An ophthalmic preparation for correcting near vision

Abstract

The present invention provides an ophthalmic preparation for correcting near vision, its preparation method and use, which are particularly suitable for treating presbyopia and mild hyperopia. The ophthalmic preparation contains pilocarpine, brimonidine, a compound containing a stin nucleus group structure, a non-steroidal anti-inflammatory drug, functional excipient A, a thickening agent, a complexing agent, a pH regulator, a bacteriostatic agent and sodium chloride. The experimental results show that the compound containing a stin nucleus group structure added to the ophthalmic preparation of the present invention has a synergistic effect with pilocarpine and brimonidine. In addition, adding functional excipient A to the ophthalmic preparation reduces the irritation of the preparation and improves the patient compliance. Compared with the commonly used drugs of the same kind clinically, the ophthalmic preparation of the present invention has the characteristics of higher efficacy and lower ocular irritation.

Description

Technical Field

[0001] The present invention belongs to the field of biological medicine technology, and particularly relates to an ophthalmic preparation for improving, alleviating and correcting near vision (especially presbyopia and mild hyperopia), a preparation method thereof and uses thereof. Background Art

[0002] The aging problem has attracted much social attention. When people enter old age, the first thing they face is presbyopia. Presbyopia, also known as presbyopia, is a symptom with an incidence rate close to 100%. The "2018 Market Scope" report shows that there are nearly 1.8 billion presbyopic patients globally. Among the population over 35 years old in China, the proportion of people with presbyopia reaches 56.9%, with a total of 390 million people; among them, the number of severe presbyopic people reaches 8 million. Presbyopia is an inevitable vision problem for middle-aged and elderly people, and the changes in modern lifestyle have exacerbated the challenge to the eye accommodation function. As the population born in the 1960s and 1970s enters middle age and old age, the consumer group is gradually iterating, and "presbyopia correction" that adapts to the multi-tasking needs has become the market mainstream.

[0003] Currently, most new drugs under research for the treatment of presbyopia mainly act based on two mechanisms: the mechanism of miosis to increase the depth of focus and the mechanism of softening the lens. One type of drug is a miotic drug, which produces a pinhole effect and increases the depth of field. The parasympathetic nervous system regulates the degree of contraction of the ciliary muscle and the iris to change the shape and position of the lens, and through activating the muscarinic receptors present in both structures, its stimulation is effective. Muscarinic agonists cause ciliary muscle contraction and an increase in lens thickness, and the induced miosis increases the depth of focus and produces pseudoaccommodation. Such eye drops for correcting presbyopia may reduce the need for surgery.

[0004] Miosis increases the depth of focus by producing a pinhole effect. Pure parasympathetic treatment will cause the pupil diameter to become smaller and a myopic shift, affecting distant vision, and muscarinic stimulation will cause various adverse reactions. Muscarinic drops stimulate the anterior uvea. For example, carbachol, pilocarpine and physostigmine can cause chronic inflammation and stimulate fixed pupils, posterior synechia and spastic contraction of the iris, pigment dispersion and myopic shift. Therefore, several other drugs have been proposed as supplements to offset these effects, including non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are used in combination with miotic drugs. It is reported that NSAIDs inhibit cyclooxygenase activity and act as anti-inflammatory drugs for the anterior uvea, reducing miosis and spastic ciliary contraction, pigment dispersion and posterior synechia.

[0005] US Patent US8524758B2 reports inhibiting the increased inflammatory risk caused by pilocarpine by significantly increasing the concentration of diclofenac sodium. However, the serious ocular adverse reactions of diclofenac sodium include persistent epithelial defect, corneal lysis and corneal perforation, etc.

[0006] WO2009077736A3 reports combinations of pilocarpine and dapiprazole, and pilocarpine and brimonidine for presbyopia. The combination of pilocarpine, dapiprazole which causes red eyes and eye irritation, and topically administered brimonidine produces (among other side effects) dizziness, lightheadedness, dry mouth, tachycardia, and stomach discomfort, which are well known to those skilled in the art and limit its use even among patients with severe eye disorders such as glaucoma.

