Dexamethasone sodium phosphate eye drops and preparation method thereof

Abstract

The invention provides dexamethasone sodium phosphate eye drops and a preparation method thereof. The dexamethasone sodium phosphate eye drops are prepared from the following components: dexamethasone sodium phosphate, glyceryl behenate, PEG-600, Tween 80, phospholipid, a preservative and the balance of sterilized water. The dexamethasone sodium phosphate eye drops are prepared by a thermal high-pressure homogenization method. According to the dexamethasone sodium phosphate eye drops provided by the invention, the dexamethasone sodium phosphate is encapsulated by the lipidosome, so that the dexamethasone sodium phosphate stays in rabbit eyes for a longer time, and the dexamethasone sodium phosphate eye drops have a certain slow release effect, so that the purpose of continuous administration is achieved. Meanwhile, liposome encapsulation can also improve cornea and conjunctiva permeability of dexamethasone sodium phosphate and improve bioavailability. In addition, the dexamethasone sodium phosphate eye drops do not cause allergy, and are safe and easy to use; the preparation method provided by the invention is simple in process, mild in condition, short in time consumption and beneficial to industrial production.

Description

Technical Field

[0001] The invention relates to the field of pharmacy, and in particular to a dexamethasone sodium phosphate eye drop and a preparation method thereof. The eye drop is used for treating eye inflammations such as iridocyclitis, iritis, keratitis, allergic conjunctivitis, blepharitis, dacryocystitis, etc. Background Art

[0002] Dexamethasone is a synthetic corticosteroid with a clinical bioequivalent dose ratio of 0.75:5 to prednisolone and a biological half-life of 36 to 54 hours. It is classified as a long-acting glucocorticoid. Like other glucocorticoids, dexamethasone has pharmacological effects such as anti-inflammatory, anti-endotoxin, immunosuppressive, anti-shock and enhanced stress response. Therefore, it is widely used in various departments to treat a variety of diseases, such as autoimmune diseases, allergies, inflammation, asthma, and dermatology and ophthalmology. Due to its extremely low water solubility, it is often used in the form of its phosphate (dexamethasone sodium phosphate) in ophthalmology clinics to treat iridocyclitis, iritis, keratitis, allergic conjunctivitis, blepharitis, dacryocystitis and other ocular inflammations. In addition, when used in combination with antibiotics, dexamethasone sodium phosphate eye drops can also be used after eye surgeries such as cataract surgery to prevent postoperative infection and inflammation.

[0003] However, due to the complex physiological structure of the eye, the bioavailability of ordinary eye drops is low. Therefore, the concentration of dexamethasone sodium phosphate eye drops commonly used on the market is usually high. However, at higher concentrations, large doses of dexamethasone sodium phosphate eye drops may cause eyelid swelling, and long-term and frequent use may also cause glaucoma, cataracts, or induce fungal blepharitis. Therefore, developing a dexamethasone sodium phosphate eye preparation with high bioavailability and low incidence of side effects is a technical problem that needs to be solved in the art. Summary of the invention

[0004] In view of this, the present invention provides a dexamethasone sodium phosphate eye drops and a preparation method thereof.

[0005] The technical solution of the present invention is as follows:

[0006] A dexamethasone sodium phosphate eye drop comprises the following components in percentage by mass: 0.1% of dexamethasone sodium phosphate, 2-5% of glyceryl behenate, 3-5% of PEG-600, 4-7% of Tween 80, 0.2-0.5% of phospholipids, 0.05-0.15% of preservatives, and the balance is sterile water.

[0007] Furthermore, the above-mentioned dexamethasone sodium phosphate eye drops include the following components in percentage by mass: 0.1% dexamethasone sodium phosphate, 3% behenic acid glyceryl, 4% PEG-600, 6% Tween 80, 0.4% phospholipids, 0.1% preservative, and the balance is sterile water.

[0008] Furthermore, in the above-mentioned dexamethasone sodium phosphate eye drops, the phospholipid is soybean lecithin and / or egg yolk lecithin.

[0009] Furthermore, in the above-mentioned dexamethasone sodium phosphate eye drops, the preservative is one or more of benzalkonium chloride, benzalkonium bromide, and povidone iodine.

