Azastine hydrochloride eye drops and preparation process thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to nitrogen hydrochloride # imgabs0 # stine eye drops and a preparation process thereof, the nitrogen hydrochloride # imgabs0 # stine eye drops comprise 0.05% of nitrogen hydrochloride # imgabs1 # stine, 0.2-0.3% of hydroxypropyl methylcellulose, 0.1-0.2% of edetate disodium, 0.12-0.15% of an isoosmotic adjusting agent, 0.04-0.07% of a preservative and 0.005-0.0075% of choline aromatic folic acid; the nitrogen hydrochloride # imgabs2 # stine eye drops prepared by the preparation method disclosed by the invention have the advantages that the adsorption of nitrogen hydrochloride # imgabs3 # stine on a low-density polyethylene bottle is well inhibited under the condition of visible light, and the reduction of the concentration of nitrogen hydrochloride # imgabs4 # stine in the eye drops is remarkably prevented, so that the medication safety is improved. Besides, the added cholinofolic acid and hydroxypropyl methylcellulose have small irritation to eyes under a specific ratio, and can also have a large enough contact angle with the eyes of rabbits at high temperature, so that the retention property of the eye drops on the eyes can be improved, and the drug effect can be favorably exerted.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to azelastine hydrochloride eyedrops and a preparation process thereof. Background Art

[0002] Azelastine hydrochloride (abbreviated as AH) is a derivative of a new structure phthalazinone, and this drug is a potential long-acting anti-allergic compound with the characteristics of an H1 receptor antagonist. Azelastine hydrochloride eyedrops are used for the treatment and prevention of symptoms of seasonal allergic conjunctivitis.

[0003] Plastic bottles are commonly used as packaging bottles for eyedrops. The main materials are low-density polyethylene (LDPE), polypropylene (PP), high-density polyethylene (HDPE), etc. LDPE is a soft and easily squeezable plastic material with good sealing performance and acid and alkali corrosion resistance, and it is one of the main materials for eyedrop bottles. Its softness makes the bottle easy to be squeezed to release the liquid, and at the same time, it is not easy to produce creases, improving the user experience of patients. Glass bottles (yb bottles, where yb usually represents pharmaceutical glass) are usually not used for eyedrops mainly because glass bottles cannot be squeezed, which will significantly affect the use experience of eyedrops.

[0004] Feng Huanhuan et al. (Analysis of the current situation of the use of bacteriostatic agents in domestic levofloxacin hydrochloride eyedrops, Drug Analysis Impurities, 2018) reported that plastic packaging materials such as polyethylene (PE) have a significant adsorption effect on certain bacteriostatic agents and drug components. For example, thimerosal is easily adsorbed by polyethylene packaging materials. Huo Dongfeng et al. (Study on the compatibility of low-density polyethylene eyedrop bottles and drugs, Heilongjiang Medicine, 2021-04-19) reported that LDPE bottles have a certain adsorption effect on the bacteriostatic agent chlorobutanol, which may lead to a decrease in the content of the bacteriostatic agent, thus affecting the bacteriostatic efficacy of eyedrops.

[0005] Hydroxypropyl methylcellulose (hydroxypropylmethylcellulose) is a high molecular polymer with good water absorption and adhesiveness, and it can form a protective lubricating film covering the surface of the eyeball. This lubricating effect can reduce discomfort symptoms such as dryness and foreign body sensation in the eyes, and at the same time prevent external irritants from damaging the cornea. Hydroxypropyl methylcellulose can simulate the viscoelastic properties of natural tears, attach to the surface of the eyeball through the adsorption of the polymer, improve the state of reduced ocular mucin, and prolong the residence time of tears in the eyes. This helps to relieve dry eye symptoms caused by insufficient tear secretion.

[0006] Disodium edetate is a potent metal chelating agent that can bind to metal cations (such as calcium ions) in the eye to form stable complexes. This property makes it play an important role in the treatment of eye diseases caused by calcium salt deposition, such as lime burns, corneal calcification, corneal band degeneration, etc. By chelating calcium ions, disodium edetate can reduce the deposition of calcium salts in the eye, thereby improving corneal transparency and visual quality. Disodium edetate also has the effect of inhibiting collagenase, which is an enzyme involved in tissue repair and corneal ulcer healing. By inhibiting collagenase activity, disodium edetate can reduce ocular inflammatory responses and oxidative stress damage, contributing to the treatment of eye diseases. In eye drops, disodium edetate can also be used as a stabilizer to prevent drug oxidation and degradation, thereby extending the shelf life of the drug and improving its efficacy.

