小 的、暂时性的远点向眼前移近，是已知涉及交感神经与副交感神经系统相互作用的调节滞后现象，NITM指的是近距工作后屈光度数(等效球镜:球镜+1/2柱镜)的改变，其大小即为近距工作后的屈光度数与近距工作前屈光度数的差值(请参见林仲等，近距工作诱导的短暂性近视的研究现状，中华眼科杂志，2012年7月，第48卷第7期，第657页)。
关于NITM，目前尚未引起足够的重视，也没有相应的有效治疗或预防手段。
发明内容
本发明人经过深入的研究和创造性的劳动，惊奇地发现，低浓度阿托品可有效治疗NITM，且治疗作用呈剂量药效关系(0.001％－0.2％)。本发明人进一步发现，使用硼酸盐体系时治疗效果优于磷酸盐缓冲体系，以多元醇调渗优于使用氯化钠等无机盐，尤其是当体系中仅使用硼酸调节pH值及渗透压时，效果最佳。本发明的药物组合物或眼用制剂中还可以含有常规眼用制剂中使用的增粘剂，优选羟丙基纤维素，药物组合物或眼用制剂中可以含有或不含有抑菌剂。
由此提供了下述发明：
本发明的一个方面涉及一种药物组合物，其包含0.001％－0.2％的阿托品或其可药用盐，以及一种或多种药学上可接受的辅料；
其中，
所述药物组合物的pH值为4.0－6.5；
所述药物组合物包含0.05％－5％的pH调节剂，所述pH调节剂选自磷酸二氢钠、磷酸氢二钠、枸橼酸、枸橼酸盐、硼酸和硼酸盐中的任意一种或多种。
所述pH调节剂可以通过固体形式使用或者添加，也可以缓冲液/缓冲体系(例如磷酸盐缓冲液、枸橼酸盐缓冲液、硼酸盐缓冲液等)的形式使用或添加。
对于pH调节剂，并不排除磷酸二氢钠、磷酸氢二钠、枸橼酸、枸橼酸盐、硼酸和/或硼酸盐还可以具有其它作用或者功效。
在本发明的一个或多个实施方案中，所述的药物组合物，其为眼用制剂，例如眼用液体制剂(如滴眼剂、洗眼剂或眼内注射溶液)、眼用半固体制剂(如眼膏剂、眼用乳膏剂或眼用凝胶剂)或者眼用固体制剂(如眼膜剂、眼丸剂或眼内插入剂)；可 选地，所述眼用液体制剂可以以固态形式包装，另备溶剂，在临用前配成溶液或混悬液。
在本发明的一个或多个实施方案中，所述的药物组合物，其中，所述阿托品或其可药用盐的浓度或含量为0.001％－0.1％，优选为0.005％－0.05％，更优选为0.005％－0.02％，进一步优选为0.005％－0.015％或0.008％－0.012％，例如0.008％、0.009％、0.010％、0.011％或0.012％，特别优选为0.01％；优选地，所述阿托品可药用盐为硫酸阿托品。
在本发明的一个或多个实施方案中，所述的药物组合物，其中，所述药物组合物的pH值为4.0－6.0，优选为4.5－6.0，更优选为4.5－5.5，例如4.5－5.0、5.5－5.5、4.5、4.6、4.7、4.8、4.9、5.0、5.1、5.2、5.3、5.4或5.5。
在本发明的一个或多个实施方案中，所述的药物组合物，其中，
所述pH调节剂的含量为0.5％－5％，更优选为1％－3％，进一步优选为1.5％－2.5％、1.5％－2.0％、1.5％－2.25％或1.75％－2.25％，例如1.5％、1.6％、1.7％、1.75％、1.8％、1.9％、2.0％、2.1％、2.2％、2.25％、2.3％、2.4％或2.5％，特别优选为1.75％－2.0％；
优选地，所述枸橼酸盐为枸橼酸钠，和/或所述硼酸盐为四硼酸钠。
在本发明的一个或多个实施方案中，所述的药物组合物，其中，所述药物组合物包含0.5％－3％、1％－3％、1.5％－2.5％、1.5％－2.25％、1.5％－2.0％、1.75％－2.25％或者1.75％－2％的硼酸，例如1.5％、1.6％、1.7％、1.75％、1.8％、1.9％、2.0％、2.1％、2.2％、2.25％、2.3％、2.4％或2.5％。
在本发明的一个或多个实施方案中，所述的药物组合物，其中，所述药物组合物还包含选自如下的1)至5)项中的任意一项或者多项(例如任意的其中2项、3项、4项或者5项)：
1)增稠剂，并且所述增稠剂选自羟丙甲纤维素、羧甲基纤维素钠和玻璃酸钠中的一种或多种；优选地，所述增稠剂的含量为0.01％－5％，优选为0.5－3％，更优选为0.5％－1.5％，例如0.5％、0.6％、0.7％、0.8％、0.9％、1.0％、1.1％、1.2％、1.3％、1.4％或1.5％；特别优选为0.8％－1.2％。
2)渗透压调节剂，例如选自甘油、甘露醇、丙二醇、氯化钠、氯化钾中的任意一种或多种；
3)防腐剂，例如选自苯扎氯铵、尼泊金酯类抑菌剂、聚季铵盐中的任意一种或多 种；
4)稳定剂，例如选自依地酸二钠、依地酸钙钠中的任意一种或多种；
5)适量的水。
在本发明的一个或多个实施方案中，所述药物组合物不含防腐剂，和/或不含稳定剂。
在本发明的一个或多个实施方案中，所述的药物组合物，除了活性成分(阿托品和/或其可药用盐，例如硫酸阿托品)和辅料之外，其余为水。
在本发明的一个或多个实施方案中，所述的药物组合物，其中，所述药物组合物的成分和含量选自如下的(1)至(8)组中的任意一组：
(1)
Figure PCTCN2018113969-appb-000001
(2)
Figure PCTCN2018113969-appb-000002
(3)
Figure PCTCN2018113969-appb-000003
(4)
Figure PCTCN2018113969-appb-000004
(5)
Figure PCTCN2018113969-appb-000005
(6)
