Ophthalmic preparation, its preparation method and use

Abstract

The present invention relates to an ophthalmic preparation. The ophthalmic preparation comprises: penehyclidine hydrochloride, phosphate buffer, sodium chloride and hypromellose; wherein, based on the total volume of the ophthalmic preparation, the concentration of the phosphate buffer is not higher than 25 mM and not 0 mM, the mass-volume ratio of penehyclidine hydrochloride is 0.01% - 2%, and the mass ratio of penehyclidine hydrochloride to sodium chloride is (0.011 - 0.85):1. The ophthalmic preparation of the present invention has the advantages of low irritation and high stability.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and particularly to an ophthalmic preparation, a preparation method thereof, and uses thereof. Background Art

[0002] Penehyclidine Hydrochloride, English name: Penehyclidine Hydrochloride, chemical name: 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy)quinuclidine hydrochloride, molecular formula C 20 H 29 NO2·HCl, molecular weight 351.92, chemical structural formula:

[0003]

[0004] As a potent selective anticholinergic drug, Penehyclidine Hydrochloride can bind to M and N cholinergic receptors, selectively act on M1, M3, N1, and N2 receptors, and has a strong anticholinergic effect on both peripheral nerves and central nerves. It has no effect on M2 receptors, and can avoid the tachycardia and the blocking of the regulatory function of the presynaptic membrane M2 receptor caused by atropine due to the lack of M receptor subtype selectivity.

[0005] Penehyclidine Hydrochloride has advantages that anticholinergic drugs such as atropine and scopolamine do not have, such as strong anticholinergic effect, long action duration, protection of the two-way regulation mechanism of heart rate, improvement of microcirculation, low toxicity and side effects, etc. It has shown broad application prospects in clinical practice: the treatment of organophosphorus pesticide poisoning, premedication for anesthesia, application in respiratory diseases, anti-shock, protection against cerebral ischemia-reperfusion injury, application in digestive tract diseases and acute abdominal pain, etc. Summary of the Invention

[0006] The present invention provides an ophthalmic preparation, a preparation method thereof, and uses thereof. The ophthalmic preparation provided by the present invention can effectively prevent or treat myopia or amblyopia, and has advantages such as low irritation and good stability, and is suitable for popularization and application.

[0007] In one aspect of the present invention, the present invention provides an ophthalmic preparation. According to an embodiment of the present invention, the ophthalmic preparation includes: Penehyclidine Hydrochloride, phosphate buffer, sodium chloride, and hypromellose; wherein, based on the total volume of the ophthalmic preparation, the concentration of the phosphate buffer is not higher than 25 mM and not 0 mM, the mass-volume ratio of Penehyclidine Hydrochloride is 0.01%-2%, and the mass ratio of Penehyclidine Hydrochloride to sodium chloride is (0.011-0.85):1.

[0008] The inventors of the present invention creatively discovered that penehyclidine hydrochloride has good curative effects on eye diseases, such as myopia or amblyopia. However, through experiments, the inventors found that penehyclidine hydrochloride has poor stability in aqueous solution, and after high temperature or long-term storage, problems such as an increase in related substances and a decrease in the content of penehyclidine hydrochloride will occur. The inventors can improve the stability of penehyclidine hydrochloride by adding excipients such as phosphate buffer, but when the excipients are not properly selected, the prepared ophthalmic preparation will cause irritation to the eyes.

[0009] Therefore, the inventors further found that when the excipients are selected as phosphate buffer and sodium chloride, and the concentration of the phosphate buffer is not higher than 25 mM and not 0 mM, the mass-volume ratio of penehyclidine hydrochloride is 0.01%-2%, and the mass ratio of penehyclidine hydrochloride to sodium chloride is (0.011-0.85):1, not only can the stability of the ophthalmic preparation be improved, but also the irritation of the ophthalmic preparation can be effectively reduced, and the irritation of the ophthalmic preparation to the eyes can be reduced or avoided.

[0010] According to an embodiment of the present invention, the mass-volume ratio of the sodium chloride is 0.3%-0.9%.

[0011] According to an embodiment of the present invention, the mass-volume ratio of the penehyclidine hydrochloride is 0.01%-0.5%.

[0012] According to an embodiment of the present invention, the mass-volume ratio of the hypromellose is 0.2%-0.8%.

