Ophthalmic formulations, methods of making and uses thereof

Abstract

The present application relates to an ophthalmic preparation, which comprises: penehyclidine hydrochloride, hypromellose and water; wherein the mass-volume ratio of the penehyclidine hydrochloride is 0.01%-2% based on the total volume of the ophthalmic preparation, the hypromellose contains 27.0%-30.0% of methoxyl groups and 7.0%-12.0% of hydroxypropoxyl groups, and the viscosity of a 0.5% hypromellose aqueous solution is 0.5-15 mPa·s. The ophthalmic preparation has the advantages of low irritation and high stability.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular to an ophthalmic preparation and a preparation method and use thereof. 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] 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 strong anticholinergic effects on peripheral nerves and central nerves, without effect on M2 receptors, thereby avoiding tachycardia and blocking presynaptic membrane M2 receptor regulation caused by lack of M receptor subtype selectivity.

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

[0006] Patent 202111023964.4 discloses the use of penehyclidine hydrochloride for preventing and treating myopia and amblyopia. The applicant found in the test that penehyclidine hydrochloride has poor stability in aqueous solution, and after long-term storage, the content of penehyclidine hydrochloride decreases and the content of related substances increases. Through detection, it is found that the main reason for the decrease of the content of penehyclidine hydrochloride is that penehyclidine hydrochloride degrades in its aqueous solution during storage, resulting in an increase in impurity content and affecting the quality of the product. SUMMARY

[0007] The present application provides an ophthalmic preparation, a preparation method and use thereof. The ophthalmic preparation provided by the present application can effectively prevent or treat myopia or amblyopia, and has the advantages of safety, effectiveness and good stability, and is suitable for popularization and application.

[0008] The eye preparation of the present application has good stability, and the impurity content can be kept at a low level during storage, especially the content of 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinine oxide (hereinafter referred to as impurity B) can be significantly inhibited from increasing. The increase of the content of impurity B can cause the quality and efficacy of the eye preparation of penehyclidine hydrochloride to be unstable. The structure of impurity B is as follows:

[0009]

[0010] In one aspect of the present application, an eye preparation is provided. According to an embodiment of the present application, the eye preparation comprises: penehyclidine hydrochloride, hypromellose, and water for injection; wherein the mass / volume ratio of penehyclidine hydrochloride is 0.001%-2%, the mass percentage of methoxyl in the hypromellose is 27.0%-30.0%, the mass percentage of hydroxypropoxyl in the hypromellose is 7.0%-12.0%, and the viscosity of 0.5% hypromellose aqueous solution is 0.5-15 mPa·s.

[0011] The inventors of the present application have found that penehyclidine hydrochloride has good efficacy for eye diseases such as myopia or amblyopia. However, the inventors have found through experiments that penehyclidine hydrochloride has poor stability in aqueous solution, and after high-temperature or long-term storage, the content of related substances increases, and the content of penehyclidine hydrochloride decreases. The inventors have unexpectedly found that the stability of penehyclidine hydrochloride can be improved and the generation of related impurities can be reduced by adding hypromellose with a certain cross-linking degree / degree of substitution.

[0012] Preferably, by selecting carboxymethyl cellulose with the following performance parameters, the mass percentage of methoxyl in the hypromellose is 27.0%-30.0%, the mass percentage of hydroxypropoxyl in the hypromellose is 7.0%-12.0%, and the viscosity of 0.5% hypromellose aqueous solution is 0.5-15 mPa·s, the stability of the preparation can be significantly improved, and the content of impurities and the content of penehyclidine hydrochloride are not likely to increase significantly during storage of the product, especially the content of impurity B in the product solution is kept low.

[0013] Preferably, the type of the carboxymethyl cellulose can be 2910E6 (also referred to as 2910(LV)E6), 2910E15 (also referred to as 2910(LV)E15), or 2910E50 (also referred to as 2910(LV)E50).

[0014] According to an embodiment of the present application, the mass percentage of methoxyl in the hypromellose is 28.0%-30.0%.

[0015] According to an embodiment of the present application, the mass percentage of hydroxypropoxyl in the hypromellose is 6.0%-9.0%.

[0016] According to an embodiment of the present application, the hydroxypropyl methyl cellulose has a viscosity of 1-10 mPa-s in 0.5% hydroxypropyl methyl cellulose aqueous solution.

[0017] According to an embodiment of the present application, the mass / volume ratio of the hydroxypropyl methyl cellulose is 0.2%-1.0% based on the total volume of the ophthalmic preparation.

[0018] According to an embodiment of the present application, the mass / volume ratio of the hydroxypropyl methyl cellulose is 0.2%-0.8% based on the total volume of the ophthalmic preparation.

[0019] According to an embodiment of the present application, the mass / volume ratio of the hydroxypropyl methyl cellulose is 0.4%-0.6% based on the total volume of the ophthalmic preparation.

[0020] According to an embodiment of the present application, the mass / volume ratio of the penehyclidine hydrochloride is 0.01%-1% based on the total volume of the ophthalmic preparation.

