Azastine hydrochloride eye drops for treating allergic conjunctivitis and preparation method thereof

Abstract

According to the nitrogen hydrochloride # imgabs0 # stine eye drops for treating allergic conjunctivitis and the preparation method of the nitrogen hydrochloride # imgabs0 # stine eye drops, the prepared eye drops can interact with the mucous layer on the surface of keratoconjunctiva by selecting specific solid lipid and a surfactant and controlling the dosage of the solid lipid and the surfactant; the retention capacity of the medicine in front of the cornea is prolonged, so that the medicine has good targeting property, the continuous release of the medicine is realized, the medication frequency can be reduced, the toxic and side effects of the medicine are reduced, the bioavailability is improved, the medication compliance of a patient is enhanced, and in the preparation and long-term storage processes, the medicine has better stability, and is suitable for popularization and application. Therefore, the problems of excessive drug due to multiple administration and poor stability of the active component nitrogen hydrochloride # imgabs1 # stine are solved.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug preparation, and specifically relates to a hydrochloric acid nitrogen compound for treating allergic conjunctivitis. Sting eye drops and preparation method thereof. Background Art

[0002] The physiological structure of the eye determines that it has multiple physiological barriers, which can effectively block the invasion of adverse external factors. However, when the eye is diseased, it is difficult for traditional eye drops to have enough drugs to reach the targeted parts inside the eyeball for treatment. This is due to the continuous flushing and loss of tears and the physiological barriers of the eye. Traditional eye drops are mainly due to the poor adhesion of drugs on the surface of the eyeball, and the retention time is short. At the same time, because the drugs need to cross the tear film barrier, corneal barrier and conjunctival barrier, the bioavailability of traditional eye drops is only 1-7%. In order to achieve the therapeutic effect of the drug, it is necessary to achieve an appropriate drug concentration in the targeted part of the eye. Increasing the frequency of administration is a common method of ocular drug administration. However, frequent administration may cause certain toxic side effects.

[0003] Solid lipid nanoparticles (SLN) are mainly composed of solid lipids at the non-polar end and the polar end, and are submicron colloidal carriers (50-1000nm). Compared with traditional dosage forms, SLN has the characteristics of targeting, controlled sustained release, reduced number of administrations, and low toxic side effects. SLN enhances the permeability of drugs in the cornea and conjunctival sac, thereby greatly improving the bioavailability of drugs in ocular tissues. In addition, SLN's controlled sustained release method delivers drugs to specific tissue sites, protects drugs from degradation and metabolism to enhance drug stability, reduce drug clearance, and maintain sustained drug release, which can also improve the bioavailability of lipophilic and hydrophilic drugs in the anterior segment of the eye.

[0004] Hydrochloric acid nitrogen Sting is slightly soluble in water, slightly soluble in methanol and ethanol, has poor corneal permeability and very low ocular bioavailability. Instructions for use of Sting Eye Drops (Trade name: ) Drug overdose records that in the case of overdose or toxic doses, central nervous system disorders may occur, which can be treated symptomatically and there is no known antidote. In addition, during the stability period, the related substance impurity A, the maximum single impurity, and the total impurity of the preparation are likely to exceed the limit when accelerated for 3 months. Summary of the invention

[0005] The purpose of the present invention is to provide a hydrochloric acid nitrogen for treating allergic conjunctivitis on the basis of the prior art. Sting eye drops.

[0006] Another object of the present invention is to provide the above-mentioned nitrogen hydrochloride for treating allergic conjunctivitis. Preparation method of Sting eye drops.

[0007] The technical solution of the present invention is as follows:

[0008] A kind of nitrogen hydrochloride for treating allergic conjunctivitis Sting eye drops, made of nitrogen hydrochloride Sting, solid lipid, surfactant, co-surfactant, osmotic pressure regulator and water for injection are made into liquid medicine, filtered for sterilization and filled to obtain the finished product. During the preparation of the liquid medicine, the pH value is adjusted to 5.5-7.5, wherein the solid lipid is one or more of laurin, monostearate and tripalmitin; the surfactant is one or more of polysorbate 80, polyoxyethylene castor oil or hydrogenated castor oil; the co-surfactant is glycerol and / or polyethylene glycol; and the osmotic pressure regulator is sodium chloride and / or boric acid.