[0007] Pilocarpine can directly stimulate M cholinergic receptors and can be used to treat presbyopia and mild hyperopia. However, a local concentration below 0.5% has minimal effect on regulating the eye, while a concentration above 0.5% causes intolerable side effects such as red eyes, eye pain, migraine, and headache. In addition, at a concentration of pilocarpine sufficient to effectively improve the reading ability of hyperopic patients, the eye presents such myopia that there is a significant decrease in the distant vision of the eye (see Gilmartin, 1995, Ophthalmic and Physiological Optics, Pergamon Press, Oxford, GB, 15(5):475 - 479). Another literature reports that using 1% pilocarpine as one of the pharmacodynamic components, 20% of the patients immediately experienced eye burning and discomfort 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.).

[0008] In view of the various defects existing in the preparations of pilocarpine used alone and in combination with other drugs for correcting near vision (especially presbyopia and mild hyperopia) commonly used clinically, developing related "synergistic effect and toxicity reduction", that is, increasing the pharmacodynamic activity and reducing the adverse reactions of patients, has more clinical prospects and social value. Summary of the Invention

[0009] To overcome the defects existing in the prior art, the present invention provides an ophthalmic preparation for correcting near vision, which is safe, effective and has low irritation. During the development process, the inventors of the present invention tried to further reduce the content of pilocarpine in the preparation, but the activity of the ophthalmic preparation also decreased accordingly, which posed a higher challenge to the research and development of the preparation. The inventors of the present invention tried to add functional excipients, especially excipients for reducing eye irritation, and found that the adverse reactions of the ophthalmic preparation decreased significantly. In particular, the use of menthol had a better improvement effect, making patients feel cool and comfortable, and increasing patient compliance.

[0010] Specifically, the present invention is achieved through the following technical solutions in several aspects:

[0011] In the first aspect, the present invention provides an ophthalmic preparation for correcting near vision, and the ophthalmic preparation comprises the following components:

[0012]

[0013] Sterile water for injection,

[0014] Wherein, the pH value of the ophthalmic preparation is 6.0.

[0015] As an optional mode, in the ophthalmic preparation, the pilocarpine or a pharmaceutically acceptable salt thereof is pilocarpine nitrate or pilocarpine hydrochloride.

[0016] Preferably, the content of the pilocarpine or a pharmaceutically acceptable salt thereof in the ophthalmic preparation is 0.5-1.5 w / v%.

[0017] The brimonidine or a pharmaceutically acceptable salt thereof is brimonidine tartrate.

[0018] Preferably, the content of the brimonidine or a pharmaceutically acceptable salt thereof in the ophthalmic preparation is 0.05-0.99 w / v%.

[0019] The non-steroidal anti-inflammatory drug is selected from one or more of aspirin, paracetamol, indomethacin, naproxen, naproxen sodium, diclofenac, ibuprofen, nimesulide, rofecoxib or celecoxib. Preferably, the content of the non-steroidal anti-inflammatory drug in the ophthalmic preparation is 0.05-0.99 w / v%.

[0020] As an optional mode, in the ophthalmic preparation, the compound containing a stin nucleus structure or a pharmaceutically acceptable salt thereof is selected from one or more of ebastine, mizolastine, epinastine, azelastine, sertastine, betastine, clemastine, acrivastine, emedastine or levocabastine.

[0021] Preferably, the compound containing the stine nuclear structure or a pharmaceutically acceptable salt thereof is selected from azelastine or a pharmaceutically acceptable salt thereof.

[0022] Additionally preferably, the content of the compound containing the stine nuclear structure or a pharmaceutically acceptable salt thereof in the ophthalmic preparation is 0.005 - 0.50 w / v%.

[0023] Among them, the compound containing the stine nuclear structure or a pharmaceutically acceptable salt thereof has a synergistic effect with pilocarpine and brimonidine.

[0024] As an alternative, in the ophthalmic preparation, the functional excipient A or a pharmaceutically acceptable salt thereof is selected from one or more of menthol, camphor, menthone, isomenthol, cineole, menthofuran, pinene, limonene, neomenthol, borneol or methyl acetate.