[0021] According to an embodiment of the present application, the mass / volume ratio of the penehyclidine hydrochloride is 0.01%-0.5% based on the total volume of the ophthalmic preparation.

[0022] According to an embodiment of the present application, the ophthalmic preparation further comprises a pharmaceutically acceptable osmotic pressure regulator, so that the osmotic pressure of the prepared ophthalmic preparation is 240-340 mOsmol / kg, which is close to the osmotic pressure of normal human tear.

[0023] According to an embodiment of the present application, the osmotic pressure regulator is sodium chloride.

[0024] According to an embodiment of the present application, the mass / volume ratio of the osmotic pressure regulator sodium chloride is 0.3%-1.4% based on the total volume of the ophthalmic preparation.

[0025] According to an embodiment of the present application, the mass / volume ratio of the osmotic pressure regulator sodium chloride is 0.5%-1.2% based on the total volume of the ophthalmic preparation.

[0026] According to an embodiment of the present application, the ophthalmic preparation further comprises a buffer, and the total concentration of the buffer is less than or equal to 50 mM.

[0027] According to an embodiment of the present application, the total concentration of the buffer in the ophthalmic preparation is not higher than 25 mM.

[0028] According to an embodiment of the present application, the total concentration of the buffer in the ophthalmic preparation is not higher than 15 mM.

[0029] According to an embodiment of the present application, the buffer in the ophthalmic preparation comprises at least one selected from phosphate buffer, citrate buffer, and tartrate buffer.

[0030] According to an embodiment of the present application, the phosphate buffer in the ophthalmic preparation 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 is citric acid and sodium citrate; and the tartrate buffer is tartaric acid and sodium tartrate.

[0031] According to an embodiment of the present application, the pH value of the ophthalmic preparation is 5.0-7.0.

[0032] According to an embodiment of the present application, the method for preparing the ophthalmic preparation comprises the following steps: dividing water for injection into three portions; adding one portion of the water for injection to hydroxypropyl methyl cellulose and stirring until the hydroxypropyl methyl cellulose is dispersed to obtain a preliminary solution 1; adding the penehyster, an osmotic pressure regulator, and a buffer to another portion of the water for injection and stirring until the penehyster, the osmotic pressure regulator, and the buffer are dissolved to obtain a preliminary solution 2; mixing the preliminary solution 1 and the preliminary solution 2, and then adding water for injection to obtain the ophthalmic preparation. In this way, the above-mentioned batch mixing method can make the substances fully dissolved and uniformly dispersed, improve the stability of the system, and help to better exert the drug efficacy. The mass / volume ratio of the penehyster is 0.01%-2%, the mass percentage of methoxyl in the hydroxypropyl methyl cellulose is 27.0%-30.0%, the mass percentage of hydroxypropoxy in the hydroxypropyl methyl cellulose is 7.0%-12.0%, and the viscosity (0.5% hydroxypropyl methyl cellulose aqueous solution) is 0.5-15 mPa·s. The method according to an embodiment of the present application is simple to operate and can produce a safe, effective, and stable ophthalmic preparation.

[0033] According to an embodiment of the present application, the amount of the water for injection used for preparing the preliminary solution 1 is 60%-80% of the total volume of the ophthalmic preparation. According to an embodiment of the present application, the amount of the water for injection used for preparing the preliminary solution 2 is 10%-30% of the total volume of the ophthalmic preparation. The inventor has found through a large number of experiments that dissolving the penehyster, the osmotic pressure regulator, and the buffer first can improve the uniformity of the ophthalmic preparation.

[0034] According to an embodiment of the present application, after the hydroxypropyl methyl cellulose is dispersed in the aqueous solution, high-temperature sterilization is performed, and the preliminary solution 1 is obtained after cooling. According to an embodiment of the present application, the sterilization temperature is 115°C-125°C, and preferably 121°C, and the sterilization time is 15 min-35 min.

[0035] According to an embodiment of the present application, the preliminary solution 2 is filtered using a 0.22 μm filter before being mixed with the preliminary solution 1.

[0036] According to an embodiment of the present application, the method further comprises: sterilely dispensing the ophthalmic preparation.

[0037] In yet another aspect of the present application, the present application provides use of the aforementioned ophthalmic preparation or the ophthalmic preparation prepared according to the aforementioned method in the preparation of a medicament for treating and / or preventing myopia and / or amblyopia.

[0038] In the present application, "myopia" generally refers to the phenomenon that a clear image cannot be formed on the retina; "amblyopia" generally refers to the phenomenon that the best corrected visual acuity of one or both eyes is lower than that of a normal child of the corresponding age during the visual development period due to abnormal visual experience, and there is no organic lesion in the eye examination. The myopia and / or amblyopia includes at least one selected from the group consisting of mild myopia, moderate myopia, high myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, reduced distance vision, exotropia, strabismic amblyopia, anisometropic amblyopia, ametropic amblyopia, unilateral form deprivation amblyopia and bilateral form deprivation amblyopia.

