Pharmaceutical composition, preparation method and use thereof

Abstract

The present application provides a pharmaceutical composition, in particular a low-concentration atropine ophthalmic preparation, as well as a method for preparing the pharmaceutical composition and use of the pharmaceutical composition in preparing a drug for preventing and / or treating visual impairment.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 201811112830.8, application date September 25, 2018, and invention name “A method for improving the stability of low-concentration atropine ophthalmic preparations”. Technical Field

[0002] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a method for improving the stability of a low-concentration atropine ophthalmic preparation, a method for preparing the ophthalmic preparation, the atropine ophthalmic preparation prepared thereby, and uses thereof. Background Art

[0003] Atropine ophthalmic preparations have been used in clinical practice for many years, mainly for mydriasis, ciliary muscle paralysis, and suppression therapy in the treatment of amblyopia. In addition, atropine is currently the only drug proven by evidence-based medicine to effectively slow the progression of myopia, and it has been used to control the progression of myopia for many years.

[0004] At present, there are few drugs used to control the progression of myopia in adolescents at home and abroad, and the side effects are large. In the past, atropine was used to treat myopia in my country for short-term treatment with high concentrations, which was used to relieve accommodative spasms, and the efficacy was not easy to consolidate after stopping the drug. The specifications of atropine ophthalmic preparations currently on the market in China are 1%. Due to the high concentration of atropine, there are side effects such as mydriasis and blurred vision, which will have a certain degree of impact on the patient's life and study, and cannot be used as a routine long-term clinical drug to control the progression of myopia.

[0005] The use of low-concentration atropine ophthalmic preparations to prevent and treat myopia in adolescents has made phased progress. For example, the Singapore Eye Research Institute and the Singapore National Eye Center have been conducting research on the treatment of myopia with low-concentration atropine for many years. The results show that the low-concentration atropine treatment group has the least number of remaining myopic children compared with other high-concentration atropine treatment groups, and the pupil dilation effect is greatly reduced, thereby greatly reducing the side effects of high-concentration atropine such as pupil dilation, blurred near vision, photophobia, conjunctivitis and dermatitis. Therefore, low-concentration atropine ophthalmic preparations are more suitable for long-term eye drops for adolescents to control the progression of myopia, and the rebound effect after discontinuation of the drug is significantly reduced.

[0006] However, as a muscarinic receptor antagonist, atropine has significantly lower stability when formulated into low-concentration preparations (e.g., 0.001% to 0.05%) than high-concentration preparations (e.g., 0.1% to 1%), which makes it more challenging to obtain low-concentration atropine preparations with high stability.

[0007] The prescription adjustment of the product is usually the most effective method to improve the stability of the preparation. Adjusting the prescription buffer system or reducing the pH value of the preparation can significantly improve the stability of atropine ophthalmic preparations. The inventors have found that a lower pH value is required for low-concentration atropine ophthalmic preparations to meet the requirements of preparation stability, but the irritation of the preparation is greatly improved, which not only affects the compliance of the patient's use, but also causes the secretion of tears due to stimulation, thereby affecting the bioavailability of atropine. Deuterated water is used to improve the stability of low-concentration atropine eye drops in patent US9421199B2, but the introduction of isotopes will inevitably affect the safety of the product, and the production and quality control requirements of the product are higher, which limits the development and promotion of the product. In summary, this area still needs a low-concentration atropine preparation with high stability. Summary of the invention

[0008] The requirements for atropine sulfate API are strict, and the quality standards are strictly defined in the pharmacopoeias of various countries, especially the content of related substances, as shown in the following table:

[0009]

[0010] The inventors unexpectedly discovered that by further controlling the total impurity and / or single impurity content of commercially available atropine bulk drugs that meet the above standards, the shelf life stability of low-concentration atropine ophthalmic preparations can be significantly improved.

[0011] Therefore, in one aspect, the present application provides a method for improving the stability of an atropine sulfate preparation, characterized in that the total impurity content of the atropine sulfate raw material is controlled to be ≤0.25% (e.g., ≤0.2%, ≤0.15%, ≤0.1%, ≤0.05% or not detected) and / or the single impurity content is controlled to be ≤0.05% (e.g., ≤0.01% or not detected).

[0012] The atropine sulfate bulk drug substance can be analyzed for impurity content by HPLC. In some embodiments, the HPLC analysis conditions are: detection wavelength 210nm; chromatographic column using octadecylsilane bonded silica gel as filler (3μm, 250mm×4.6mm), [3.5g / L potassium dihydrogen phosphate solution (pH adjusted to 3.3 with phosphoric acid) 606ml and acetonitrile 320ml mixed solution] (containing 1.7g sodium dodecyl sulfate) as mobile phase A, acetonitrile as mobile phase B, and gradient elution according to the following table.

[0013]

[0014] The concentration of the test solution is 1 mg / ml.

[0015] In some preferred embodiments, the preparation is an ophthalmic liquid preparation (eg, eye drops). In some preferred embodiments, the concentration of atropine sulfate in the preparation is 0.001-0.1% (preferably 0.005-0.05%).