[0007] During the drug light resistance test conducted by the R & D personnel of our unit, it was found that in olopatadine hydrochloride eye drops containing excipients such as hypromellose, disodium edetate, preservatives, pH regulators, and isotonicity regulators (hereinafter referred to as the existing olopatadine hydrochloride eye drops), the existing olopatadine hydrochloride eye drops packaged in brown LDPE bottles when stored under light for 1 month, the content of olopatadine hydrochloride will decrease by more than 25%, far greater than the requirement of the pharmacopoeia that the content change of drugs within the validity period should not exceed 5%. During the simulation test, if the existing olopatadine hydrochloride eye drops are stored in colorless glass bottles and stored under light for 3 months, the decrease in the content of olopatadine hydrochloride does not exceed 5%; for the existing olopatadine hydrochloride eye drops packaged in brown LDPE bottles when stored in the dark for 3 months, the decrease in the content of olopatadine hydrochloride does not exceed 5%. Based on the above, the reason may be that in olopatadine hydrochloride eye drops containing excipients such as hypromellose, disodium edetate, preservatives, pH regulators, and isotonicity regulators there may be impurities generated by the degradation products, microbial contamination products, and light-induced impurities of olopatadine hydrochloride (the total impurity content is still within 0.5% and thus still meets the pharmacopoeia requirements), but among these impurities, some impurities have a covalent bond with the more electronegative nitrogen atom in olopatadine hydrochloride through hydrogen bonds (this interaction binds through a hydrogen atom as a proton donor and another electronegative atom "nitrogen" as an electron acceptor, thereby enhancing the intermolecular binding force), and there are 3 nitrogen atoms in olopatadine hydrochloride therefore, under light conditions, the content of olopatadine hydrochloride will decrease. In olopatadine hydrochloride eye drops containing excipients such as hypromellose, disodium edetate, preservatives, pH regulators, and isotonicity regulators, it may be that olopatadine hydrochloride due to degradation products, microbial contamination products, and impurities induced by light (the total impurity content is still within 0.5% and thus still meets the pharmacopoeia requirements), but among these impurities, some impurities have a covalent bond with the more electronegative nitrogen atom in olopatadine hydrochloride through hydrogen bonds (this interaction binds through a hydrogen atom as a proton donor and another electronegative atom "nitrogen" as an electron acceptor, thereby enhancing the intermolecular binding force), and there are 3 nitrogen atoms in olopatadine hydrochloride so, under light conditions, olopatadine hydrochloride will decrease. Sting will be largely adsorbed on the inner wall of the LDPE bottle; in this regard, by draining the liquid medicine in the LDPE bottle and then wiping and sampling with a blank test paper, it is found that in the liquid medicine sampled from the inner wall of the LDPE bottle, the content of azelastine hydrochloride far exceeds the formulated amount (0.05%); for the same eye drops stored in a glass bottle, the above situation will not occur, which can be used as evidence.

[0008] Although based on the above research, as long as the existing azelastine hydrochloride eye drops are always stored in the dark, there will be no problem of significant decline in the active ingredient; however, through research, it is found that most customers usually take and place the eye drops as needed during the use process, and usually do not put them back into the medicine box and store them strictly in the dark after use; moreover, generally after using the eye drops to relieve symptoms, they will not be used again, and will be used again when the symptoms appear again; this makes the above technical defects evolve into potential risks. And it is well-known that the bioavailability of eye drops is low. The tear volume of normal people is about 7 μL, and the volume without blinking is about 30 μL. Usually, 1 drop of eye drops is about 50-70 μL. Most of the liquid medicine overflows and is lost from the eye, and coupled with the dilution of the eye drops by tears, it greatly affects the drug effect; if the active ingredient of the eye drops further decreases due to bad usage habits, the drug effect will be further weakened.

[0009] And most of the azelastine hydrochloride on the market now is packaged in LDPE bottles (such as the original research 0.05% azelastine hydrochloride of German Muro Pharmaceutical Company with two specifications of 3 ml 1.5 mg and 6 mL 3 mg), how to solve the problem of "when placed in the light, azelastine hydrochloride will be adsorbed by the LDPE bottle, resulting in a decrease in the active ingredient" is the research topic of the present invention.

[0010] Based on this, the present invention is proposed. Summary of the Invention

[0011] The purpose of the present invention is to provide an azelastine hydrochloride eye drop and its preparation process to solve the above problems.