[0039] In yet another aspect of the present application, the present application provides a method for treating and / or preventing myopia and / or amblyopia. According to an embodiment of the present application, the method comprises: administering an effective amount of the aforementioned ophthalmic preparation or the ophthalmic preparation prepared according to the aforementioned method to a subject. The method of the present application can effectively treat and / or prevent myopia and / or amblyopia.

[0040] Compared with the prior art, the ophthalmic preparation provided by the present application has the following beneficial effects:

[0041] 1. The ophthalmic preparation of the present application has good stability, mainly reflected in that the content of the main drug, ICI, is stable, and the content of impurities, especially the content of impurity B, can be kept at a low level during the storage of the product, meeting the requirements of product quality standards;

[0042] 2. The ophthalmic preparation of the present application has good safety and less eye irritation, and has good patient compliance;

[0043] 3. The ophthalmic preparation of the present application has good prevention and treatment effects on mild myopia, moderate myopia, high myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, reduced distance vision, exotropia, strabismic amblyopia, anisometropic amblyopia, ametropic amblyopia, unilateral form deprivation amblyopia and bilateral form deprivation amblyopia.

[0044] Additional aspects and advantages of the present application will be partially given in the following description, partially will become obvious from the following description, or will be understood by the practice of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0045] Hereinafter, embodiments of the present application will be described in detail with reference to the accompanying drawings.

[0046] Figure 1 HPLC profile of the 6th month sample solution in the accelerated stability study test for Sample 4 DETAILED DESCRIPTION

[0047] Embodiments of the present application are described in detail herein. The embodiments described herein are examples only and are not intended to limit the present application, which is defined by the claims.

[0048] It should be noted that the terms "first", "second" and the like are used merely to describe the elements and do not imply or create any relative importance or a limitation on the scope of the indicated technical features. Thus, a feature defined with "first", "second" can include one or more of the features explicitly or implicitly. Further, in the description of the present application, unless otherwise stated, the meaning of "a plurality" is two or more.

[0049] The endpoints of the ranges and any values described herein are not limited to the precise values stated. The ranges and values should be construed to be roughly about the ranges or values. For ranges, the endpoints are included as well as intervening points within the range. For values, the value includes the stated value as well as approximately the stated value.

[0050] In this document, the terms "comprise" or "comprising" are open- ended, that is, they mean "including, but not limited to".

[0051] In this document, the terms "optionally", "optional" or "option" generally mean that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0052] In this document, the term "treatment" refers to obtaining a desired pharmacological and / or physiologic effect. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or can be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. "Treatment" as used herein covers the treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease or condition from occurring in an individual which can be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving the disease, i.e., causing the partial or complete regression of the symptoms of the disease. "Treatment" as used herein covers any use of a drug or compound to treat, cure, relieve, alleviate, alter, improve, diminish, or inhibit a disease in an individual, including, but not limited to, administering a drug comprising a compound described herein to an individual in need thereof.

[0053] It should be explained that the unit mM in the present application is millimoles per liter, i.e. 1 mM = 1 mmol / L; the mass volume ratio in the present application refers to the weight (unit: g) of each component in 1 ml of the ophthalmic preparation system; the mass percentage in the present application refers to the percentage of the mass of methoxy or hydroxypropoxy contained in the hydroxypropyl methyl cellulose in the total mass. The viscosity values of the hydroxypropyl methyl cellulose in the present application are determined in 0.5% (W / V) hydroxypropyl methyl cellulose aqueous solution.

[0054] The scheme of the present application will be explained below in combination with examples. Those skilled in the art will understand that the following examples are only used to illustrate the present application and should not be regarded as limiting the scope of the present application. If the specific techniques or conditions are not specified in the examples, the techniques or conditions described in the literature in the art or according to the product instructions are used. If the reagents or instruments are not specified by the manufacturer, they are all conventional products that can be obtained by purchase.

[0055] Example 1: Evaluation of different types of hydroxypropyl methyl cellulose

[0056] The method for preparing the ophthalmic preparation comprises the following steps:

[0057] S1. Take 70% of the total volume of the ophthalmic preparation of water for injection, add hydroxypropyl methyl cellulose, stir and disperse, then perform high-temperature sterilization under the conditions of 121℃×15min, and cool to below 25℃ to obtain a prepared solution 1;

[0058] S2. Weigh 20% of the total amount of water for injection, add sodium chloride, penehyclidine hydrochloride and phosphate buffer solution according to the prescription amount in Table 1, stir until completely dissolved to obtain a prepared solution 2;

[0059] S3. Mix the prepared solution 2 filtered through a 0.22μm filter with the prepared solution 1, stir until uniform after constant volume, to prepare the ophthalmic preparation, and control the pH value of the ophthalmic preparation to be 5.0-7.0;

[0060] S4. Perform filling by sterile dispensing, perform lamp inspection, and take the ophthalmic preparation after passing the inspection.

[0061] In the table, the percentage is the mass volume ratio (unit: g / ml) of each raw material to the ophthalmic preparation, and the pH value is the measured value of each ophthalmic preparation sample.

[0062] Table 1: Prescription using different types of hydroxypropyl methyl cellulose

[0063]

[0064] Method for detecting related substances:

[0065] The related substances of the preparation of the present example are determined by HPLC method.