[0010] The present invention also provides a method for preparing any of the above-mentioned dexamethasone sodium phosphate eye drops, comprising the following steps:

[0011] S1) Weighing the prescribed amount of raw materials and sterilizing each raw material;

[0012] S2) under sterile conditions, adding behenic acid glyceryl and PEG-600 to a reaction container, heating and stirring, adding dexamethasone sodium phosphate to the reaction container, and stirring until the dexamethasone sodium phosphate is completely dissolved and no solid components are visible in the mixture;

[0013] S3) taking another reaction container, heating Tween 80, phospholipids, and sterilized water, and stirring evenly to prepare the aqueous phase;

[0014] S4) adding the mixture obtained in S2 to the aqueous phase obtained in S3, stirring at high speed to form a pre-emulsion;

[0015] S5) high-pressure homogenizing the pre-emulsion prepared in S4, cooling to room temperature, and adding a preservative to obtain dexamethasone sodium phosphate eye drops.

[0016] Furthermore, in the above preparation method, in step S2, glyceryl behenate and PEG-600 are heated to 75° C. and stirred at a speed of 200 rpm.

[0017] Furthermore, in the above preparation method, in step S3, Tween 80, phospholipids and sterilized water are heated to 75° C. and stirred at a speed of 200 rpm.

[0018] Furthermore, in the above preparation method, in step S4, the stirring speed is 8000 rpm and the stirring time is 10 minutes.

[0019] Furthermore, in the above preparation method, in step S5, the high-pressure homogenization pressure is 1200 bar, and the cycle is repeated 3 to 5 times.

[0020] The beneficial effects of the present invention are as follows: the dexamethasone sodium phosphate eye drops provided by the present invention can make the dexamethasone sodium phosphate stay in the rabbit eyes for a longer time by encapsulating the dexamethasone sodium phosphate through liposomes, and have a certain sustained release effect, thereby achieving the purpose of continuous administration. At the same time, liposome encapsulation can also increase the corneal and conjunctival permeability of dexamethasone sodium phosphate and improve bioavailability. In addition, the dexamethasone sodium phosphate eye drops of the present invention do not cause allergies, are safe and easy to use; the preparation method provided by the present invention has a simple process, mild conditions, a short time, and is conducive to industrial production. DETAILED DESCRIPTION

[0021] The experimental methods used in the following examples are conventional methods unless otherwise specified; the reagents, materials, etc. used in the following examples are commercially available products, or can be prepared by known methods unless otherwise specified. The experimental methods in the following examples without specifying specific conditions are usually carried out according to conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer.

[0022] Example 1

[0023] S1) weighing 1 g of dexamethasone sodium phosphate, 30 g of glyceryl behenate, 40 g of PEG-600, 60 g of Tween 80, 4 g of soy lecithin, 1 g of povidone iodine, and 864 g of purified water, and sterilizing each raw material;

[0024] S2) under sterile conditions, add behenic acid glyceryl and PEG-600 into a reaction kettle, heat to 75° C., start stirring at a stirring speed of 200 rpm, and add dexamethasone sodium phosphate while stirring until the dexamethasone sodium phosphate is completely dissolved and no solid component is visible in the mixture;

[0025] S3) Take another reaction kettle, heat Tween 80, soybean lecithin, and sterilized purified water to 75° C., start stirring at a stirring speed of 200 rpm, and stir evenly to serve as the aqueous phase;

[0026] S4) adding the mixture obtained in S2 to the aqueous phase obtained in S3, stirring at 8000 rpm for 10 minutes to form a pre-emulsion;

[0027] S5) adding the pre-emulsion prepared in S4 into a high-pressure homogenizer, circulating 4 times at 1200 bar, cooling to room temperature, adding povidone iodine, and obtaining dexamethasone sodium phosphate eye drops.

[0028] Example 2

[0029] S1) weighing 1 g of dexamethasone sodium phosphate, 20 g of glyceryl behenate, 30 g of PEG-600, 40 g of Tween 80, 2 g of soy lecithin, 0.5 g of benzalkonium chloride, and 906.5 g of purified water, and sterilizing each raw material;

[0030] S2) under sterile conditions, add behenic acid glyceryl and PEG-600 into a reaction kettle, heat to 75° C., start stirring at a stirring speed of 200 rpm, and add dexamethasone sodium phosphate while stirring until the dexamethasone sodium phosphate is completely dissolved and no solid component is visible in the mixture;

[0031] S3) Take another reaction kettle, heat Tween 80, soybean lecithin, and sterilized purified water to 75° C., start stirring at a stirring speed of 200 rpm, and stir evenly to serve as the aqueous phase;

[0032] S4) adding the mixture obtained in S2 to the aqueous phase obtained in S3, stirring at 8000 rpm for 10 minutes to form a pre-emulsion;

[0033] S5) adding the pre-emulsion prepared in S4 into a high-pressure homogenizer, circulating 3 times at 1200 bar, cooling to room temperature, adding benzalkonium chloride, and obtaining dexamethasone sodium phosphate eye drops.

