TW202320773A - Atropine eye drops and preparation method therefor - Google Patents

Abstract

The present invention belongs to the field of medicine, and specifically relates to atropine eye drops and a preparation method therefor. The atropine eye drops provided in the present invention comprise: by mass concentration, 0.10-0.20 g/L of atropine or a pharmaceutically acceptable salt thereof, 0-1.00 g/L of a chelating agent, and 7.80-9.00 g/L of an osmotic pressure regulator, a pH regulator and water for injection. The pH regulator is a combination of citric acid and borax or a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid, and the amount of the pH regulator used is based on adjusting the pH value to 4.5-5.5. The atropine eye drops prepared according to the above prescription have good stability, low total impurities, low toxicity and do not irritate to eyes.

Description

Atropine eye drops and preparation method thereof

The invention belongs to the field of medicine, and in particular relates to an atropine eye drop and a preparation method thereof.

Atropine is a natural compound that can be extracted from belladonna or other plants of the nightshade family. In clinical medicine, atropine is mainly used to relieve smooth muscle spasm, improve microcirculation, inhibit glandular secretion, and relieve the inhibition of vagus nerve on the heart. Atropine sulfate (atropine sulfate) is a kind of salt of atropine, according to clinical records, the pharmacological action of atropine sulfate ophthalmic preparation is better, has quite high selectivity to M receptor, and blocks M choline receptor, makes the pupil The sphincter and ciliary muscles relax, creating a pupil-dilation mechanism that relieves pain caused by swelling and inflammation of the eye.

Years of studies have confirmed that atropine ophthalmic preparations can stretch the originally tense ciliary muscles of adolescents and children, and further restore their regulatory function during sleep, effectively delaying and treating the development of myopia. However, currently commercially available atropine ophthalmic preparations (such as Meioupin, Yatamine, Letropine, USP1%, etc.) are easily decomposed during storage, and related substances (tropine acid, anhydroatropine, any single unknown related substances) Substances and the total amount of related substances, etc.) will affect the effectiveness and safety of drugs.

Therefore, developing an atropine ophthalmic drug with good storage stability is a technical problem to be solved urgently in this field.

The problem to be solved by the invention

Aiming at the defects existing in the prior art, the present invention provides an atropine eye drop, which has good stability and low total impurities through raw material selection and prescription optimization.

Furthermore, the present invention also provides a method for preparing the above-mentioned atropine eye drops. The atropine eye drops prepared by this method have good stability and low total impurities, and are suitable for long-term storage. solutions to problems

The present invention provides a kind of atropine eye drop, comprises the following components: by mass concentration, atropine or its pharmaceutically acceptable salt 0.10~0.20g/L, chelating agent 0~1.00g/L, osmotic pressure regulator 7.80~ 9.00g/L, pH regulator and water for injection; Wherein, the pH regulator is a combination of citric acid and borax or a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid, and the dosage of the pH regulator is based on adjusting the pH value to 4.5-5.5.

Preferably, in terms of mass concentration, in the combination of citric acid and borax, citric acid is 0.50～2.00g/L, and borax is 1.00～2.00g/L; In terms of mass concentration, in the combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid, sodium dihydrogen phosphate is 1.49~6.00g/L, disodium hydrogen phosphate is 0.43~0.88g/L, hydrochloric acid is 0.04~0.13g/L L.

Further preferably, the atropine eye drops of the present invention comprises the following components: in terms of mass concentration, 0.10-0.20 g/L of atropine or a pharmaceutically acceptable salt thereof, 0-1.00 g/L of a chelating agent, and osmotic Pressure regulator 7.80~9.00g/L, citric acid 0.50g/L, borax 1.05g/L and water for injection.

Further preferably, the atropine eye drops of the present invention comprises the following components: in terms of mass concentration, 0.10-0.20 g/L of atropine or a pharmaceutically acceptable salt thereof, 0-1.00 g/L of a chelating agent, and osmotic Pressure regulator 7.80~9.00g/L, sodium dihydrogen phosphate 1.95g/L, disodium hydrogen phosphate 0.56g/L, hydrochloric acid 0.076g/L and water for injection.

Preferably, in the atropine eye drops of the present invention, the pharmaceutically acceptable salt is sulfate.

Preferably, in the atropine eye drops of the present invention, the chelating agent includes one or a combination of two or more of edetate disodium, edetate sodium calcium and edetate.

Further preferably, in the atropine eye drops of the present invention, the chelating agent is disodium edetate.

Preferably, in the atropine eye drops of the present invention, the osmotic pressure regulator includes one or a combination of two or more of sodium chloride, mannitol and glycerin; Further preferably, in the atropine eye drops of the present invention, the osmotic pressure regulator is sodium chloride.

The present invention provides a kind of preparation method of atropine eye drops according to the present invention, comprises the following steps: Dissolving the chelating agent, osmotic pressure regulator, and pH regulator in the prescribed amount in the water for injection to obtain solution A; Adding the atropine or its pharmaceutically acceptable salt of prescription amount in described solution A, obtains solution B; The solution B is filtered, filled, and obtained.

Preferably, in the preparation method of the present invention, the temperature of the water for injection is below 40°C.

Further preferably, in the preparation method of the present invention, the temperature of the water for injection is 21.4-24.4°C.

Preferably, in the preparation method of the present invention, the solution B is filtered through a microfiltration membrane with a pore size of 0.22 μm, and the microfiltration membrane is a PVDF membrane. The effect of the invention

The atropine eye drop provided by the invention achieves the beneficial effects of product stability and less impurities by selecting a specific chelating agent, an osmotic pressure regulator, and a pH regulator, and is suitable for long-term storage. Surprisingly, compared with the commercially available atropine eye drops, the atropine eye drops provided by the present invention passed through 30 days of influence factors and 6 months of accelerated tests and other stability tests, and its total impurity content was significantly lower than that of the commercially available atropine eye drops. The American-European product, yatromin and letopine sold, the prescription of the present invention has unexpected technical effect on stability.

Furthermore, the atropine eye drops provided by the present invention do not contain thickeners and preservatives, and have low toxicity; the pH value is closer to neutral, and has no irritation to eyes.

Furthermore, the atropine eye drops provided by the present invention use a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid as the pH regulator, which has higher safety and is more suitable for long-term medication for children.

Further, the present invention provides a preparation method of atropine eye drops, the atropine eye drops prepared by this method has good stability, low total impurities, and is suitable for long-term storage.

Detailed ways

Various illustrative embodiments, features, and aspects of the invention are described in detail below. The word "exemplary" is used exclusively herein to mean "serving as an example, embodiment, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as superior or better than other embodiments.

In addition, in order to better illustrate the present invention, numerous specific details are given in the specific embodiments below. It will be understood by those skilled in the art that the present invention may be practiced without certain of the specific details. In other instances, methods, means, devices and steps well known to those skilled in the art are not described in detail in order to highlight the gist of the present invention.

Unless otherwise stated, the units used in this specification are all international standard units, and the numerical values and numerical ranges appearing in the present invention should be understood as including inevitable systematic errors in industrial production.

In this specification, the numerical range represented by "numerical value A~numerical value B" refers to the range including numerical value A and B of the endpoint.

In this specification, "optional" or "optionally" means that the next described event or situation may or may not occur, and that the description includes situations where the event occurs and situations where the event does not occur.