[0066] Chromatographic conditions: according to the test of high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition four parts general test 0512), octadecyl silane bonded silica gel is used as the filler; 0.02 mol / L potassium dihydrogen phosphate solution-methanol-acetonitrile (50:45:5) is used as the mobile phase A, and 0.02 mol / L potassium dihydrogen phosphate solution-methanol-acetonitrile (30:5:65) is used as the mobile phase B; gradient elution is carried out according to the following table, the detection wavelength is 210 nm, the column temperature is 30°C, the flow rate is 1.0 ml per minute, and the injection amount is 100 μl. The solvent composition is 0.02 mol / L potassium dihydrogen phosphate solution-acetonitrile (80:20). The specific elution program is shown in the following table 2.

[0067] Table 2: Elution program of mobile phase for related substance detection method

[0068]

[0069] Preparation of impurity B stock solution: an appropriate amount of impurity B reference substance was accurately weighed, dissolved and quantitatively diluted with acetonitrile to prepare a solution containing about 2 μg of impurity B per 1 ml.

[0070] Preparation of penehyclidine hydrochloride reference solution: an appropriate amount of penehyclidine hydrochloride reference substance was accurately weighed, dissolved and quantitatively diluted with acetonitrile to prepare a solution containing about 0.2 mg of penehyclidine hydrochloride per 1 ml; an appropriate amount was accurately measured and quantitatively diluted with solvent to prepare a solution containing about 0.2 μg of penehyclidine hydrochloride per 1 ml.

[0071] Preparation of test solution: an appropriate amount of the product was accurately measured and diluted with solvent to 0.1 mg / ml.

[0072] Determination method: 100 μl of the reference solution and the test solution were accurately measured and injected into the liquid chromatograph, respectively, the chromatogram was recorded, and the impurity content was calculated according to the following formula I.

[0073]

[0074] In the formula: A 杂 - is the peak area of the impurity in the chromatogram of the test solution;

[0075] A 对 - is the peak area of penehyclidine hydrochloride in the chromatogram of the reference solution;

[0076] C 样 - is the concentration of the test solution, mg / mL;

[0077] V 对 - is the dilution volume of the reference solution, ml;

[0078] m 对 - the amount of the sample to be tested, mg;

[0079] % 对 - the content of the control.

[0080] The content of the related substances of Samples 1-6 was determined by the above method, and the results are shown in Table 3.

[0081] Table 3: Determination results of related substances

[0082]

[0083] Example 2: Consideration of different amounts of hydroxypropyl methyl cellulose

[0084] The method for preparing the ophthalmic preparation is as described in Example 1, and the amounts of the raw materials of the ophthalmic preparation are shown in Table 4. The percentages in the table are the mass / volume ratios (unit: g / ml) of the raw materials to the ophthalmic preparation, and the pH values are the measured values of the samples of the ophthalmic preparation.

[0085] Table 4: Formulations with different amounts of hydroxypropyl methyl cellulose

[0086]

[0087] The content of the related substances of Samples 7-11 was determined by the method of Example 1, and the results are shown in Table 5.

[0088] Table 5: Determination results of related substances

[0089]

[0090]

[0091] Experimental conclusion: During the preparation of the preparation, it was found that when the amount of hydroxypropyl methyl cellulose reached 1.2%, the viscosity of the drug solution was relatively large, which led to filter core blockage during the filtration in Step S3, and the product yield was only 40%-50% of the theoretical yield.

[0092] Example 3: Consideration of different amounts of penehyclidine hydrochloride

[0093] The method for preparing the ophthalmic preparation is as described in Example 1, and the amounts of the raw materials of the ophthalmic preparation are shown in Table 6. The percentages in the table are the mass / volume ratios (unit: g / ml) of the raw materials to the ophthalmic preparation, and the pH values are the measured values of the samples of the ophthalmic preparation.

[0094] Table 6: Formulations with different amounts of penehyclidine hydrochloride

[0095]

[0096] The related substance content of samples 12-16 was determined by the related substance detection method of Example 1, and the results are shown in Table 7.

[0097] Table 7: Related substance detection results

[0098]

[0099]

[0100] Example 4 and Example 5:

[0101] The method for preparing the ophthalmic preparation is as described in Example 1, and the amounts of the raw materials of the ophthalmic preparation are shown in Table 8. The percentages in the table are the mass / volume ratios (unit: g / ml) of the raw materials to the ophthalmic preparation, and the pH values are the measured values of the ophthalmic preparation samples.

[0102] Table 8: Prescription composition of Example 4 and Example 5

[0103]

[0104] The related substance content of samples 17-18 was determined by the related substance detection method of Example 1, and the results are shown in Table 9.

[0105] Table 9: Related substance detection results

[0106]

[0107] Test Example 1: Hydroxypropyl methyl cellulose viscosity determination and methoxy, hydroxypropoxy content determination.

