An ophthalmic formulation, method of preparation and use

Abstract

The application relates to an ophthalmic preparation, a preparation method and use. The ophthalmic preparation comprises: a pentetrazol hydrochloride, a buffer and water for injection, wherein the mass / volume ratio of the pentetrazol hydrochloride is 0.001%-2%, and the total concentration of the buffer is less than or equal to 50 mM. The ophthalmic preparation can effectively treat and / or prevent visual impairment eye diseases, and has the advantages of safety, effectiveness, good stability and the like, and is suitable for popularization and application.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular to an ophthalmic preparation, a preparation method and use. BACKGROUND

[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 structure formula:

[0003]

[0004] Penehyclidine hydrochloride is a strong selective anticholinergic drug, which can bind to M and N cholinergic receptors, selectively act on M1, M3, N1 and N2 receptors, and has strong anticholinergic effect on peripheral nerves and central nerves, has no effect on M2 receptors, and can avoid the tachycardia and blocking of presynaptic membrane M2 receptor regulation function caused by lack of M receptor subtype selectivity.

[0005] Penehyclidine hydrochloride has advantages that atropine, anisodamine and other anticholinergic drugs do not have, such as strong anticholinergic effect, long duration of action, protection of bidirectional regulation mechanism of heart rate, improvement of microcirculation, low toxicity and side effects, etc. In clinical practice, it has shown a broad application prospect: treatment of organophosphorus pesticide poisoning, preoperative medication, application in respiratory diseases, anti-shock, protection against cerebral ischemia-reperfusion injury, application in digestive tract diseases and acute abdominal pain, etc. SUMMARY

[0006] The present application provides an ophthalmic preparation, a preparation method and use. The ophthalmic preparation provided by the present application can effectively prevent or treat myopia or amblyopia, and has the advantages of safety, effectiveness, stability, etc., and is suitable for popularization and application.

[0007] In one aspect of the present application, an ophthalmic preparation is provided. According to an embodiment of the present application, the ophthalmic preparation comprises the following components: penehyclidine hydrochloride, a buffer and water for injection; wherein the mass / volume ratio of penehyclidine hydrochloride is 0.001%-2%, and the total concentration of the buffer is less than or equal to 50mM.

[0008] At present, penehyclidine hydrochloride mainly exists in the form of injection solution, and is widely applied to pre-anesthesia administration to inhibit secretion of salivary glands and airway glands, emergency treatment of organophosphorus poison (pesticide) poisoning, and maintenance of atropinization after cholinesterase aging. The inventor of the present application has creatively found that penehyclidine hydrochloride has good curative effect on eye diseases such as myopia or amblyopia. Further, it is prepared into an ophthalmic preparation.

[0009] Further, at present, penehyclidine hydrochloride has poor stability in aqueous solution. After penehyclidine hydrochloride solution is stored for a long time at high temperature, the content of penehyclidine hydrochloride decreases and the related substances increase, thereby affecting the drug efficacy. The existence of impurities also easily causes side effects, and the safety of drug use is difficult to guarantee.

[0010] Therefore, the inventor has found through a large number of experiments that the stability of the system can be improved by adding a buffer, and the problems such as the increase of related substances and the decrease of the content of penehyclidine hydrochloride do not easily occur during long-term storage of the product, and the addition of no chelating agent and preservative is beneficial to improve the safety of use by patients.

[0011] According to the embodiments of the present application, the ophthalmic preparation can further include at least one of the following additional technical features:

[0012] According to the embodiments of the present application, the mass-volume ratio of penehyclidine hydrochloride is 0.01%-1% based on the total volume of the ophthalmic preparation. Thus, the prepared ophthalmic preparation has good drug efficacy.

[0013] According to the embodiments of the present application, the pH value of the ophthalmic preparation is 5.0-7.0. Thus, the pH value of the prepared ophthalmic preparation is close to that of tears, thereby avoiding discomfort to patients.