[0013] Thus, the irritation of the ophthalmic preparation can be further reduced.

[0014] According to an embodiment of the present invention, based on the total volume of the ophthalmic preparation, the concentration of the phosphate buffer is not higher than 15 mM, preferably 1 mM-15 mM. Thus, the stability of the ophthalmic preparation can be further improved and the irritation of the ophthalmic preparation can be reduced.

[0015] According to an embodiment of the present invention, the phosphate buffer includes a buffer pair of disodium hydrogen phosphate and sodium dihydrogen phosphate; or the phosphate buffer includes a buffer pair of dipotassium hydrogen phosphate and potassium dihydrogen phosphate. Thus, the stability of the ophthalmic preparation can be further improved and the irritation of the ophthalmic preparation can be reduced.

[0016] According to an embodiment of the present invention, the pH value of the ophthalmic preparation is 5.0-7.0.

[0017] According to an embodiment of the present invention, based on the total volume of the ophthalmic preparation, the mass-volume ratio of the hypromellose is 0.2%-0.8%, preferably 0.4%-0.6%. Thus, the viscosity of the ophthalmic preparation can be controlled within an acceptable range for the human eye, thereby effectively controlling the residence time of the drug in the eye.

[0018] In yet another aspect of the present invention, the present invention provides a method for preparing an ophthalmic preparation. According to an embodiment of the present invention, the method includes: dividing the water for injection into three portions; adding one portion of the water for injection to hydroxypropyl methylcellulose and stirring until dispersed, and obtaining a preliminary solution 1 after cooling; adding the penehyclidine hydrochloride, sodium chloride, and phosphate buffer to another portion of the water for injection, stirring until dissolved, and obtaining a preliminary solution 2 after filtration; mixing the preliminary solution 1 and the preliminary solution 2, and making up the volume with the remaining water for injection to prepare the ophthalmic preparation; wherein, based on the total volume of the ophthalmic preparation, the concentration of the phosphate buffer is not higher than 25 mM and not 0 mM, the mass-volume ratio of the penehyclidine hydrochloride is 0.01%-2%, and the mass ratio of the penehyclidine hydrochloride to sodium chloride is (0.011-0.85):1. The method according to the embodiment of the present invention is simple to operate and can produce a safe, effective, and stable-quality ophthalmic preparation.

[0019] According to an embodiment of the present invention, the amount of the water for injection used to prepare the preliminary solution 1 is 60%-80% of the total volume of the ophthalmic preparation. Thereby, the stability of the system can be improved and the impurity content in the ophthalmic preparation can be reduced.

[0020] According to an embodiment of the present invention, after the hydroxypropyl methylcellulose is dispersed in the aqueous solution, high-temperature sterilization is carried out, and a preliminary solution 1 is obtained after cooling.

[0021] According to an embodiment of the present invention, the sterilization temperature is 115°C-125°C, preferably 121°C, and the sterilization time is 15 min-35 min. The aseptic level of the preliminary solution and the stability of the preparation can be effectively ensured.

[0022] According to an embodiment of the present invention, the final temperature of the cooling is 0°C-25°C.

[0023] According to an embodiment of the present invention, the amount of the water for injection used to prepare the preliminary solution 2 is 10%-30% of the total volume of the ophthalmic preparation. The inventors found through a large number of experiments that dissolving the penehyclidine hydrochloride, sodium chloride, and phosphate buffer first can improve the stability of the ophthalmic preparation and reduce the impurity content in the ophthalmic preparation.

[0024] According to an embodiment of the present invention, before the preliminary solution 2 is mixed with the preliminary solution 1, the preliminary solution 2 is filtered using a 0.22 μm filter element. Thereby, the microorganisms in the ophthalmic preparation can be removed, the aseptic guarantee level can be improved, and the medication safety of patients can be ensured.

[0025] According to an embodiment of the present invention, the method further includes: aseptically filling the ophthalmic preparation.

[0026] In another aspect of the present invention, there is provided the use of the aforementioned ophthalmic preparation or an ophthalmic preparation prepared according to the aforementioned method in the preparation of a medicament for treating and / or preventing myopia and / or amblyopia.