[0034] Example 3

[0035] S1) weighing 1 g of dexamethasone sodium phosphate, 50 g of behenic acid glyceryl, 50 g of PEG-600, 70 g of Tween 80, 5 g of egg yolk lecithin, 0.15 g of benzalkonium bromide, and 823.85 g of purified water, and sterilizing each raw material;

[0036] S2) under sterile conditions, add behenic acid glyceryl and PEG-600 into a reaction kettle, heat to 75° C., start stirring at a stirring speed of 200 rpm, and add dexamethasone sodium phosphate while stirring until the dexamethasone sodium phosphate is completely dissolved and no solid component is visible in the mixture;

[0037] S3) Take another reaction kettle, heat Tween 80, soybean lecithin, and sterilized purified water to 75° C., start stirring at a stirring speed of 200 rpm, and stir evenly to serve as the aqueous phase;

[0038] S4) adding the mixture obtained in S2 to the aqueous phase obtained in S3, stirring at 8000 rpm for 10 minutes to form a pre-emulsion;

[0039] S5) adding the pre-emulsion prepared in S4 into a high-pressure homogenizer, circulating 5 times at 1200 bar, cooling to room temperature, adding benzalkonium bromide, and obtaining dexamethasone sodium phosphate eye drops.

[0040] Comparative Example 1

[0041] S1) weighing 1 g of dexamethasone sodium phosphate, 30 g of glyceryl behenate, 10 g of PEG-600, 60 g of Tween 80, 4 g of soy lecithin, 1 g of povidone iodine, and 894 g of purified water, and sterilizing each raw material separately. PEG-600 is insufficient in this formula;

[0042] S2) under sterile conditions, add behenic acid glyceryl and PEG-600 into a reaction kettle, heat to 75° C., start stirring at a stirring speed of 200 rpm, and add dexamethasone sodium phosphate while stirring until the dexamethasone sodium phosphate is completely dissolved and no solid component is visible in the mixture;

[0043] S3) Take another reaction kettle, heat Tween 80, soybean lecithin, and sterilized purified water to 75° C., start stirring at a stirring speed of 200 rpm, and stir evenly to serve as the aqueous phase;

[0044] S4) adding the mixture obtained in S2 to the aqueous phase obtained in S3, stirring at 8000 rpm for 10 minutes to form a pre-emulsion;

[0045] S5) adding the pre-emulsion prepared in S4 into a high-pressure homogenizer, circulating 4 times at 1200 bar, cooling to room temperature, adding povidone iodine, and obtaining dexamethasone sodium phosphate eye drops.

[0046] Comparative Example 2

[0047] S1) weighing 1 g of dexamethasone sodium phosphate, 30 g of glyceryl behenate, 40 g of PEG-600, 60 g of Tween 80, 1 g of povidone iodine, and 868 g of purified water, and sterilizing each raw material separately. This formula lacks phospholipids;

[0048] S2) under sterile conditions, add behenic acid glyceryl and PEG-600 into a reaction kettle, heat to 75° C., start stirring at a stirring speed of 200 rpm, and add dexamethasone sodium phosphate while stirring until the dexamethasone sodium phosphate is completely dissolved and no solid component is visible in the mixture;

[0049] S3) Take another reaction kettle, heat Tween 80, soybean lecithin, and sterilized purified water to 75° C., start stirring at a stirring speed of 200 rpm, and stir evenly to serve as the aqueous phase;

[0050] S4) adding the mixture obtained in S2 to the aqueous phase obtained in S3, stirring at 8000 rpm for 10 minutes to form a pre-emulsion;

[0051] S5) adding the pre-emulsion prepared in S4 into a high-pressure homogenizer, circulating 4 times at 1200 bar, cooling to room temperature, adding povidone iodine, and obtaining dexamethasone sodium phosphate eye drops.