[0014] According to the embodiments of the present application, the total concentration of the buffer in the ophthalmic preparation is less than or equal to 50mM and is not 0mM. Thus, the content of related substances in the ophthalmic preparation can be reduced and the stability of the ophthalmic preparation can be improved.

[0015] According to the embodiments of the present application, the total concentration of the buffer in the ophthalmic preparation is 5-50mM. Thus, the content of related substances in the ophthalmic preparation can be reduced and the stability of the ophthalmic preparation can be improved.

[0016] According to the embodiments of the present application, the total concentration of the buffer in the ophthalmic preparation is less than or equal to 25mM. The inventor has found that when the total concentration of the buffer is 25mM or less, the related substance level of the prepared ophthalmic preparation is low during stability study.

[0017] According to an embodiment of the present application, the total concentration of the buffer in the ophthalmic preparation is 5-25 mM. Thus, the content of related substances in the ophthalmic preparation can be further reduced and the stability of the ophthalmic preparation can be improved.

[0018] According to an embodiment of the present application, the buffer comprises at least one selected from a phosphate buffer pair, a citrate buffer pair and a tartrate buffer pair.

[0019] According to an embodiment of the present application, the phosphate buffer pair is selected from a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate or a combination of dipotassium hydrogen phosphate and potassium dihydrogen phosphate; or the citrate buffer pair is selected from citric acid and sodium citrate; or the tartrate buffer pair is selected from tartaric acid and sodium tartrate. Among them, disodium hydrogen phosphate, sodium citrate, sodium tartrate, dipotassium hydrogen phosphate are basic salts in the buffer; sodium dihydrogen phosphate, citric acid, tartaric acid, potassium dihydrogen phosphate are acidic salts in the buffer.

[0020] According to an embodiment of the present application, in the phosphate buffer pair, the content of the acid salt is greater than that of the base salt; in the citrate buffer pair and the tartrate buffer pair, the content of the acid salt is less than that of the base salt.

[0021] Exemplarily, in the ophthalmic preparation, the total concentration of the buffer is less than or equal to 50 mM, wherein the addition amount of sodium dihydrogen phosphate is greater than that of disodium hydrogen phosphate; the addition amount of citric acid is less than that of sodium citrate; and the addition amount of tartaric acid is less than that of sodium tartrate. Thus, the prepared ophthalmic preparation has the advantages of low impurity content and stability.

[0022] According to an embodiment of the present application, the ophthalmic preparation further comprises an osmotic pressure regulator and / or a thickening agent.

[0023] According to an embodiment of the present application, the mass-volume ratio of the osmotic pressure regulator is 0.3%-5% based on the total volume of the ophthalmic preparation. According to an embodiment of the present application, a pharmaceutically acceptable osmotic pressure regulator is selected to make the osmotic pressure of the prepared ophthalmic preparation be 240 mOsmol / kg-340 mOsmol / kg, which is close to the osmotic pressure of normal human tear fluid.

[0024] According to an embodiment of the present application, the osmotic pressure regulator comprises but is not limited to at least one selected from sodium chloride, glucose, glycerol and sorbitol.

[0025] According to an embodiment of the present application, the mass-volume ratio of the thickening agent is 0.2%-6% based on the total volume of the ophthalmic preparation.

[0026] According to an embodiment of the present application, the ophthalmic preparation is prepared by using a pharmaceutically acceptable thickening agent, so that the viscosity of the ophthalmic preparation is less than 45 mPa.s, which is acceptable in human eyes and can effectively control the residence time of the drug in the eyes.

[0027] According to an embodiment of the present application, the thickening agent includes, but is not limited to, at least one selected from the group consisting of hydroxypropyl methyl cellulose, polyvinyl alcohol, cross-linked polyvidone, chitosan and sodium hyaluronate.

[0028] In another aspect of the present application, a method for preparing the ophthalmic preparation is provided. According to an embodiment of the present application, the method includes the step of mixing the ivisatide hydrochloride, the buffer and the water for injection to prepare the ophthalmic preparation. The method according to an embodiment of the present application is simple to operate and can produce the ophthalmic preparation which is safe, effective and stable in quality.