In this specification, the meaning expressed by "may" includes the meaning of performing certain processing and not performing certain processing.

In this specification, references to "some specific/preferred embodiments", "other specific/preferred embodiments", "embodiments" and the like refer to specific elements described in relation to the embodiments (for example, A feature, structure, property, and/or characteristic) is included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it is to be understood that the described elements may be combined in any suitable manner in the various embodiments. [Atropine eye drops]

The present invention provides a kind of atropine eye drop, comprises the following components: by mass concentration, atropine or its pharmaceutically acceptable salt 0.10~0.20g/L, chelating agent 0~1.00g/L, osmotic pressure regulator 7.80~ 9.00g/L, pH regulator and water for injection; Wherein, the pH regulator is a combination of citric acid and borax or a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid, and the dosage of the pH regulator is based on adjusting the pH value to 4.5-5.5.

In some specific embodiments of the present invention, in terms of mass concentration, in the combination of the above-mentioned citric acid and borax, citric acid is 0.50~2.00g/L, and borax is 1.00~2.00g/L; in terms of mass concentration, the above-mentioned dihydrogen phosphate In the combination of sodium, disodium hydrogen phosphate and hydrochloric acid, sodium dihydrogen phosphate is 1.49~6.00g/L, disodium hydrogen phosphate is 0.43~0.88g/L, and hydrochloric acid is 0.04~0.13g/L.

The atropine eye drop provided by the invention has good stability and low total impurities through raw material selection and prescription optimization, and is suitable for long-term storage; moreover, the pH value is 4.5-5.5, which is closer to neutral, and has no irritation to eyes.

In some preferred embodiments of the present invention, the atropine eye drop consists of the following components: in terms of mass concentration, atropine or its pharmaceutically acceptable salt 0.10~0.20g/L, chelating agent 0~1.00g/L , osmotic pressure regulator 7.80~9.00g/L, pH regulator and water for injection; Wherein, the pH regulator is a combination of citric acid and borax or a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid; in terms of mass concentration, citric acid is 0.50~2.00g/L, borax is 1.00~2.00g/L, phosphoric acid Sodium dihydrogen 1.49~6.00g/L, disodium hydrogen phosphate 0.43~0.88g/L, hydrochloric acid 0.04~0.13g/L.

The present invention further optimizes above-mentioned prescription, makes it not contain thickener [such as hypromellose (60SH)], can avoid the influence of thickener on product stability; Ammonium, etc.), high safety and low toxicity. Atropine or its pharmaceutically acceptable salt

Atropine drugs are currently the most effective drugs for preventing myopia in adolescents and children. They can stretch the originally tense ciliary muscle and further restore its regulatory function during sleep.

In some specific embodiments of the present invention, in terms of mass concentration, atropine or a pharmaceutically acceptable salt thereof is 0.10~0.20g/L, illustratively, its mass concentration can be 0.10g/L, 0.12g/L, 0.14g/L, 0.15g/L, 0.16g/L, 0.18g/L, 0.20g/L, etc. Clinical studies have found that within a certain range, the higher the concentration of atropine or its pharmaceutically acceptable salt, the better the effect of its prevention and/or treatment of myopia, but the concentration is too high (such as 1% concentration, 0.5% concentration, 0.1 % concentration, and its mass concentration is 10g/L, 5g/L, 1g/L respectively) will be accompanied by many adverse reactions, such as strong mydriasis and increased intraocular pressure. In contrast, low-concentration eye drops can minimize adverse reactions while ensuring a better effect of preventing and/or treating myopia. The study found that atropine eye drops with a concentration of 0.01% (mass concentration of 0.1g/L) are suitable for the correction of progressive myopia in children and adolescents; highest concentration.

In some preferred embodiments of the present invention, the mass concentration of atropine or a pharmaceutically acceptable salt thereof is 0.10 g/L or 0.20 g/L.

In some preferred embodiments of the present invention, the pharmaceutically acceptable salt is sulfate (ie, atropine sulfate). Chelating agent

Considering that the packaging container used for atropine eye drops may be made of low-density polyethylene, and its raw materials contain metal elements harmful to the human body; moreover, in actual production, the liquid distribution tank and production pipelines are made of stainless steel. It is also possible to introduce metal ions. Trace heavy metals can catalyze the decomposition of active ingredients in atropine eye drops through oxidation or other mechanisms. Therefore, the addition of chelating agents can form stable complexes with various metal ions to prevent the decomposition of active ingredients, making atropine eye drops The liquid has good stability and low total impurities.

In some specific embodiments of the present invention, the chelating agent includes one or a combination of two or more of edetate disodium, edetate sodium calcium and edetate.

In some preferred embodiments of the invention, the chelating agent is disodium edetate.

In some specific embodiments of the present invention, the mass concentration of the chelating agent is 0~1.00g/L, illustratively, its mass concentration can be 0, 0.10g/L, 0.20g/L, 0.40g/L, 0.50 g/L, 0.60g/L, 0.80g/L, 1.00g/L, etc. osmotic regulator

The osmotic pressure regulator is used to control the osmotic pressure of the atropine eye drops within an appropriate range.

In some specific embodiments of the present invention, the osmotic pressure regulator includes one or a combination of two or more of sodium chloride, mannitol and glycerin.

In some preferred embodiments of the present invention, the osmotic pressure regulator is sodium chloride, and the stability of the atropine eye drops using sodium chloride is better than that using mannitol or glycerin.

The osmotic pressure range that the human eye can tolerate is relatively wide, which is equivalent to the osmotic pressure molar concentration of 0.5~1.5% w/v sodium chloride solution. Ideally, eye drops should be isotonic with tear fluid, equivalent to 0.09% w/v sodium chloride solution. Considering that other salt components in atropine eye drops will also affect its osmotic pressure, the dosage of osmotic pressure regulator should be comprehensively studied. In some specific embodiments of the present invention, the mass concentration of the osmotic pressure regulator is 7.80~9.00g/L. Exemplarily, its mass concentration can be 7.80g/L, 8.00g/L, 8.20g/L, 8.40 g/L, 8.60g/L, 8.80g/L, 9.00g/L, etc. When the mass concentration is lower than 7.80g/L or higher than 9.00g/L, the osmotic pressure will exceed the tolerance range of human eyes, thus causing eye discomfort.

In some preferred embodiments of the present invention, the mass concentration of the osmotic pressure regulator is 8.30 g/L and 8.70 g/L. pH regulator

The pH regulator is used to adjust the pH value of the atropine eye drops to 4.5~5.5, making it close to neutral and non-irritating to the eyes. The molecular structure of atropine or atropine sulfate contains ester groups, which are prone to hydrolysis when the pH value is high, and the hydrolysis products are tropic acid and tropinol, which cause quality problems of eye drops.

In some specific embodiments of the present invention, the pH adjusting agent is a combination of citric acid and borax.

In other specific embodiments of the present invention, the pH regulator is a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid.

in: When the pH regulator is a combination of citric acid and borax, in some specific embodiments of the present invention, the atropine eye drops include the following components: in terms of mass concentration, 0.10 to 0.20 g of atropine or a pharmaceutically acceptable salt thereof /L, chelating agent 0~1.00g/L, osmotic pressure regulator 7.80~9.00g/L, citric acid 0.50~2.00g/L, borax 1.00~2.00g/L and water for injection.