[0108] Experimental method:

[0109] (1) Hydroxypropyl methyl cellulose viscosity determination:

[0110] When determining the viscosity of samples of 0.5% (W / V) hydroxypropyl methyl cellulose 2910E6, 2910E15 type and 2910E50 type, the sample was determined at 20℃±0.1℃, with an outflow time of not less than 200 seconds, and a suitable inner diameter of the Ubbelohde viscometer was selected to determine the kinematic viscosity (v, m 2 / s) of the solution (Chinese Pharmacopoeia 2020 Edition Volume IV General Rules 0633 First Method), and the density (p, g / cm 3 ) of the solution was determined under the same conditions, and the dynamic viscosity η was calculated according to the following formula II:

[0111] η = p.v Formula II

[0112] v = K.t

[0113] K is the viscosity constant of the standard liquid with known viscosity, mm 2 / s 2

[0114] t is the measured average outflow time, s

[0115] The sample viscosity was measured by adding 0.5% (W / V) of hydroxypropyl methyl cellulose 2910 E4M and 2208 K4M type. The sample was measured at 20℃±0.1℃, using a suitable single column type rotary viscometer (Brookfield type LV model), Chinese Pharmacopoeia 2020 edition four general rules 0633 third method, using a 4 type rotor, rotating at 60 rpm / min, reading after 2 minutes of rotation, stopping for 2 minutes, and repeating the experiment twice, taking the average of the three experiments.

[0116] The above determination results are shown in Table 10.

[0117] (2) Determination of methoxy and hydroxypropoxy content in hydroxypropyl methyl cellulose:

[0118] The determination method was determined according to Chinese Pharmacopoeia 2020 edition four general rules 0712 method, and the determination results are shown in Table 10.

[0119] Table 10: Determination results of viscosity and methoxy, hydroxypropoxy content of hydroxypropyl methyl cellulose

[0120]

[0121] Test Example 2: Myopia model experiment of off-focus mirror

[0122] Experimental method: Using ordinary male three-color guinea pigs, randomly divided into 8 groups according to body weight: normal control group, model control group, positive control group (0.5% atropine sulfate eye preparation), 5 dose groups of test drugs (Example 3 samples 12-16), 12 in each group, except that the normal control group was not treated, the rest of the groups were fixed with-10.0D simple spherical resin lens on the right eye of the animal, to prepare the optical off-focus myopia model, the right eye was the modeling eye, and the left eye was the control eye. At the same time of modeling, the right eye was given eye drops, the normal control group and the model control group were given solvent, and each drug group was given corresponding drug, the volume of each drug was 20 μL / one, once a day, for 42 days (6 weeks) of continuous administration, and 2 weeks of observation after drug withdrawal. The body weight of the animals was detected every week, the refractive power and the axial length of the eyes were detected every 2 weeks, and after 2 weeks of observation after drug withdrawal (total 8 weeks), the animals were sacrificed, the eyeballs were taken, the equatorial diameter and the anteroposterior diameter were detected, and the paraffin sections were prepared, HE staining was performed, and histopathological examination was performed.

[0123] Test results:

[0124] (1) Effect on refractive power

[0125] During the molding and administration of 6 weeks, drug withdrawal observation for 2 weeks, the refractive power of the model animal control eye had no obvious change, the refractive power of the model eye was obviously reduced, the model formed mild to moderate myopia (refractive power number -2.0 to -6.0D), and the refractive power difference of the two eyes was obviously reduced; compared with the model control group, the positive drug 0.5% atropine sulfate eye drops and samples 12-16 each dose can obviously delay the refractive power reduction of the model animal molding eye and the refractive power difference of the two eyes; after drug withdrawal for 2 weeks, there is still a certain delay myopia effect; the refractive power improvement effect of samples 12-15 is positively correlated with the dose; the refractive power delay effect of 0.5% positive drug is equivalent to the results of 0.01% and 0.05% dose groups of the test product group, and is obviously lower than that of 0.5%, 0.2% and 0.1% dose groups (Table 11). It shows that the eye preparation of the application has a delay effect on the progression of mild to moderate axial myopia caused by refractive error, and the effect is better than that of the 0.05% atropine group.

[0126] Table 11: Refractive power results

[0127]

[0128]

[0129] (2) Effect on eye axial length

[0130] During the molding and administration of 6 weeks, drug withdrawal observation for 2 weeks, the refractive power of the model animal control eye had no obvious change, the refractive power of the model eye was obviously reduced, the model formed mild to moderate myopia (refractive power number -2.0 to -6.0D), and the refractive power difference of the two eyes was obviously reduced; compared with the model control group, the positive drug 0.5% atropine sulfate eye drops and samples 12-16 each dose can obviously delay the refractive power reduction of the model animal molding eye and the refractive power difference of the two eyes; after drug withdrawal for 2 weeks, there is still a certain delay myopia effect; the refractive power improvement effect of samples 12-15 is positively correlated with the dose; the refractive power delay effect of 0.5% positive drug is equivalent to the results of 0.01% and 0.05% dose groups of the test product group, and is obviously lower than that of 0.5%, 0.2% and 0.1% dose groups (Table 11). It shows that the eye preparation of the application has a delay effect on the progression of mild to moderate axial myopia caused by refractive error, and the effect is better than that of the 0.05% atropine group.