[0029] According to an embodiment of the present application, when the ophthalmic preparation is in a liquid form, the method further includes the steps of: dividing the water for injection into three portions; adding one portion of the water for injection to the thickening agent and stirring until the thickening agent is dispersed to obtain a first preparation; adding the ivisatide hydrochloride, the osmotic pressure adjusting agent and the buffer to another portion of the water for injection and stirring until the ivisatide hydrochloride, the osmotic pressure adjusting agent and the buffer are dissolved to obtain a second preparation; mixing the first preparation and the second preparation, and then adding the remaining portion of the water for injection to prepare the ophthalmic preparation. In this way, the above batch mixing method can make the substances fully dissolved and uniformly dispersed, thereby improving the stability of the system and helping to better exert the drug efficacy.

[0030] According to an embodiment of the present application, the amount of the water for injection used for preparing the first preparation is 60% to 80% of the total volume of the ophthalmic preparation. In this way, the thickening agent can be fully dissolved, the stability of the system can be improved, and the impurity content in the ophthalmic preparation can be reduced.

[0031] According to an embodiment of the present application, the amount of the water for injection used for preparing the second preparation is 10% to 30% of the total volume of the ophthalmic preparation. The inventors have found through a large number of experiments that dissolving the ivisatide hydrochloride, the osmotic pressure adjusting agent and the buffer first can improve the stability of the ophthalmic preparation and reduce the impurity content in the ophthalmic preparation.

[0032] According to an embodiment of the present application, the second preparation is filtered before being mixed with the first preparation. In this way, the microorganisms in the ophthalmic preparation can be removed, thereby prolonging the shelf life.

[0033] According to an embodiment of the present application, the method further includes that the ophthalmic preparation is sterilely divided into single doses and packaged in a single-dose package. In this way, the single sample of the product can effectively avoid the contamination of the sample due to storage after opening, thereby prolonging the shelf life.

[0034] In yet another aspect of the present application, the present application provides use of the above-mentioned ophthalmic preparation or the ophthalmic preparation prepared by the above-mentioned method in the preparation of a medicament for treating and / or preventing a visual impairment eye disease, especially for treating and / or preventing myopia and / or amblyopia and the like visual impairment eye disease, wherein the myopia and / or amblyopia include, but are not limited to, one or more of mild myopia, moderate myopia, high myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, reduced distance vision, visual fatigue, exotropia, strabismic amblyopia, elongation of the eye axis, fundus damage, visual obstruction, metamorphopsia, multiple images, color vision abnormality, light perception abnormality, decreased contrast sensitivity, aniseikonic amblyopia, ametropic amblyopia, unilateral form deprivation amblyopia, bilateral form deprivation amblyopia. The cause of the myopia and / or amblyopia is selected from one or more of myopic shift of diopter, elongation of myopic vitreous cavity depth, elongation of myopic eye axial length, form deprivation, aniseikonia and astigmatism. It should be noted that the visual impairment eye disease described in the present application does not include visual problems caused by trauma.

[0035] Additional aspects and advantages of the present application will be in part apparent and in part pointed out below in the description of embodiments of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0036] The above and / or additional aspects and advantages of the present application will become apparent and be readily appreciated from the following description of embodiments, given by way of example, and with reference to the following drawings, wherein:

[0037] Figure 1 The diopter measurement results of the model eyes of each group of animals in Example 6 of the present application at 0 days before the test, 30 days after the test and 60 days after the test, respectively;

[0038] Figure 2 The axial length measurement results of the model eyes of each group of animals in Example 6 of the present application at 0 days before the test, 30 days after the test and 60 days after the test, respectively. DETAILED DESCRIPTION

[0039] Embodiments of the present application are described in detail below. The embodiments described below are exemplary only and are not to be construed as limiting the present application.