In some preferred embodiments of the present invention, atropine eye drops comprises the following components: in terms of mass concentration, atropine or its pharmaceutically acceptable salt 0.10~0.20g/L, chelating agent 0~1.00g/L, osmotic Pressure regulator 7.80~9.00g/L, citric acid 0.50g/L, borax 1.05g/L and water for injection.

In some more preferred embodiments of the present invention, atropine eye drops comprises the following components: by mass concentration, atropine or its pharmaceutically acceptable salt 0.10g/L, chelating agent 1.00g/L, osmotic pressure regulator 8.70g/L, 0.50g/L anhydrous citric acid, 1.05g/L borax and water for injection.

In some other more preferred embodiments of the present invention, atropine eye drops comprise the following components: in terms of mass concentration, atropine or its pharmaceutically acceptable salt 0.20g/L, chelating agent 1.00g/L, osmotic pressure adjustment Agent 8.70g/L, anhydrous citric acid 0.50g/L, borax 1.05g/L and water for injection.

When the pH regulator is a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid, in some specific embodiments of the present invention, the atropine eye drops include the following components: in terms of mass concentration, atropine or its pharmaceutically acceptable Accepted salt 0.10~0.20g/L, chelating agent 0~1.00g/L, osmotic pressure regulator 7.80~9.00g/L, sodium dihydrogen phosphate 1.49~6.00g/L, disodium hydrogen phosphate 0.43~0.88g/L L, hydrochloric acid 0.04~0.13g/L and water for injection.

When sodium dihydrogen phosphate and disodium hydrogen phosphate are higher than 6.00g/L and 0.88g/L respectively, the impurity content in the eye drops will increase; moreover, the two phosphates themselves have certain osmotic pressure, if The dosage is relatively large. In order to achieve isotonicity, it is necessary to adjust the dosage of the osmotic pressure regulator, and the osmotic pressure regulator (especially sodium chloride) has a certain stabilizing effect on atropine or atropine sulfate, which can inhibit the growth of tropic acid. Therefore, in order to ensure the stability of atropine eye drops, two kinds of phosphates and the osmotic pressure regulator consumption need to be adjusted synergistically. In the eye drops of the present invention, the quality of sodium dihydrogen phosphate, disodium hydrogen phosphate and osmotic pressure regulator The concentrations are 1.49~6.00g/L, 0.43~0.88g/L and 7.80~9.00g/L respectively.

In some preferred embodiments of the present invention, atropine eye drops comprise the following components: in terms of mass concentration, atropine or its pharmaceutically acceptable salt 0.10~0.20g/L, chelating agent 0~1.00g/L, osmotic pressure Regulator 7.80~9.00g/L, sodium dihydrogen phosphate 1.95g/L, disodium hydrogen phosphate 0.56g/L, hydrochloric acid 0.076g/L and water for injection.

In some more preferred embodiments of the present invention, atropine eye drops comprises the following components: in terms of mass concentration, atropine or its pharmaceutically acceptable salt 0.10g/L, chelating agent 1.00g/L, osmotic pressure regulator 8.30g/L g/L, sodium dihydrogen phosphate 1.95g/L, disodium hydrogen phosphate 0.56g/L, hydrochloric acid 0.076g/L and water for injection.

In some other more preferred embodiments of the present invention, atropine eye drops comprise the following components: in terms of mass concentration, atropine or its pharmaceutically acceptable salt 0.20g/L, chelating agent 1.00g/L, osmotic pressure adjustment Agent 8.30g/L, sodium dihydrogen phosphate 1.95g/L, disodium hydrogen phosphate 0.56g/L, hydrochloric acid 0.076g/L and water for injection.

In some preferred embodiments of the present invention, the dosage specification of the atropine eye drops is 0.5mL/bottle, which is suitable for single-dose single-bottle administration by the user, and there is no problem of drug contamination, which is safer and more reliable. [Preparation]

The invention provides the preparation method of above-mentioned atropine eye drops, comprises the following steps: Dissolving the chelating agent, osmotic pressure regulator and pH regulator in the prescribed amount in water for injection to obtain solution A; Adding atropine or its pharmaceutically acceptable salt of prescription amount in solution A, obtains solution B; Filter the solution B, fill it, and get it.

The atropine eye drop prepared by the method has good stability, low total impurities and is suitable for long-term storage.

The dosing temperature affects the stability of the atropine eye drops. In some specific embodiments of the present invention, the temperature of the water for injection (i.e. the dosing temperature) is controlled below 40°C, preferably 21.4 to 24.4°C. Exemplarily, it The temperature may be 21.4°C, 22.5°C, 24.4°C, etc.

In some specific embodiments of the present invention, the pH value of solution A is 4.99-5.01. Exemplarily, the pH value may be 4.99, 5.00, 5.01, etc.

In some specific embodiments of the present invention, the pH value of solution B is 4.98-5.01. Exemplarily, the pH value may be 4.98, 5.00, 5.01, etc.

In some specific embodiments of the present invention, solution B is filtered through a microfiltration membrane with a pore size of 0.22 μm. Atropine eye drops is a sterile preparation, and the purpose of filtering through the microfiltration membrane is to sterilize and make the product meet the standard. In some specific embodiments of the present invention, at least two microfiltration membranes are provided, and the sterilization effect is better.

In some specific embodiments of the present invention, the microfiltration membrane adopts PVDF membrane, and if the microfiltration membrane of other materials is used, impurities may be introduced.

The above-mentioned pH regulator is a combination of citric acid and borax or a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid.

Wherein, when the pH regulator is the combination of citric acid and borax, "combination of citric acid and borax" represents the solute existence form of the pH regulator in the atropine eye drops, and in the actual preparation process, the added raw materials can be It is a mixture of anhydrous citric acid or its hydrate and borax or its hydrate, specifically, it can be a mixture of anhydrous citric acid and borax, it can also be a mixture of citric acid monohydrate and borax decahydrate, etc., and its addition amount is Measured by mass concentration of solute.

In some more specific embodiments of the present invention, the preparation method of atropine eye drops comprises the following steps: Measure an appropriate amount of water for injection, and control the temperature at 21.4~22.5°C; Add the prescribed amount of stabilizer, osmotic pressure regulator, anhydrous citric acid and borax, stir to dissolve, the stirring speed is 50~300rpm, and the stirring time is 10~30min, then add an appropriate amount of water for injection to the preset volume to obtain solution A , the pH value of the system at this time is 4.99~5.01; Add atropine or a pharmaceutically acceptable salt thereof in a prescription amount to solution A, the stirring speed is 50-300 rpm, and the stirring time is 10-30 min to obtain solution B, and the system pH value is 4.7-5.3 at this time; The solution B is filtered through a microfiltration membrane, and after passing the inspection, it is filled and sealed to obtain the product.

When the pH regulator is a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid, similarly, "the combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid" means the pH regulator in atropine eye drops. Solute exists in the form, in the actual preparation process, the raw material added can be a mixture of sodium dihydrogen phosphate or its hydrate, disodium hydrogen phosphate or its hydrate and hydrochloric acid, such as sodium dihydrogen phosphate dihydrate, dihydrogen phosphate A mixture of sodium dihydrate and hydrochloric acid, etc.; wherein the hydrochloric acid can be commercially available concentrated hydrochloric acid, or dilute hydrochloric acid of other concentrations prepared by oneself.