[0012] An azelastine hydrochloride eye drop, comprising the following components in weight percentage:

[0013] Azelastine hydrochloride : 0.05%;

[0014] Hydroxypropyl methylcellulose: 0.2-0.3%;

[0015] Disodium edetate: 0.1-0.2%;

[0016] Isotonicity regulator: 0.12 - 0.15%;

[0017] Preservative: 0.04 - 0.07%;

[0018] Choline gentisate: 0.005 - 0.0075%;

[0019] pH regulator: Adjust the pH of azelastine hydrochloride eye drops to 6.0 ± 0.2.

[0020] For further improvement, the isotonicity regulator is one or more of sorbitol, mannitol, glycerol, sodium dihydrogen phosphate, and disodium hydrogen phosphate.

[0021] For further improvement, the preservative is benzalkonium chloride or chlorobutanol.

[0022] For further improvement, the pH regulator is sodium hydroxide solution.

[0023] For further improvement, the mass fraction of hydroxypropyl methylcellulose is 0.2%, and the mass fraction of choline gentisate is 0.005%.

[0024] An azelastine hydrochloride Preparation process of eye drops, comprising the following steps:

[0025] Step 1: First dissolve hydroxypropyl methylcellulose in water to obtain a first solution;

[0026] Step 2: Dissolve and mix azelastine hydrochloride, hydroxypropyl methylcellulose, disodium edetate, sorbitol, benzalkonium chloride, and choline gentisate in water for injection to obtain a second solution;

[0027] Step 3: Mix the first solution and the second solution evenly, and then use a pH regulator to adjust the pH of azelastine hydrochloride eye drops to 6.0 ± 0.2, make up the volume, filter, sterilize, and obtain azelastine hydrochloride eye drops.

[0028] For further improvement, in Step 1, the temperature at which hydroxypropyl methylcellulose is dissolved in water is greater than or equal to 90°C.

[0029]

[0029] For further improvement, in Step 1, the temperature of the first solution is below 50°C.

[0030] Choline geranate (abbreviated as CAGE) is an ionic liquid composed of choline and geranic acid. CAGE binds to drug molecules through hydrogen bonding to form stable supramolecular structures or ion clusters, thereby regulating the release rate and permeability of drugs. For example, in insulin delivery, CAGE regulates the structure of lipids by interacting with stratum corneum lipids, thereby enhancing drug penetration. CAGE has been applied to various drug delivery methods, including transdermal, oral, sustained release, and tissue ablation, etc.

[0031] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0032] The azelastine hydrochloride eye drops prepared by the present invention have good inhibition of the adsorption of azelastine hydrochloride on low-density polyethylene bottles under visible light conditions, significantly preventing the decrease in the concentration of azelastine hydrochloride in the eye drops, thereby improving the safety of drug use.

[0033] In addition, the added choline geranate and hypromellose have little irritation to the eyes under specific ratios, and at high temperatures, they can also have a large enough contact angle with the eyes of rabbits, which will improve the retention of the eye drops on the eyes, thereby facilitating the exertion of drug efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 is the chromatogram of the azelastine hydrochloride eye drops of the present invention;

[0035] Figure 2 is the change curve of the decline rate of different concentrations of choline geranate and the content of AH. DETAILED DESCRIPTION OF THE INVENTION

[0036] The present invention will be further described in detail below through specific examples in conjunction with the drawings.

[0037] Example 1

[0038] Formula 1:

[0039] Azelastine hydrochloride : 0.05%;

[0040] Hypromellose: 0.2%;

[0041] Disodium edetate: 0.1%;

[0042] Sorbitol: 0.12%;

[0043] Benzalkonium chloride: 0.04%;

[0044] ​Choline gentisate: 0.005%;

[0045] Sodium hydroxide solution: adjust the pH of azelastine hydrochloride eye drops to 6.0 ± 0.2.

[0046] Preparation method:

[0047] 1. Weigh 0.5 g of azelastine hydrochloride, 2 g of hypromellose, 1 g of disodium edetate, 1.2 g of sorbitol, 0.4 g of benzalkonium chloride, and 0.05 g of choline gentisate;

[0048] 2. First, dissolve hypromellose in purified water at 90 °C, and after cooling to 50 °C, obtain the first solution;

[0049] 3. Dissolve and mix azelastine hydrochloride, hypromellose, disodium edetate, sorbitol, benzalkonium chloride, and choline gentisate in purified water to obtain the second solution;

[0050] 4. Mix the first solution and the second solution evenly, and then adjust the pH of azelastine hydrochloride eye drops to 6.0 ± 0.2 with sodium hydroxide solution, make up the volume (add up to 1000 g), filter, and sterilize to obtain azelastine hydrochloride eye drops. The report of the content determination by high performance liquid chromatography is shown in Figure 1 .