[0040] It should be noted that the terms "first", "second" are used only for descriptive purposes and should not be construed as indicating or implying relative importance or a specific number of the technical features indicated. Thus, the features defined with "first", "second" can explicitly or implicitly include one or more of the features. Further, in the description of the present application, unless otherwise specified, the meaning of "a plurality of" is two or more.

[0041] The schemes of the present application will be explained below in connection with examples. Those skilled in the art will understand that the examples below are only for illustration of the present application and should not be regarded as limiting the scope of the present application. The specific techniques or conditions not mentioned in the examples are carried out according to the techniques or conditions described in the literature in the art or according to the product instructions. The reagents or instruments not mentioned by the manufacturer are all conventional products that can be obtained commercially.

[0042] It should be explained that the unit mM in the present application is millimoles per liter, i.e. 1 mM = 1 mmol / L; "W / V" and "mass volume ratio" in the present application are synonymous, which means the weight (unit g) of the ingredient contained in each 1 ml of liquid system, with the unit g / ml.

[0043] It should be explained that "related substances" in the examples refer to the impurity content.

[0044] The buffer in the examples of the present application is anhydrous.

[0045] Test Example 1: Stability study of aqueous solution of pentaerythrityl tetranitrate

[0046] The method for preparing the aqueous solution of pentaerythrityl tetranitrate comprises the following steps:

[0047] Different amounts of pentaerythrityl tetranitrate were taken, water for injection was added and stirred until completely dissolved, then filtered through a 0.22 μm filter membrane, and the pH value was adjusted to 6.0-6.2 to prepare the aqueous solution of pentaerythrityl tetranitrate with different concentrations as shown in Table 1.

[0048] Among them, the amounts of each raw material of the aqueous solution of pentaerythrityl tetranitrate are shown in Table 1, wherein the percentage in Table 1 is the mass volume ratio (W / V) of each raw material to the aqueous solution of pentaerythrityl tetranitrate; the test results of solution influencing factors are shown in Table 2.

[0049] Table 1: Amounts of each component of the aqueous solution of pentaerythrityl tetranitrate

[0050] Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Pentetrazol 0.001％ 0.01％ 0.1％ 1％ 2％ 1 mol / L hydrochloric acid solution q.s. q.s. q.s. q.s. q.s. 1 mol / L sodium hydroxide solution q.s. q.s. q.s. q.s. q.s. Water for injection q.s. to 2 L q.s. to 2 L q.s. to 2 L q.s. to 2 L q.s. to 2 L

[0051] Table 2: Test results of influencing factors of samples 1-5

[0052]

[0053]

[0054] As shown in Table 1-2, the aqueous solution of penehyclidine hydrochloride with the specifications of 0.001%-2% (W / V) is placed under high temperature and light for 30 days, the quality indexes such as the product properties and content of different specifications all meet the requirements, the pH value fluctuates in the range of 5.0-7.0, the change is within the acceptable range, but the content of related substances such as the maximum single impurity and total impurities increases obviously. It is indicated that when no auxiliary materials such as buffer are added, the stability of penehyclidine hydrochloride in the aqueous solution is poor, and if the aqueous preparation such as injection or eye drop is prepared, the quality of the product will obviously decrease with the storage of the preparation.

[0055] Example 1: Influence of different concentrations of buffer on the stability of aqueous solution of penehyclidine hydrochloride

[0056] The method for preparing the aqueous solution of penehyclidine hydrochloride containing buffer comprises the following steps:

[0057] The total amount of water for injection is weighed, the buffer, penehyclidine hydrochloride and sodium chloride are added according to the prescription amount, and stirred until completely dissolved. After being filtered through a 0.22 μm filter membrane, the solution is stirred to uniformity, and the aqueous solution of penehyclidine hydrochloride with different buffer concentrations as shown in Table 3 is prepared.

[0058] The use amount of each raw material of the aqueous solution of penehyclidine hydrochloride is shown in Table 3, and the percentage in the table is the mass / volume ratio of each raw material to the aqueous solution. The buffer feeding ratio is shown in the following table. The solution influence factor test results are shown in Table 4.