[0027] As used herein, "myopia" generally refers to the phenomenon that a clear image cannot be formed on the retina; "amblyopia" generally refers to a condition in which the best corrected visual acuity of one or both eyes is lower than that of normal children of the corresponding age due to abnormal visual experience during the visual development period, and there is no organic lesion upon ophthalmic examination. The myopia and / or amblyopia include at least one selected from the group consisting of mild myopia, moderate myopia, high myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, reduced distant vision, asthenopia, exotropia, strabismic amblyopia, elongation of the eye axis, fundus damage, visual occlusion, metamorphopsia, diplopia, color vision abnormality, light perception abnormality, decreased contrast sensitivity, anisometropic amblyopia, ametropic amblyopia, unilateral form deprivation amblyopia, and bilateral form deprivation amblyopia.

[0028] It should be noted that the causes of the myopia and / or amblyopia include but are not limited to at least one selected from the group consisting of myopic shift of refractive power, elongation of myopic vitreous cavity depth, elongation of myopic eye axis length, form deprivation, anisometropia, and astigmatism.

[0029] In another aspect of the present invention, there is provided a method for treating and / or preventing myopia and / or amblyopia. According to an embodiment of the present invention, the method includes: administering an effective amount of the aforementioned ophthalmic preparation or an ophthalmic preparation prepared according to the aforementioned method to a subject. The method of the present invention can effectively treat and / or prevent myopia and / or amblyopia.

[0030] Additional aspects and advantages of the present invention will be given in part in the following description, become apparent in part from the following description, or be learned through the practice of the present invention. Detailed Description of the Invention

[0031] Embodiments of the present invention will be described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0032] It should be noted that the terms "first" and "second" are only used for descriptive purposes and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include one or more of such features. Further, in the description of the present invention, unless otherwise specified, the meaning of "a plurality" is two or more.

[0033] The endpoints and any values in the ranges disclosed in this document are not limited to the exact ranges or values. These ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered specifically disclosed in this document.

[0034] In this document, the term "comprising" or "including" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other aspects of the content.

[0035] In this document, the terms "optionally", "optional" or "option" generally mean that the subsequent events or conditions may but do not necessarily occur, and this description includes the cases where the events or conditions occur and the cases where the events or conditions do not occur.

[0036] In this document, the term "treatment" is used to refer to obtaining the desired pharmacological and / or physiological effects. The effects can be preventive in terms of completely or partially preventing a disease or its symptoms, and / or can be therapeutic in terms of partially or completely curing a disease and / or the adverse effects caused by the disease. "Treatment" as used herein covers diseases of mammals, especially humans, including: (a) preventing the occurrence of a disease or disorder in an individual who is susceptible to the disease but has not been diagnosed with the disease; (b) inhibiting the disease, such as blocking the development of the disease; or (c) alleviating the disease, such as reducing the symptoms associated with the disease. "Treatment" as used herein covers any administration of a drug or compound to an individual to treat, cure, alleviate, improve, reduce or inhibit the disease of the individual, including but not limited to administering a drug containing the compound described herein to an individual in need.

[0037] It should be explained that the unit mM involved in the present invention is millimole per liter, that is, 1 mM = 1 mmol / L; the mass-volume ratio in the present invention refers to the weight (unit: g) of each component in every 1 ml of the ophthalmic preparation (or eye drops) system, and the unit is g / ml.

[0038] The solution of the present invention will be explained below in conjunction with the examples. Those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the examples regarding specific techniques or conditions, they shall be carried out according to the techniques or conditions described in the literature in this field or according to the product specifications. For reagents or instruments not specified for the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0039] Example 1: Consideration of Phosphate Buffers with Different Concentrations

[0040] The method for preparing eye drops comprises the following steps:

[0041] S1. Take 70% of the total volume of the eye drops as water for injection, add hydroxypropyl methylcellulose, stir and disperse, then perform high-temperature sterilization under the conditions of 121°C for 15 minutes, and cool to below 25°C to obtain Preparation Liquid 1;

[0042] S2. Weigh 20% of the total prescription amount of water for injection, add sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, and penehyclidine hydrochloride according to the prescription amounts in Table 1, stir until completely dissolved to obtain Preparation Liquid 2;

[0043] S3. Filter Preparation Liquid 2 through a 0.22-μm filter membrane and mix it with Preparation Liquid 1, make up the volume, and stir until evenly mixed to prepare the eye drops, and control the pH value of the eye drops to be 5.0 - 7.0;

[0044] S4. Perform filling by aseptic sub-packaging, conduct lamp inspection, and take the qualified eye drops.

