CN116270442A - Ophthalmic preparation for correcting near vision - Google Patents

Ophthalmic preparation for correcting near vision Download PDF

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CN116270442A
CN116270442A CN202111571169.9A CN202111571169A CN116270442A CN 116270442 A CN116270442 A CN 116270442A CN 202111571169 A CN202111571169 A CN 202111571169A CN 116270442 A CN116270442 A CN 116270442A
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pharmaceutically acceptable
acceptable salt
ophthalmic
ophthalmic formulation
buffer system
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凌彦博
崔佳敏
景博阳
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Zhejiang Ruitong Biotechnology Co ltd
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    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
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    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides an ophthalmic preparation for correcting near vision, a preparation method and application thereof, which are particularly suitable for treating presbyopia and mild hyperopia. The ophthalmic preparation comprises pilocarpine, brimonidine, a compound containing a statin core group structure, a non-steroidal anti-inflammatory drug, a functional auxiliary material A, a thickening agent, a complexing agent, a pH regulator, a bacteriostatic agent and sodium chloride. Experimental results show that the compound containing the statin core group structure added into the ophthalmic preparation provided by the invention has a synergistic effect with pilocarpine and brimonidine. In addition, the addition of the functional auxiliary material A to the ophthalmic preparation reduces the irritation of the preparation and improves the compliance of patients. Compared with similar medicines commonly used in clinic, the ophthalmic preparation provided by the invention has the characteristics of higher curative effect and lower eye irritation.

Description

Ophthalmic preparation for correcting near vision
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an ophthalmic preparation for improving, relieving and correcting near vision (especially presbyopia and mild hyperopia), and a preparation method and application thereof.
Background
The problem of aging is concerned by society, and the eye presbyopia is the first thing the old people walk into. Presbyopia, also known as presbyopia, is a symptom with a morbidity approaching 100%. The 2018mark Scope report shows that there are nearly 18 hundred million presbyopic patients worldwide. In the population over 35 years old, the proportion of people with presbyopia problems reaches 56.9 percent, and the total number of people is 3.9 hundred million; wherein the number of the severe presbyopia crowd reaches 800 ten thousand. Presbyopia is a vision problem that the middle aged and elderly people must face, and changes in modern lifestyle exacerbate the challenges of eye accommodation. As the population born in 1960-70 s steps into middle-aged and elderly people, consumer groups gradually iterate, and the "presbyopia correction" adapting to the multi-task demands becomes the main stream of the market.
The majority of new drugs currently under investigation for the treatment of presbyopia are mainly based on two mechanisms of action: pupil reduction to increase the depth of focus and mechanisms to soften the crystal. One type of drug is miotic, which produces a pinhole effect and increases depth of field. The parasympathetic nervous system regulates the extent of ciliary muscle and iris contraction to alter the shape and position of the lens and its stimulation is effective by activating muscarinic receptors present in both structures. Muscarinic agonists result in ciliary muscle contraction and increased lens thickness, induced pupil constriction increasing depth of focus and producing pseudoaccommodation. Such presbyopic eye drops may reduce the surgical need.
Pupil miosis increases depth of focus by creating a pinhole effect. Pure parasympathetic treatment can lead to decreased pupil diameter and myopia shift, affecting distance vision, and muscarinic stimulation can lead to a variety of adverse effects. Muscarinic drops stimulate anterior uvea, such as carbachol, pilocarpine and physostigmine, which can cause chronic inflammation and stimulate fixation of pupils, posterior adhesions and iris spasmodic contractions, pigment dispersion and myopia metastasis. Thus, several other drugs have been proposed as supplements to counteract these effects, including non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are used in combination with miotics, which are reported to inhibit cyclooxygenase activity and act as anti-inflammatory agents of anterior uvea, reducing pupil constriction and spasmodic cilia constriction, pigment dispersion and post-adhesions.
US patent 8524758B2 reports the inhibition of the risk of inflammation by increased pilocarpine by a greatly increased concentration of diclofenac sodium. Whereas serious ocular adverse reactions of diclofenac sodium include persistent epithelial defects, corneal lysis, and corneal perforation, etc.