Figure PCTCN2018113969-appb-000006
(7)
Figure PCTCN2018113969-appb-000007
(8)
Figure PCTCN2018113969-appb-000008
本发明的药物组合物可以采用本领域技术人员知悉的技术手段制备。
本发明的另一方面涉及阿托品或其可药用盐或者含有阿托品或其可药用盐的药物组合物在制备治疗和/或预防NITM(近距离工作诱导的短暂性近视)的药物中的用途；
优选地，所述可药用盐为硫酸阿托品；
优选地，所述药物组合物还包含一种或多种药学上可接受的辅料；
优选地，所述药物组合物为本发明中任一项所述的药物组合物。
在本发明的一个或多个实施方案中，所述的用途，其中，所述药物为眼用制剂，优选为滴眼剂。
在本发明的一个或多个实施方案中，所述的用途，其中，所述滴眼剂每日或隔日给药一次，每次1－2滴；优选地，所述滴眼剂滴于结膜囊内。
在本发明的一个或多个实施方案中，所述的用途，其中，所述滴眼剂的受试者为近距离用眼人员或近视易感人员；
优选地，所述近距离用眼人员为近视患者或者非近视患者；
优选地，所述近视易感人员为6－18岁的人员。
本发明的再一方面涉及一种药盒产品，其包含药物和产品说明书；
其中，所述药物为阿托品或其可药用盐，或者为含有阿托品或其可药用盐的药物组合物；
优选地，所述可药用盐为硫酸阿托品；
优选地，所述药物组合物还包含一种或多种药学上可接受的辅料；
优选地，所述药物组合物为本发明中任一项所述的药物组合物；
优选地，所述药物为眼用制剂，优选为滴眼剂。
在本发明的一个或多个实施方案中，所述的药盒产品，其中，所述产品说明书记载所述滴眼剂每日或隔日给药一次，每次1－2滴；
优选地，所述产品说明书还记载所述滴眼剂滴于结膜囊内。
在本发明的一个或多个实施方案中，所述的药盒产品，其中，所述产品说明书记载所述滴眼剂的受试者为近视患者或者非近视患者；
优选地，所述产品说明书记载所述滴眼剂的受试者为近距离用眼人员；
优选地，所述产品说明书记载所述滴眼剂的受试者为近距离用眼的近视患者或者非近视患者；
优选地，所述产品说明书记载所述滴眼剂的受试者为近视易感人员；
优选地，所述产品说明书记载所述滴眼剂的受试者为6－18岁的人员，例如6－18岁的近视患者或者6－18岁的非近视患者。
本发明的再一方面涉及阿托品或其可药用盐，或者含有阿托品或其可药用盐的药物组合物，其用于治疗和/或预防NITM(近距离工作诱导的短暂性近视)；
优选地，所述可药用盐为硫酸阿托品；
优选地，所述药物组合物还包含一种或多种药学上可接受的辅料；
优选地，所述药物组合物为本发明中任一项所述的药物组合物。
在本发明的一个或多个实施方案中，所述药物组合物为眼用制剂，优选为滴眼剂。
在本发明的一个或多个实施方案中，所述阿托品或其可药用盐，或者所述的含有阿托品或其可药用盐的药物组合物，其中，所述滴眼剂每日或隔日给药一次，每次1－2滴；优选地，所述滴眼剂滴于结膜囊内。
在本发明的一个或多个实施方案中，所述阿托品或其可药用盐，或者所述的含有阿托品或其可药用盐的药物组合物，其中，所述滴眼剂的受试者为近距离用眼人员或近视易感人员；
优选地，所述近距离用眼人员为近视患者或者非近视患者；
优选地，所述近视易感人员为6－18岁的人员。
本发明的再一方面涉及一种治疗和/或预防NITM的方法，包括给予有需求的受试者以有效量的药物的步骤，其中，所述药物为阿托品或其可药用盐，或者为含有阿托品或其可药用盐的药物组合物；
优选地，所述可药用盐为硫酸阿托品；
优选地，所述药物组合物还包含一种或多种药学上可接受的辅料；
优选地，所述药物组合物为本发明中任一项所述的药物组合物；
优选地，所述药物组合物为眼用制剂，优选为滴眼剂。
在本发明的一个或多个实施方案中，所述的治疗和/或预防NITM的方法，其中，所 述滴眼剂每日或隔日给药一次，每次1－2滴；优选睡前给药；
优选地，所述滴眼剂滴于结膜囊内。
在本发明的一个或多个实施方案中，所述的治疗和/或预防NITM的方法，其中，所述滴眼剂的受试者为近视患者或者非近视患者；
优选地，所述滴眼剂的受试者为近距离用眼人员；
优选地，所述滴眼剂的受试者为近距离用眼的近视患者或者非近视患者；
优选地，所述滴眼剂的受试者为近视易感人员，例如6－18岁的人员；
优选地，所述近视易感人员为近视患者或者非近视患者。
实际使用的给药剂量和给药周期可以根据受试者自身的身体状况或者遵照医嘱确定，通常情况下，可以短期或长期给药，例如1个月、2个月、3个月、4个月、5个月、6个月、1年、1.5年、2年、2.5年、3年或3年以上。
下面对本发明涉及的部分术语进行解释：
阿托品的结构式如下面的式I所示：
Figure PCTCN2018113969-appb-000009
硫酸阿托品的结构如下面的式II所示：
Figure PCTCN2018113969-appb-000010
本发明中，术语“近距离用眼人员”是指眼睛与注视目标距离较近，并且在一段时间内保持持续注视的人。狭义上：术语“近距离用眼人员”，其中“近距离”或“距离较近”是指眼睛与注视目标的直线距离为10cm－50cm；“一段时间”是指至少30分钟、至少45分钟、至少1小时、至少1.5小时、至少2小时、至少2.5小时、至少3小时、至少4小时或4小时以上。其中，“持续注视”是指不间断地注视；在个别情况下，可以允许1次、2次或3次的间断，但每次间断时间不超过5秒钟，优选不超过3秒钟或不超过2秒钟。广义上，近距离用眼人员包括但不限于中小学生、办公室白领、从事电子游戏或视频的人员，等等；注视目标包括但不限于，电子显示装置(手机显示屏、电脑显示屏、电子阅读器等)、书籍、试卷，等等。所述近距离用眼人员包括近视患者和非近视患者。