[0045] Among them, the dosages of each raw material of the eye drops are shown in Table 1. The percentages in the table are the mass-volume ratios of each raw material to the eye drops (unit: g / ml), and the pH values are the measured values of each eye drop sample.

[0046] Table 1: Dosages of Each Raw Material of the Eye Drops

[0047] Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Total concentration of phosphate buffer 0 mM 5 mM 15 mM 25 mM 50 mM Penehyclidine hydrochloride 0.1％ 0.1％ 0.1％ 0.1％ 0.1％ Hypromellose 0.5％ 0.5％ 0.5％ 0.5％ 0.5％ Disodium hydrogen phosphate / 0.009％ 0.027％ 0.044％ 0.088％ Sodium dihydrogen phosphate / 0.053％ 0.159％ 0.267％ 0.525％ Sodium chloride 0.9％ 0.9％ 0.9％ 0.9％ 0.9％ Hydrochloric acid Appropriate amount / / / / Sodium hydroxide / / / / / Water for injection Make up to 2 L Make up to 2 L Make up to 2 L Make up to 2 L Make up to 2 L pH value 6.0 6.0 6.0 6.0 6.0

[0048] Example 2: Consideration of Different Ratios of Penehyclidine Hydrochloride to Sodium Chloride

[0049] The method for preparing the eye drops refers to Example 1. The dosages of each raw material of the eye drops are shown in Table 2. The percentages in the table are the mass-volume ratios of each raw material to the eye drops.

[0050] Table 2: Dosages of Each Raw Material of the Eye Drops

[0051]

[0052]

[0053] Example 3: Consideration of Different Concentrations of Hydroxypropyl Methylcellulose

[0054] The method for preparing the eye drops refers to Example 1. The dosages of each raw material of the eye drops are shown in Table 3. The percentages in the table are the mass-volume ratios of each raw material to the eye drops.

[0055] Table 3: Dosages of Each Raw Material of the Eye Drops

[0056] Prescription information Sample 10 Sample 11 Sample 12 Concentration of phosphate buffer 15 mM 15 mM 15 mM Penehyclidine hydrochloride 0.01％ 0.01％ 0.01％ Hypromellose 0.2％ 0.5％ 0.8％ Disodium hydrogen phosphate 0.027％ 0.027％ 0.027％ Sodium dihydrogen phosphate 0.159％ 0.159％ 0.159％ Sodium chloride 0.8％ 0.8％ 0.8％ Water for injection Make up to 2 L Make up to 2 L Make up to 2 L pH value 6.0 6.0 6.0

[0057] Test Example 1: Irritation Test of Ocular Administration in Rabbits

[0058] 1.1 Experimental materials and instruments:

[0059] 1.1.1 Experimental animals

[0060] Dutch rabbits were purchased, weighing 2.0 - 2.5 kg, with an equal number of males and females. The animals were screened.

[0061] Observed macroscopically, the corneas were not cloudy, the conjunctivas were not congested, edematous or secreting, the pupils were round, equal in size on both sides, and the light reflex was good. Examined with a slit lamp, the corneas were transparent, without nebulae or maculae; the iris texture was clear, without congestion or edema. Fluorescein staining was performed. 10% sodium fluorescein injection was diluted 5 times with normal saline temporarily. One drop was instilled into each rabbit eye and then rinsed with normal saline. Those with non-stained corneas were considered to have normal corneas. After the above pre-selection, 48 healthy Dutch rabbits without eye diseases were used for this experiment.

[0062] 1.1.2 Experimental instruments

[0063] LYL-II slit lamp microscope: Phoenix Optical Instruments

[0064] 1.2 Experimental methods

[0065] 1.2.1 Fundus examination before animal administration

[0066] 24 hours before the experiment, 1% sodium fluorescein was used to examine the eyes of each animal. Animals with eye irritation symptoms, corneal defects and conjunctival injuries could not be used for the experiment.

[0067] 1.2.2 Animal grouping

[0068] 48 Dutch rabbits were randomly divided into 12 groups, including the penehyclidine hydrochloride eye drop sample group and the penehyclidine hydrochloride excipient solution group, with 4 animals in each group, and an equal number of males and females.