[0131] Table 12: Eye axial length growth results

[0132]

[0133] (3) Histopathological examination

[0134] All animals' cornea, sclera, iris, retina structure had no abnormal change, which may be related to the fact that the model animal myopia has not reached pathological myopia.

[0135] Test conclusion:

[0136] Under the present experimental conditions, the optical defocus guinea pig myopia model was prepared, the right eye was the modeling eye, and the left eye was the control eye. The eye drops of penehyclidine hydrochloride were administered at concentrations of 0.01%, 0.05%, 0.1%, 0.2% and 0.5% (samples 16-12) at 20 μL, once a day, for 6 consecutive weeks, and the observation was made for 2 weeks after the administration was stopped. The results showed that the eye drops of the present application had no obvious effect on the body weight of the animals, could obviously delay the decrease of the refractive power of the modeling eyes of the model animals, and the effect was still maintained to a certain extent after the administration was stopped. The axial length of the model animals was obviously improved after the administration for 4 weeks. No pathological changes were found in the cornea, sclera, iris and retina of the model animals and the animals in the sample 12-16 groups, which should be related to the fact that the myopia of the model animals had not reached the pathological myopia. In comprehensive comparison, the 0.5% atropine sulfate eye drops and the 0.01% and 0.05% samples of the present application had equivalent effects, which were lower than those of the 0.5%, 0.1% and 0.2% samples.

[0137] Test Example 3: Irritation test of rabbit eye administration

[0138] 1.1, Experimental materials and instruments:

[0139] 1.1.1, Experimental animals

[0140] The Dutch rabbits were purchased, 2.0-2.5 kg, half male and half female, and the animals were screened.

[0141] The naked eye observation showed that the cornea was not turbid, the conjunctiva was not congested, edematous or secreted, the pupil was round, both sides were equal, the light reflex was good, the slit lamp examination showed that the cornea was transparent, and there was no nebula or nebula; the iris texture was clear, and there was no congestion and edema. Fluorescein staining, 10% fluorescein sodium injection was diluted with physiological saline 5 times, one drop was dropped into each rabbit eye, and then washed with physiological saline, and the cornea without coloring was observed to be normal. 40 healthy Dutch rabbits without eye diseases were selected by the above-mentioned pre-selection for the experiment.

[0142] 1.1.2, Experimental instruments

[0143] LYL-II slit lamp microscope: Phoenix optical instruments

[0144] 1.2, Experimental method

[0145] 1.2.1, Fundus examination before animal administration

[0146] The eyes of each animal were examined with 1% fluorescein sodium 24 hours before the test, and the animals with eye irritation symptoms, corneal defects and conjunctival damage could not be used for the test.

[0147] 1.2.2, Animal grouping

[0148] 40 Dutch rabbits were randomly divided into 10 groups, including samples 7-11 in Example 2, 4 in each group, half male and half female.

[0149] 1.2.3, Dose and frequency of administration

[0150] The clinical dose is 2 times a day, morning and evening, 1-2 drops each time. The experimental design is consistent with the clinical administration route. The dose and frequency of administration are 30 μL (about one drop) each time, 1 time a day in the morning and evening, and the administration period is 7 days.

[0151] 1.3, Blinking frequency determination

[0152] Take 40 pre-selected healthy animals, half male and half female. Cut off the eyelashes of each group of animals, and each animal's left eye conjunctival sac is dripped with the test substance (30 μL / eye). Observe the eye irritation within 1 minute after each administration of each animal, record the blinking frequency within 60 seconds, calculate the average blinking frequency of each group of animals, and evaluate the irritation of the drug to the eye (the more the blinking frequency, the greater the irritation).

[0153] 1.4, Eye irritation test

[0154] Take 40 pre-selected healthy animals, half male and half female. Cut off the eyelashes of each group of animals, and each group of animals is administered to the left eye. Each animal's left eye conjunctival sac is dripped with the test substance (30 μL / eye). Each group is given eye drops once in the morning and evening, for 7 consecutive days. Record the local irritation reaction of the eye at 1, 4, 24, and 48 hours after the last administration. Each animal is observed for eye conditions before each administration, and the observation includes but is not limited to redness, swelling, conjunctival hyperemia, and discharge.

[0155] 1.5, Results

[0156] 1.5.1, Animal blinking frequency determination Record the blinking frequency of each group of animals within 60 seconds after eye drops.

[0157] 1.5.2, Eye irritation test results

[0158] According to the requirements of Table 13, add the irritation reaction scores of each animal's cornea, iris, and conjunctiva at each observation time to get the total score, and divide the total score of a group by the number of animals to get the final score. According to the blinking frequency of the animals calculated in step 1.5.1, judge the irritation degree.