WO2009077736A3 reports a combination of pilocarpine and dapiprazole, and pilocarpine and brimonidine for presbyopia. The combination of pilocarpine and redefined and eye-irritating dapiprazole and topically applied brimonidine produces (among other side effects) dizziness, dry mouth, tachycardia and gastric discomfort, which are well known to those skilled in the art and limit use even between patients suffering from serious eye diseases such as glaucoma.
Pilocarpine directly excites M cholinergic receptors and is useful in the treatment of presbyopia and mild hyperopia, but local concentrations below 0.5% produce minimal effects on the mediating eye, while concentrations above 0.5% cause intolerance of side effects such as red eye, ocular pain, migraine and headache. In addition, at concentrations of pilocarpine sufficient to effectively improve the reading power of hyperopic patients, the eye exhibits such myopia that there is a significant reduction in the far vision of the eye (see Gilmartin,1995,0phthalmic and Physiological Optics,Pergamon Press,Oxford,GB,15 (5): 475-479). Another literature reports that with pilocarpine 1% as one of the pharmacodynamic components, 20% of patients develop ocular burning and discomfort immediately after instillation (see Benozzi J, benozzi G, orman B.Presbyopia: a new potential pharmacological treatment [ J ]. Medical Hypothesis, discovery and Innovation in Ophthalmology,2012,1 (1): 3.).
In view of the defects of single pilocarpine and the preparation combined with other medicines for correcting near vision (especially presbyopia and mild hyperopia) which are commonly used clinically at present, the development of related 'synergistic attenuation', namely novel medicine combination which increases the pharmacodynamic activity and reduces adverse reactions of patients, has more clinical prospect and social value.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a safe, effective and low-irritation ophthalmic preparation for correcting near vision. During development, the inventors sought to further reduce the level of pilocarpine in the formulation, but the activity of the ophthalmic formulation was also reduced, which presented a greater challenge to formulation development. The inventor tries to add functional auxiliary materials, especially auxiliary materials for reducing eye irritation, and finds that adverse reactions of the ophthalmic preparation are obviously reduced, especially menthol is adopted to improve the effect better, so that a patient feels cool and comfortable, and the compliance of the patient is increased.
Specifically, the invention is realized through the following technical schemes:
in a first aspect, the present invention provides an ophthalmic formulation for correcting near vision, the ophthalmic formulation comprising the following ingredients:
Figure BDA0003423749280000031
the water for injection is sterilized and used for injection,
wherein the pH of the ophthalmic formulation is 6.0.
Alternatively, in the ophthalmic formulation, wherein the pilocarpine or pharmaceutically acceptable salt thereof is pilocarpine nitrate or pilocarpine hydrochloride.
Preferably, the pilocarpine or pharmaceutically acceptable salt thereof is present in the ophthalmic formulation in an amount of 0.5-1.5w/v%.
The brimonidine or pharmaceutically acceptable salt thereof is brimonidine tartrate.
Preferably, the brimonidine or a pharmaceutically acceptable salt thereof is present in the ophthalmic formulation in an amount of 0.05-0.99w/v%.
The non-steroidal anti-inflammatory drug is selected from one or more of aspirin, acetaminophen, indomethacin, naproxen, diclofenac, ibuprofen, nimesulide, rofecoxib or celecoxib. Preferably, the non-steroidal anti-inflammatory drug is present in the ophthalmic formulation in an amount of 0.05-0.99w/v%.
Alternatively, in the ophthalmic formulation, the compound containing a statin core structure or a pharmaceutically acceptable salt thereof is selected from one or more of ebastine, mizolastine, epistine, azelastine, sitastine, bepotastine, chloromatastine, atorvastatin, emedastine or levocabastine.
Preferably, the compound containing a statin core structure or a pharmaceutically acceptable salt thereof is selected from azelastine or a pharmaceutically acceptable salt thereof.
Further preferably, the content of the statin core structure-containing compound or a pharmaceutically acceptable salt thereof in the ophthalmic preparation is 0.005 to 0.50w/v%.
Wherein the compound containing a statin core structure or a pharmaceutically acceptable salt thereof produces a synergistic effect with pilocarpine and brimonidine.
Alternatively, in the ophthalmic formulation, wherein the functional adjuvant a or a pharmaceutically acceptable salt thereof is selected from one or more of menthol, camphor, menthone, isopulegol, eucalyptol, menthofuran, pinene, limonene, neomenthol, borneol or methyl acetate.