[0051] Example 2

[0052] Formula 2:

[0053] Azelastine hydrochloride: 0.05%;

[0054] Hypromellose: 0.2%;

[0055] Disodium edetate: 0.15%;

[0056] Sorbitol: 0.13%;

[0057] Benzalkonium chloride: 0.05%;

[0058] Choline gentisate: 0.005%;

[0059] Sodium hydroxide solution: adjust the pH of azelastine hydrochloride eye drops to 6.0 ± 0.2.

[0060] Preparation method:

[0061] 1. Weigh 0.5 g of azelastine hydrochloride, Sting, 2 g of hydroxypropyl methylcellulose, 1.5 g of disodium edetate, 1.3 g of sorbitol, 0.5 g of benzalkonium chloride, 0.05 g of choline gentisate;

[0062] 2. First, dissolve hydroxypropyl methylcellulose in injection water at 90 °C. After cooling to 50 °C, obtain the first solution;

[0063] 3. Dissolve Sting, hydroxypropyl methylcellulose, disodium edetate, sorbitol, benzalkonium chloride, and choline gentisate in injection water and mix evenly to obtain the second solution;

[0064] 4. Mix the first solution and the second solution evenly, and then adjust the pH of the Sting eye drops to 6.0 ± 0.2 with sodium hydroxide solution, make up the volume (add up to 1000 g), filter, and sterilize to obtain the Sting eye drops. Sting eye drops.

[0065] Example 3

[0066] Formula 3:

[0067] Sting : 0.05%;

[0068] Hydroxypropyl methylcellulose: 0.2%;

[0069] Disodium edetate: 0.2%;

[0070] Sorbitol: 0.15%;

[0071] Benzalkonium chloride: 0.07%;

[0072] Choline gentisate: 0.005%;

[0073] Sodium hydroxide solution: Adjust the pH of the Sting eye drops to 6.0 ± 0.2.

[0074] Preparation method:

[0075] 1. Weigh 0.5 g of Sting , 2 g of hydroxypropyl methylcellulose, 2 g of disodium edetate, 1.5 g of sorbitol, 0.7 g of benzalkonium chloride, 0.05 g of choline gentisate;

[0076] 2. First, dissolve hydroxypropyl methylcellulose in injection water at 90 °C. After cooling to 50 °C, obtain the first solution;

[0077] 3. Dissolve Sting, hydroxypropyl methylcellulose, disodium edetate, sorbitol, benzalkonium chloride, and choline gentisate in injection water and mix evenly to obtain the second solution;​​

[0078] 4. Mix the first solution and the second solution evenly, and then adjust the mixture to a concentration of 1% hydrochloric acid and 1% nitrogen with sodium hydroxide solution. The pH of Sting eye drops was adjusted to 6.0 ± 0.2, the volume was fixed (added to 1000 g), filtered, sterilized, and the hydrochloric acid nitrogen solution was obtained. Sting eye drops.

[0079] Comparative Example 1

[0080] Hydrochloric acid nitrogen Sting: 0.05%;

[0081] Hydroxypropyl methylcellulose: 0.2%;

[0082] Edetate disodium: 0.1%;

[0083] Sorbitol: 0.12%;

[0084] Benzalkonium chloride: 0.04%;

[0085] Sodium hydroxide solution: Adjust to hydrochloric acid nitrogen The pH of Sting eye drops was adjusted to 6.0 ± 0.2.

[0086] Preparation method:

[0087] 1. Weigh 0.5g of nitrogen hydrochloride Sting, 2g of hypromellose, 1g of disodium edetate, 1.2g of sorbitol, 0.4g of benzalkonium chloride;

[0088] 2. First, dissolve the hydroxypropyl methylcellulose in 90°C water for injection, and then cool it to 50°C to obtain the first solution;

[0089] 3. Add hydrochloric acid nitrogen Dissolve Sting, Hydroxypropyl Methylcellulose, Disodium Edetate, Sorbitol, and Benzalkonium Chloride in water for injection and mix well to obtain a second solution;

[0090] 4. Mix the first solution and the second solution evenly, and then adjust the mixture to a concentration of 1% hydrochloric acid and 1% nitrogen with sodium hydroxide solution. The pH of Sting eye drops was adjusted to 6.0±0.2, the volume was fixed (added to 1000 g), filtered, and sterilized to obtain control solution 1.