[0009] In a preferred embodiment, the surfactant is polysorbate 80; the co-surfactant is glycerol; and the osmotic pressure regulator is sodium chloride.

[0010] In a preferred embodiment, during the preparation of the drug solution, the pH value is adjusted to 6.0-7.0.

[0011] For the present invention, by selecting specific solid lipids and surfactants and controlling the dosage of solid lipids and surfactants, the active ingredient hydrochloric acid nitrogen is added. Sting is constructed into a local ocular drug delivery system - solid lipid nanoparticles, which can interact with the mucus layer on the surface of the cornea and conjunctiva, prolonging the ability of the drug to stay in front of the cornea, making the drug have good targeting, achieving sustained release of the drug, reducing the frequency of medication, reducing the toxic and side effects of the drug, improving bioavailability, and enhancing patient compliance. It also has better stability during preparation and long-term storage, thereby solving the problem of drug overdose caused by multiple administrations and the active ingredient nitrogen hydrochloride. Sting's poor stability.

[0012] In a preferred embodiment, the hydrochloric acid nitrogen for treating allergic conjunctivitis provided by the present invention is Each 6 ml of Sting eye drops contains the following components by weight: hydrochloric acid nitrogen Sting 2-4mg, solid lipid 35-85mg, polysorbate 8025-55mg, glycerol 80-120mg, sodium chloride 40-60mg.

[0013] In a more preferred embodiment, the hydrochloric acid nitrogen for treating allergic conjunctivitis provided by the present invention is Each 6 ml of Sting eye drops contains the following components by weight: hydrochloric acid nitrogen Sting 3mg, solid lipid 40-80mg, polysorbate 8030-50mg, glycerol 100mg, sodium chloride 50mg.

[0014] In a particularly preferred embodiment, the hydrochloric acid nitrogen for treating allergic conjunctivitis provided by the present invention is Each 6 ml of Sting eye drops contains the following components by weight:

[0015] For example, hydrochloric acid nitrogen Sting 3mg, glyceryl monolaurate 40mg, polysorbate 80 40mg, glycerol 100mg, sodium chloride 50mg.

[0016] For example, hydrochloric acid nitrogen Sting 3mg, glyceryl monolaurate 60mg, polysorbate 80 40mg, glycerol 100mg, sodium chloride 50mg.

[0017] For example, hydrochloric acid nitrogen Sting 3mg, glyceryl monolaurate 80mg, polysorbate 80 40mg, glycerol 100mg, sodium chloride 50mg.

[0018] For example, hydrochloric acid nitrogen Sting 3mg, glyceryl monolaurate 60mg, polysorbate 80 30mg, glycerol 100mg, sodium chloride 50mg.

[0019] For example, hydrochloric acid nitrogen Sting 3mg, glyceryl monolaurate 60mg, polysorbate 80 50mg, glycerol 100mg, sodium chloride 50mg.

[0020] For example, hydrochloric acid nitrogen Sting 3mg, glyceryl monostearate 60mg, polysorbate 80 40mg, glycerol 100mg, sodium chloride 50mg;

[0021] For example, hydrochloric acid nitrogen Sting 3mg, tripalmitin 60mg, polysorbate 80 40mg, glycerol 100mg, sodium chloride 50mg.

[0022] The present invention also provides the above-mentioned nitrogen hydrochloride for treating allergic conjunctivitis. The preparation method of Sting eye drops comprises the following steps:

[0023] (1) Oil phase preparation: Sting, solid lipid, surfactant and co-surfactant are mixed and stirred at 50-90°C until completely dissolved;

[0024] (2) Preparation of aqueous phase: Mix the osmotic pressure regulator with water for injection and stir until completely dissolved;

[0025] (3) Mixing: slowly adding the aqueous phase obtained in step (2) to the oil phase obtained in step (1), adjusting the pH value to 5.5-7.5 during stirring, adding the remaining water for injection to make up the volume, and stirring to obtain a drug solution;

[0026] (4) After the preparation of the drug solution is completed, it is sterilized, filtered, and filled to obtain the finished product.

[0027] For the present invention, the solid lipid is one or more of laurin, monostearate, and tripalmitin; the surfactant is one or more of polysorbate 80, polyoxyethylene castor oil, or hydrogenated castor oil, preferably polysorbate 80; the co-surfactant is glycerol and / or polyethylene glycol, preferably glycerol; the osmotic pressure regulator is sodium chloride and / or boric acid, preferably sodium chloride.