[0059] Table 3: Use amount of each component of the aqueous solution of penehyclidine hydrochloride

[0060] Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Total concentration of buffer 0 mM 5 mM 25 mM 50 mM 75 mM Pentetrazol 0.1％ 0.1％ 0.1％ 0.1％ 0.1％ Disodium hydrogen phosphate / 0.009％ 0.044％ 0.088％ 0.132％ Monosodium phosphate / 0.053％ 0.267％ 0.525％ 0.78％ Hydrochloric acid q.s. / / / / Sodium hydroxide q.s. / / / / Water for injection q.s. to 2 L q.s. to 2 L q.s. to 2 L q.s. to 2 L q.s. to 2 L

[0061] Table 4: Influence factor test results of samples 1-5

[0062]

[0063]

[0064] Example 2: Influence of thickening agent and osmotic pressure regulator on penehyclidine hydrochloride eye drops

[0065] The thickening agent and osmotic pressure regulator are added to prepare the penehyclidine hydrochloride eye drops, and the method comprises the following steps:

[0066] S1, 70% of the total volume of the composition is taken as water for injection, the thickening agent (hydroxypropyl methyl cellulose) is added and stirred to disperse sufficiently, and the prepared solution 1 is obtained;

[0067] S2, 20% of the total amount of water for injection is weighed, and the buffer, osmotic pressure regulator (sodium chloride) and penehyclidine hydrochloride are added according to the prescription amount, and stirred until completely dissolved, and the prepared solution 2 is obtained;

[0068] S3, after the preparation solution 2 is filtered through a 0.22 μm filter membrane, the preparation solution 1 is mixed, and after constant volume, stirring is performed until the mixture is uniform, to prepare an eye drop solution;

[0069] S4, sterile dispensing is used for filling, lamp inspection is performed, and the qualified eye drop solution is taken.

[0070] Among them, the amount of each raw material of penehyclidine hydrochloride eye drops is shown in Table 5, wherein the percentage in the table is the mass volume ratio (W / V) of each raw material to the eye drops; the test results of the influencing factors are shown in Table 6.

[0071] Table 5: Penehyclidine hydrochloride eye drops with different prescription compositions

[0072] Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Total concentration of buffer 0 mM 5 mM 25 mM 50 mM 75 mM Pentetrazol 0.1％ 0.1％ 0.1％ 0.1％ 0.1％ Hydroxypropyl methylcellulose 0.5％ 0.5％ 0.5％ 0.5％ 0.5％ Disodium hydrogen phosphate / 0.009％ 0.044％ 0.088％ 0.132％ Monosodium phosphate / 0.053％ 0.267％ 0.525％ 0.788％ Hydrochloric acid q.s. / / / / Sodium hydroxide q.s. / / / / Sodium chloride 0.85％ 0.85％ 0.85％ 0.85％ 0.85％ Water for injection q.s. to 2 L q.s. to 2 L q.s. to 2 L q.s. to 2 L q.s. to 2 L

[0073] Table 6: Test results of influencing factors of samples 1-5

[0074]

[0075]

[0076] The above results show that when phosphoric acid buffer salt is added to penehyclidine hydrochloride eye drops, the stability of the preparation is significantly improved, mainly in that the unknown maximum single impurity and total impurity content remain at a low level within 30 days under the influence factor test conditions. However, the inventors found that not all concentrations of phosphoric acid buffer salt can achieve better impurity reduction effect. When the concentration of the phosphoric acid buffer salt is equal to or lower than 50 mM, the impurity content of the solution is lower within 30 days, and the impurity content reduction effect of different concentrations of buffer salt is relatively stable. However, when the concentration of the buffer salt is greater than 50 mM (for example, reaching 75 mM), the impurity content of penehyclidine hydrochloride eye drops still shows a significant upward trend. This result shows that the concentration of the buffer has a significant effect on the stability of penehyclidine hydrochloride eye drops.