In some more specific embodiments of the present invention, the preparation method of atropine eye drops comprises the following steps: preparing 0.1-1mol/L hydrochloric acid for standby; taking an appropriate amount of water for injection, and controlling the temperature at 24.4°C; Stabilizer, osmotic pressure regulator, sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate dihydrate, stir to dissolve, the stirring speed is 50~300rpm, the stirring time is 10~30min, and the pH value of the system at this time is 5.86 ~5.87, then add the prepared hydrochloric acid, adjust the pH value to 5.00, and then add an appropriate amount of water for injection to the preset volume to obtain solution A. At this time, the pH value of the system is 5.00~5.01; Its pharmaceutically acceptable salt, the stirring speed is 50~300rpm, the stirring time is 10~30min, and the solution B is obtained, and the pH value of the system is 5.01 at this time; the solution B is filtered through a microfiltration membrane, and after passing the inspection, it is filled. Seal it, and you get it. Example

Embodiments of the present invention will be described in detail below in conjunction with examples, but those skilled in the art will understand 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. Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be obtained from the market. Example 1

The present embodiment provides a kind of atropine eye drops, and its prescription is as shown in table 1: Table 1 prescription of atropine eye drops Original adjuvant name Specification: 0.01% Mass (mg)/branch (calculated by solute) Mass (g)/1 L (calculated as solute) Atropine sulfate 0.05 0.10 anhydrous citric acid 0.25 0.50 Borax 0.53 1.05 Edetate disodium 0.50 1.00 Sodium chloride 4.35 8.70 Water for Injection Make up to 0.5 mL Add to 1 L

The present embodiment provides the preparation method of above-mentioned atropine eye drops, comprises the following steps: (1) Measure 900 mL of water for injection with 90% of the prescription volume at a temperature of 22.5°C; (2) Add the prescribed amount of edetate disodium, sodium chloride, borax and anhydrous citric acid, stir to dissolve, the stirring speed is 200 rpm, the stirring time is 10 min, add water for injection to 1000 mL, and obtain solution A , the pH value of the measuring system is 5.01; (3) Add the atropine sulfate of recipe quantity in solution A, stirring speed is 200 rpm, and stirring time is 10 min, obtains solution B, and measuring system pH value is 4.98; (4) Filtrate with a 0.22 μm PVDF filter membrane, and the obtained medicinal solution is sent for analysis to detect the content of atropine sulfate; (5) Fill 0.5 mL of liquid medicine into a 1 mL eye drop bottle with a glass syringe, a total of 162 tubes, heat-melt and seal, and check for leaks after the bottle mouth cools to room temperature; the rest of the liquid medicine is sealed in glass bottles Store at room temperature. Example 2

The present embodiment provides a kind of atropine eye drops, and its prescription is as shown in table 2: Table 2 prescription of atropine eye drops Original adjuvant name Specification: 0.02% Mass (mg)/branch (calculated by solute) Mass (g)/1 L (calculated as solute) Atropine sulfate 0.10 0.20 anhydrous citric acid 0.25 0.50 Borax 0.53 1.05 Edetate disodium 0.50 1.00 Sodium chloride 4.35 8.70 Water for Injection Make up to 0.5 mL Add to 1 L

The present embodiment provides the preparation method of above-mentioned atropine eye drops, comprises the following steps: (1) Measure 900 mL of water for injection with 90% of the prescription volume at a temperature of 21.4°C; (2) Add the prescribed amount of edetate disodium, sodium chloride, borax and anhydrous citric acid, stir to dissolve, the stirring speed is 200 rpm, the stirring time is 10 min, add water for injection to 1000 mL, and obtain solution A , the pH value of the measuring system is 4.99; (3) Add the atropine sulfate of recipe quantity in solution A, stirring speed is 200 rpm, and stirring time is 10 min, obtains solution B, and measuring system pH value is 4.98; (4) Filtrate with a 0.22 μm PVDF filter membrane, and the obtained medicinal solution is sent for analysis to detect the content of atropine sulfate; (5) Fill 0.5 mL of the filtrate into a 1 mL eye drop bottle with a glass syringe, a total of 150, heat-melt the seal, and check for leaks after the bottle mouth cools to room temperature; the rest of the liquid medicine is sealed in the glass bottle Store at room temperature. Example 3

The present embodiment provides a kind of atropine eye drops, and its prescription is as shown in table 3: Table 3 prescription of atropine eye drops Original adjuvant name Specification: 0.01% Mass (mg)/branch (calculated as solute) Mass (g)/1 L (calculated as solute) Atropine sulfate 0.05 0.10 Sodium dihydrogen phosphate dihydrate 0.98 1.95 Disodium hydrogen phosphate dihydrate 0.28 0.56 Edetate disodium 0.50 1.00 Sodium chloride 4.15 8.30 hydrochloric acid 0.038 0.076 Water for Injection Make up to 0.5 mL Add to 1 L

The present embodiment provides the preparation method of above-mentioned atropine eye drops, comprises the following steps: (1) Precisely measure 0.9 mL of 36% hydrochloric acid, add it to 100 mL of water for injection, and prepare 0.1 mol/L hydrochloric acid for later use; (2) Measure 900 mL of water for injection with 90% of the prescription volume, and the temperature is 24.4°C; (3) Add the prescribed amount of edetate disodium, sodium chloride, sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate dihydrate, stir to dissolve, the stirring speed is 200 rpm, and the stirring time is 10 min. The pH value of the measuring system is 5.87; Adjust the pH value to 5.00 with 0.1 mol/L hydrochloric acid, add water for injection to 1000 mL to obtain solution A, and measure the pH value of the system to 5.00; (4) Add the atropine sulfate of recipe quantity in solution A, stirring speed is 200 rpm, and stirring time is 10 min, obtains solution B, and measuring system pH value is 5.01; (5) Filtrate with a 0.22 μm PVDF filter membrane, and the obtained medicinal solution is sent for analysis to detect the content of atropine sulfate; (6) Fill 0.5 mL of liquid medicine into a 1 mL eye drop bottle with a glass syringe, a total of 156 tubes, heat-melt and seal, and check for leaks after the mouth of the bottle cools to room temperature; the rest of the liquid medicine is sealed in glass bottles Store at room temperature. Example 4

The present embodiment provides a kind of atropine eye drops, and its prescription is as shown in table 4: Table 4 prescription of atropine eye drops Original adjuvant name Specification: 0.02% Mass (mg)/branch (calculated by solute) Mass (g)/1 L (calculated as solute) Atropine sulfate 0.10 0.20 Sodium dihydrogen phosphate dihydrate 0.98 1.95 Disodium hydrogen phosphate dihydrate 0.28 0.56 Edetate Disodium 0.50 1.00 Sodium chloride 4.15 8.30 hydrochloric acid 0.038 0.076 Water for Injection Make up to 0.5 mL Add to 1 L