Preferably, the functional adjuvant a or a pharmaceutically acceptable salt thereof is selected from menthol.
Further preferably, the content of the functional auxiliary material A or the pharmaceutically acceptable salt thereof in the ophthalmic preparation is 0.05-0.99w/v%.
Wherein the functional auxiliary material A or the pharmaceutically acceptable salt thereof reduces the function of eye irritation.
Alternatively, in the ophthalmic formulation, wherein the thickener is selected from one or more of cellulose derivatives, crosslinked polyvinylpyrrolidone, sodium hyaluronate, polyvinylpyrrolidone, polyvinyl alcohol, or polyethylene glycol.
Preferably, the thickener is selected from cellulose derivatives selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose or sodium carboxymethylcellulose.
More preferably, the thickener is selected from hydroxypropyl methylcellulose.
Further preferably, the thickener is present in the ophthalmic formulation in an amount of 0.5-10w/v%.
Alternatively, in the ophthalmic formulation, wherein the complexing agent is selected from one or more of edetic acid, disodium edentate, or sodium calcium edentate.
Preferably, the complexing agent is selected from disodium edentate.
Further preferably, the complexing agent is present in the ophthalmic formulation in an amount of 0-0.01w/v%.
The pH buffer system is selected from one or more of phosphoric acid buffer system, acetic acid buffer system, carbonic acid buffer system, citric acid buffer system, tris buffer system, barbituric acid buffer system, boric acid, borax, sodium hydroxide, hydrochloric acid or citric acid and salts thereof.
Preferably, the pH buffer system is selected from boric acid or a phosphate buffer system, for example, a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer system or a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer system.
The bacteriostatic agent is one or more selected from benzalkonium chloride, benzalkonium bromide, cetrimonium bromide, phenoxyethanol, phenethyl alcohol or parahydroxybenzoate bacteriostatic agent.
Preferably, the bacteriostatic agent is selected from benzalkonium chloride.
Further preferably, the bacteriostatic agent is present in the ophthalmic formulation in an amount of 0% to 0.03w/v%.
In a second aspect, the present invention provides a method for preparing an ophthalmic formulation according to the first aspect, the method comprising the steps of: adding a proper amount of sterilizing water for injection, dispersing, boiling and dissolving, cooling the dissolved substances, adding pilocarpine or pharmaceutically acceptable salt thereof, brimonidine or pharmaceutically acceptable salt thereof, a compound containing a statin parent nucleus group structure or pharmaceutically acceptable salt thereof, a non-steroidal anti-inflammatory agent, a functional auxiliary material A or pharmaceutically acceptable salt thereof, a complexing agent, a bacteriostatic agent (if any) and sodium chloride (if any), regulating the pH value to 6.0 by hydrochloric acid, and fixing the volume to the total volume by using the sterilizing water for injection.
In a third aspect, the present invention provides the use of an ophthalmic formulation as described in the first aspect above or an ophthalmic formulation prepared according to the preparation method described in the second aspect above in the manufacture of a medicament for correcting near vision.
Alternatively, in the above use, the indication of the medicament is presbyopia or mild hyperopia.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a safe, effective and low-irritation ophthalmic preparation for correcting near vision, a preparation method and application thereof. Experimental results show that the compound containing the statin core group structure added into the ophthalmic preparation provided by the invention has a synergistic effect with pilocarpine and brimonidine. In addition, the addition of the functional auxiliary material A to the ophthalmic preparation reduces the irritation of the preparation and improves the compliance of patients. Compared with similar medicines commonly used in clinic, the ophthalmic preparation provided by the invention has the characteristics of higher curative effect and lower eye irritation.
Drawings
The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate the invention and together with the embodiments of the invention, serve to explain the invention. In the drawings:
fig. 1 shows the time course of the near vision (UCVA) average results for the subjects of example 1 and comparative example 1.
Detailed Description
The invention will be further illustrated with reference to specific examples. It should be understood that the detailed description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the invention.
The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or equipment used were conventional products available for purchase through regular channels, with no manufacturer noted.
The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the examples described below, unless otherwise specified, are all commercially available products.
Preparation examples:
the ophthalmic formulations of the present invention were formulated according to the corresponding formulas in table 1 below.