[0025] Preferably, the functional excipient A or a pharmaceutically acceptable salt thereof is selected from menthol.

[0026] Additionally preferably, the content of the functional excipient A or a pharmaceutically acceptable salt thereof in the ophthalmic preparation is 0.05 - 0.99 w / v%.

[0027] Among them, the functional excipient A or a pharmaceutically acceptable salt thereof reduces the function of ocular irritation.

[0028] As an alternative, in the ophthalmic preparation, the thickening agent is selected from one or more of cellulose derivatives, cross-linked polyvinylpyrrolidone, sodium hyaluronate, polyvinylpyrrolidone, polyvinyl alcohol or polyethylene glycol.

[0029] Preferably, the thickening agent is selected from cellulose derivatives, and the cellulose derivatives are selected from one or more of hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose or sodium carboxymethylcellulose.

[0030] More preferably, the thickening agent is selected from hydroxypropyl methylcellulose.

[0031] Additionally preferably, the content of the thickening agent in the ophthalmic preparation is 0.5 - 10 w / v%.

[0032] As an alternative, in the ophthalmic preparation, the complexing agent is selected from one or more of edetic acid, disodium edetate or calcium disodium edetate.

[0033] Preferably, the complexing agent is selected from disodium edetate.

[0034] Additionally preferably, the content of the complexing agent in the ophthalmic preparation is 0 - 0.01 w / v%.

[0035] 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(hydroxymethyl)aminomethane buffer system, a barbituric acid buffer system, boric acid, borax, sodium hydroxide, hydrochloric acid, or citric acid and its salts.

[0036] 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.

[0037] The bacteriostatic agent is selected from one or more of benzalkonium chloride, benzalkonium bromide, cetrimide, phenoxyethanol, phenethyl alcohol, or a parabens bacteriostatic agent.

[0038] Preferably, the bacteriostatic agent is selected from benzalkonium chloride.

[0039] Additionally preferably, the content of the bacteriostatic agent in the ophthalmic preparation is 0% - 0.03 w / v%.

[0040] In a second aspect, the present invention provides a method for preparing the ophthalmic preparation described in the first aspect above. The preparation method includes the following steps: Take an appropriate amount of sterile water for injection, add a thickening agent, disperse and dissolve by boiling, cool the dissolved substance, and add pilocarpine or a pharmaceutically acceptable salt thereof, brimonidine or a pharmaceutically acceptable salt thereof, a compound containing a stin nucleus group structure or a pharmaceutically acceptable salt thereof, a non - steroidal anti - inflammatory drug, functional excipient A or a pharmaceutically acceptable salt thereof, a complexing agent, a bacteriostatic agent (if any), and sodium chloride (if any). Adjust the pH to 6.0 with hydrochloric acid, and make up the volume to the total volume with sterile water for injection.

[0041] In a third aspect, the present invention provides the use of the ophthalmic preparation described in the first aspect above or the ophthalmic preparation prepared according to the preparation method described in the second aspect above in the preparation of a drug for correcting near vision.

[0042] As an alternative, in the above - mentioned use, the indication of the drug is presbyopia or mild hyperopia.

[0043] The present invention has the following beneficial effects compared with the prior art:

[0044] The present invention provides an ophthalmic preparation for correcting near vision, which is safe, effective and low-irritating, and its preparation method and uses. Experimental results show that the compound containing the stin nucleus group structure added to the ophthalmic preparation of the present invention has a synergistic effect with pilocarpine and brimonidine. In addition, adding functional excipient A to the ophthalmic preparation reduces the irritation of the preparation and improves patient compliance. Compared with the commonly used drugs of the same kind clinically, the ophthalmic preparation of the present invention has the characteristics of higher efficacy and lower ocular irritation. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] The drawings are used to provide a further understanding of the present invention, and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention, but do not constitute a limitation to the present invention. In the drawings:

[0046] Figure 1 Shows the change curve of the average results of near vision (UCVA) of the subjects in Example 1 group and Comparative Example 1 group over time. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0047] The present invention will be further described below with reference to specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and do not limit the scope of the present invention.