[0028] In a preferred embodiment, in step (1), stirring is performed at 65-75° C. until the mixture is completely dissolved.

[0029] In a preferred embodiment, in step (3), during stirring, the pH value is adjusted to 6.0-7.0.

[0030] Adopt the technical scheme of the present invention, the advantages are as follows:

[0031] The invention provides a hydrochloric acid nitrogen for treating allergic conjunctivitis Sting eye drops, by selecting specific solid lipids and surfactants and controlling the dosage of solid lipids and surfactants, the active ingredient, nitrogen hydrochloride, is Sting is constructed into a local ocular drug delivery system - solid lipid nanoparticles, which can interact with the mucus layer on the surface of the cornea and conjunctiva, prolonging the ability of the drug to stay in front of the cornea, making the drug have good targeting, achieving sustained release of the drug, reducing the frequency of medication, reducing the toxic and side effects of the drug, improving bioavailability, and enhancing patient compliance. It also has better stability during preparation and long-term storage, thereby solving the problem of drug overdose caused by multiple administrations and the active ingredient nitrogen hydrochloride. Sting's poor stability.

[0032] The entire preparation method is simple, has low requirements on production equipment, reduces production energy consumption, simplifies production steps, can ensure product quality and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0033] The following is an example of a hydrochloric acid nitrogen compound for treating allergic conjunctivitis according to the present invention. Sting eye drops and its preparation method are further described in detail, but this should not be understood as the scope of the above subject matter of the present invention is limited to the following examples. All technologies realized based on the above content of the present invention belong to the scope of the present invention.

[0034] Examples 1-7

[0035] A kind of nitrogen hydrochloride for treating allergic conjunctivitis Sting eye drops are made of the following components by weight. The components and weights of Examples 1-7 are specifically shown in Table 1.

[0036] Table 1 Components and dosage

[0037]

[0038] Wherein, in Example 2, the hydrochloric acid nitrogen The preparation method of Sting eye drops is as follows:

[0039] (1) Oil phase preparation: Sting, solid lipid lauric acid glyceryl, surfactant polysorbate 80 and co-surfactant glycerol are mixed and stirred at 65-75°C until completely dissolved;

[0040] (2) Preparation of aqueous phase: Mix the osmotic pressure regulator sodium chloride with water for injection and stir until completely dissolved;

[0041] (3) Mixing: slowly add the aqueous phase obtained in step (2) to the oil phase obtained in step (1), adjust the pH value to 6.0-7.0 during stirring, add the remaining water for injection to make up to 6 mL, and stir to obtain a drug solution;

[0042] (4) After the preparation of the drug solution is completed, it is sterilized, filtered, and filled to obtain the finished product.

[0043] The eye drops in Example 2 were tested for basic items, as shown in Table 2 below.

[0044] Table 2 Test results

[0045]

[0046] As can be seen from Table 1, the quality of the eye drops prepared in Example 2 of the present invention meets the standard requirements.

[0047] In the process of the preparation method, compared with Example 2, the preparation methods of Examples 1 and 3-5 are basically the same, and the difference between Examples 6-7 is that laurin is replaced with monostearic acid glyceryl and tripalmitin in sequence. Among them, other examples are also tested for basic items, similar to Example 2, and the quality meets the standard requirements.

[0048] Comparative Examples 1-5

[0049] A kind of nitrogen hydrochloride for treating allergic conjunctivitis Sting eye drops are made from the following components by weight. The components and weights of Comparative Examples 1-5 are specifically shown in Table 3.

[0050] Table 3 Components and dosage

[0051]

[0052] Among them, in Comparative Example 1, the hydrochloric acid nitrogen The preparation method of Sting eye drops is as follows:

[0053] (1) Oil phase preparation: Sting, solid lipid lauric acid glyceryl, surfactant polysorbate 80 and co-surfactant glycerol are mixed and stirred at 65-75°C until completely dissolved;

[0054] (2) Preparation of aqueous phase: Mix the osmotic pressure regulator sodium chloride with water for injection and stir until completely dissolved;

[0055] (3) Mixing: slowly add the aqueous phase obtained in step (2) to the oil phase obtained in step (1), adjust the pH value to 6.0-7.0 during stirring, add the remaining water for injection to make up to 6 mL, and stir to obtain a drug solution;

[0056] (4) After the preparation of the drug solution is completed, it is sterilized, filtered, and filled to obtain the finished product.