The preparation method comprises the following steps: adding a proper amount of sterilized injection water into hydroxypropyl methylcellulose (HPMC), dispersing, boiling for dissolution, cooling the dissolved substances, adding pilocarpine hydrochloride, brimonidine tartrate, azelastine hydrochloride, indomethacin, menthol, monobasic sodium phosphate, disodium hydrogen phosphate, sodium chloride, disodium edentate and benzalkonium chloride, stirring for dissolution, adjusting the pH value to 6.0 by hydrochloric acid, and fixing the volume to 100mL by sterilized injection water.
Table 1: prescription of the ophthalmic preparation of the present invention
Component (A) Example 1 Example 2 Example 3 Comparative example 1 Comparative example 2
Pilocarpine hydrochloride 0.85g 0.9g 1.0g 0.85g 0.85g
Brimonidine tartrate 0.2g 0.15g 0.1g 0.2g 0.2g
Azelastine hydrochloride 0.05g 0.08g 0.09g - 0.05g
Indometacin 0.2g 0.3g 0.35g 0.2g 0.2g
Menthol 0.008g 0.008g 0.008g 0.008g -
Sodium dihydrogen phosphate monohydrate 0.250g 0.250g 0.250g 0.250g 0.250g
Disodium hydrogen phosphate 0.025g 0.025g 0.025g 0.025g 0.025g
Sodium chloride - - - - -
Edetic acid disodium salt 0.010g 0.010g 0.010g 0.010g 0.010g
HPMC 1.000g 1.000g 1.000g 1.000g 1.000g
Benzalkonium chloride 0.010g 0.010g 0.010g 0.010g 0.010g
Water for injection Allowance of Allowance of Allowance of Allowance of Allowance of
Table 1: prescription of the ophthalmic preparation (Xueshang table)
Figure BDA0003423749280000071
Figure BDA0003423749280000081
Table 1: prescription of the ophthalmic preparation (Xueshang table)
Component (A) Example 9 Example 10
Pilocarpine hydrochloride 0.8g 0.8g
Brimonidine tartrate 0.2g 0.15g
Levocabastine hydrochloride 0.06g 0.08g
Indometacin 0.2g 0.3g
Menthol 0.008g 0.008g
Sodium dihydrogen phosphate monohydrate 0.250g 0.250g
Disodium hydrogen phosphate 0.025g 0.025g
Sodium chloride - -
Edetic acid disodium salt 0.010g 0.010g
HPMC 1.000g 1.000g
Benzalkonium chloride 0.010g 0.010g
Water for injection Allowance of Allowance of
Effect example 1:
a group of 20 subjects with average age of 52.6 years old were included. The 20 subjects had no history of ophthalmic surgery, both eyes were emmetropic, and had no diabetes, hypertension, and aids.
One drop (about 0.05 mL) of the example 1 ophthalmic formulation was administered to the left eye of each subject, one drop (about 0.05 mL) of the comparative example 1 ophthalmic formulation was administered to the right eye, and near vision (UCVA) was measured as a core index using the standard logarithmic near vision chart 5 minute recording method with "E" as a visual target, at 0 hour, 1 hour, 2 hours, 4 hours, 5 hours, 6.5 hours, and 9 hours, respectively, after each eye drop.
Table 2: example 1 and comparative example 1 near vision (UCVA) average results
Figure BDA0003423749280000091
# Example 1 and comparative example 1 were subjected to t-test analysis at each time point.
The test results for near vision for both eyes suggest (see table 2 and fig. 1), that both example 1 and comparative example 1 have a certain effect on the correction of presbyopia, and that the results of example 1 are significantly better than those of comparative example 1; especially at 2hr, the difference reached 0.44, and the improvement of near vision was greater than 4 lines of the visual acuity chart. In standard log 5-minute near vision, the difference for each row is 0.1. The results show that the addition of the statin compound in the formulation prescription of the example 1 synergistically optimizes the induction of pilocarpine hydrochloride and brimonidine tartrate, the near vision is obviously improved, and the improvement effect of the example 1 is better than that of the comparative example 1. This may be a pupil-induced focal depth enhancement. Example 1 was compared with comparative example 1, and t-test analysis was performed, p <0.01 in 1 to 6.5 hours, and the difference in these time points was statistically significant.