本发明中，术语“近视易感人员”包括容易患近视但是尚未患近视的人员，或者已经患近视而且容易进一步加重近视程度的人员。一般而言，6－18岁的人员(儿童、青少年)，由于眼睛和视神经系统尚未完全发育成熟，或者由于学习压力较大，或者接触电子游戏或视频较频繁，属于近视易感人员。所述近视易感人员包括近视患者和非近视患者，优选为6－18岁的近视患者或非近视患者。
本发明中，所述阿托品或其可药用盐(例如硫酸阿托品)的浓度，如果没有特别说明，是指质量体积百分比浓度本发明中，所述阿托品或其可药用盐(例如硫酸阿托品)的含量，如果没有特别说明，是指质量/体积(g/ml)百分比含量。
本发明中，所述某种辅料(如硼酸)的含量，如果没有特别说明，是指质量/体积(g/ml)百分比含量。
质量/体积百分比是指每百毫升体积中含有的溶质克数，本发明中涉及的液体制剂相对密度约为1.0，因此在实际配制过程中，可按每百毫升百克计算。因此，质量/体积(g/ml)百分比也可以近似地为质量/质量(g/g)百分比。
发明的有益效果
本发明取得了如下技术效果中的一项或多项：
(1)对于本发明的药物组合物，使用硼酸和/或硼酸盐调节pH值和/或调节渗透压的效果非常好，优于其它的pH调节剂和/或渗透压调节剂；
(2)使用硼酸和/或硼酸盐能够增强治疗和/或预防NITM的效果；
(3)使用硼酸和/或硼酸盐能够一定程度上降低阿托品的散瞳副作用；
(4)阿托品或其可药用盐(例如硫酸阿托品)，或者含有阿托品或其可药用盐(例如硫酸阿托品)的药物组合物，能够有效地治疗和/或预防NITM。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1：NITM治疗实验
1.实验药品
0.9％生理盐水配制0.01％硫酸阿托品滴眼剂，用盐酸调pH值至6.0。用于试验组给药。
2.实验方法
选取30名6－18岁的近视眼患者。入选眼屈光度在-0.50DS～-5.00DS，散光≤-1.0DC；初始NITM值≥-0.25D；眼压正常，不超过21mmHg。随机分为2组，每组15例。试验组滴用前述实验药品，对照组滴用0.9％生理盐水；各组均每天给药1次，每次每眼1滴，睡前滴于结膜囊内，连续用药6个月。在设定时间进行NITM检测，记录初始NITM值、NITM衰减时间和矫正到最佳视力所佩戴眼镜的等效球镜度数，以 初始NITM值降低超过或等于0.20D为有效，可用于计算药物的有效率。
按给药后初始NITM值与基线时初始NITM相比降低超过或等于0.20D，判定该病例用药有效。
有效率＝有效病例数/用药人数×100％。
其中，基线时NITM是指给药前，即0天NITM值，基线时初始NITM即为给药前0天近距工作后10s内眼屈光度的平均值与近距工作前的屈光度的差值。基线时NITM的测量方法与下面给药后各时间点NITM测量方法一致。
NITM测量：综合验光仪验光(非睫状肌麻痹)，根据验光结果，配戴全矫框架眼镜使远视力矫正到最佳视力，得到等效球镜度数。在完全的暗室中休息10分钟，以放松可能存在的调节。然后使用红外自动验光仪(日本贵精工WAM-5500)，双眼注视5m远视标，测量右眼远距屈光度数，记录数据。然后开始近距工作，近距工作采用双眼阅读，阅读内容为简体中文12pt字体，阅读距离为35－40cm，阅读时间1h。受试者均要注意力集中地注视着文字，且保持文字清晰，中途不可分散注意力。在完成近距工作后，受试者迅速(2s内)注视远视标。并再次测量右眼戴全矫框架眼镜的远距屈光度，记录为初始NITM，初始NITM是近距离工作后10s内的屈光度数与近距离工作前屈光度数的差值(表1)，NITM衰减时间指的是初始NITM减少至零所用时间(衰减时间反映了眼睛近距工作引起暂时性近视后回复到日常水平的快慢。单位：秒)。
3.实验结果
如下面的表1－表4所示。
表1：0.01％硫酸阿托品滴眼剂
不同时间点对眼初始NITM值的影响(
Figure PCTCN2018113969-appb-000011
n＝15)
Figure PCTCN2018113969-appb-000012
表2：0.01％硫酸阿托品滴眼剂
不同时间点对眼NITM衰减时间的影响(
Figure PCTCN2018113969-appb-000013
n＝15)
Figure PCTCN2018113969-appb-000014
Figure PCTCN2018113969-appb-000015
表3：0.01％硫酸阿托品滴眼剂
不同时间点对眼NITM的有效率(
Figure PCTCN2018113969-appb-000016
n＝15)
Figure PCTCN2018113969-appb-000017
表4：0.01％硫酸阿托品滴眼剂
不同时间点对眼等效球镜度数的影响(
Figure PCTCN2018113969-appb-000018
n＝15)
Figure PCTCN2018113969-appb-000019
注：屈光度分球镜屈光度(近视、远视，本发明中指近视)和柱镜屈光度(散光)；等效球镜度数＝球镜屈光度+1/2柱镜屈光度。