[0016] In another aspect, the present application provides a method for refining atropine sulfate, comprising the following steps:

[0017] The atropine sulfate bulk drug is washed with a washing solvent a, a washing solvent b and a washing solvent c respectively; wherein,

[0018] The pulp washing solvent a is a low polarity solvent;

[0019] The pulp washing solvent b is an acetone-water mixed solvent (the volume of water accounts for 2-10%, for example, 5%);

[0020] The pulp washing solvent c is a low polarity solvent.

[0021] In some preferred embodiments, the pulping solvent a is acetone, ethanol-acetone mixed solvent, ether, ethanol-ether mixed solvent, methyl tert-butyl ether, isopropyl ether, petroleum ether (e.g., petroleum ether (60-90), petroleum ether (90-120)) or any combination thereof. In some preferred embodiments, the amount of pulping solvent a is 3-30 ml (e.g., 5, 10, 15 or 20 ml) of pulping solvent a per gram of atropine sulfate. In some preferred embodiments, the temperature for pulping with pulping solvent a is 0-50°C (e.g., room temperature, 40°C). In some preferred embodiments, the time for pulping with pulping solvent a is 0.5-6h (e.g., 3h).

[0022] In some preferred embodiments, the amount of the washing solvent b is 5-20 ml (e.g., 10 or 15 ml) of the washing solvent b per gram of atropine sulfate. In some preferred embodiments, the temperature for washing with the washing solvent b is 0-50° C. (e.g., room temperature, 40° C.). In some preferred embodiments, the time for washing with the washing solvent b is 0.5-6 h (e.g., 4 h).

[0023] In some preferred embodiments, the pulping solvent c is an ethanol-acetone mixed solvent, an ethanol-ether mixed solvent, acetone or any combination thereof. In some preferred embodiments, the amount of pulping solvent c is 3-30 ml (e.g., 5 or 10 ml) of pulping solvent c per gram of atropine sulfate. In some preferred embodiments, the temperature for pulping with the pulping solvent c is 0-room temperature (e.g., 10°C). In some preferred embodiments, the time for pulping with the pulping solvent c is 0.5-6h (e.g., 1.5h).

[0024] In some preferred embodiments, the method further comprises the step of crushing the atropine sulfate bulk drug before pulping. In some preferred embodiments, the method further comprises the step of passing the crushed atropine sulfate bulk drug through a 30-100 mesh sieve.

[0025] In some preferred embodiments, the step of filtering and / or drying is further included after pulp washing. In some preferred embodiments, the filtering is selected from suction filtration, pressure filtration and rejection filtration. In some preferred embodiments, the drying is reduced pressure drying.

[0026] In another aspect, the present application provides atropine sulfate, which is prepared by the above method; or its total impurity content is ≤0.25% (for example, ≤0.2%, ≤0.15%, ≤0.1%, ≤0.05% or not detected) and / or its single impurity content is ≤0.05% (for example, ≤0.01% or not detected).

[0027] In another aspect, the present application provides a pharmaceutical composition, which contains the above-mentioned atropine sulfate and pharmaceutically acceptable excipients.

[0028] In some preferred embodiments, the pharmaceutical composition is an ophthalmic liquid preparation, such as eye drops. In some preferred embodiments, the concentration of atropine sulfate in the pharmaceutical composition is 0.001-0.1% (preferably 0.005-0.05%).

[0029] In some preferred embodiments, the pharmaceutical composition by weight is:

[0030]

[0031] and, the balance of water;

[0032] Optionally, it also contains 0.001 to 0.05% of an antibacterial agent;

[0033] Optionally, it further contains 0.1-2% of an osmotic pressure regulator.

[0034] In some preferred embodiments, the thickener is selected from cellulose derivatives, cross-linked polyvinyl pyrrolidone, sodium hyaluronate, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and any combination thereof. In some preferred embodiments, the cellulose derivative is selected from hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and sodium carboxymethyl cellulose and any combination thereof. In some preferred embodiments, the thickener is hydroxypropyl methylcellulose. In some preferred embodiments, the weight content of the thickener in the pharmaceutical composition is 0.5-10%, for example 0.5-8%, 0.5-5%, 0.5-3% or 1-3%.

[0035] In some preferred embodiments, the complexing agent is selected from edetic acid, edetate disodium and edetate calcium sodium, preferably edetate disodium. In some preferred embodiments, the weight content of the complexing agent in the pharmaceutical composition is 0.005-0.05%, such as 0.005-0.03%, 0.005-0.02%, 0.005-0.01% or 0.008-0.01%.

[0036] In some preferred embodiments, the antibacterial agent is selected from benzalkonium chloride, benzalkonium bromide, cetrimonium bromide, phenoxyethanol, phenylethanol, paraben antibacterial agents and any combination thereof. In some preferred embodiments, the antibacterial agent is benzalkonium chloride, ethyl paraben or any combination thereof. In some preferred embodiments, the antibacterial agent is benzalkonium chloride. In some preferred embodiments, the weight content of the antibacterial agent in the pharmaceutical composition is 0.005-0.03%, for example, 0.005-0.02%, 0.006-0.02%, 0.006-0.012% or 0.008-0.01%.