The present embodiment provides the preparation method of the above-mentioned atropine eye drops, comprising the following steps: (1) accurately measure 0.9 mL of 36% hydrochloric acid, add it to 100 mL of water for injection, and prepare 0.1 mol/L hydrochloric acid for subsequent use; 2) Measure 900 mL of water for injection with 90% of the prescribed amount at 24.4°C; (3) Add the prescribed amount of edetate disodium, sodium chloride, sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate dihydrate Stir to dissolve the substance, the stirring speed is 200 rpm, the stirring time is 10 min, and the pH value of the measuring system is 5.86; the pH value is adjusted to 5.00 with 0.1 mol/L hydrochloric acid, and water for injection is added to 1000 mL to obtain solution A. The pH value of the measurement system is 5.01; (4) Add atropine sulfate in the prescription amount to solution A, the stirring speed is 200 rpm, and the stirring time is 10 min to obtain solution B, and the pH value of the measurement system is 5.01; (5) Use 0.22 μm Filtrate through a PVDF filter membrane, and the resulting medicinal solution is sent for analysis to detect the content of atropine sulfate; (6) Fill 0.5 mL of the filtrate into a 1 mL eye drop bottle with a glass syringe, a total of 104, heat-melt and seal, and wait for the bottle to cool to room temperature. After warming, check for leaks; the rest of the liquid medicine is sealed in a glass bottle and stored at room temperature. Test Example 1 Atropine Eye Drops Test of Influencing Factors 1.1 The Atropine Eye Drops Prepared in Example 1 and Example 2

Adopted pH regulator among the embodiment 1 and embodiment 2 is the combination of citric acid and borax. For the atropine eye drops, its influence factor test studied the conditions of high temperature (40°C and 50°C) and strong light irradiation (5000lx); considering the possible transportation conditions, low temperature test (4°C) and freezing Melt test (-18 ℃) research. The research results are shown in Table 5 and Table 6 respectively: Table 5 The test results of the influencing factors of the atropine eye drops prepared in Example 1 Specification: 0.01% Example 1 time pH value Osmolality mOsmol/kg Atropine sulfate content% relative substance Tropic acid% Dehydrated atropine% Maximum unknown single impurity % Total impurity % 0 days 4.98 299 101.46 ND ND ND ND 40℃-5 days 4.99 301 101.78 0.043 ND ND 0.043 40℃-10 days 5.01 305 103.20 0.087 ND 0.037 0.151 40℃-30 days 4.97 309 104.71 0.263 0.030 0.061 0.463 50℃-5 days 4.99 305 102.67 0.133 0.016 0.127 0.394 50℃-10 days 5.03 314 104.58 0.282 0.038 0.131 0.715 50℃-30 days 4.98 331 110.14 0.841 0.121 0.168 1.950 5 days of light 5.00 302 101.14 ND ND 0.028 0.141 10 days of light 5.03 304 101.81 0.018 ND 0.220 0.616 30 days of light 4.97 301 96.74 0.094 ND 1.718 4.71 low temperature 5.01 299 101.19 0.058 ND ND 0.058 freeze-thaw 5.02 302 101.01 0.054 ND ND 0.054 Note: Anhydroatropine, an impurity in related substances, is obtained by dehydration of atropine, which has antispasmodic effect and is highly toxic. Table 6 The test results of the influencing factors of the atropine eye drops prepared in Example 2 Specification: 0.02% Example 2 time pH value Osmolality mOsmol/kg Atropine sulfate content % relative substance Tropic acid% Dehydrated atropine% Maximum unknown single impurity % Total impurity% 0 days 4.98 301 100.33 ND ND ND ND 40℃-5 days 4.99 302 100.93 0.044 ND ND 0.044 40℃-10 days 5.00 306 101.90 0.084 ND 0.01 0.094 40℃-30 days 4.96 315 103.27 0.264 0.030 0.027 0.321 50℃-5 days 4.99 307 101.91 0.139 0.018 0.068 0.291 50℃-10 days 5.01 312 103.20 0.282 0.039 0.066 0.472 50℃-30 days 4.98 328 108.27 0.819 0.115 0.087 1.371 5 days of light 4.99 301 100.40 ND ND 0.027 0.027 10 days of light 5.00 304 100.85 0.013 ND 0.188 0.315 30 days of light 4.96 305 98.45 0.061 ND 1.264 2.728 low temperature 5.00 302 100.10 0.053 ND ND 0.053 freeze-thaw 4.97 302 100.36 0.052 ND 0.040 0.092

According to the test results of Table 5 and Table 6, it can be seen that as time increases, the content of atropine sulfate in the atropine eye drops provided by the present invention is on the rise at high temperatures of 40°C and 50°C, and the content of atropine sulfate at 50°C is higher than that at 40°C. Obviously, this is because the inner packaging material used in the atropine eye drops provided by the present invention is a semi-permeable container, which has the property of dehydration, which leads to an increase in the content of atropine sulfate in the eye drops. In the eye drops provided by the invention, under the conditions of high temperature of 50° C. and strong light irradiation, the growth trend of tropic acid and anhydroatropine is remarkable. Therefore, the atropine eye drops provided by the present invention should avoid high temperature and strong light irradiation during storage and transportation. 1.2 The atropine eye drops test prepared by embodiment 3 and embodiment 4

The pH adjuster that embodiment 3 and embodiment 4 adopt is the combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid. For the atropine eye drops, its influencing factor test studied the conditions of high temperature (40°C and 50°C) and strong light irradiation (5000lx); considering the possible transportation conditions, low temperature test (4°C) and freezing Melt test (-18 ℃) research. The results of the study are shown in Table 7 and Table 8 respectively: The test results of the influencing factors of the atropine eye drops prepared in Table 7 Example 3 Specification: 0.01% Example 3 time pH value Osmolality mOsmol/kg Atropine sulfate content % relative substance Tropic acid% Dehydrated atropine% Maximum unknown single impurity % Total impurity% 0 days 5.01 304 101.41 ND ND ND ND 40℃-5 days 5.04 308 101.84 0.044 ND ND 0.044 40℃-10 days 5.08 310 103.21 0.094 ND 0.033 0.172 40℃-30 days 5.01 319 106.44 0.284 0.030 0.051 0.506 50℃-5 days 5.05 314 102.42 0.135 0.018 0.108 0.451 50℃-10 days 5.05 319 105.04 0.305 0.043 0.144 1.056 50℃-30 days 5.02 338 111.79 0.874 0.130 0.158 1.965 5 days of light 5.04 308 101.42 ND ND ND ND 10 days of light 5.08 309 102.41 0.014 ND 0.064 0.415 30 days of light 5.00 308 100.29 0.074 ND 1.868 3.966 low temperature 5.02 304 102.76 0.062 ND ND 0.062 freeze-thaw 5.00 304 103.55 0.058 ND ND 0.058 Table 8 The test results of the influencing factors of the atropine eye drops prepared in Example 4 Specification: 0.02% Example 4 time pH value Osmolality mOsmol/kg Atropine sulfate content% relative substance Tropic acid% Dehydrated atropine% Maximum unknown single impurity % Total impurity% 0 days 5.01 301 99.62 ND ND ND ND 40℃-5 days 5.02 308 100.90 0.039 ND ND 0.039 40℃-10 days 5.05 312 101.43 0.089 0.011 ND 0.100 40℃-30 days 5.00 313 103.77 0.266 0.032 0.025 0.352 50℃-5 days 5.00 308 100.32 0.113 0.033 0.049 0.227 50℃-10 days 5.06 314 102.55 0.239 0.036 0.079 0.523 50℃-30 days 4.98 338 108.88 0.794 0.121 0.076 1.273 5 days of light 5.01 307 100.53 ND ND ND ND 10 days of light 5.05 306 100.62 0.011 ND 0.093 0.124 30 days of light 4.98 305 100.21 0.095 ND 0.733 1.754 low temperature 5.00 302 101.15 0.060 ND ND 0.056 freeze-thaw 5.00 302 101.23 0.064 ND ND 0.064