由表1至表4数据可以看出，持续给药6个月后，对照组近视进展为-0.36±0.13D，试验组近视进展为-0.07±0.15D。即对近视度数增长具有一定的控制作用，然而由于给药周期较短，对照组与受试组数据无统计学差异。这与近年来低浓度阿托品控制近视进展的研究结果潜在地一致：新加坡ATOM1安慰剂组2年内近视进展率为-1.20±0.69D，ATOM2试验中0.01％阿托品组2年时近视进展为-0.49±0.63D；即低浓度阿托品长期给药可控制近视的发展。
然而在本研究中，本发明人意外地发现，0.01％阿托品在短时间内对近距离工作导 致的暂时性近视具有治疗作用，给药1个月后对照组和试验组初始NITM值和衰减时间均具有显著性差异(单因素方差分析)，用药有效率在给药90天后基本达到稳态(大于80.00％)，从30天开始，试验组与对照组相比有效率由统计学差异(χ 2检验)。
实施例2：不同浓度的硫酸阿托品滴眼剂治疗NITM的效果和副作用研究
1.实验药品
使用0.9％生理盐水，分别配制浓度为0.001％、0.005％、0.01％、0.02％、0.05％、0.1％、0.2％的硫酸阿托品滴眼剂，并分别用盐酸调pH值至5.5。用于试验组给药。
2.实验方法
选取120名6－18岁的近视眼患者。入选眼屈光度在-0.50DS～-5.00DS，散光≤-1.0DC；初始NITM值≥-0.25D；眼压正常，不超过21mmHg。随机分为8组，每组15例。7个试验组分别滴用0.9％生理盐水配制的0.001％、0.005％、0.01％、0.02％、0.05％、0.1％、0.2％硫酸阿托品滴眼剂，对照组滴用0.9％生理盐水；各组均每天给药1次，每次每眼1滴，睡前晚9点滴于结膜囊内，连续用药2周。在第0天、7天、14天早7点进行NITM检测，记录测得的初始NITM值、NITM衰减时间和瞳孔直径。
综合验光仪验光(非睫状肌麻痹)，并测量瞳孔直径，根据验光结果，配戴全矫框架眼镜使远视力矫正到最佳视力，得到等效球镜度数。在完全的暗室中休息10分钟，以放松可能存在的调节。然后使用红外自动验光仪(日本贵精工WAM-5500)，双眼注视5m远视标，测量右眼远距屈光度数，记录数据。然后开始近距工作，近距工作采用双眼阅读，阅读内容为简体中文12pt字体，阅读距离为35－40cm，阅读时间1h。受试者均要注意力集中地注视着文字，且保持文字清晰，中途不可分散注意力。在完成近距工作后，受试者迅速(2s内)注视远视标。并再次测量右眼戴全矫框架眼镜的远距屈光度。
3.实验结果
如下面的表5－表7所示。
表5：不同浓度硫酸阿托品滴眼剂
对眼初始NITM值的影响(
Figure PCTCN2018113969-appb-000020
n＝15)
Figure PCTCN2018113969-appb-000021
Figure PCTCN2018113969-appb-000022
表6：不同浓度硫酸阿托品滴眼剂
对眼NITM衰减时间的影响(
Figure PCTCN2018113969-appb-000023
n＝15)
Figure PCTCN2018113969-appb-000024
表7：不同浓度硫酸阿托品滴眼剂
对眼瞳孔直径的影响(
Figure PCTCN2018113969-appb-000025
n＝15)
Figure PCTCN2018113969-appb-000026
Figure PCTCN2018113969-appb-000027
治疗作用通过初始NITM值和NITM衰减时间结合判断，具有统计差异即为有效。具体地，以初始NITM值为主，衰减时间为辅。初始NITM值有差异即可。统计采用单因素方差分析，以P＜0.05为有统计学差异。
由表5、表6、表7中数据可见，低浓度阿托品对NITM具有治疗作用，且成剂量-效应关系；当剂量增加至0.02％时治疗效果增强的幅度降低，滴眼14天后瞳孔直径逐渐呈现出显著性差异。
实施例3：不同pH值的硫酸阿托品滴眼剂治疗NITM的效果研究
1.实验药品
分别采用0.9％氯化钠溶液配制0.01％硫酸阿托品滴眼剂，分别用盐酸调pH值至4.0、4.5、5.0、5.5、6.0、6.5。用于试验组给药。
2.实验方法
选取105名6－18岁的近视眼患者。入选眼屈光度在-0.50DS～-5.00DS，散光≤-1.0DC；初始NITM值≥-0.25D；眼压正常，不超过21mmHg。随机分为7组，每组15例。6个试验组分别滴用前面配制的阿托品溶液(pH值分别为4.0、4.5、5.0、5.5、6.0、6.5)，对照组滴用0.9％生理盐水；各组均每天给药1次，每次每眼1滴，睡前滴于结膜囊内，连续用药2周。在第0天、7天、14天进行NITM检测，记录测得的初始NITM值及NITM衰减时间。
综合验光仪验光(非睫状肌麻痹)，根据验光结果，配戴全矫框架眼镜使远视力矫正到最佳视力，得到等效球镜度数。在完全的暗室中休息10分钟，以放松可能存在的调节。然后使用红外自动验光仪(日本贵精工WAM-5500)，双眼注视5m远视标，测量右眼远距屈光度数，记录数据。然后开始近距工作，近距工作采用双眼阅读，阅读内容为简体中文12pt字体，阅读距离为35－40cm，阅读时间1h。受试者均要注意力集中地注视着文字，且保持文字清晰，中途不可分散注意力。在完成近距工作后， 受试者迅速(2s内)注视远视标。并再次测量右眼戴全矫框架眼镜的远距屈光度。
3.实验结果
如下面的表8－表9所示。
表8：不同pH硫酸阿托品滴眼剂
对眼初始NITM值的影响(
Figure PCTCN2018113969-appb-000028
n＝15)
Figure PCTCN2018113969-appb-000029