[0037] In some preferred embodiments, the pH regulator is selected from one or more of a carbonate buffer system, a phosphate buffer system, a citric acid buffer system, an acetic acid buffer system, a barbituric acid buffer system, a tris(hydroxymethyl)aminomethane buffer system, boric acid, borax, sodium hydroxide, hydrochloric acid and citric acid and salts thereof. In some preferred embodiments, the pH regulator is a boric acid and phosphate buffer system (e.g., a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer system, a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer system). In some preferred embodiments, the content of the pH regulator in the pharmaceutical composition is such that the pH of the pharmaceutical composition is 4.0 to 6.0, e.g., 4.5 to 5.5.

[0038] In some preferred embodiments, the osmotic pressure regulator is selected from sodium chloride, glycerol, propylene glycol, mannitol and any combination thereof. In some preferred embodiments, the osmotic pressure regulator is propylene glycol. In some preferred embodiments, the weight content of the osmotic pressure regulator in the pharmaceutical composition is 0.1-1%, 0.1-0.5% or 0.1-0.3%.

[0039] In some preferred embodiments, the pharmaceutical composition is selected from formula 1-4:

[0040] Recipe 1:

[0041]

[0042] and, the balance of water;

[0043] Recipe 2:

[0044]

[0045] and, the balance of water;

[0046] Recipe 3:

[0047]

[0048] and, the balance of water;

[0049] Recipe 4:

[0050]

[0051] And, the balance of water.

[0052] In another aspect, the present application provides a method for preparing the above-mentioned pharmaceutical composition, comprising the following steps:

[0053] The thickener is dispersed and swelled by adding water at 60-90°C (e.g., 70-90°C, 80-90°C), and then further dissolved by adding water at 20-30°C (e.g., 20-25°C) to obtain liquid A;

[0054] Dissolve the pH regulator, complexing agent, antibacterial agent and optional osmotic pressure regulator in water at 60-80° C. (e.g., 65-80° C., 65-75° C.) respectively, and add atropine sulfate when the temperature drops below 30° C. (e.g., room temperature) to dissolve to obtain liquid B;

[0055] Mixing liquid a and liquid b, and adding the remaining amount of water to obtain the pharmaceutical composition;

[0056] Optionally, the method further comprises filtering the obtained pharmaceutical composition, preferably using a 0.22 μm filter membrane.

[0057] In another aspect, the present application also provides use of the pharmaceutical composition in the preparation of a drug for preventing and / or treating visual impairment (eg, myopia, especially myopia in children or adolescents).

[0058] In particular, the present invention can be implemented as follows:

[0059] 1. A method for improving the stability of an atropine sulfate preparation, characterized in that the total impurity content of the atropine sulfate raw material is controlled to be ≤0.25% (e.g., ≤0.2%, ≤0.15%, ≤0.1%, ≤0.05% or not detected) and / or the single impurity content is ≤0.05% (e.g., ≤0.01% or not detected); preferably, the preparation is an ophthalmic liquid preparation (e.g., eye drops); further preferably, the concentration of atropine sulfate in the preparation is 0.001-0.1% (preferably 0.005-0.05%).

[0060] 2. A method for refining atropine sulfate, comprising the following steps:

[0061] The atropine sulfate bulk drug is washed with a washing solvent a, a washing solvent b and a washing solvent c respectively; wherein,

[0062] The pulping solvent a is a low polar solvent, such as acetone, ethanol-acetone mixed solvent, ether, ethanol-ether mixed solvent, methyl tert-butyl ether, isopropyl ether, petroleum ether (such as petroleum ether (60-90), petroleum ether (90-120)) or any combination thereof; preferably, the amount of pulping solvent a is 3-30 ml (such as 5, 10, 15 or 20 ml) of pulping solvent a per gram of atropine sulfate; preferably, the pulping temperature is 0-50° C. (such as room temperature, 40° C.); preferably, the pulping time is 0.5-6 h (such as 3 h);

[0063] The pulping solvent b is an acetone-water mixed solvent (the volume of water accounts for 2-10%, such as 5%); preferably, the amount of the pulping solvent b is 5-20 ml (such as 10 or 15 ml) of the pulping solvent b per gram of atropine sulfate; preferably, the pulping temperature is 0-50° C. (such as room temperature, 40° C.); preferably, the pulping time is 0.5-6 h (such as 4 h);

[0064] The pulping solvent c is a low polar solvent, such as an ethanol-acetone mixed solvent, an ethanol-ether mixed solvent, acetone or any combination thereof; preferably, the dosage of the pulping solvent c is 3-30 ml (e.g. 5 or 10 ml) of pulping solvent c per gram of atropine sulfate; preferably, the pulping temperature is 0-room temperature (e.g. 10°C); preferably, the pulping time is 0.5-6h (e.g. 1.5h).

[0065] 3. The method of item 2 further comprises the step of crushing the atropine sulfate API before pulping; preferably, the method further comprises the step of passing the crushed atropine sulfate API through a 30-100 mesh sieve;

[0066] Preferably, after pulping, the process further comprises filtering and / or drying steps; preferably, the filtering is selected from suction filtration, pressure filtration and rejection filtration; preferably, the drying is reduced pressure drying.