According to the test results of Table 7 and Table 8, it can be seen that as time increases, the content of atropine sulfate in the atropine eye drops provided by the present invention shows an upward trend at high temperatures of 40°C and 50°C, and the content of atropine sulfate at 50°C is higher than that at 40°C. Obviously, this is because the inner packaging material used in the atropine eye drops provided by the present invention is a semi-permeable container, which has the property of dehydration, which leads to an increase in the content of atropine sulfate in the eye drops. In the eye drops provided by the invention, under the conditions of high temperature of 50° C. and strong light irradiation, the growth trend of tropic acid and anhydroatropine is remarkable. Therefore, the atropine eye drops provided by the invention should avoid high temperature and strong light irradiation during storage and transportation. 2 Comparison of stability data between self-made eye drops and commercially available eye drops sample time Related substances (area normalized) Tropic acid% Dehydrated atropine% Maximum unknown single impurity % Total impurity% homemade eye drops Homemade sample 1 0 days ND ND ND ND 40℃-5 days 0.082 ND 0.029 0.111 40℃-10 days 0.165 ND 0.036 0.236 40℃-30 days 0.468 0.057 0.076 0.795 Homemade sample 2 0 days ND ND ND ND 40℃-5 days 0.085 ND ND 0.085 40℃-10 days 0.168 ND 0.036 0.230 40℃-30 days 0.499 0.059 0.060 0.725 Homemade Sample 3 0 days ND ND ND ND 40℃-5 days 0.087 0.022 0.026 0.136 40℃-10 days 0.159 ND 0.024 0.183 40℃-30 days 0.490 0.063 0.082 0.837 Homemade sample 4 0 days ND ND ND ND 40℃-5 days 0.086 ND ND 0.086 40℃-10 days 0.181 ND 0.032 0.256 40℃-30 days 0.536 0.059 0.078 0.781 Homemade sample 5 0 days ND ND ND ND 40℃-5 days 0.078 ND ND 0.078 40℃-10 days 0.148 0.031 ND 0.179 40℃-30 days 0.439 0.055 0.036 0.593 commercially available eye drops American and European products 0 days 0.061 0.117 0.241 1.132 40℃-30 days 0.505 0.170 0.240 1.676 Yatomin 0 days 0.238 0.072 10.05 12.634 40℃-5 days 0.305 0.057 6.158 8.698 40℃-10 days 0.331 0.061 3.742 6.246 40℃-30 days 0.464 0.084 0.506 2.974 Lotropine 0 days 1.341 0.089 0.264 2.073 40℃-5 days 1.585 0.086 0.231 2.321 40℃-10 days 1.766 0.090 0.206 2.376 40℃-30 days 2.495 0.135 0.193 3.437 Note: In this form, the self-made sample 1 is consistent with the prescription of Example 1, and the batch size is 100mL; the self-made sample 2 is the atropine eye drops prepared in Example 1; the self-made sample 3 is the same as the prescription of Example 3, and the batch size is 100mL; Sample 4 is the atropine eye drops prepared in Example 3; self-made sample 5 is consistent with the prescription of Example 3, and the batch size is 500mL.

According to the test results, it can be known that for self-made eye drops, no matter what kind of prescription provided by the present invention, after long-term (40°C-30 days) storage at high temperature, its stability has no significant difference, and the total impurity content (0.593%-0.837% ) was significantly less than that of commercially available American and European products (1.676%), yatromin (2.974%) and lautropine (3.437%), all of which were lower than those of commercially available preparations. Table 10 Comparison of strong light exposure data between self-made eye drops and commercially available eye drops sample time Related substances (area normalized) Tropic acid% Dehydrated atropine% Maximum unknown single impurity % Total impurity% homemade eye drops Homemade sample 1 0 days ND ND ND ND Light - 5 days ND ND 0.027 0.139 Light - 10 days 0.034 ND 0.214 0.618 Light - 30 days 0.185 ND 1.687 4.767 Homemade sample 2 0 days ND ND ND ND Light - 5 days ND ND ND ND Light - 10 days 0.027 ND 0.193 0.417 Light - 30 days 0.146 ND 1.424 3.556 Homemade Sample 3 0 days ND ND ND ND Light - 5 days ND ND 0.067 0.067 Light - 10 days ND ND 0.153 0.394 Light - 30 days 0.153 ND 1.121 3.505 commercially available eye drops American and European products 0 days 0.061 0.117 0.241 1.132 Light - 30 days 0.115 0.103 13.217 15.884 Yatomin 0 days 0.238 0.072 10.05 12.634 Light - 5 days 0.242 0.049 9.582 16.082 Light - 10 days 0.239 0.048 9.108 17.314 Light - 30 days 0.236 0.059 7.222 17.866 Lotropine 0 days 1.341 0.089 0.264 2.073 Light - 5 days 1.354 0.067 4.691 7.199 Light - 10 days 1.346 0.069 6.335 9.085 Light - 30 days 1.435 0.070 7.699 11.638 Note: In this table, self-made sample 1 is the atropine eye drops prepared in Example 1; self-made sample 2 is the atropine eye drops prepared in Example 3; self-made sample 3 has the same prescription as Example 3, and the batch size is 500mL.

According to the test results, compared with the commercially available eye drops, the self-made eye drops of the present invention produce less unknown impurities, and the unknown impurities are caused by the complexity of the sample retention environment in the light stability box used, and its total impurities are still low. Compared with commercially available preparations, the self-made eye drops of the present invention should be kept away from light. Table 11 Comparison of accelerated test (40°C, 25%RH) data between self-made eye drops and commercially available eye drops sample time Related substances (area normalized) Tropic acid% Dehydrated atropine% Maximum unknown single impurity % Total impurity % homemade eye drops Homemade sample 1 0 days ND ND ND ND Accelerate January 0.428 0.045 0.025 0.498 Accelerate February 0.870 0.081 0.024 0.997 Accelerate March 1.361 0.163 0.037 1.611 Accelerate June 1.726 0.199 0.079 2.120 Homemade sample 2 0 days ND ND ND ND Accelerate January 0.494 0.055 0.039 0.613 Accelerate February 0.963 0.094 0.040 1.144 Accelerate March 1.495 0.190 0.073 1.805 Accelerate June 1.808 0.220 0.112 2.261 commercially available eye drops American and European products 0 days 0.061 0.117 0.241 1.132 Accelerate January 0.480 0.167 0.291 2.061 Accelerate February 0.869 0.244 0.245 2.603 Accelerate March 1.283 0.262 0.641 3.917 Accelerate June 2.411 0.413 0.173 5.000 Lotropine 0 days 1.341 0.089 0.264 2.073 Accelerate January 2.475 0.125 0.372 3.461 Accelerate February 3.606 0.186 0.271 4.477 Accelerate March 4.587 0.229 0.215 5.354 Accelerate June 8.753 0.473 0.513 9.953 Note 1: In this form, the data of tropic acid and anhydroatropine have not been processed by the correction factor; Note 2: In this form, the self-made sample 1 is consistent with the prescription in Example 1, and the batch size is 100mL; the self-made sample 2 is the same as that in the implementation In example 3, the prescription is the same, and the batch size is 100mL.