表9：不同pH硫酸阿托品滴眼剂
对眼NITM衰减时间的影响(
Figure PCTCN2018113969-appb-000030
n＝15)
Figure PCTCN2018113969-appb-000031
由表8、表9数据可以看出，pH值对阿托品治疗NITM的效果有影响，在pH值4.5－5.5范围内，治疗效果最优，pH提高至6.0及以上时，疗效有所下降，提示治疗NITM的阿托品滴眼剂pH值范围最优先4.5－5.5。
实施例4－8：不同处方的硫酸阿托品滴眼剂治疗NITM的效果研究(1)
1.实验药品及其制备方法
表A：实验药品处方组成
组份 实施例4 实施例5 实施例6 实施例7 实施例8
硫酸阿托品 0.005g 0.010g 0.020g 0.010g 0.020g
羟丙甲纤维素 —— —— —— 1.000g 1.000g
磷酸二氢钠 0.250g 0.250g 0.250g 0.250g 0.250g
磷酸氢二钠 0.0025g 0.0025g 0.0025g 0.0025g 0.0025g
依地酸二钠 0.010g 0.010g 0.010g 0.010g 0.010g
氯化钠 0.76g 0.76g 0.76g 0.76g 0.76g
苯扎氯铵 0.010g 0.010g 0.010g 0.010g 0.010g
注射用水加至 100ml 100ml 100ml 100ml 100ml
制备方法如下：
(1)取10g的80℃－90℃的注射用水，加入处方量的羟丙基甲基纤维素(如果有的话)，补30℃以下注射用水至20g，搅拌溶解至透明溶液，备用；
(2)取50g的65℃－75℃注射用水，依次溶解处方量的一水磷酸二氢钠、磷酸氢二钠、氯化钠、依地酸二钠和苯扎氯铵，放至30℃以下，加入处方量的硫酸阿托品，搅拌溶解；
(3)将(1)所得的羟丙基甲基纤维素溶液与(2)所得的溶液混合均匀；
(4)补水至全量100g，搅拌均匀，0.22μm滤膜过滤除菌，灌装。
用于试验组给药。
2.实验方法
选取90名6－18岁的近视眼患者。入选眼屈光度在-0.50DS～-5.00DS，散光≤-1.0DC；初始NITM值≥-0.25D；眼压正常，不超过21mmHg。随机分为6组，每组15例。5个试验组分别滴用阿托品滴眼剂(实施例4－8制得)，对照组滴用0.9％生理盐水；各组均每天给药1次，每次每眼1滴，睡前滴于结膜囊内，连续用药2周。在第0天、7天、14天进行NITM检测，记录初始NITM值及衰减时间。
综合验光仪验光(非睫状肌麻痹)，根据验光结果，配戴全矫框架眼镜使远视力 矫正到最佳视力，得到等效球镜度数。在完全的暗室中休息10分钟，以放松可能存在的调节。然后使用红外自动验光仪(日本贵精工WAM-5500)，双眼注视5m远视标，测量右眼远距屈光度数，记录数据。然后开始近距工作，近距工作采用双眼阅读，阅读内容为简体中文12pt字体，阅读距离为35－40cm，阅读时间1h。受试者均要注意力集中地注视着文字，且保持文字清晰，中途不可分散注意力。在完成近距工作后，受试者迅速(2s内)注视远视标。并再次测量右眼戴全矫框架眼镜的远距屈光度，记录初始NITM。
3.实验结果
如下面的表10－表11所示。
表10：不同处方硫酸阿托品滴眼剂
对眼初始NITM值的影响(
Figure PCTCN2018113969-appb-000032
n＝15)
Figure PCTCN2018113969-appb-000033
表11：不同处方硫酸阿托品滴眼剂
对眼NITM衰减时间的影响(
Figure PCTCN2018113969-appb-000034
n＝15)
Figure PCTCN2018113969-appb-000035
Figure PCTCN2018113969-appb-000036
由表10、表11数据可以看出，将阿托品制成滴眼剂后，从0.005％到0.02％浓度，阿托品滴眼剂治疗NITM呈剂量-效应关系。处方中加入羟丙甲纤维素后，治疗效果有增强趋势，由其是在高浓度制剂中，趋势更明显；但相比于治疗浓度的改变，其增强作用较弱。然而仍提示，在相同的硫酸阿托品浓度下，制剂中优选加入羟丙甲纤维素。
实施例9－13：不同处方的硫酸阿托品滴眼剂治疗NITM的效果研究(2)
1.实验药品及其制备方法
表B：实验药品处方组成
组份 实施例9 实施例10 实施例11 实施例12 实施例13
硫酸阿托品 0.010g 0.020g 0.010g 0.020g 0.010g
羟丙甲纤维素 1.000g 1.000g 1.000g 1.000g 1.000g
丙二醇 0.300g 0.300g —— —— ——
氯化钠 —— —— 0.135g 0.135g ——
硼酸 1.750g 1.750g 1.750g 1.750g 2.0g
依地酸二钠 0.010g 0.010g 0.010g 0.010g 0.010g
苯扎氯铵 0.010g —— —— 0.010g ——
注射用水加至 100ml 100ml 100ml 100ml 100ml
制备方法：
(1)取10g的80℃－90℃的注射用水，加入处方量的羟丙基甲基纤维素充分分散溶胀，补30℃以下注射用水至20g，搅拌溶解至透明溶液，备用；
(2)取50g的65℃－75℃注射用水，依次溶解处方量的硼酸、丙二醇或氯化钠(如果有的话)、依地酸二钠和苯扎氯铵，放至30℃以下，加入处方量的硫酸阿托品，搅拌溶解；