[0067] 4. Atropine sulfate, which is prepared by the method of item 2 or 3; or its total impurity content is ≤0.25% (for example, ≤0.2%, ≤0.15%, ≤0.1%, ≤0.05% or not detected) and / or its single impurity content is ≤0.05% (for example, ≤0.01% or not detected).

[0068] 5. A pharmaceutical composition comprising the atropine sulfate described in item 4 and a pharmaceutically acceptable excipient; preferably, the composition is a liquid preparation for the eye, such as eye drops; further preferably, the concentration of atropine sulfate in the pharmaceutical composition is 0.001 to 0.1% (preferably 0.005-0.05%).

[0069] 6. The pharmaceutical composition of item 5, which has a weight composition of:

[0070]

[0071] and, the balance of water;

[0072] Optionally, it also contains 0.001 to 0.05% of an antibacterial agent;

[0073] Optionally, it further contains 0.1-2% of an osmotic pressure regulator.

[0074] 7. The pharmaceutical composition of item 6, wherein the thickener is selected from cellulose derivatives, cross-linked polyvinyl pyrrolidone, sodium hyaluronate, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and any combination thereof; preferably, the cellulose derivative is selected from hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and sodium carboxymethyl cellulose and any combination thereof, preferably hydroxypropyl methylcellulose; preferably, the weight content of the thickener in the pharmaceutical composition is 0.5-10%, for example 0.5-8%, 0.5-5%, 0.5-3% or 1-3%;

[0075] Preferably, the complexing agent is selected from edetic acid, edetate disodium and edetate calcium sodium, preferably edetate disodium; preferably, the weight content of the complexing agent in the pharmaceutical composition is 0.005-0.05%, such as 0.005-0.03%, 0.005-0.02%, 0.005-0.01% or 0.008-0.01%;

[0076] Preferably, the antibacterial agent is selected from benzalkonium chloride, benzalkonium bromide, cetrimonium bromide, phenoxyethanol, phenylethanol, paraben antibacterial agents and any combination thereof, preferably benzalkonium chloride, ethyl paraben or any combination thereof, more preferably benzalkonium chloride; preferably, the weight content of the antibacterial agent in the pharmaceutical composition is 0.005-0.03%, for example, 0.005-0.02%, 0.006-0.02%, 0.006-0.012% or 0.008-0.01%;

[0077] Preferably, the pH regulator is selected from one or more of a carbonate buffer system, a phosphate buffer system, a citric acid buffer system, an acetic acid buffer system, a barbituric acid buffer system, a tris(hydroxymethyl)aminomethane buffer system, boric acid, borax, sodium hydroxide, hydrochloric acid and citric acid and salts thereof, preferably a boric acid and phosphate buffer system (e.g., a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer system, a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer system); preferably, the content of the pH regulator in the pharmaceutical composition is such that the pH of the pharmaceutical composition is 4.0 to 6.0, e.g., 4.5 to 5.5;

[0078] Preferably, the osmotic pressure regulator is selected from sodium chloride, glycerol, propylene glycol, mannitol and any combination thereof; preferably propylene glycol; preferably, the weight content of the osmotic pressure regulator in the pharmaceutical composition is 0.1-1%, 0.1-0.5% or 0.1-0.3%.

[0079] 8. The composition of item 6, which is selected from formulas 1-4:

[0080] Recipe 1:

[0081]

[0082] and, the balance of water;

[0083] Recipe 2:

[0084]

[0085] and, the balance of water;

[0086] Recipe 3:

[0087]

[0088] and, the balance of water;

[0089] Recipe 4:

[0090]

[0091] And, the balance of water.

[0092] 9. A method for preparing the pharmaceutical composition according to any one of items 6 to 8, comprising the following steps: adding 60-90°C (e.g. 70-90°C, 80-90°C) water to disperse and swell the thickener, and further adding 20-30°C (e.g. 20-25°C) water to dissolve the thickener to obtain liquid A;

[0093] Dissolve the pH regulator, complexing agent, antibacterial agent and optional osmotic pressure regulator in water at 60-80° C. (e.g., 65-80° C., 65-75° C.) respectively, and add atropine sulfate when the temperature drops below 30° C. (e.g., room temperature) to dissolve to obtain liquid B;

[0094] Mixing liquid a and liquid b, and adding the remaining amount of water to obtain the pharmaceutical composition;

[0095] Optionally, the method further comprises filtering the obtained pharmaceutical composition, preferably using a 0.22 μm filter membrane.