For examples 2 to 10, we performed the effect verification described above in the same way, and obtained the same effect as in example 1.
Effect example 2:
the ophthalmic formulations of example 1 and comparative example 2 were prepared 100mL each according to the corresponding formulation ratios in table 1. Wherein the order of the solutions of the components of the formulations listed in the preparation examples was not changed.
Multiple dosing ocular irritation comparative test of formulations
Sample to be measured: example 1 and comparative example 2
Test animals: the male and female rabbits (purchased from Experimental animal center of Beijing university of traditional Chinese medicine) are used as healthy New Zealand rabbits, and 10 rabbits are selected respectively by adopting a self-control method on the left side and the right side of the same body.
The test method comprises the following steps: each animal was examined 24 hours prior to the test for 1% sodium fluorescein for both eyes and animals with symptoms of eye irritation, corneal defects and conjunctival damage were not available for the test. The experimental rabbits of example 1 group were left-eye-dropped with the eye drop of example 1 for 2, and then the eyelids were gently closed for about 10s, and the same experimental rabbits of comparative example 2 were right-eye-dropped with the eye drop of comparative example 2 for 2, and then the eyelids were gently closed for about 10s. The administration was continued for 28 days 3 times a day with an interval of about 4 hours.
Eyes were inspected with 1% sodium fluorescein and with slit lamps for conjunctiva, cornea, iris and other lesions before daily dosing and 1, 2, 4, 24, 48 and 72 hours after the last dosing, and rabbits were scored according to table 3 and photographed within 24 hours before trial and 1, 2, 4, 24, 48 and 72 hours after the last dosing, and since animals had been inspected for eyes within 24 hours before dosing, no inspection was done the day before the first dosing. The sum of the scores of the stimulus responses of the cornea, iris and conjunctiva of each animal at each observation time is added to obtain a total score, and the sum of the scores of one group is divided by the number of animals to obtain a final score.
Table 3: eye irritation response score
Figure BDA0003423749280000101
Figure BDA0003423749280000111
Table 4: evaluation criteria for eye irritation
Figure BDA0003423749280000112
Figure BDA0003423749280000121
The eye irritation data of each group of animals were counted according to the standard values of the scores in Table 4, and the results are shown in Table 5.
Table 5: eye irritation scoring of test rabbits
Figure BDA0003423749280000122
# T-test analysis was performed for example 1 and comparative example 2.
Conclusion of the test: the animals in each group have no stronger irritation to eyes of the tested animals after the eye preparation medicine is given; according to the data presented in Table 5, the addition of menthol to the formulation (example 1) significantly reduced irritation and the improvement in irritation of example 1 was more pronounced than the formulation without menthol (comparative example 2). In comparison with comparative example 2, each time point of example 1 was statistically significant using t-test, p <0.01, and each time point difference. The conclusion suggests that the addition of menthol to the ophthalmic formulation of the present invention will be beneficial in reducing irritation of the ophthalmic formulation while increasing patient compliance.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments. Those skilled in the art will appreciate that, in light of the principles of the present invention, improvements and modifications can be made without departing from the scope of the invention.

Claims (9)

1. An ophthalmic formulation for correcting near vision, characterized by: the ophthalmic formulation comprises the following ingredients:
Figure FDA0003423749270000011
wherein the ophthalmic formulation has a pH of 6.0.
2. An ophthalmic formulation according to claim 1, characterized in that: wherein the pilocarpine or pharmaceutically acceptable salt thereof is pilocarpine nitrate or pilocarpine hydrochloride, preferably, the content of pilocarpine or pharmaceutically acceptable salt thereof in the ophthalmic preparation is 0.5-1.5w/v%; and/or the brimonidine or pharmaceutically acceptable salt thereof is brimonidine tartrate, preferably the content of brimonidine or pharmaceutically acceptable salt thereof in the ophthalmic preparation is 0.05-0.99w/v%; and/or the non-steroidal anti-inflammatory drug is selected from one or more of aspirin, acetaminophen, indomethacin, naproxen, diclofenac, ibuprofen, nimesulide, rofecoxib or celecoxib, preferably, the content of the non-steroidal anti-inflammatory drug in the ophthalmic preparation is 0.05-0.99w/v%.