[0159] Table 13: Evaluation of eye irritation score index

[0160]

[0161]

[0162] Table 14: Eye irritation evaluation criteria

[0163] Score Evaluation 0-3 Non-irritant 4-8 Mildly irritant 9-12 Moderately irritant 13-16 Severely irritant

[0164] Table 15 Results of blink frequency determination experiment

[0165]

[0166] Table 16 Eye irritation test

[0167]

[0168] The results show that when the eye preparation of sample 7 to sample 10 is given, the blink frequency of the Holland rabbit is low, which indicates that the eye preparation of penehyclidine hydrochloride prepared by using hydroxypropyl methyl cellulose with a mass-volume ratio of 0.1% to 0.8% has basically no irritation. When the eye preparation of sample 11 is given, the blink frequency of the Holland rabbit is significantly higher than that of other groups, which indicates that the eye preparation has certain irritation to the eye, and the irritation has no direct correlation with the pH value.

[0169] Therefore, when the mass-volume ratio of hydroxypropyl methyl cellulose in the eye preparation of the present application is 0.1% to 1.0%, the irritation of the eye preparation product can be effectively guaranteed.

[0170] Test Example 4: Stability test

[0171] 4.1 Accelerated stability test:

[0172] The samples 1 to 11 and samples 17 to 18 of Example 1, Example 2, Example 4 and Example 5 were subjected to accelerated stability test, and the accelerated stability test conditions were as follows:

[0173] The product was packaged by using a commercially available package, and was placed at 40±2℃ and 25%±5% RH for 6 months.

[0174] Table 17: Results of stability test

[0175]

[0176]

[0177]

[0178] The experimental results show that, compared with samples 1 to 3 in Example 1, sample 1 is significantly more stable than samples 2 and 3. This is mainly reflected in the fact that sample 1 maintained a more stable pentoxyverine hydrochloride content, with a decrease of only 1.7% over 6 months; the change in impurity content was also smaller, with a total impurity content increase of only 0.24% and impurity B content increase of only 0.17% over 6 months. In contrast, after 6 months of stability testing, samples 2 and 3 showed decreases in pentoxyverine hydrochloride content of 3.8% and 3.7% respectively, increases in impurity B content of 0.58% and 0.64% respectively, and increases in total impurity content of 1.14% and 1.18% respectively. Comparing samples 4 to 6, sample 4 is significantly more stable than samples 5 and 6, mainly reflected in the fact that sample 4 maintained a more stable pentoxyverine hydrochloride content, with a decrease of only 1.3% over 6 months (e.g., ...). Figure 1 As shown, impurity B is a chiral compound, with isomer B1 having a retention time of 10.415 and isomer B2 having a retention time of 11.391. The content of impurities also showed smaller changes; the total impurity content increased by only 0.11% over 6 months, and the impurity B content increased by only 0.14% over 6 months. After 6 months of stability testing, the content of pentoxyverine hydrochloride decreased by 3.1% and 3.2% for samples 5 and 6, respectively, while the content of impurity B increased by 0.44% and 0.45%, respectively, and the total impurity content increased by 0.74% and 0.79%, respectively. Compared with sample 1, sample 4 showed better stability, indicating that the addition of buffer solution maintained both the active ingredient content and impurity content within a more stable range. However, the test results show that the stability of sample 1 already meets the quality standard requirements. This indicates that when the hydroxypropyl methylcellulose used contains 27.0%–30.0% methoxyl content and 7.0%–12.0% hydroxypropoxyl content, and the viscosity of a 0.5% hydroxypropyl methylcellulose aqueous solution is 0.5–15 mPa·s, the stability of the obtained ophthalmic formulation is significantly improved compared to other types of hydroxypropyl methylcellulose, and the product can maintain better quality.

[0179] Comparative Example 2, it is found that the stability of Sample 7 is significantly decreased compared with other samples, which is mainly embodied in that the content of penehyclidine hydrochloride in Sample 7 is decreased by 2.7% in 6 months, the total impurity content is increased by 0.61%, and the content of impurity B is increased by 0.33% in 6 months; while the detection indexes of Samples 8-10 all meet the requirements, and the changes of the content of main component and impurities are small, which indicates that when the content of methoxyl in the hydroxypropyl methyl cellulose used in the present application is 27.0%-30.0%, the content of hydroxypropoxy is 7.0%-12.0%, and the viscosity of 0.5% hydroxypropyl methyl cellulose aqueous solution is 0.5-15 mPa·s, the sample stability is decreased when the mass / volume ratio of hydroxypropyl methyl cellulose is less than 0.2%; while when the mass / volume ratio of hydroxypropyl methyl cellulose is greater than 1.0% (such as Sample 11), although the stability requirement can be maintained, it is not suitable for being used as the prescription of ophthalmic preparation due to the problems of great irritation, operation difficulty in preparation process, low product yield and the like.

[0180] The stability of Sample 17 and Sample 18 is almost the same as that of Sample 4, and the content of penehyclidine hydrochloride and the content of impurities in the ophthalmic preparation are changed little during the stability study, especially the content changes of impurity B and total impurities are significantly decreased, which indicates that when the content of methoxyl in the hydroxypropyl methyl cellulose used in the ophthalmic preparation of penehyclidine hydrochloride is 27.0%-30.0%, the content of hydroxypropoxy is 7.0%-12.0%, and the viscosity of 0.5% hydroxypropyl methyl cellulose aqueous solution is 0.5-15 mPa·s, the preparation can ensure good stability, and the content of impurities, especially the content of impurity B, changes less.