(3)将(1)所得的羟丙基甲基纤维素溶液与(2)所得的溶液混合均匀；
(4)向(3)所得的混合溶液中，补水至全量100g，搅拌均匀，0.22μm滤膜过滤除菌，灌装。
用于试验组给药。
2.实验方法
选取90名6－18岁的近视眼患者。入选眼屈光度在-0.50DS～-5.00DS，散光≤-1.0DC；初始NITM值≥-0.25D；眼压正常，不超过21mmHg。随机分为6组，每组15例。5个试验组分别滴用阿托品滴眼剂(实施例9－13制得)，对照组滴用0.9％生理盐水；各组均每天给药1次，每次每眼1滴，睡前滴于结膜囊内，连续用药2周。在第0天、7天、14天进行NITM检测，记录初始NITM值、衰减时间及NITM测试前瞳孔直径。
综合验光仪验光(非睫状肌麻痹)并测量瞳孔直径，根据验光结果，配戴全矫框架眼镜使远视力矫正到最佳视力，得到等效球镜度数。在完全的暗室中休息10分钟，以放松可能存在的调节。然后使用红外自动验光仪(日本贵精工WAM-5500)，双眼注视5m远视标，测量右眼远距屈光度数，记录数据。然后开始近距工作，近距工作采用双眼阅读，阅读内容为简体中文12pt字体，阅读距离为35－40cm，阅读时间1h。受试者均要注意力集中地注视着文字，且保持文字清晰，中途不可分散注意力。在完成近距工作后，受试者迅速(2s内)注视远视标。并再次测量右眼戴全矫框架眼镜的远距屈光度。
3.实验结果
如下面的表12－表14所示。
表12：不同处方硫酸阿托品滴眼剂
对眼初始NITM值的影响(
Figure PCTCN2018113969-appb-000037
n＝15)
Figure PCTCN2018113969-appb-000038
表13：不同处方硫酸阿托品滴眼剂
对眼NITM衰减时间的影响(
Figure PCTCN2018113969-appb-000039
n＝15)
Figure PCTCN2018113969-appb-000040
表14：不同处方硫酸阿托品滴眼剂
对眼瞳孔直径的影响(
Figure PCTCN2018113969-appb-000041
n＝15)
Figure PCTCN2018113969-appb-000042
表12、表13中数据对比可以看出，当使用硼酸为缓冲体系时，阿托品滴眼剂对NITM的治疗效果优于磷酸盐缓冲体系，当使用多元醇为渗透压调节剂时，治疗效果略优于无机盐渗透压调节剂，然而本发明人意外的发现，当仅使用硼酸作为pH调节剂且同时调整渗透压时，获得了更佳的治疗效果。
表14中数据可以看出，硼酸缓冲盐体系不仅可以提高NITM的治疗效果，且散瞳副作用低，尤其是单一使用硼酸时(实施例13)散瞳作用最弱。
实施例14－18：不同处方的硫酸阿托品滴眼剂治疗NITM的效果研究(3)
1.实验药品及其制备方法
表C：实验药品处方组成
Figure PCTCN2018113969-appb-000043
制备方法：
(1)取10g的80℃－90℃的注射用水，加入处方量的羟丙基甲基纤维素或玻璃酸钠(如果有的话)充分分散溶胀，补30℃以下注射用水至20g，搅拌溶解至透明溶液，备用；
(2)取50g的65℃－75℃注射用水，依次溶解处方量的硼酸、依地酸二钠和苯扎氯铵(如果有的话)，放至30℃以下，加入处方量的硫酸阿托品，搅拌溶解；
(3)将(1)所得的溶液与(2)所得的溶液混合均匀；
(4)向(3)所得的混合溶液中，补水至全量100g，搅拌均匀，0.22μm滤膜过滤除菌，灌装。
用于试验组给药。
2.实验方法
选取90名6－18岁的近视眼患者。入选眼屈光度在-0.50DS～-5.00DS，散光≤-1.0DC；初始NITM值≥-0.25D；眼压正常，不超过21mmHg。随机分为6组，每组15例。5个试验组分别滴用阿托品滴眼剂(实施例14－18制得)，对照组滴用0.9％生理盐水；各组均每天给药1次，每次每眼1滴，睡前滴于结膜囊内，连续用药2周。在第0天、7天、14天进行NITM检测，记录初始NITM值及衰减时间。
综合验光仪验光(非睫状肌麻痹)并测量瞳孔直径，根据验光结果，配戴全矫框架眼镜使远视力矫正到最佳视力，得到等效球镜度数。在完全的暗室中休息10分钟， 以放松可能存在的调节。然后使用红外自动验光仪(日本贵精工WAM-5500)，双眼注视5m远视标，测量右眼远距屈光度数，记录数据。然后开始近距工作，近距工作采用双眼阅读，阅读内容为简体中文12pt字体，阅读距离为35－40cm，阅读时间1h。受试者均要注意力集中地注视着文字，且保持文字清晰，中途不可分散注意力。在完成近距工作后，受试者迅速(2s内)注视远视标。并再次测量右眼戴全矫框架眼镜的远距屈光度，记录初始NITM。
3.实验结果
如下面的表15－表16所示。
表15：不同处方硫酸阿托品滴眼剂
对眼初始NITM值的影响(
Figure PCTCN2018113969-appb-000044
n＝15)
Figure PCTCN2018113969-appb-000045
表16：不同处方硫酸阿托品滴眼剂
对眼NITM衰减时间的影响(
Figure PCTCN2018113969-appb-000046
n＝15)
Figure PCTCN2018113969-appb-000047
结果显示，本发明的药物组合物能够有效地治疗和/或预防近视患者的NITM。另外，结果还显示，实施例14－17制得的药物组合物的效果接近，实施例18的药物组合物的效果相对差一些，故优选的pH为6.0以下。
实施例19－23：不同处方的硫酸阿托品滴眼剂治疗NITM的效果研究(4)