[0057] In the process of the preparation method, compared with Comparative Example 1, the preparation methods of Comparative Examples 2-4 are basically the same, while the difference of Comparative Example 5 is that laurin glyceride is replaced with ethyl oleate in sequence.

[0058] The samples in Comparative Examples 1-5 were tested for basic items, and some experimental data were extracted, as shown in Tables 4 and 5 below, for comparison with the data in the examples.

[0059] Table 4 Test results

[0060]

[0061] Table 5 Dissolution data

[0062]

[0063]

[0064] Note: Dynamic dialysis method was used, and the concentrations of the components in the medium were: NaCl 6.7 g / L, NaHCO3 2.0 g / L, CaCl (monohydrate) 8.0 g / L.

[0065] As shown in Table 4, in Comparative Example 1, Examples 1-3 and Comparative Example 2, the dosage of solid lipid lauric acid glyceryl was increased from 30 mg to 90 mg. When the dosage of solid lipid lauric acid glyceryl was increased, the particle size and encapsulation efficiency became larger. When the dosage of lauric acid glyceryl was 90 mg, the particle size D 90 , the encapsulation rate has exceeded the limit and does not meet the regulations. As shown in Table 5, increasing the dosage of solid lipid lauric acid glyceride will slow down the in vitro release rate. When the dosage is 30mg and 90mg, the particle size D 90 , the encapsulation rate has exceeded the limit, and the in vitro release no longer meets the requirements. Therefore, in the samples of Examples 1-3, the amount of solid lipid lauric acid glyceride in the formula is 40mg-80mg, and the particle size D 90 It complies with the regulations, has a high encapsulation rate, the in vitro dissolution rate complies with the regulations, and the dissolution effect is good.

[0066] In Comparative Examples 3 to 4, Examples 2, 4 to 5, the dosage of the surfactant polysorbate 80 was increased from 20 mg to 60 mg. When the dosage of the surfactant polysorbate 80 was increased, the particle size and encapsulation rate did not change much. However, the in vitro release rate was accelerated. When the dosage of polysorbate 80 was 20 mg, the cumulative release amount in 12 h was <80%. When the dosage of polysorbate 80 was 60 mg, there was a burst release phenomenon. Therefore, in Examples 4 to 5, the dosage of polysorbate 80 in the formula was 30-50 mg, and the particle size D of the drug solution was 90 It complies with regulations, has a high encapsulation rate, a high in vitro dissolution rate, and a good dissolution effect.

[0067] In Examples 2, 6-7, and Comparative Example 5, different types of solid lipids have a certain influence on the particle size and encapsulation efficiency. The encapsulation efficiency of the drug solution prepared by monostearate and tripalmitin is close to the lower limit; the particle size D of the drug solution prepared by ethyl oleate is 90 The limit was exceeded and the in vitro release did not meet the regulations. Therefore, the best solid lipid is laurin.

[0068] Commercially available preparations The samples in the examples and comparative examples were placed under accelerated conditions (40±2°C, relative humidity 75±5%) to compare their stability. The test data are shown in the following table:

[0069]

[0070]

[0071] From the above data, it can be seen that the samples prepared according to the formula and method of the present invention meet the requirements for the 0-day sample test. At the same time, the test data at various time points from 0 days to 6 months under accelerated conditions show that the related substances of the samples prepared in Example 2 of the present invention are significantly better than those of the commercially available preparations. This shows that the samples prepared in the examples of the present invention have excellent stability.

[0072] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A nitrogen hydrochloride for treating allergic conjunctivitis Sting eye drops, characterized in that Hydrochloric acid nitrogen Sting, solid lipid, surfactant, co-surfactant, osmotic pressure regulator and water for injection are made into liquid medicine, filtered for sterilization and filled to obtain the finished product. During the preparation of the liquid medicine, the pH value is adjusted to 5.5-7.5, wherein the solid lipid is one or more of laurin, monostearate and tripalmitin; the surfactant is one or more of polysorbate 80, polyoxyethylene castor oil or hydrogenated castor oil; the co-surfactant is glycerol and / or polyethylene glycol; the osmotic pressure regulator is sodium chloride and / or boric acid.