3. The ophthalmic formulation according to claim 1 or claim 2, characterized in that: wherein the statin core structure containing compound or pharmaceutically acceptable salt thereof is selected from one or more of ebastine, mizolastine, epinastine, azelastine, sitostatin, bepotastine, chloromatastine, atorvastatin, emedastine or levocabastine, preferably the statin core structure containing compound or pharmaceutically acceptable salt thereof is selected from azelastine or pharmaceutically acceptable salt thereof, further preferably the statin core structure containing compound or pharmaceutically acceptable salt thereof is present in the ophthalmic formulation in an amount of 0.005-0.50w/v%, wherein the statin core structure containing compound or pharmaceutically acceptable salt thereof produces a synergistic effect with pilocarpine and brimonidine.
4. An ophthalmic formulation according to any one of claims 1 to 3, characterized in that: wherein the functional auxiliary material A or pharmaceutically acceptable salt thereof is selected from one or more of menthol, camphor, menthone, isopulegol, eucalyptol, menthofuran, pinene, limonene, neomenthol, borneol or methyl acetate, preferably, the functional auxiliary material A or pharmaceutically acceptable salt thereof is selected from menthol, and further preferably, the content of the functional auxiliary material A or pharmaceutically acceptable salt thereof in the ophthalmic preparation is 0.05-0.99w/v%, wherein the functional auxiliary material A or pharmaceutically acceptable salt thereof reduces the function of eye irritation.
5. The ophthalmic formulation according to any one of claims 1 to 4, characterized in that: wherein the thickener is selected from one or more of cellulose derivatives, crosslinked polyvinylpyrrolidone, sodium hyaluronate, polyvinylpyrrolidone, polyvinyl alcohol or polyethylene glycol, preferably the thickener is selected from cellulose derivatives selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose or sodium carboxymethylcellulose, more preferably the thickener is selected from hydroxypropyl methylcellulose, further preferably the thickener is present in the ophthalmic formulation in an amount of 0.5 to 10w/v%.
6. The ophthalmic formulation according to any one of claims 1 to 5, characterized in that: wherein the complexing agent is selected from one or more of edetic acid, disodium edentate or sodium calcium edentate, preferably the complexing agent is selected from disodium edentate, further preferably the complexing agent is present in the ophthalmic formulation in an amount of 0-0.01w/v%; and/or the pH buffer system is selected from one or more of a phosphate buffer system, an acetate buffer system, a carbonate buffer system, a citrate buffer system, a tris buffer system, a barbituric acid buffer system, boric acid, borax, sodium hydroxide, hydrochloric acid or citric acid and salts thereof, preferably the pH buffer system is selected from boric acid or a phosphate buffer system, for example, a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer system or a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer system; and/or the bacteriostatic agent is selected from one or more of benzalkonium chloride, benzalkonium bromide, cetrimide, phenoxyethanol, phenethyl alcohol or a paraben bacteriostatic agent, preferably the bacteriostatic agent is selected from benzalkonium chloride, and further preferably the bacteriostatic agent is contained in the ophthalmic preparation in an amount of 0% -0.03w/v%.
7. A method of preparing an ophthalmic formulation as claimed in any one of claims 1 to 6, characterized in that: the preparation method comprises the following steps: adding a proper amount of sterilizing water for injection, dispersing, boiling and dissolving, cooling the dissolved substances, adding pilocarpine or pharmaceutically acceptable salt thereof, brimonidine or pharmaceutically acceptable salt thereof, a compound containing a statin parent nucleus group structure or pharmaceutically acceptable salt thereof, a non-steroidal anti-inflammatory agent, a functional auxiliary material A or pharmaceutically acceptable salt thereof, a complexing agent, a bacteriostatic agent (if any) and sodium chloride (if any), regulating the pH value to 6.0 by hydrochloric acid, and fixing the volume to the total volume by using the sterilizing water for injection.
8. Use of an ophthalmic formulation according to any one of claims 1 to 6 or prepared according to the preparation method of claim 7 in the preparation of a medicament for correcting near vision.
9. Use according to claim 8, characterized in that: the indication of the medicine is presbyopia or mild hyperopia.
CN202111571169.9A 2021-12-21 2021-12-21 Ophthalmic preparation for correcting near vision Pending CN116270442A (en)

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