1.实验药品及其制备方法
实施例19－23使用的实验药品分别与前面实施例14－18使用的实验药品完全相同。
用于试验组给药。
2.实验方法
选取90名6－18岁正常视力人员。初始NITM值≥-0.20D；眼压正常，不超过21mmHg。随机分为6组，每组15例。5个试验组分别滴用阿托品滴眼剂(实施例14－18制得)，对照组滴用0.9％生理盐水；各组均每天给药1次，每次每眼1滴，睡前滴于结膜囊内，连续用药2周。在第0天、7天、14天进行NITM检测，记录初始NITM值及衰减时间。
综合验光仪验光(非睫状肌麻痹)并测量瞳孔直径，根据验光结果，配戴全矫框架眼镜使远视力矫正到最佳视力，得到等效球镜度数。在完全的暗室中休息10分钟，以放松可能存在的调节。然后使用红外自动验光仪(日本贵精工WAM-5500)，双眼注视5m远视标，测量右眼远距屈光度数，记录数据。然后开始近距工作，近距工作采用双眼阅读，阅读内容为简体中文12pt字体，阅读距离为35－40cm，阅读时间1h。受试者均要注意力集中地注视着文字，且保持文字清晰，中途不可分散注意力。在完成近距工作后，受试者迅速(2s内)注视远视标。并再次测量右眼戴全矫框架眼镜的远距屈光度，记录初始NITM。
3.实验结果
如下面的表17－表18所示。
表17：不同处方硫酸阿托品滴眼剂
对正视眼初始NITM值的影响(
Figure PCTCN2018113969-appb-000048
n＝15)
Figure PCTCN2018113969-appb-000049
Figure PCTCN2018113969-appb-000050
表18：不同处方硫酸阿托品滴眼剂
对正视眼NITM衰减时间的影响(
Figure PCTCN2018113969-appb-000051
n＝15)
Figure PCTCN2018113969-appb-000052
结果显示，本发明的药物组合物能够有效地治疗和/或预防正常视力的受试者的NITM。另外，结果还显示，实施例14－17制得的药物组合物的效果接近，实施例18的药物组合物的效果相对差一些，故优选的pH为6.0以下。
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解。根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (23)

  1. 一种药物组合物，其包含0.001％－0.2％的阿托品或其可药用盐，以及一种或多种药学上可接受的辅料；
    其中，
    所述药物组合物的pH值为4.0－6.5；
    所述药物组合物包含0.05％－5％的pH调节剂，所述pH调节剂选自磷酸二氢钠、磷酸氢二钠、枸橼酸、枸橼酸盐、硼酸和硼酸盐中的一种或多种。
  2. 根据权利要求1所述的药物组合物，其为眼用制剂，例如眼用液体制剂(如滴眼剂、洗眼剂或眼内注射溶液)、眼用半固体制剂(如眼膏剂、眼用乳膏剂或眼用凝胶剂)或者眼用固体制剂(如眼膜剂、眼丸剂或眼内插入剂)；可选地，所述眼用液体制剂可以以固态形式包装，另备溶剂，在临用前配成溶液或混悬液。
  3. 根据权利要求2所述的药物组合物，其中，所述阿托品或其可药用盐的浓度或含量为0.001％－0.1％，优选为0.005％－0.05％，更优选为0.005％－0.02％，进一步优选为0.005％－0.015％，特别优选为0.01％；优选地，所述阿托品可药用盐为硫酸阿托品。
  4. 根据权利要求1至3中任一权利要求所述的药物组合物，其中，所述药物组合物的pH值为4.0－6.0，优选为4.5－6.0，更优选为4.5－5.5。
  5. 根据权利要求1至3中任一权利要求所述的药物组合物，其中，
    所述pH调节剂的含量为0.5％－5％，更优选为1％－3％，进一步优选为1.5％－2.5％，特别优选为1.75％－2.0％；
    优选地，所述枸橼酸盐为枸橼酸钠，和/或所述硼酸盐为四硼酸钠。
  6. 根据权利要求1至3中任一权利要求所述的药物组合物，其中，所述药物组合物包含0.5％－3％、1％－3％、1.5％－2.5％、1.75％－2.25％或者1.75％－2％的硼酸。
  7. 根据权利要求1至3中任一权利要求所述的药物组合物，其中，所述药物组合物还包含选自如下的1)至5)项中的任意一项或者多项：
    1)增稠剂，并且所述增稠剂选自羟丙甲纤维素、羧甲基纤维素钠和玻璃酸钠中的一种或多种；优选地，所述增稠剂的含量为0.01％－5％，优选为0.5－3％，更优选为0.5％－1.5％，特别优选为0.8％－1.2％。
    2)渗透压调节剂，例如选自甘油、甘露醇、丙二醇、氯化钠、氯化钾中的任意一种或多种；
    3)防腐剂，例如选自苯扎氯铵、尼泊金酯类抑菌剂、聚季铵盐中的任意一种或多种；
    4)稳定剂，例如选自依地酸二钠、依地酸钙钠中的任意一种或多种；
    5)适量的水。
  8. 根据权利要求1至3中任一权利要求所述的药物组合物，其中，所述药物组合物的成分和含量选自如下的(1)至(8)组中的任意一组：
    (1)
    Figure PCTCN2018113969-appb-100001
    (2)
    Figure PCTCN2018113969-appb-100002
    Figure PCTCN2018113969-appb-100003
    (3)
    Figure PCTCN2018113969-appb-100004