According to the accelerated test data in Table 11, it can be seen that the tropic acid of the self-made eye drops is slightly higher than that of the commercially available eye drops—the American and European products during the accelerated 3-month period. The reason is that the pH value of the American and European products is 4.7. The pH value of eye drops is closer to 5.0, and tropic acid is greatly affected by the pH value, so the tropic acid of self-made eye drops will be slightly higher. Tropic acid is a hydrolysis product of atropine, and it is a metabolite in the body. In the quality standard of the United States Pharmacopoeia 1% specification atropine sulfate eye drops, the limit of tropic acid is 7.0%, so the tropic acid of self-made eye drops will not impact on security. However, at the accelerated 6-month period, compared with homemade eye drops, the content of tropic acid was significantly increased in commercially available eye drops. During the whole research period, the contents of tropic acid, dehydrated atropine and the largest unknown single impurity in the self-made eye drops remained at a low level, and the impurities produced were less, and the total impurities were lower than those of the commercially available eye drops. better. 3 Effect of thickener on product impurities

Add thickeners to the formulation and study the effect of thickeners on product stability. Considering that the impurity in the product may be the result of the joint action of the pH regulator and the thickener, the present invention further comprehensively studies the influence of the thickener on product stability by changing the amount of the pH regulator. See Table 12~Table 13 for the composition of the sample prescription and the experimental results. Table 12 Prescription of Atropine Eye Drops Added Thickener Hypromellose prescription composition Prescription 1 Mass (g)/1L (calculated as solute) Prescription 2 Mass (g)/1L (calculated as solute) Prescription 3 Mass (g)/1L (based on solute) Prescription 4 Mass (g)/1L (based on solute) Atropine Sulfate (Minsheng) 0.10 0.10 0.10 0.10 Sodium dihydrogen phosphate dihydrate 9.60 2.70 / / Disodium hydrogen phosphate dihydrate 1.50 0.40 / / boric acid / / 14.70 4.30 Edetate disodium 1.00 1.00 1.00 1.00 Sodium chloride 9.00 9.00 9.00 9.00 Hypromellose (60SH) 5.00 5.00 5.00 5.00 Water for Injection Make up to 100 mL Add to 100mL Add to 100mL Add to 100mL pH value 5.0 5.0 5.0 5.0

The preparation method of the above prescription can be prepared according to the preparation method of Example 1-2. Specifically, the corresponding product was prepared according to the preparation method of Example 1. Table 13 Effect of adding thickener on product stability Product (identified by prescription number) time Related substances (area normalization method) Tropic acid (%) Dehydrated atropine(%) The largest unknown single impurity (%) Total impurities (%) Prescription 1 0 days 0.077 0.129 0.021 0.227 Prescription 2 0.074 0.073 0.020 0.165 Prescription 3 0.074 0.068 / 0.142 Prescription 4 0.074 0.115 0.062 0.211 Prescription 1 40℃-5 days 0.126 0.086 0.104 0.573 Prescription 2 0.160 0.093 0.287 0.890 Prescription 3 0.178 0.106 0.316 0.973 Prescription 4 0.161 0.144 0.232 1.008 Prescription 1 40℃-10 days 0.334 0.199 0.139 1.139 Prescription 2 0.214 0.168 2.541 5.397 Prescription 3 0.441 0.196 2.789 6.101 Prescription 4 0.226 0.172 2.966 6.153 Prescription 1 40℃-30 days 0.817 0.252 1.261 3.521 Prescription 2 0.539 0.152 0.522 2.222 Prescription 3 0.932 0.148 0.542 2.729 Prescription 4 0.498 0.196 1.612 3.849

Based on Table 12 and Table 13, it can be seen that all formulations 1-4 have added thickeners, and the corresponding products have poor stability after long-term storage at high temperature (40°C, 30 days). Among them, Prescription 1 and Prescription 2 both added phosphate and thickener, Prescription 3 and Prescription 4 both added boric acid and thickener, and there was no significant difference in product stability, which shows that the reason for the deterioration of product stability is not the addition of Phosphate or boric acid; formulation 1 and formulation 2 have different phosphate concentrations, but there is no significant difference in product stability, which shows that the reason for the poor product stability is not the difference in phosphate concentration; formulation 3 and formulation 4 have different boric acid concentrations , there is no significant difference in product stability, which shows that the reason for product stability is not that the concentration of boric acid is different.

In summary, adding the thickener hypromellose will make the product less stable and more impurities. The atropine eye drop provided by the invention does not contain a thickener through raw material selection and prescription optimization, has good stability and low total impurities, and is suitable for long-term storage. 4. Study on Phosphate Concentration

Halve the phosphate concentration and study its effect on sample stability. See Table 14~Table 15 for sample prescription composition and experimental results. Table 14 Prescription of atropine eye drops with different phosphate concentrations prescription composition Specification: 0.01% Prescription 1 Mass (g)/1L (calculated as solute) Prescription 2 Mass (g)/1L (based on solute) Atropine sulfate 0.10 0.10 Sodium dihydrogen phosphate dihydrate 7.80 3.90 Disodium hydrogen phosphate dihydrate 2.20 1.10 Sodium chloride 9.00 9.00 hydrochloric acid Appropriate amount Appropriate amount Water for Injection Make up to 100 mL Make up to 100 mL pH value 5.0 5.0 Table 15 Research Results of Different Phosphate Concentrations—Influencing Factor Test (40°C) Product (identified by prescription number) time Related substances (area normalization method) Tropic acid (%) Dehydrated atropine(%) The largest unknown single impurity (%) Total impurities (%) Prescription 1 0 days 0.106 0.127 ND 0.233 Prescription 2 0.106 0.115 0.025 0.247 Prescription 1 40℃-5 days 0.192 0.137 0.04 0.465 Prescription 2 0.171 0.127 0.077 0.475 Prescription 1 40℃-10 days 0.319 0.168 0.089 0.837 Prescription 2 0.272 0.15 0.134 0.857 Prescription 1 40℃-30 days 0.718 0.236 0.238 1.356 Prescription 2 0.589 0.206 0.245 1.268

According to the experimental results in Table 15, it can be known that the growth of tropic acid is affected by the concentration of phosphate, and when the concentration of phosphate is low, the growth of tropic acid is relatively slow, which is unexpected. At the same time, the largest unknown single impurity increases relatively quickly, and the total impurities will also increase. From this point of view, the concentration of phosphate in atropine eye drops should be controlled at a slightly higher level. However, considering that phosphate itself also has a certain osmotic pressure, if the amount of phosphate is large, in order to achieve isotonicity, the amount of sodium chloride needs to be adjusted; and sodium chloride also has a certain impact on the stability of atropine sulfate. Therefore, from the perspective of ensuring the stability and osmotic pressure of atropine eye drops, it is necessary to coordinate the dosage of the two phosphates and sodium chloride. 5 Study on the concentration of sodium chloride