[0096] 10. Use of the pharmaceutical composition according to any one of items 6 to 8 in the preparation of a medicament for preventing and / or treating visual impairment (such as myopia, especially myopia in children or adolescents). BRIEF DESCRIPTION OF THE DRAWINGS

[0097] Figure 1 The HPLC analysis profile of commercially available atropine sulfate bulk drug B160903 is shown;

[0098] Figure 2 The HPLC analysis chart of 160903-P01 obtained by refining the commercially available atropine sulfate bulk drug B160903 is shown. DETAILED DESCRIPTION

[0099] The embodiments of the present invention will be described in detail below in conjunction with the examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. If the specific conditions are not specified in the examples, the conditions are carried out according to normal conditions or manufacturer recommendations. If the reagents or instruments used do not specify the manufacturer, they are all conventional products that can be obtained commercially. If the detection method is not specified in the examples, it can be detected using methods commonly used in the art, or with reference to the detection method specified in the Pharmacopoeia of the People's Republic of China (2015 edition).

[0100] The impurity codes and structures in atropine sulfate raw materials are as follows:

[0101]

[0102]

[0103] Example 1 Purification of Atropine Sulfate API

[0104] Place the commercially available atropine sulfate raw material A or B with a purity of more than 99% in a grinder with a 60-mesh screen, slowly crush and sieve, and collect the raw materials under the screen for later use. Take 50g of the crushed raw material and place it in a 3000mL three-necked flask, add 20 times the amount of anhydrous acetone, stir and wash at 40°C for 3h, filter and obtain wet product 1. Take the wet product 1, place it in a 3000mL three-necked flask, add 15 times the amount of 5% acetone aqueous solution, stir and wash at 40°C for 4h, filter and obtain wet product 2. Take the wet product 2 and place it in a 1000mL three-necked flask, add 10 times the amount of acetone, stir and wash at 5°C for 1.5h, filter and dry under reduced pressure for 6h to obtain 41g of atropine sulfate, with a yield of 82%. HPLC was used for impurity analysis, and the results are as follows: Figure 1-2 As shown in Table 1-2.

[0105] The HPLC analysis method is as follows:

[0106] Take the above sample, add mobile phase A to dissolve and dilute to make a solution containing 1 mg per 1 ml as the test solution; take an appropriate amount of the test solution, add mobile phase A to dissolve and dilute to make a solution containing 1 μg of atropine sulfate per 1 ml as the control solution; take an appropriate amount of atropine sulfate and impurity B, add mobile phase to dissolve and dilute to make a mixed solution containing about 1 μg / ml of impurity B and about 1 mg / ml of atropine sulfate per 1 ml as the system suitability test solution. Test according to high performance liquid chromatography (General Principle 0512 of the 2015 edition of the Chinese Pharmacopoeia). Use octadecylsilane bonded silica gel as filler (3μm, 250mm×4.6mm); use [606ml of 3.5g / L potassium dihydrogen phosphate solution (adjust pH to 3.3 with phosphoric acid) and 320ml of acetonitrile mixed solution] (containing 1.7g sodium dodecyl sulfate) as mobile phase A, acetonitrile as mobile phase B, gradient elution according to the table below, detection wavelength is 210nm. Accurately measure 10μl of system suitability test solution and inject it into the liquid chromatograph. The separation degree of atropine sulfate and impurity B chromatographic peaks should be not less than 2.0. Accurately measure 10μl of control solution and test solution and inject them into the liquid chromatograph.

[0107]

[0108] If there are impurity peaks in the chromatogram of the test solution, excluding the impurity peaks before the relative retention time of 0.25, the peak areas of impurities A, B, C, J and K (relative retention time and correction factor are shown in the table below) shall not be greater than the main peak area of ​​the control solution (0.1%), and the peak areas of other individual impurities shall not be greater than the main peak area of ​​the control solution (0.1%), and the sum of the peak areas of all impurities shall not be greater than 5 times the main peak area of ​​the control solution (0.5%). Chromatographic peaks in the chromatogram of the test solution that are less than 0.5 times the main peak area of ​​the control solution are ignored.

[0109]

[0110]

[0111] Table 1 Comparison of the purity of commercially available atropine sulfate raw material A before and after refining

[0112]

[0113] Table 2 Comparison of the purity of commercially available atropine sulfate raw material B before and after refining

[0114]

[0115] Embodiment 2 to Embodiment 6

[0116] According to the corresponding prescription ratio in Table 3, the atropine ophthalmic preparation was prepared by the following preparation method.

[0117] Preparation method:

[0118] (1) Take 10g of 80-90℃ water for injection, add the prescribed amount of hydroxypropyl methylcellulose or sodium hyaluronate to fully disperse and swell, add water for injection below 30℃ to 20g, stir and dissolve until a transparent solution is obtained, and set aside;

[0119] (2) Take 50 g of 65-75° C. water for injection, dissolve the prescribed amounts of sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate, edetate disodium and benzalkonium chloride in sequence, place the mixture at a temperature below 30° C., add the prescribed amount of atropine sulfate purified by the method in Example 1, and stir to dissolve;

[0120] (3) uniformly mixing the hydroxypropyl methylcellulose solution obtained in (1) and the solution obtained in (2);

[0121] (4) Add water to the mixed solution obtained in (3) to a total of 100 g, stir evenly, filter through a 0.22 μm filter membrane for sterilization, and fill.