    (4)
    Figure PCTCN2018113969-appb-100005
    (5)
    Figure PCTCN2018113969-appb-100006
    Figure PCTCN2018113969-appb-100007
    (6)
    Figure PCTCN2018113969-appb-100008
    (7)
    Figure PCTCN2018113969-appb-100009
    (8)
    Figure PCTCN2018113969-appb-100010
    Figure PCTCN2018113969-appb-100011
  9. 阿托品或其可药用盐或者含有阿托品或其可药用盐的药物组合物在制备治疗和/或预防NITM的药物中的用途；
    优选地，所述可药用盐为硫酸阿托品；
    优选地，所述药物组合物还包含一种或多种药学上可接受的辅料；
    优选地，所述药物组合物为权利要求1至8中任一权利要求所述的药物组合物。
  10. 根据权利要求9所述的用途，其中，所述药物为眼用制剂，优选为滴眼剂。
  11. 根据权利要求10所述的用途，其中，所述滴眼剂每日或隔日给药一次，每次1－2滴；优选地，所述滴眼剂滴于结膜囊内。
  12. 根据权利要求10或11所述的用途，其中，所述滴眼剂的受试者为近距离用眼人员或近视易感人员；
    优选地，所述近距离用眼人员为近视患者或者非近视患者；
    优选地，所述近视易感人员为6－18岁的人员；
    优选地，所述近视易感人员为近视患者或者非近视患者。
  13. 一种药盒产品，其包含药物和产品说明书；
    其中，所述药物为阿托品或其可药用盐，或者为含有阿托品或其可药用盐的药物组合物；
    优选地，所述可药用盐为硫酸阿托品；
    优选地，所述药物组合物还包含一种或多种药学上可接受的辅料；
    优选地，所述药物组合物为权利要求1至8中任一权利要求所述的药物组合物；
    优选地，所述药物为眼用制剂，优选为滴眼剂。
  14. 根据权利要求11所述的药盒产品，其中，所述产品说明书记载所述滴眼剂每日或隔日给药一次，每次1－2滴；
    优选地，所述产品说明书还记载所述滴眼剂滴于结膜囊内。
  15. 根据权利要求13或14所述的药盒产品，其中，所述产品说明书记载所述滴眼剂的受试者为近视患者或者非近视患者；
    优选地，所述产品说明书记载所述滴眼剂的受试者为近距离用眼人员；
    优选地，所述产品说明书记载所述滴眼剂的受试者为近距离用眼的近视患者或者非近视患者；
    优选地，所述产品说明书记载所述滴眼剂的受试者为近视易感人员；
    优选地，所述产品说明书记载所述滴眼剂的受试者为6－18岁的人员，例如6－18岁的近视患者或者6－18岁的非近视患者。
  16. 阿托品或其可药用盐，或者含有阿托品或其可药用盐的药物组合物，其用于治疗和/或预防NITM；
    优选地，所述可药用盐为硫酸阿托品；
    优选地，所述药物组合物还包含一种或多种药学上可接受的辅料；
    优选地，所述药物组合物为权利要求1至8中任一权利要求所述的药物组合物。
  17. 根据权利要求16所述的阿托品或其可药用盐，或者含有阿托品或其可药用盐的药物组合物，其中，所述药物组合物为眼用制剂，优选为滴眼剂。
  18. 根据权利要求17所述的阿托品或其可药用盐，或者含有阿托品或其可药用盐的药物组合物，其中，所述滴眼剂每日或隔日给药一次，每次1－2滴；优选地，所述滴眼剂滴于结膜囊内。
  19. 根据权利要求17或18所述的阿托品或其可药用盐，或者含有阿托品或其可药用盐的药物组合物，其中，所述滴眼剂的受试者为近距离用眼人员或近视易感人员；
    优选地，所述近距离用眼人员为近视患者或者非近视患者；
    优选地，所述近视易感人员为6－18岁的人员。
  20. 一种治疗和/或预防NITM的方法，包括给予有需求的受试者以有效量的药物的步骤，其中，所述药物为阿托品或其可药用盐，或者为含有阿托品或其可药用盐的药物组合物；
    优选地，所述可药用盐为硫酸阿托品；
    优选地，所述药物组合物还包含一种或多种药学上可接受的辅料；
    优选地，所述药物组合物为权利要求1至8中任一权利要求所述的药物组合物。
  21. 根据权利要求20所述的治疗和/或预防NITM的方法，其中，所述药物组合物为眼用制剂，优选为滴眼剂。
  22. 根据权利要求21所述的治疗和/或预防NITM的方法，其中，所述滴眼剂每日或隔日给药一次，每次1－2滴；优选睡前给药；
    优选地，所述滴眼剂滴于结膜囊内。
  23. 根据权利要求21或22所述的治疗和/或预防NITM的方法，其中，所述滴眼剂的受试者为近视患者或者非近视患者；
    优选地，所述滴眼剂的受试者为近距离用眼人员；
    优选地，所述滴眼剂的受试者为近距离用眼的近视患者或者非近视患者；
    优选地，所述滴眼剂的受试者为近视易感人员，例如6－18岁的人员；
    优选地，所述近视易感人员为近视患者或者非近视患者。
PCT/CN2018/113969 2018-09-25 2018-11-05 防治nitm的药物组合物及其医药用途 WO2020062445A1 (zh)

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