[0077] To study other factors affecting the stability of pirenzepine hydrochloride eye drops, the effects of thickening agent and osmotic pressure regulator on the stability were also investigated. It was found that the addition of thickening agent and osmotic pressure regulator did not affect the stability of pirenzepine hydrochloride eye drops maintained by phosphate buffer. The main results are as follows: when only thickening agent and osmotic pressure regulator were added without phosphate buffer, the impurity content increased significantly within 30 days under the influence of the test conditions. When thickening agent, osmotic pressure regulator and phosphate buffer were added at the same time, the impurity content remained at a low level within 30 days under the influence of the test conditions. When the concentration of phosphate buffer in the solution was less than or equal to 50 mM, the impurity remained at a lower level. When the concentration of phosphate buffer in the solution was greater than 50 mM (e.g. 75 mM), the impurity content showed a significant upward trend. This result indicates that the thickening agent and osmotic pressure regulator have no significant effect on the stability of pirenzepine hydrochloride eye drops.

[0078] In summary, the stability of pirenzepine hydrochloride eye drops mainly depends on the concentration of the buffer.

[0079] Example 3: Investigation of accelerated and long-term stability

[0080] The samples 2-5 in Example 2 were stored at 40°C ± 2°C and 75% RH ± 5% RH for accelerated stability study, and the test results are shown in Table 7. The samples were stored at 25°C ± 2°C and 60% RH ± 5% RH for long-term stability study, and the test results are shown in Table 8.

[0081] Table 7: Test results of accelerated test

[0082]

[0083]

[0084]

[0085] The results of accelerated and long-term tests are consistent with the trend of the results of the influence factor test. However, the increase in impurity content of sample 5 is more obvious in the long-term stability test, further confirming the effect of buffer and buffer concentration on the stability of the preparation. When the buffer concentration is 50 mM or less, the properties, pH value, content and related substances of the preparation do not change significantly. When the buffer concentration is 75 mM, the product quality still meets the requirements at 0 days, but the related substance content increases significantly as the stability study time increases.

[0086] Example 4: Effect of buffer on pirenzepine hydrochloride eye drops with different concentrations

[0087] The method for preparing eye drops comprises the following steps:

[0088] S1, take the total volume of 80% of the injection water, add thickening agent (sodium hyaluronate), stirring to make it fully dispersed, get the preparation liquid 1;

[0089] S2, take the total volume of 10% of the injection water, according to the prescription amount of buffer, osmotic pressure regulator (glucose), adding penehyclidine hydrochloride, stirring to completely dissolved, get the preparation liquid 2;

[0090] S3, the preparation liquid 2 is filtered through 0.22 μm filter membrane and mixed with the preparation liquid 1, constant volume after stirring to mix evenly, prepared eye drops;

[0091] S4, using sterile way of filling, lamp inspection, take the qualified eye drops.

[0092] Among them, the dosage of each raw material of eye drops is shown in table 9, wherein the percentage in the table is the mass volume ratio (W / V) of each raw material and eye drops; the test results of influencing factors are shown in table 10.

[0093] Table 9: the dosage of each component of eye drops

[0094] Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Total concentration of buffer 25 mM 25 mM 25 mM 25 mM 25 mM Pentetrazol 0.001％ 0.01％ 0.1％ 1％ 2％ Sodium hyaluronate 0.2％ 0.2％ 0.2％ 0.2％ 0.2％ Disodium hydrogen phosphate 0.044％ 0.044％ 0.044％ 0.044％ 0.044％ Monosodium phosphate 0.267％ 0.267％ 0.267％ 0.267％ 0.267％ Glucose 4％ 4％ 4％ 4％ 4％ Water for injection q.s. to 2 L q.s. to 2 L q.s. to 2 L q.s. to 2 L q.s. to 2 L

[0095] Table 10: test results of eye drops

[0096]

[0097] From table 9-10, it can be seen that the penehyclidine hydrochloride eye drops in the specification of 0.001%-2% (W / V), after adding buffer, the quality indexes of product such as appearance, pH value, content, related substances are stable and meet the requirements, especially the impurity content is at a low level, which shows that the eye drops show good stability.