[0048] For those not specifying specific technologies or conditions in the embodiments, they shall be in accordance with the technologies or conditions described in the literature in the field or in accordance with the product specifications. For reagents or instruments not indicating the manufacturer, they are all conventional products that can be obtained through regular channels.

[0049] The experimental methods in the following examples are all conventional methods unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.

[0050] PREPARATION EXAMPLE:

[0051] Prepare the ophthalmic preparation of the present invention according to the corresponding prescription in Table 1 below.

[0052] The preparation method includes: taking an appropriate amount of sterile injection water, adding hydroxypropyl methylcellulose (HPMC), dispersing and boiling to dissolve, cooling the dissolved substance, adding pilocarpine hydrochloride, brimonidine tartrate, azelastine hydrochloride, indomethacin, menthol, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate, sodium chloride, disodium edetate, benzalkonium chloride, stirring to dissolve, adjusting the pH value to 6.0 with hydrochloric acid, and making up the volume to 100 mL with sterile injection water.

[0053] Table 1: Prescription of the ophthalmic preparation of the present invention

[0054] Component 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 - - - - - Disodium Edetate 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 Balance Balance Balance Balance Balance

[0055] Table 1: Prescription of the ophthalmic preparation of the present invention (continued from the above table)

[0056]

[0057]

[0058] Table 1: Prescription of the ophthalmic preparation of the present invention (continued from the above table)

[0059] Component 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 - - Disodium Edetate 0.010g 0.010g HPMC 1.000g 1.000g Benzalkonium Chloride 0.010g 0.010g Water for Injection Balance Balance

[0060] Effect Example 1:

[0061] A group of 20 presbyopic subjects with an average age of 52.6 years was enrolled. None of these 20 subjects had a history of ophthalmic surgery, both eyes were emmetropic, and they had no diabetes, hypertension, or AIDS.

[0062] One drop (about 0.05 mL) of the ophthalmic preparation of Example 1 was instilled into the left eye of each subject, and one drop of the ophthalmic preparation of Comparative Example 1 was instilled into the right eye. The core index of near vision was measured at 0 hour, 1 hour, 2 hours, 4 hours, 5 hours, 6.5 hours, and 9 hours after instillation in each eye. The uncorrected visual acuity at near (UCVA) was measured using a standard logarithmic near vision chart with an "E" visual target and a 5-point recording method.

[0063] Table 2: Average results of near vision (UCVA) in Example 1 and Comparative Example 1

[0064]

[0065] # A t-test analysis was performed between Example 1 and Comparative Example 1 at each time point.

[0066] The test results for binocular near vision suggest (see Table 2 and Figure 1 ), both Example 1 and Comparative Example 1 had a certain effect on the correction of presbyopia, and the results of Example 1 were significantly better than those of Comparative Example 1; especially at the 2-hour mark, the difference reached 0.44, and the improvement in near vision was greater than 4 lines on the vision chart. In the standard logarithmic 5-point near vision, the difference between each line is 0.1. The results show that the addition of the stin compound in the preparation prescription of Example 1 synergistically optimized the effects caused by pilocarpine hydrochloride and brimonidine tartrate, and the near vision was significantly improved, and the improvement effect of Example 1 was better than that of Comparative Example 1. This may be due to the enhanced depth of focus caused by miosis. When comparing Example 1 with Comparative Example 1 and performing a t-test analysis, p < 0.01 within 1 - 6.5 hours, and the differences at these time points were statistically significant.

[0067] For Examples 2 - 10, we also carried out the above-mentioned effect verification and obtained the same effects as those of Example 1.

[0068] Effect Example 2:

[0069] Prepare 100 mL of the ophthalmic preparations of Example 1 and Comparative Example 2 according to the corresponding prescription ratios in Table 1. Among them, the solution order of each component in the prescription listed in the preparation example is not changed.

[0070] Comparative Test of Ocular Irritation after Multiple Dosing of the Preparation

[0071] Samples to be tested: Example 1 and Comparative Example 2

[0072] Test animals: Healthy New Zealand white rabbits (purchased from the Experimental Animal Center of Beijing University of Chinese Medicine), both male and female, using the self-control method of the left and right sides of the same body, and 10 rabbits are selected for each.