[0052] Comparative Example 3

[0053] S1) weighing 1 g of dexamethasone sodium phosphate, 30 g of glyceryl behenate, 40 g of PEG-600, 60 g of Tween 80, 4 g of soy lecithin, 1 g of povidone iodine, and 864 g of purified water, and sterilizing each raw material;

[0054] S2) under sterile conditions, add behenic acid glyceryl and PEG-600 into a reaction kettle, heat to 75° C., start stirring at a stirring speed of 200 rpm, and add dexamethasone sodium phosphate while stirring until the dexamethasone sodium phosphate is completely dissolved and no solid component is visible in the mixture;

[0055] S3) Take another reaction kettle, heat Tween 80, soybean lecithin, and sterilized purified water to 75° C., start stirring at a stirring speed of 200 rpm, and stir evenly to serve as the aqueous phase;

[0056] S4) adding the mixture obtained in S2 to the aqueous phase obtained in S3, wherein the aqueous phase is not prepared as a pre-emulsion in this method;

[0057] S5) adding the aqueous phase containing the mixture obtained in S4 into a high-pressure homogenizer, circulating 4 times at 1200 bar, cooling to room temperature, adding povidone iodine, and obtaining dexamethasone sodium phosphate eye drops.

[0058] Comparative Example 4

[0059] S1) weighing 1 g of dexamethasone sodium phosphate, 30 g of glyceryl behenate, 40 g of PEG-600, 60 g of Tween 80, 4 g of soy lecithin, 1 g of povidone iodine, and 864 g of purified water, and sterilizing each raw material;

[0060] S2) under sterile conditions, add behenic acid glyceryl and PEG-600 into a reaction kettle, heat to 75° C., start stirring at a stirring speed of 200 rpm, and add dexamethasone sodium phosphate while stirring until the dexamethasone sodium phosphate is completely dissolved and no solid component is visible in the mixture;

[0061] S3) Take another reaction kettle, heat Tween 80, soybean lecithin, and sterilized purified water to 75° C., start stirring at a stirring speed of 200 rpm, and stir evenly to serve as the aqueous phase;

[0062] S4) adding the mixture obtained in S2 to the aqueous phase obtained in S3, stirring at 8000 rpm for 10 minutes to form a pre-emulsion;

[0063] S5) adding the pre-emulsion prepared in S4 into a high-pressure homogenizer, circulating once at 1200 bar, cooling to room temperature, adding povidone iodine, and obtaining dexamethasone sodium phosphate eye drops.

[0064] Comparative Example 5

[0065] S1) weighing 1 g of dexamethasone sodium phosphate, 30 g of glyceryl behenate, 40 g of PEG-600, 60 g of Tween 80, 4 g of soy lecithin, 1 g of povidone iodine, and 864 g of purified water, and sterilizing each raw material;

[0066] S2) under sterile conditions, add behenic acid glyceryl and PEG-600 into a reaction kettle, heat to 75° C., start stirring at a stirring speed of 200 rpm, and add dexamethasone sodium phosphate while stirring until the dexamethasone sodium phosphate is completely dissolved and no solid component is visible in the mixture;

[0067] S3) Take another reaction kettle, heat Tween 80, soybean lecithin, and sterilized purified water to 75° C., start stirring at a stirring speed of 200 rpm, and stir evenly to serve as the aqueous phase;

[0068] S4) adding the mixture obtained in S2 to the aqueous phase obtained in S3, stirring at 8000 rpm for 10 minutes to form a pre-emulsion;

[0069] S5) adding the pre-emulsion prepared in S4 into a high-pressure homogenizer, circulating 7 times at 1200 bar, cooling to room temperature, adding povidone iodine, and obtaining dexamethasone sodium phosphate eye drops.

[0070] Performance Testing

[0071] (1) Appearance

[0072] The dexamethasone sodium phosphate eye drops prepared in Examples 1-3 and Comparative Examples 1-5 were observed with naked eyes at room temperature and tested on a clean glass plate.

[0073] Table 1 Preparation process of each sample

[0074]

[0075]

[0076] As shown in the above table, the dexamethasone sodium phosphate eye drops prepared in the examples and comparative examples are all white solutions with a slight opalescence and do not separate when shaken.