[0098] Example 5: buffer type investigation

[0099] The method for preparing eye drops comprises the following steps:

[0100] S1, take the total volume of 60% of the injection water, add thickening agent (hydroxypropyl methyl cellulose), stirring to make it fully dispersed, get the preparation liquid 1;

[0101] S2, take the total volume of 30% of the injection water, according to the prescription amount of buffer, osmotic pressure regulator (sodium chloride), adding penehyclidine hydrochloride, stirring to completely dissolved, get the preparation liquid 2;

[0102] S3, the preparation liquid 2 is filtered through 0.22 μm filter membrane and mixed with the preparation liquid 1, constant volume after stirring to mix evenly, prepared eye drops;

[0103] S4, filling by aseptic packaging, lamp inspection, and taking the qualified eye drops.

[0104] The amount of each raw material of the eye drops is shown in Table 11, wherein the percentage in the table is the mass / volume ratio (W / V) of each raw material to the eye drops; and the test results of the influence factors are shown in Table 12.

[0105] Table 11: Amount of each component of the eye drops

[0106] Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Total concentration of buffer 5 mM 5 mM 5 mM 5 mM 5 mM Pentetrazol 0.01％ 0.01％ 0.01％ 0.01％ 0.01％ Hydroxypropyl methylcellulose 0.5％ 0.5％ 0.5％ 0.5％ 0.5％ Disodium hydrogen phosphate 0.009％ 0.058％ / / / Monosodium phosphate 0.053％ 0.003％ / / / Citric acid / / 0.02％ 0.098％ / Sodium citrate / / 0.12％ 0.01％ / Tartaric acid / / / / 0.001％ Sodium tartrate / / / / 0.112％ Hydrochloric acid / q.s. / / / Sodium hydroxide / / / q.s. / Sodium chloride 0.85％ 0.85％ 0.85％ 0.85％ 0.85％ Water for injection q.s. to 2 L q.s. to 2 L q.s. to 2 L q.s. to 2 L q.s. to 2 L

[0107] Table 12: Test results of the influence factors of the eye drops

[0108]

[0109]

[0110] As shown in Tables 11-12, when other buffer agents such as citrate buffer or tartrate buffer are used, the maximum unknown single impurity and total impurity contents are low and do not change significantly within 30 days under the influence factor test conditions, and the stability of the preparation is good. The inventors have also found that when the content of the acid salt of the phosphate buffer is greater than that of the alkali salt, and the content of the acid salt of the citrate buffer pair and the tartrate buffer pair is less than that of the alkali salt, the impurity level of the preparation is kept in a lower range, and the stability of the preparation is optimal.

[0111] Example 6: Rabbit experimental form deprivation myopia model experiment

[0112] Experimental animals: New Zealand white rabbits, irradiated with natural light during the day, the light and dark cycle ratio is 12h:12h, and the room temperature is controlled at 20-23℃. The left eye was used for modeling (i.e. the modeling eye), and the right eye was not treated (i.e. the control eye).

[0113] New Zealand rabbits were screened for 40, randomly divided into 5 groups: test product group to select Example 4 samples 1-4, negative control group to select PBS, 8 in each group. The modeling method is isoflurane inhalation anesthesia, using cyano acrylate glue, the self-made styrene plastic diffuser nylon fastener bottom and the skin around the eye are bonded, confirming the bonding is firm, the diffuser can be freely installed and removed, there is no light leakage except the diffuser, the disinfection and surgical process is controlled within 3-5 minutes, the animals wake up after 5-10 minutes, on the same day of modeling, samples 1-4 of Example 4, phosphate buffered saline (PBS) are used, and eye drops are given in the conjunctival sac of the modeling eye, 1 time / day, 20 μl / eye / time, for 60 consecutive days. During the test period, the animal state and diffuser adhesion state are observed once a day. The refractive power and eye axial length of the modeling eye and the control eye are measured using a retinoscope and A-mode before the test (0 months), 30 days after the test (1 month), and 60 days after the test (2 months), respectively. The results show that, compared with the control eye, the refractive power of the modeling eye is significantly reduced, that is, the myopia model of the modeling eye is successfully modeled. The effects of samples 1-4 and PBS on the refractive power and eye axial length of the modeling eye are shown in Table 1. Figures 1-2 .