[0122] Table 3 Prescription ratio

[0123] Components Example 2 Example 3 Example 4 Example 5 Example 6 Atropine sulfate 0.005g 0.010g 0.050g 0.010g 0.020g Hydroxypropyl methylcellulose 1.000g 1.000g 1.000g 1.000g 1.000g Sodium hyaluronate - - - 2.0g 2.0g Sodium dihydrogen phosphate monohydrate 0.250g 0.250g 0.250g 0.250g 0.250g Disodium hydrogen phosphate 0.0025g 0.0025g 0.0025g 0.0025g 0.0025g Edetate Disodium 0.010g 0.010g 0.010g 0.010g 0.010g Benzalkonium chloride 0.010g 0.010g 0.010g 0.010g 0.010g Water for injection margin margin margin margin margin

[0124] Reality Examples 7 ～ Reality Examples 9

[0125] According to the corresponding prescription ratio in Table 4, the atropine ophthalmic preparation was prepared by the following preparation method.

[0126] Preparation method:

[0127] (1) Take 10g of 80-90℃ water for injection, add the prescribed amount of hydroxypropyl methylcellulose to fully disperse and swell, add water for injection below 30℃ to 20g, stir and dissolve until a transparent solution is obtained, and set aside;

[0128] (2) Take 50 g of 65-75° C. water for injection, dissolve the prescribed amount of boric acid, disodium edetate and benzalkonium chloride in sequence, place the mixture at a temperature below 30° C., add the prescribed amount of atropine sulfate purified by the method in Example 1, and stir to dissolve;

[0129] (3) uniformly mixing the hydroxypropyl methylcellulose solution obtained in (1) and the solution obtained in (2);

[0130] (4) Add water to the mixed solution obtained in (3) to a total of 100 g, stir evenly, filter through a 0.22 μm filter membrane for sterilization, and fill.

[0131] Table 4 Prescription ratio

[0132] Components Example 7 Example 8 Example 9 Atropine sulfate 0.005g 0.010g 0.050g Hydroxypropyl methylcellulose 1.000g 1.000g 1.000g Propylene glycol 0.300g - 0.300g Boric acid 1.800g 1.800g 1.800g Edetate Disodium 0.010g 0.010g 0.010g Benzalkonium chloride 0.010g - 0.010g Water for injection margin margin margin

[0133] Comparative Example 1 to Comparative Example 5

[0134] According to the corresponding prescription ratio in Table 3, the atropine ophthalmic preparation was prepared by the following preparation method.

[0135] Preparation method:

[0136] (1) Take 10g of 80-90℃ water for injection, add the prescribed amount of hydroxypropyl methylcellulose or sodium hyaluronate to fully disperse and swell, add water for injection below 30℃ to 20g, stir and dissolve until a transparent solution is obtained, and set aside;

[0137] (2) Take 50 g of 65-75°C water for injection, dissolve the prescribed amount of sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate, edetate disodium and benzalkonium chloride in sequence, place below 30°C, add the prescribed amount of atropine sulfate API B160903, and stir to dissolve;

[0138] (3) uniformly mixing the hydroxypropyl methylcellulose solution obtained in (1) and the solution obtained in (2);

[0139] (4) Add water to a total of 100 g, stir evenly, filter through a 0.22 μm filter membrane to sterilize, and fill.

[0140] Comparative Examples 6 to 8

[0141] According to the corresponding prescription ratio in Table 4, the atropine ophthalmic preparation was prepared by the following preparation method.

[0142] Preparation method:

[0143] (1) Take 10g of 80-90℃ water for injection, add the prescribed amount of hydroxypropyl methylcellulose to fully disperse and swell, add water for injection below 30℃ to 20g, stir and dissolve until a transparent solution is obtained, and set aside;

[0144] (2) Take 50 g of 65-75°C water for injection, dissolve the prescribed amount of boric acid, disodium edetate and benzalkonium chloride in sequence, place below 30°C, add the prescribed amount of atropine sulfate API B160903, and stir to dissolve;

[0145] (3) uniformly mixing the hydroxypropyl methylcellulose solution obtained in (1) and the solution obtained in (2);

[0146] (4) Add water to the mixed solution obtained in (3) to a total of 100 g, stir evenly, filter through a 0.22 μm filter membrane for sterilization, and fill.

[0147] Experimental Example 1: Accelerated stability test of refined atropine sulfate API

[0148] The atropine sulfate bulk drug (batch number: 160903-P01) obtained by the purification in Example 1 was packaged (inner layer of medicinal low-density polyethylene bag plastic-sealed, outer layer of aluminum barrel), and placed under the conditions of 40°C ± 2°C and relative humidity of 75% ± 5%. The product changes were observed at 0 month, 1 month, 2 months, 3 months, and 6 months. The results are shown in Table 5.

[0149]

[0150] Experimental Example 1: Comparative Stability Test of Low-Concentration Atropine Ophthalmic Preparations

[0151] The atropine ophthalmic preparations obtained in Examples 2 to 9 and Comparative Examples 1 to 8 were placed at a temperature of 40°C ± 2°C and a relative humidity of 25% ± 5%, and the content of the active ingredient and the content of the main degradation product impurity C were tested at 0 month, 1 month, 2 months, 3 months, and 6 months. The results are shown in Table 6.