[0069] 1.2.3 Administration dose and frequency

[0070] The clinically proposed dose was to administer the drug 2 times a day, once in the morning and once in the evening, 1 - 2 drops each time. The experimental design was consistent with the clinical administration route. The administration dose and frequency were 30 μL (about one drop) each time, administered once in the morning and once in the evening every day, and the administration cycle was 7 days.

[0071] 1.3 Determination of blinking frequency

[0072] 48 pre-selected healthy animals, with an equal number of males and females, were taken. The eyelashes of each group of animals were cut off, and the test substance (30 μL / eye) was instilled into the left conjunctival sac of each animal. The eye irritation was observed within 1 minute after each administration to each animal, and the number of blinks within 60 s was recorded. The average number of blinks of the left eyes of each group of animals was calculated respectively to evaluate the eye irritation of the drug (the greater the number of blinks, the greater the irritation).

[0073] 1.4. Ocular Irritation Test

[0074] Select 48 pre - selected healthy animals, with an equal number of males and females. Cut the eyelashes of each group of animals. For each group of animals, the left eye is used for drug administration, and the test substance (30 μL / eye) is instilled into the left eye conjunctival sac of each animal. Each group is instilled once in the morning and once in the evening for 7 consecutive days. Record the local irritation responses of the eyes at 1, 4, 24, and 48 hours after the last drug administration. Observe the eye conditions with the naked eye before each drug administration to each animal. The observation contents include but are not limited to redness, swelling, conjunctival congestion, and secretions.

[0075] 1.5. Results

[0076] 1.5.1. Recording of the results of the determination of the number of animal blinks Record the number of blinks within 60 s after instilling eye drops in each group of animals. The results are shown in Table 4.

[0077] Table 4: Statistics of the number of blinks

[0078] Sample information Blinking frequency / 60 s Sample information Blinking frequency / 60 s Sample 1 4±2 Sample 7 4±1 Sample 2 3±2 Sample 8 3±2 Sample 3 2±2 Sample 9 20±1 Sample 4 3±2 Sample 10 2±2 Sample 5 21±2 Sample 11 2±2 Sample 6 2±2 Sample 12 3±1

[0079] The results in Table 4 show that for Samples 1 - 4, the blinking frequency of Dutch rabbits is relatively low, indicating that the eye drops of penehyclidine hydrochloride with a phosphate buffer concentration of 0 mM - 25 mM have good irritation properties. However, the blinking frequency of Dutch rabbits for Sample 5 is significantly higher than that of other groups, and its pH value is comparable to that of Samples 1 - 4, indicating that when the phosphate buffer concentration is 50 mM, the eye drops have certain irritation to the eyes, and this irritation has no direct relationship with the pH value.

[0080] For Samples 6 - 8, the blinking frequency of Dutch rabbits is relatively low and there is no difference from that of Samples 1 - 4. In Sample 9, the dosage ratio of penehyclidine hydrochloride to sodium chloride is 1.25:1, which exceeds the dosage ratio range of penehyclidine hydrochloride to sodium chloride protected by the present invention, and the blinking frequency of Dutch rabbits is significantly higher than that of others, indicating that Sample 9 has certain irritation to the eyes.

[0081] There is no significant difference in the blinking frequency of Dutch rabbits for Samples 10 - 12, indicating that the use of hypromellose in the prescription has no effect on the irritation of the eye drops.

[0082] Therefore, for this ophthalmic preparation, when the buffer concentration is below 25 mM and the dosage ratio of penehyclidine hydrochloride to sodium chloride is (0.011 - 0.85):1, the irritation of the eye drops product can be effectively guaranteed to be small.

[0083] 1.5.2. Results of the ocular irritation test

[0084] According to the requirements of Table 5, add the irritation response scores of the cornea, iris, and conjunctiva of each animal at each observation time to obtain the total score. Divide the total score of a group by the number of animals to obtain the final score. Judge the irritation degree according to Table 6. The results are shown in Table 7.

[0085] Table 5: Scoring Criteria for Ocular Irritation Evaluation

[0086]

[0087]

[0088] Table 6: Criteria for Ocular Irritation Evaluation

[0089] Score Evaluation 0-3 Non-irritating 4-8 Mildly irritating 9-12 Moderately irritating 13-16 Severely irritating

[0090] Table 7: Ocular Irritation Test of Penehyclidine Hydrochloride Eye Drops

[0091] [[ID=!21]]

[0092]

[0093]

[0094] As can be seen from Table 7, after repeated administration of penehyclidine hydrochloride eye drops for 7 days, moderate irritation occurred in groups of sample 5 and sample 9, and no irritation reaction was observed in the remaining administration groups.