[0114] The results show that, compared with 0 months, the refractive power values of each group of modeling eyes in different time periods are statistically different. After 30 days of administration, the PBS eye drop group induced-2.10±1.03 relative myopia in the modeling eye, and the refractive power of each administration group was shifted towards myopia. After 60 days of administration, the PBS group induced-3.00±0.91 relative myopia in the modeling eye, and the samples 1-4 groups induced-0.82±0.17, -0.67±0.19, -0.35±0.35, and -0.23±1.12 relative myopia in the modeling eye, respectively, and the refractive power values of each administration group were significantly lower than those of the PBS group (P<0.05%).

[0115] After 60 days of administration, the eye axial lengths of the samples 1-4 modeling eye groups were 13.49±0.21, 13.36±0.24, 13.18±0.32, and 13.23±0.25, respectively, which were much lower than the 13.80±0.36 of the PBS group, and the increase in eye axial length of each administration group after 60 days was lower than that of the PBS group compared with 0 days. It shows that the penehyclidine hydrochloride eye preparation has obvious therapeutic effect on myopia.

[0116] In the description of the specification, the description of the terms "one embodiment", "some embodiments", "an example", "a specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are contained in at least one embodiment or example of the present application. In the specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any suitable manner in any one or more embodiments or examples. In addition, the person skilled in the art can combine and combine the different embodiments or examples described in the specification and the features of the different embodiments or examples without contradiction.

[0117] Although the embodiments of the present application have been shown and described above, it is understood that the above-described embodiments are exemplary and are not to be construed as limiting the present application, and the person skilled in the art can make changes, modifications, replacements and variations to the above-described embodiments within the scope of the present application.

Claims

1. An ophthalmic formulation characterized in that, The ophthalmic preparation comprises: penehyclidine hydrochloride, a buffer, and water for injection; wherein the mass / volume ratio of penehyclidine hydrochloride is 0.001%-2% based on the total volume of the ophthalmic preparation; the total concentration of the buffer is less than or equal to 50 mM; the buffer comprises at least one of a phosphate buffer pair, a citrate buffer pair, and a tartrate buffer pair; the phosphate buffer pair is selected from the group consisting of a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate or a combination of dipotassium hydrogen phosphate and potassium dihydrogen phosphate; the citrate buffer pair is selected from citric acid and sodium citrate; and the tartrate buffer pair is selected from tartaric acid and sodium tartrate.

2. The ophthalmic formulation of claim 1, wherein, The mass / volume ratio of penehyclidine hydrochloride is 0.01%-1% based on the total volume of the ophthalmic preparation.

3. The ophthalmic formulation of claim 1, wherein, The total concentration of the buffer is less than or equal to 25 mM.

4. The ophthalmic formulation according to any one of claims 1 to 3, characterized in that, Further comprising an osmotic pressure regulator and / or a thickening agent.

5. The ophthalmic formulation of claim 1, wherein The ophthalmic preparation can comprise a pH regulator, and the pH value of the ophthalmic preparation is in the range of 5.0-7.

0.

6. Use of the ophthalmic preparation according to any one of claims 1-5 in the preparation of a medicament for treating and / or preventing myopia.

7. Use according to claim 6, characterized in that, The cause of the myopia is selected from one or more of myopic shift in diopter, elongation of myopic vitreous cavity depth, and elongation of myopic axial length.

8. Use according to claim 6, characterized in that, The myopia comprises one or more of mild myopia, moderate myopia, high myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, and reduced distance vision. The myopia comprises one or more of mild myopia, moderate myopia, high myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, and reduced distance vision.

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