2. Hydrochloric acid nitrogen according to claim 1 Sting eye drops, characterized in that The surfactant is polysorbate 80; the co-surfactant is glycerol; the osmotic pressure regulator is sodium chloride; and during the preparation of the drug solution, the pH value thereof is adjusted to 6.0-7.

0.

3. Hydrochloric acid nitrogen according to claim 2 Sting eye drops, characterized in that Each 6 ml of solution contains the following components by weight: hydrochloric acid nitrogen Sting 2-4mg, solid lipid 35-85mg, polysorbate 8025-55mg, glycerol 80-120mg, sodium chloride 40-60mg.

4. Hydrochloric acid nitrogen according to claim 3 Each 6 ml of Sting eye drops contains the following components by weight: hydrochloric acid nitrogen Sting 3mg, solid lipid 40-80mg, polysorbate 80 30-50mg, glycerol 100mg, sodium chloride 50mg.

5. Nitrogen hydrochloride according to claim 4 Each 6 ml of Sting eye drops contains the following components by weight: hydrochloric acid nitrogen Sting 3mg, glyceryl laurate 40mg, polysorbate 80 40mg, glycerol 100mg, sodium chloride 50mg; Hydrochloric acid nitrogen Sting 3mg, glyceryl laurate 60mg, polysorbate 80 40mg, glycerol 100mg, sodium chloride 50mg; Hydrochloric acid nitrogen Sting 3mg, glyceryl monolaurate 80mg, polysorbate 80 40mg, glycerol 100mg, sodium chloride 50mg.

6. Hydrochloric acid nitrogen according to claim 4 Each 6 ml of Sting eye drops contains the following components by weight: Hydrochloric acid nitrogen Sting 3mg, glyceryl laurate 60mg, polysorbate 80 30mg, glycerol 100mg, sodium chloride 50mg; Hydrochloric acid nitrogen Sting 3mg, glyceryl monolaurate 60mg, polysorbate 80 50mg, glycerol 100mg, sodium chloride 50mg.

7. Hydrochloric acid nitrogen according to claim 4 Each 6 ml of Sting eye drops contains the following components by weight: Hydrochloric acid nitrogen Sting 3mg, glyceryl monostearate 60mg, polysorbate 80 40mg, glycerol 100mg, sodium chloride 50mg; Hydrochloric acid nitrogen Sting 3mg, tripalmitin 60mg, polysorbate 80 40mg, glycerol 100mg, sodium chloride 50mg.

8. The hydrochloric acid nitrogen for treating allergic conjunctivitis according to claim 1 The preparation method of Sting eye drops is characterized in that: The steps include: (1) Oil phase preparation: Sting, solid lipid, surfactant and co-surfactant are mixed and stirred at 50-90°C until completely dissolved; (2) Preparation of aqueous phase: Mix the osmotic pressure regulator with water for injection and stir until completely dissolved; (3) Mixing: slowly adding the aqueous phase obtained in step (2) to the oil phase obtained in step (1), adjusting the pH value to 5.5-7.5 during stirring, adding the remaining water for injection to make up the volume, and stirring to obtain a drug solution; (4) After the preparation of the drug solution is completed, it is sterilized, filtered, and filled to obtain the finished product.

9. Nitrogen hydrochloride for treating allergic conjunctivitis according to claim 8 The preparation method of Sting eye drops is characterized in that: The solid lipid is one or more of lauric acid glyceryl, monostearate glyceryl, and tripalmitin glyceryl; the surfactant is one or more of polysorbate 80, polyoxyethylene castor oil, or hydrogenated castor oil, preferably polysorbate 80; the co-surfactant is glycerol and / or polyethylene glycol, preferably glycerol; The osmotic pressure regulator is sodium chloride and / or boric acid, preferably sodium chloride.

10. Nitrogen hydrochloride for treating allergic conjunctivitis according to claim 8 The preparation method of Sting eye drops is characterized in that: In step (1), stirring is performed at 65-75° C. until the mixture is completely dissolved; in step (3), during stirring, the pH value is adjusted to 6.0-7.0.

Images