[0091] Comparative Example 2

[0092] Compared with Example 1, in this example, naproxen choline ionic liquid (an ionic liquid formed by combining naproxen with choline, used to improve the water solubility and bioavailability of the drug) was used to replace choline geranic acid, and the rest was the same, to obtain control solution 2.

[0093] Comparative Example 3

[0094] Compared with Example 1, in this example, choline glycine ionic liquid (used to improve the solubility of the drug) was used to replace choline geranic acid, and the rest was the same, thereby obtaining control solution 3.

[0095] Choline geranic acid, naproxen choline ionic liquid and choline glycine ionic liquid are all medicinal choline-based ionic liquids.

[0096] LDPE bottle adsorption test

[0097] The eye drops stored in brown LDPE bottles were placed in accordance with the requirements of the Guidelines for Stability Testing of Raw Materials and Preparations (Guidelines 9001 Guidelines for Stability Testing of Raw Materials and Preparations, Chinese Pharmacopoeia 2020 Edition, Part IV) under light (light intensity 4500±500lux) and no light (sealed in a black box) for 1 month (storage temperature 10℃~25℃, relative humidity 35%~75%) for accelerated test. The results of the content detection of AH and related substances are shown in Tables 1 and 2:

[0098] Table 1 (with light)

[0099]

[0100] Table 2 (no light)

[0101]

[0102]

[0103] As shown in Table 1 and Table 2, in the hydrochloric acid nitrogen containing auxiliary materials such as hydroxypropyl methylcellulose, disodium edetate, preservatives, pH regulators, isotonic regulators, etc. In the Sting eye drops system, by adding choline geranyl acid to it, it can effectively inhibit the hydrochloric acid nitrogen The adsorption of Sting on the low-density polyethylene bottle significantly prevented the hydrochloric acid nitrogen in the eye drops. The reason may be that, as an ionic liquid, the effect of anions and cations in the ionic liquid on hydrogen bonds is greater than the combination of hydrogen bonds with nitrogen atoms. Hydrogen bonds also promote the cluster structure of the ionic liquid to form a more stable molecular cluster structure, thereby inhibiting the hydrochloric acid nitrogen However, different types of ionic liquids have different abilities to bind hydrogen bonds; in the system of the present invention, choline geranyl acid is preferred.

[0104] Comparative Example 4

[0105] Based on Example 1, different concentrations of choline geranyl acid were stored under light conditions for 30 days, and the corresponding decrease in AH content was as follows: Figure 2As shown; therefore, preferably, in the present invention, the concentration of choline bongkrekic acid is 0.005%.

[0106] In the system of the present invention, if the content of choline bongkrekic acid is too high, it will instead lead to a larger decrease in the content of AH. The reason may be that the anions and cations in the ionic liquid have too strong an interaction with the hydrogen bond, and may instead form strong hydrogen bond acceptors. Once other impurities containing hydrogen bonds adsorbed on the inner wall of the low-density polyethylene bottle bind to it, they will be firmly adsorbed on the inner wall of the low-density polyethylene bottle.

[0107] Eye irritation test

[0108] Shave the hair around the eyes of the mice, fix the heads of the mice with a headgear, drop the test eye drops or physiological saline into the eyes of the mice, and record the number of blinks of the mice. The test results are shown in Table 3:

[0109] Table 3

[0110] Blinking frequency (times / minute) Example 1 6.3±0.5 Example 2 6.3±0.3 Example 3 6.5±0.2 Normal saline 6.1±0.3 Comparative Example 1 5.9±0.4 Control solution 4 6.2±0.4 Control solution 5 6.1±0.5 Control solution 6 10.4±0.4 Control solution 7 13.1±0.5

[0111] In Table 3, compared with Example 1, the mass concentration of hypromellose in Control Solution 4 is 0.1%, and the rest are the same; compared with Example 1, the concentration of hypromellose in Control Solution 5 is 0.3%, and the rest are the same; compared with Example 1, the concentration of hypromellose in Control Solution 6 is 0.4%, and the rest are the same; compared with Example 1, the concentration of hypromellose in Control Solution 7 is 0.5%, and the rest are the same.