[0095] Test Example 2: Stability Test

[0096] Samples 1 - sample 4 and sample 8 were taken for a 30-day stress test to investigate the stability of the samples. The test results are shown in Table 8.

[0097] Table 8: Test Results of Stress Test

[0098]

[0099]

[0100] The above results show that samples 2 - sample 4 and sample 8 have good stability, and the unknown maximum single impurity and total impurity contents remained at a low level within 30 days under the stress test conditions. However, the impurity content of sample 1 showed a significant upward trend, indicating that the addition or not of the buffer has a certain impact on the stability of penehyclidine hydrochloride eye drops. In order to ensure the stability of the product while reducing its irritation, the concentration of the phosphate buffer was selected to be no higher than 25 mM and not 0 mM.

[0101] Test Example 3: Long-Term Toxicity Experiment of Ocular Administration in Rabbits

[0102] Observe the possible toxic reactions in Dutch rabbits after repeated conjunctival sac instillation of this product once a day for 12 consecutive weeks.

[0103] 3.1 Experimental Animals

[0104] Ordinary grade Dutch rabbits, weighing 2.0 - 3.5 kg, starting age of drug administration: 4 - 7 months old, number: 12, half male and half female, and the animals were screened.

[0105] 3.2. Animal grouping and drug administration dose

[0106] Samples 6 - 8 were selected, and the drug administration doses are shown in Table 9.

[0107] Table 9: Drug administration doses

[0108]

[0109] 3.3. Drug administration

[0110] Route of drug administration: Instillation into the conjunctival sac;

[0111] Frequency of drug administration: Instill once a day for a total of 84 days. The first day of drug administration is D1;

[0112] Volume of drug administration: 30 μL / eye / time, instill into both eyes;

[0113] Method of drug administration: The animals were administered drugs by instilling into the conjunctival sacs of both eyes according to the drug administration doses listed in Table 9 using a pipette and appropriate tips. The method of drug administration is to gently open the lower eyelid of the animal, instill 30 μL of the test article / solvent control into the eye, and close the eyelid for about 10 seconds to complete the drug administration.

[0114] 3.4. Ophthalmological examination

[0115] All animals underwent general ophthalmological examinations of the anterior segment of the eye before drug administration on D1, D8, D15, D29, D43, D57, D71, and D85. The anterior segment of the eye of all animals (eyelids, cornea, sclera, conjunctiva, iris, and lens) was observed using a slit lamp, corneal fluorochrome staining was performed using a sodium fluorescein ophthalmic test strip, and scoring was performed according to the Modified MacDonald - Shadduck Scoring System.

[0116] Anterior segment of the eye: Before drug administration, no abnormalities were observed in the anterior segment of the eye of each group of animals, and corneal fluorochrome staining was negative for all. Abnormalities in the general ophthalmological examination after drug administration are shown in Table 10. During the test period, corneal fluorochrome staining was observed in groups 1 - 4 (i.e., the solvent control group and the test article groups). Corneal fluorochrome staining indicates corneal epithelial defects, but due to the low incidence and mild degree, it is sporadic.

[0117] Table 10: Abnormalities in the general ophthalmological examination after drug administration

[0118]

[0119] Note: "+", "++", "+++", "++++" indicate slight, mild, moderate, and severe, respectively.

[0120] Fundus: No abnormalities were observed in the fundus of the animals in Groups 1-4 during the experiment.

[0121] Under the conditions of this experiment, rabbits of the Dutch breed were repeatedly instilled with phencynonate hydrochloride eye drops (Samples 6-8) into the conjunctival sacs of both eyes at a dose of 30 μL / eye / time, once a day for 12 consecutive weeks. No systemic toxic reactions were observed in the animals of each dose group. Except for an increase in the blinking frequency and mydriasis after administration, no other abnormalities were found in the eye examinations.