[0152] The method for determining the content of the active ingredient is as follows: take about 0.5 g of the ophthalmic preparation, weigh it accurately, add 40 ml of acetic anhydride to dissolve it, add 1 to 2 drops of crystal violet indicator solution, titrate with perchloric acid titration solution (0.1 mol / L) until the solution turns pure blue, and correct the titration result with a blank test. Each 1 ml of perchloric acid titration solution (0.1 mol / L) is equivalent to 67.68 mg of (C 17 H 23 NO3)2·H2SO4.

[0153] The method for determining the content of impurity C is based on the HPLC method in Example 1.

[0154] Table 6 Stability data of low concentration atropine ophthalmic preparations

[0155]

[0156]

[0157] It can be seen from the data in Table 5 that, compared with the products prepared by conventional processes, the degradation rate of the active ingredient of the low-concentration ophthalmic preparation prepared by the atropine sulfate of the present application is significantly slowed down, the content of the main degradation product impurity C is significantly reduced, and the stability of the low-concentration atropine sulfate ophthalmic preparation is significantly improved, thereby improving the quality of the product and effectively extending the shelf life of the product.

[0158] Although the specific embodiments of the present invention have been described in detail, according to all the teachings disclosed, those skilled in the art can make various modifications and substitutions to the details of the technical solution of the present invention, and these changes are within the protection scope of the present invention. The full scope of the present invention is given by the attached claims and any equivalents thereof.

Claims

1. A pharmaceutical composition comprising atropine sulfate having a total impurity content of ≤0.25% and a single impurity content of ≤0.05%, and a pharmaceutically acceptable excipient, The atropine sulfate is prepared by a refining method consisting of the following steps: The atropine sulfate API with a purity of more than 99% is crushed, the crushed atropine sulfate API is passed through a 60-mesh sieve, and then washed with a washing solvent a, a washing solvent b, and a washing solvent c respectively, and the method further comprises filtering and / or drying steps after washing; in, The pulping solvent a is acetone, and its dosage is 20 ml per gram of atropine sulfate, the pulping temperature is 40°C, and the pulping time is 3 hours; The pulping solvent b is an acetone-water mixed solvent, wherein the volume of water accounts for 5%, the dosage of the pulping solvent b is 15 ml per gram of atropine sulfate, the pulping temperature is 40° C., and the pulping time is 4 hours; The pulping solvent C is acetone, and its dosage is 10 ml per gram of atropine sulfate. The pulping temperature is 5° C. and the pulping time is 1.5 h.

2. The pharmaceutical composition according to claim 1, in, The total impurity content is ≤0.2%.

3. The pharmaceutical composition according to claim 1, in, The total impurity content is ≤0.15%.

4. The pharmaceutical composition according to claim 1, in, The total impurity content is ≤0.1%.

5. The pharmaceutical composition according to claim 1, in, The total impurity content is ≤0.05%.

6. The pharmaceutical composition according to claim 1, in, The total impurity content was not detected.

7. The pharmaceutical composition according to claim 1, in, The single impurity content is ≤0.01%.

8. A pharmaceutical composition according to claim 1, in, The single impurity content was not detected.

9. The pharmaceutical composition according to claim 1, which is a liquid preparation for ophthalmology.

10. The pharmaceutical composition according to claim 1, which is an eye drop.

11. The pharmaceutical composition according to claim 1, in, The concentration of the atropine sulfate is 0.001-0.1%.

12. The pharmaceutical composition according to claim 1, The concentration of the atropine sulfate is 0.005-0.05%.

13. The pharmaceutical composition according to claim 1, which consists by weight of: Optional 0.001-0.05% antibacterial agent; Optional 0.1-2% osmotic pressure regulator; And, the balance of water.

14. A pharmaceutical composition according to claim 13, in, The concentration of the atropine sulfate is 0.005-0.05%.

15. The pharmaceutical composition according to claim 13, in, The thickener is selected from cellulose derivatives, cross-linked polyvinyl pyrrolidone, sodium hyaluronate, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and any combination thereof.

16. The pharmaceutical composition according to claim 13, in, The cellulose derivative is selected from hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose and any combination thereof.

17. The pharmaceutical composition according to claim 13, in, The cellulose derivative is hydroxypropyl methylcellulose.

18. The pharmaceutical composition according to claim 13, in, The weight content of the thickener in the pharmaceutical composition is 0.5-10%.

19. The pharmaceutical composition according to claim 13, in, The weight content of the thickener in the pharmaceutical composition is 0.5-8%.

20. The pharmaceutical composition according to claim 13, in, The weight content of the thickener in the pharmaceutical composition is 0.5-5%.

21. The pharmaceutical composition according to claim 13, in, The weight content of the thickener in the pharmaceutical composition is 0.5-3%.

22. The pharmaceutical composition according to claim 13, in, The weight content of the thickener in the pharmaceutical composition is 1-3%.

23. The pharmaceutical composition according to claim 13, in, The complexing agent is selected from edetic acid, edetate disodium and edetate calcium sodium.