[0181] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "an example", "a specific example", or "some examples" and the like means 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 application. In the present 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 appropriate manner in any one or more embodiments or examples. In addition, different embodiments or examples described in the present specification and the features of different embodiments or examples can be combined and modified by those skilled in the art without contradiction.

[0182] Although the embodiments of the present application have been shown and described above, it should be understood that the above embodiments are exemplary and should not be construed as limiting the present application, and those skilled in the art can make changes, modifications, replacements and variations to the above embodiments within the scope of the present application.

Claims

1. An ophthalmic formulation characterized in that, comprises: penehyclidine hydrochloride, hydroxypropyl methylcellulose, and water; wherein the mass / volume ratio of the penehyclidine hydrochloride is 0.01%-2%, the mass percentage of methoxyl groups of the hydroxypropyl methylcellulose is 27.0%-30.0%, the mass percentage of hydroxypropoxy groups of the hydroxypropyl methylcellulose is 7.0%-12.0%, and the viscosity of the hydroxypropyl methylcellulose is 0.5-15 mPa·s, based on a 0.5% hydroxypropyl methylcellulose aqueous solution, with respect to the total volume of the ophthalmic preparation.

2. The ophthalmic formulation of claim 1, wherein, The mass percentage of methoxyl groups of the hydroxypropyl methylcellulose is 28.0%-30.0%.

3. The ophthalmic formulation of claim 1, wherein, The mass percentage of hydroxypropoxy groups of the hydroxypropyl methylcellulose is 7.0%-10.0%.

4. The ophthalmic formulation of claim 1, wherein, The viscosity of the hydroxypropyl methylcellulose is 1-10 mPa·s.

5. The ophthalmic formulation of claim 1, wherein, The mass percentage of methoxyl groups of the hydroxypropyl methylcellulose is 28.5%-30.0%.

6. The ophthalmic formulation of claim 1, wherein, The mass percentage of hydroxypropoxy groups of the hydroxypropyl methylcellulose is 7.0%-9.0%.

7. The ophthalmic formulation of claim 1, wherein, The viscosity of the hydroxypropyl methylcellulose is 2-10 mPa·s.

8. The ophthalmic preparation of claim 1, wherein The hydroxypropyl methylcellulose is one or more of 2910 E6, 2910 E15, and 2910 E50.

9. The ophthalmic formulation of claim 1, wherein, The mass / volume ratio of the hydroxypropyl methylcellulose is 0.2%-1.0%, based on the total volume of the ophthalmic preparation.

10. The ophthalmic preparation of claim 1, wherein The mass / volume ratio of the hydroxypropyl methylcellulose is 0.2%-0.8%.

11. The ophthalmic formulation of claim 1, wherein, The mass / volume ratio of the hydroxypropyl methylcellulose is 0.4%-0.6%.

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

13. The ophthalmic formulation of claim 1, wherein, The mass / volume ratio of the penehyclidine hydrochloride is 0.01%-0.5%, based on the total volume of the ophthalmic preparation.

14. The ophthalmic preparation of claim 1, wherein Further comprising an osmotic pressure regulator.

15. The ophthalmic formulation of claim 14, wherein, The osmotic pressure regulator is sodium chloride.

16. The ophthalmic formulation of claim 15, wherein, The mass / volume ratio of the sodium chloride is 0.3%-1.4%, based on the total volume of the ophthalmic preparation.

17. The ophthalmic formulation of claim 15, wherein, The mass / volume ratio of the sodium chloride is 0.5%-1.2%, based on the total volume of the ophthalmic preparation.

18. The ophthalmic formulation of claim 1, wherein, Further comprising a buffer, and the total concentration of the buffer is less than or equal to 50 mM.

19. The ophthalmic formulation of claim 18, wherein, The total concentration of the buffer is not higher than 25 mM.

20. The ophthalmic formulation of claim 18, wherein, The total concentration of the buffer is not higher than 15 mM.

21. The ophthalmic formulation of claim 18, wherein, The buffer comprises at least one selected from a phosphate buffer, a citrate buffer, and a tartrate buffer.

22. The ophthalmic formulation of claim 21, wherein, The phosphate buffer is a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate or a combination of dipotassium hydrogen phosphate and potassium dihydrogen phosphate; the citrate buffer is citric acid and sodium citrate; and the tartrate buffer is tartaric acid and sodium tartrate.

23. The ophthalmic formulation of claim 1, wherein, The pH of the ophthalmic preparation is 5.0-7.

0.

24. Use of the ophthalmic preparation of any one of claims 1-23 in the preparation of a medicament for treating and / or preventing myopia and / or amblyopia.

25. Use according to claim 24, characterized in that, The myopia and / or amblyopia comprises one or more of mild myopia, moderate myopia, high myopia, axial myopia, refractive myopia, simple myopia, pathological myopia, hypometropia, exotropia, strabismic amblyopia, aniseikonic amblyopia, ametropic amblyopia, unilateral form deprivation amblyopia, and bilateral form deprivation amblyopia.

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