[0073] Test method: 24 h before the test, each animal's eyes were examined with 1% sodium fluorescein. Animals with eye irritation symptoms, corneal defects and conjunctival injuries cannot be used for the test. Two drops of the eye drops of Example 1 were instilled into the left eye of the experimental rabbits in the Example 1 group, and then the eyelids were gently closed for about 10 s. Two drops of the eye drops of Comparative Example 2 were instilled into the right eye of the same experimental rabbits in the Comparative Example 2 group, and then the eyelids were gently closed for about 10 s. Three times a day, the dosing interval is about 4 h each time, and the drug is administered continuously for 28 d.

[0074] Before each daily drug administration and at 1, 2, 4, 24, 48 and 72 h after the last drug administration, 1% sodium fluorescein was instilled into both eyes and the eyes were examined with a slit lamp to observe the conjunctiva, cornea, iris and other injuries, and scored according to Table 3. Photographs of the rabbit eyes were taken within 24 h before the test and at 1, 2, 4, 24, 48 and 72 h after the last drug administration. Since the eyes of the animals have been examined within 24 h before drug administration, they are not examined on the day before the first drug administration. The irritation response scores of the cornea, iris and conjunctiva of each animal at each observation time were added up to obtain the total score, and the total score of a group was divided by the number of animals to obtain the final score.

[0075] Table 3: Eye irritation response scores

[0076]

[0077]

[0078] Table 4: Eye irritation evaluation criteria

[0079]

[0080]

[0081] According to the scoring standard values in Table 4, the eye irritation data of each group of animals were statistically analyzed, and the results are shown in Table 5.

[0082] Table 5: Eye irritation scores of the test rabbits

[0083]

[0084] # Example 1 and Comparative Example 2 were subjected to t-test analysis.

[0085] Test conclusion: No strong irritation to the eyes of the test animals was found after administration of the ophthalmic preparation at each time point for each group of animals; according to the data listed in Table 5, the irritation of the preparation with menthol added (Example 1) was significantly reduced compared with the preparation without menthol added (Comparative Example 2), and the improvement of irritation in Example 1 was more prominent. When comparing each time point of Example 1 with Comparative Example 2 using the t-test, p < 0.01, and the differences at each time point were statistically significant. The conclusion suggests that adding menthol to the ophthalmic preparation of the present invention will help reduce the irritation of the ophthalmic preparation and increase the compliance of patients.

[0086] The above description of the embodiments is to enable those of ordinary skill in the art to understand and use the present invention. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative efforts. Therefore, the present invention is not limited to the above embodiments. Improvements and modifications made by those skilled in the art based on the principles of the present invention without departing from the scope of the present invention should be within the protection scope of the present invention.

Claims

1. An ophthalmic preparation for correcting presbyopia, characterized in that: The ophthalmic preparation contains the following components: ； Among them, the sodium dihydrogen phosphate - disodium hydrogen phosphate buffer system is sodium dihydrogen phosphate monohydrate and disodium hydrogen phosphate, and the pH of the ophthalmic preparation is 6.

0.

2. The ophthalmic preparation according to claim 1, characterized in that: Among them, azelastine hydrochloride has a synergistic effect with pilocarpine hydrochloride and brimonidine tartrate.

3. The ophthalmic preparation according to claim 1, wherein: Among them, menthol reduces the function of eye irritation.

4. A method for preparing the ophthalmic preparation according to any one of claims 1 to 3, characterized in that: The preparation method includes the following steps: Take an appropriate amount of sterile water for injection, add hydroxypropyl methylcellulose, disperse and boil to dissolve, cool the dissolved substance, add pilocarpine hydrochloride, brimonidine tartrate, azelastine hydrochloride, indomethacin, menthol, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate, sodium chloride, disodium edetate, benzalkonium chloride, stir to dissolve, adjust the pH to 6.0 with hydrochloric acid, and make up the volume to the total volume with sterile water for injection.

5. Use of the ophthalmic preparation according to any one of claims 1 to 3 or the ophthalmic preparation prepared by the preparation method according to claim 4 in the preparation of a drug for correcting presbyopia.

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