The present invention preliminarily sets the mass concentrations of sodium dihydrogen phosphate and disodium hydrogen phosphate as 1.95g/L and 0.56g/L respectively, and studies the influence of sodium chloride dosage on osmotic pressure under these conditions. Blank adjuvant solutions containing different concentrations of sodium chloride were prepared and the osmolarity of the samples was measured. The sample formulation and osmotic pressure results are shown in Table 16. Table 16 Blank adjuvant solution prescription and osmotic pressure results of different sodium chloride concentrations prescription composition Prescription 1 Mass (g)/1 L (calculated as solute) Prescription 2 Mass (g)/1 L (calculated as solute) Prescription 3 Mass (g)/1 L (calculated as solute) Prescription 4 Mass (g)/1 L (calculated as solute) Prescription 5 mass (g)/1 L (calculated as solute) Sodium dihydrogen phosphate dihydrate 1.95 1.95 1.95 1.95 1.95 Disodium hydrogen phosphate dihydrate 0.56 0.56 0.56 0.56 0.56 Sodium chloride 7.80 8.10 8.30 8.50 9.00 Edetate Disodium 1.00 1.00 1.00 1.00 1.00 Water for Injection 100mL 100mL 100mL 100mL 100mL Osmolality (mOsmol/kg) 283 294 298 306 309

Based on the isotonic requirement of eye drops and tears, the present invention selects an osmotic pressure range of 280-320 mOsmol/kg, and the corresponding sodium chloride dosage is 7.80-9.00 g/L. In conjunction with the osmotic pressure of existing commercially available preparations, the osmotic pressure of the atropine eye drops of the present invention is preliminarily determined as about 300mOsmol/kg, and the corresponding sodium chloride consumption is 8.30g/L this moment, expand the sodium chloride concentration to A study of stability effects.

Samples were prepared according to the prescription after adjusting the amount of sodium chloride, and the stability of the samples was studied. See Table 17~Table 18 for sample formulation composition and experimental results. Table 17 Prescription of atropine eye drops with different sodium chloride concentrations prescription composition Prescription 1 Mass (g)/1 L (calculated as solute) Prescription 2 Mass (g)/1 L (calculated as solute) Atropine Sulfate (Homemade) 0.10 0.10 Sodium dihydrogen phosphate dihydrate 1.95 1.95 Disodium hydrogen phosphate dihydrate 0.56 0.56 Sodium chloride 9.00 8.30 Edetate disodium 1.00 1.00 hydrochloric acid 0.076 0.076 Water for Injection 100mL 100mL pH value 5.0 5.0 Table 18 Research results on the dosage of osmotic pressure regulators—influencing factor test (40°C) Product (identified by prescription number) time Related substances (area normalization method) Tropic acid (%) Dehydrated atropine(%) The largest unknown single impurity (%) Total impurities (%) Prescription 1 0 days ND ND ND 0 Prescription 2 ND ND ND 0 Prescription 1 40℃-5 days 0.093 ND ND 0.093 Prescription 2 0.087 0.022 0.026 0.136 Prescription 1 40℃-10 days 0.189 ND 0.029 0.218 Prescription 2 0.159 ND 0.024 0.183 Prescription 1 40℃-30 days 0.587 0.053 0.066 0.759 Prescription 2 0.490 0.063 0.082 0.837

According to the test results of influencing factors, it can be seen that the amount of sodium chloride is adjusted from 9.00g/L to 8.30g/L, which does not affect the stability of the sample. This shows that under the condition of ensuring product stability, the concentration of sodium chloride should be further reduced The dosage can improve the safety and overall quality of atropine eye drops.

Based on the above, in order to ensure the stability of atropine eye drops, it is necessary to coordinately adjust the dosage of the two phosphates and the osmotic pressure regulator. According to the above-mentioned research, in the eye drops of the present invention, the mass concentrations of sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium chloride are 1.49~6.00g/L, 0.43~0.88g/L and 7.80~9.00g/L respectively. g/L; and, the present invention is further screened, and when the mass concentrations of sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium chloride are respectively 1.95g/L, 0.56g/L, and 8.30g/L, the eye drops The stability is better.

Having described various embodiments of the present disclosure above, the foregoing description is illustrative, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and alterations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principle of each embodiment, practical application or improvement of technology in the market, or to enable other ordinary skilled in the art to understand each embodiment disclosed herein.

Claims (10)

A kind of atropine eye drop, it is characterized in that, comprises following component: by mass concentration, atropine or its pharmaceutically acceptable salt 0.10～0.20g/L, chelating agent 0～1.00g/L, osmotic pressure adjusting agent 7.80g/L ~9.00g/L, pH regulator and water for injection; Wherein, the pH regulator is a combination of citric acid and borax or a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid, and the dosage of the pH regulator is based on adjusting the pH value to 4.5-5.5. According to the atropine eye drops described in claim 1, it is characterized in that, in terms of mass concentration, in the combination of citric acid and borax, citric acid is 0.50 ~ 2.00g/L, and borax is 1.00 ~ 2.00g/L; In terms of mass concentration, in the combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid, sodium dihydrogen phosphate is 1.49~6.00g/L, disodium hydrogen phosphate is 0.43~0.88g/L, hydrochloric acid is 0.04~0.13g/L L. According to the atropine eye drop described in claim 2, it is characterized in that it comprises the following components: in terms of mass concentration, atropine or its pharmaceutically acceptable salt 0.10~0.20g/L, chelating agent 0~1.00g/L , osmotic pressure regulator 7.80~9.00g/L, citric acid 0.50g/L, borax 1.05g/L and water for injection. According to the atropine eye drop described in claim 2, it is characterized in that it comprises the following components: in terms of mass concentration, atropine or its pharmaceutically acceptable salt 0.10~0.20g/L, chelating agent 0~1.00g/L , osmotic pressure regulator 7.80~9.00g/L, sodium dihydrogen phosphate 1.95g/L, disodium hydrogen phosphate 0.56g/L, hydrochloric acid 0.076g/L and water for injection. According to the atropine eye drop described in any one of claims 1 to 4, it is characterized in that the pharmaceutically acceptable salt is sulfate. According to the atropine eye drops described in any one of claims 1 to 4, it is characterized in that the chelating agent comprises one or more of edetate disodium, edetate sodium calcium and edetate combination, preferably disodium edetate. According to the atropine eye drops described in any one of claims 1 to 4, it is characterized in that the osmotic pressure regulator comprises one or more combinations of sodium chloride, mannitol and glycerin, preferably chlorinated sodium. A preparation method according to the atropine eye drops described in any one of claim items 1 to 7, is characterized in that, comprises the following steps: Dissolving the chelating agent, osmotic pressure regulator, and pH regulator in the prescribed amount in the water for injection to obtain solution A; Adding the atropine or its pharmaceutically acceptable salt of prescription amount in described solution A, obtains solution B; The solution B is filtered, filled, and obtained. According to the preparation method described in Claim 8, it is characterized in that the temperature of the water for injection is controlled below 40°C, preferably 21.4-24.4°C. According to the preparation method described in Claim 8 or 9, it is characterized in that the solution B is filtered through a microfiltration membrane with a pore size of 0.22 μm, and the microfiltration membrane is a PVDF membrane.