[0112] Based on Example 1, when the concentration of choline bongkrekic acid exceeds 0.0075%, after storing in a high-temperature (40 °C) and high-humidity (relative humidity ≥ 90%) environment for 3 months, the eye drops will become significantly turbid. Considering the drug safety, the concentration of choline bongkrekic acid is adjusted to 0.005%.

[0113] Therefore, when the concentration of choline bongkrekic acid is 0.005%, adjust the concentration of hypromellose. When its concentration is 0.1 - 0.3%, the irritation to the eyes of rabbits is the smallest. The reason may be that the anions and cations in the choline bongkrekic acid ionic liquid can act as electron donors or acceptors to form a complex structure with hypromellose; once the concentration of hypromellose is too high, the complex structure is unstable and may exacerbate the irritation to the eyes.

[0114] Retention test of eye drops on the eyes

[0115] Use the eyes of dead rabbits for the contact angle test. Operate them on a water bath at 20 - 21 °C and a water bath at 34 - 35 °C respectively, and keep the eye temperature of the rabbits at 20 - 21 °C or 34 - 35 °C.

[0116] For most liquids, in the lower temperature range, the contact angle may remain stable, but it significantly decreases at higher temperatures. Therefore, in the present invention, it is necessary to test the contact angle at high temperatures because the temperature of the human eye usually remains at 34 - 35°C. Under normal circumstances, a larger contact angle may be more beneficial for improving the retention of eye drops.

[0117] The test results are shown in Table 4

[0118] Table 4

[0119] #imgpt64#

[0120] In Table 4, the control solution 8 only contains AH, choline gentisate, and hypromellose. The concentration of AH is 0.05%, the concentration of choline gentisate is 0.005%, and the concentration of hypromellose is 0.2%.

[0121] As can be seen from Table 4, for the solution system containing AH, choline gentisate, and hypromellose, in the lower temperature range (20 - 21°C), the contact angle is more than twice that of the prior art (Comparative Example 1), and it can still remain stable at higher temperatures (34 - 35°C), only slightly decreasing, but still greater than the prior art. And a larger contact angle is beneficial for improving the retention of eye drops on the eye, thus facilitating the exertion of the drug effect.

[0122] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A nitrogen hydrochloride Sting eye drops, characterized by: The composition includes the following weight percentages: Hydrochloric acid nitrogen Sting: 0.05%; Hydroxypropyl methylcellulose: 0.2-0.3%; Disodium edetate: 0.1-0.2%; Isotonicity regulator: 0.12-0.15%; Preservatives: 0.04-0.07%; Choline geranyl acid: 0.005~0.0075%; pH adjuster: adjust to hydrochloric acid nitrogen The pH of Sting eye drops was adjusted to 6.0 ± 0.

2.

2. A nitrogen hydrochloride according to claim 1 Sting eye drops, characterized by: The isotonicity regulator is one or more of sorbitol, mannitol, glycerol, sodium dihydrogen phosphate, and disodium hydrogen phosphate.

3. A nitrogen hydrochloride according to claim 1 Sting eye drops, characterized by: The preservative is benzalkonium chloride or chlorobutanol.

4. A nitrogen hydrochloride according to claim 1 Sting eye drops, characterized by: The pH regulator is sodium hydroxide solution.

5. A nitrogen hydrochloride according to claim 1 Sting eye drops, characterized by: The mass fraction of the hypromellose is 0.2%, and the mass fraction of the choline geranic acid is 0.005%.

6. A nitrogen hydrochloride according to any one of claims 1 to 5 The preparation process of Sting eye drops is characterized by: The following steps are involved: Step 1, dissolving hypromellose in water to obtain a first solution; Step 2: Add hydrochloric acid to nitrogen Dissolve Sting, Hydroxypropyl Methylcellulose, Disodium Edetate, Sorbitol, Benzalkonium Chloride, Choline Geranyl Acid in water for injection and mix well to obtain a second solution; Step 3: Mix the first solution and the second solution evenly, and then adjust the pH to HCl-N The pH of Sting eye drops was adjusted to 6.0 ± 0.2, fixed to volume, filtered, sterilized, and the hydrochloric acid nitrogen was obtained. Sting eye drops.

7. A nitrogen hydrochloride according to claim 6 The preparation process of Sting eye drops is characterized by: In step 1, the temperature at which HPMC is dissolved in water is greater than or equal to 90°C.

8. A nitrogen hydrochloride according to claim 6 The preparation process of Sting eye drops is characterized by: In step 1, in step 1, the temperature of the first solution is below 50°C.

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