24. The pharmaceutical composition according to claim 13, in, The complexing agent is disodium edetate.

25. The pharmaceutical composition according to claim 13, in, The weight content of the complexing agent in the pharmaceutical composition is 0.005-0.05%.

26. A pharmaceutical composition according to claim 13, in, The weight content of the complexing agent in the pharmaceutical composition is 0.005-0.03%.

27. The pharmaceutical composition according to claim 13, in, The weight content of the complexing agent in the pharmaceutical composition is 0.005-0.02%.

28. A pharmaceutical composition according to claim 13, in, The weight content of the complexing agent in the pharmaceutical composition is 0.005-0.01%.

29. The pharmaceutical composition according to claim 13, in, The weight content of the complexing agent in the pharmaceutical composition is 0.008-0.01%.

30. The pharmaceutical composition according to claim 13, in, The antibacterial agent is selected from benzalkonium chloride, benzalkonium bromide, cetrimide bromide, phenoxyethanol, phenethyl alcohol, paraben antibacterial agents and any combination thereof.

31. A pharmaceutical composition according to claim 13, in, The antibacterial agent is benzalkonium chloride, ethyl p-hydroxybenzoate or any combination thereof.

32. A pharmaceutical composition according to claim 13, in, The antibacterial agent is benzalkonium chloride.

33. A pharmaceutical composition according to claim 13, in, The weight content of the antibacterial agent in the pharmaceutical composition is 0.005-0.03%.

34. A pharmaceutical composition according to claim 13, in, The weight content of the antibacterial agent in the pharmaceutical composition is 0.005-0.02%.

35. A pharmaceutical composition according to claim 13, in, The weight content of the antibacterial agent in the pharmaceutical composition is 0.006-0.02%.

36. A pharmaceutical composition according to claim 13, in, The weight content of the antibacterial agent in the pharmaceutical composition is 0.006-0.012%.

37. A pharmaceutical composition according to claim 13, in, The weight content of the antibacterial agent in the pharmaceutical composition is 0.008-0.01%.

38. A pharmaceutical composition according to claim 13, in, The pH regulator is selected from one or more of a carbonate buffer system, a phosphate buffer system, a citric acid buffer system, an acetic acid buffer system, a barbituric acid buffer system, a tris(hydroxymethyl)aminomethane buffer system, boric acid, borax, sodium hydroxide, hydrochloric acid, citric acid and salts thereof.

39. A pharmaceutical composition according to claim 13, in, The pH regulator is one or more selected from boric acid and phosphate buffer systems.

40. A pharmaceutical composition according to claim 13, in, The pH regulator is a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer system.

41. A pharmaceutical composition according to claim 13, in, The pH regulator is a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer system.

42. A pharmaceutical composition according to claim 13, in, The content of the pH adjuster in the pharmaceutical composition is such that the pH of the pharmaceutical composition is 4.0 to 6.

0.

43. A pharmaceutical composition according to claim 13, in, The content of the pH adjuster in the pharmaceutical composition is such that the pH of the pharmaceutical composition is 4.5 to 5.

5.

44. A pharmaceutical composition according to claim 13, in, The osmotic pressure regulator is selected from sodium chloride, glycerol, propylene glycol, mannitol and any combination thereof.

45. A pharmaceutical composition according to claim 13, in, The osmotic pressure regulator is propylene glycol.

46. ​​A pharmaceutical composition according to claim 13, in, The weight content of the osmotic pressure regulator in the pharmaceutical composition is 0.1-1%.

47. A pharmaceutical composition according to claim 13, in, The weight content of the osmotic pressure regulator in the pharmaceutical composition is 0.1-0.5%.

48. A pharmaceutical composition according to claim 13, in, The weight content of the osmotic pressure regulator in the pharmaceutical composition is 0.1-0.3%.

49. A pharmaceutical composition according to claim 13, selected from formula 1-4: Recipe 1: and, the balance of water; Recipe 2: and, the balance of water; Recipe 3: and, the balance of water; Recipe 4: And, the balance of water.

50. A method for preparing a pharmaceutical composition according to any one of claims 13 to 49, wherein The following steps are involved: The thickener is dispersed and swelled in water at 60-90°C, and then further dissolved in water at 20-30°C to obtain liquid A; Dissolve the pH regulator, complexing agent, optional antibacterial agent and optional osmotic pressure regulator in 60-80°C water respectively, and add atropine sulfate when the temperature drops below 30°C to dissolve to obtain liquid B; Liquid A and liquid B are mixed, and the remaining amount of water is added to obtain the pharmaceutical composition.

51. The method according to claim 50, further comprising the step of filtering the resulting pharmaceutical composition.

52. The method according to claim 50, further comprising the step of filtering the obtained pharmaceutical composition using a 0.22 μm filter membrane.

53. Use of the pharmaceutical composition according to any one of claims 13 to 49 in the preparation of a medicament for preventing and / or treating visual impairment.

54. The use according to claim 53, in, The visual impairment is myopia.

55. The use according to claim 53, in, The visual impairment is myopia in children or adolescents.

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