[0122] In the description of this specification, the descriptions with reference to terms such as "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0123] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. An ophthalmic preparation, characterized in that, Comprising: Penehyclidine hydrochloride, phosphate buffer, sodium chloride and hydroxypropyl methylcellulose; Wherein, based on the total volume of the ophthalmic preparation, the concentration of the phosphate buffer is not higher than 25 mM and not 0 mM, the mass - volume ratio of penehyclidine hydrochloride is 0.01% - 2%, and the mass ratio of penehyclidine hydrochloride to sodium chloride is (0.011 - 0.85):

1.

2. The ophthalmic preparation according to claim 1, wherein The mass - volume ratio of penehyclidine hydrochloride is 0.01% - 0.5%.

3. The ophthalmic preparation according to claim 1, wherein, The mass - volume ratio of sodium chloride is 0.3% - 0.9%.

4. The ophthalmic preparation according to claim 1, wherein The mass - volume ratio of hydroxypropyl methylcellulose is 0.2% - 0.8%.

5. The ophthalmic preparation according to claim 1, characterized in that, Based on the total volume of the ophthalmic preparation, the concentration of the phosphate buffer is not higher than 15 mM.

6. The ophthalmic preparation according to claim 1, wherein Based on the total volume of the ophthalmic preparation, the concentration of the phosphate buffer is 1 mM - 15 mM.

7. The ophthalmic preparation according to claim 1, characterized in that, The phosphate buffer comprises a buffer pair of disodium hydrogen phosphate and sodium dihydrogen phosphate; or The phosphate buffer comprises a buffer pair of dipotassium hydrogen phosphate and potassium dihydrogen phosphate.

8. The ophthalmic preparation according to claim 1, wherein The pH value of the ophthalmic preparation is 5.0 - 7.

0.

9. The ophthalmic preparation according to claim 1, wherein, Based on the total volume of the ophthalmic preparation, the mass - volume ratio of hydroxypropyl methylcellulose is 0.4% - 0.6%.

10. A method for preparing an ophthalmic preparation, characterized in that, Comprising: Dividing the water for injection into three portions; Adding one portion of the water for injection to hydroxypropyl methylcellulose and stirring until dispersed, and obtaining the preliminary solution 1 after cooling; Adding penehyclidine hydrochloride, sodium chloride and phosphate buffer to another portion of the water for injection, stirring until dissolved, and obtaining the preliminary solution 2 after filtration; Mixing the preliminary solution 1 and the preliminary solution 2, and making up the volume with the remaining water for injection to prepare the ophthalmic preparation; Wherein, based on the total volume of the ophthalmic preparation, the concentration of the phosphate buffer is not higher than 25 mM and not 0 mM, the mass - volume ratio of penehyclidine hydrochloride is 0.01% - 2%, and the mass ratio of penehyclidine hydrochloride to sodium chloride is (0.011 - 0.85):

1.

11. The method according to claim 10, wherein After the hydroxypropyl methylcellulose is dispersed in the aqueous solution, high - temperature sterilization is carried out, and the preliminary solution 1 is obtained after cooling.

12. The method according to claim 11, wherein The temperature of the sterilization is 115°C - 125°C.

13. The method according to claim 11, wherein The temperature of the sterilization is 121°C.

14. The method according to claim 11, wherein The time of the sterilization is 15 min - 35 min.

15. The method according to claim 10, characterized in that, The amount of water for injection used to prepare the preliminary solution 1 is 60% - 80% of the total volume of the ophthalmic preparation.

16. The method according to claim 10, wherein The final temperature of the cooling is 0°C - 25°C.

17. The method according to claim 10, wherein The amount of water for injection used to prepare the preliminary solution 2 is 10% - 30% of the total volume of the ophthalmic preparation.

18. The method according to claim 10, wherein Before the preliminary solution 2 is mixed with the preliminary solution 1, the preliminary solution 2 is filtered using a 0.22 - μm filter element.

19. The method according to claim 10, wherein The method further comprises: aseptically filling the ophthalmic preparation.

20. Use of the ophthalmic preparation according to any one of claims 1 to 9 or the ophthalmic preparation prepared by the method according to any one of claims 10 to 19 in the preparation of a medicament for treating and / or preventing myopia and / or amblyopia, wherein, The myopia is selected from mild myopia, moderate myopia or high myopia.

21. The use according to claim 20, wherein, The myopia includes at least one of axial myopia, refractive myopia, simple myopia, and pathological myopia.

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