[0077] (2) Determination of encapsulation efficiency (EE) and drug loading (DL)

[0078] The centrifugal ultrafiltration method was used to determine the liposome encapsulation rate of the prepared dexamethasone sodium phosphate eye drops. Accurately measure 20μl of the liposome suspension of the obtained preparation, add anhydrous ethanol to fully dissolve to 10ml, break the emulsion and centrifuge, take the supernatant to measure the dexamethasone sodium phosphate concentration and record c (mg / mL); take the same colloidal solution, use ultrafiltration centrifuge tube for centrifugation, and also take the supernatant to measure the dexamethasone sodium phosphate concentration and record c' (mg / mL). M (mg / ml) is the ratio of the amount of carrier added to the volume of liposomes. The calculation formula is as follows:

[0079]

[0080]

[0081] The test results are shown in Table 2 below.

[0082] Table 2 Dexamethasone sodium phosphate eye drops liposome encapsulation efficiency and drug loading test results

[0083]

[0084]

[0085] Encapsulation efficiency and drug loading are important physical and chemical properties of liposomes. As shown in the table above, the encapsulation efficiency of dexamethasone sodium phosphate eye drops prepared in each embodiment is about 62%, and the drug loading rate exceeds 90%, while the encapsulation efficiency and drug loading rate of dexamethasone sodium phosphate eye drops prepared in each comparative example are much lower than those in each embodiment. Among them, comparative example 1 is due to the lack of PEG-600, which causes dexamethasone sodium phosphate to be completely dispersed in behenic acid glyceride; comparative example 2 is difficult to form a liposome encapsulation system due to the lack of phospholipids. Comparative examples 3 and 4 also failed to form a good liposome encapsulation system due to the lack of pre-emulsion and insufficient number of cycles. Increasing the number of cycles (comparative example 5) did not significantly improve the encapsulation efficiency and drug loading rate of the liposomes.

[0086] (3) Pharmacodynamics experiments

[0087] The efficacy of the dexamethasone sodium phosphate eye drops (experimental group) prepared in Example 1 was tested based on a rabbit ocular inflammation model induced by puncture combined with intracameral injection of LPS. The blank group was the basic liposome eye drops prepared by the preparation method of Example 1 without dexamethasone sodium phosphate, and the control group was commercially available dexamethasone sodium phosphate eye drops.

[0088] Healthy adult New Zealand white rabbits (2.2-2.5 kg) were selected for the experiment, half male and half female, and randomly divided into groups according to body weight, with 5 rabbits in each group. The animal model was established 48 hours before the start of the experiment. 24 hours after model establishment, the eyes of each rabbit were graded according to the degree of inflammation, and the scoring criteria are shown in Table 3.

[0089] Table 3 Scoring criteria for rabbit ocular inflammation

[0090]

[0091]

[0092] Administration began 24 hours after infection (D0), and was administered for a total of 8 days. Rabbits in the experimental group were given 0.1 mL of dexamethasone sodium phosphate eye drops prepared in Example 1, which were dripped into the lower eyelid twice a day; the control group was given an equal amount of commercially available dexamethasone sodium phosphate eye drops at the same time; the blank group was given an equal amount of basic liposome eye drops at the same time, and ocular inflammation was scored at the beginning of the experiment (D0), the first day of administration, the fourth day, and the eighth day (D1, D4, D7), and the total score was the average score of each part.

[0093] The experimental results are shown in Table 4 below.

[0094] Table 4 Rabbit ocular inflammation scores

[0095]

[0096]

[0097] As shown in Table 4 above, compared with the blank group, both the control group and the experimental group effectively reduced the eye inflammation score of the New Zealand white rabbits, and the eye inflammation score of the experimental group was lower than that of the control group. This is because the liposome-encapsulated dexamethasone sodium phosphate can stay in the rabbit eyes for a longer time and has a certain sustained release effect, achieving the purpose of continuous administration. At the same time, liposome encapsulation can also increase the corneal and conjunctival permeability of dexamethasone sodium phosphate and improve bioavailability.

[0098] In addition, during use, no allergic reaction occurred in the rabbits of each group, which shows that the dexamethasone sodium phosphate eye drops prepared in Example 1 have a low incidence of adverse reactions, which is similar to the commercially available dexamethasone sodium phosphate eye drops, and can ensure the comfort and safety of patients.

[0099] Although the embodiments of the present application have been shown and described above, it is understood that the above embodiments are exemplary and cannot be construed as limitations on the present application. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present application.

Claims

1. A dexamethasone sodium phosphate eye drops, characterized in that: The invention comprises the following components in percentage by weight: 0.1% of dexamethasone sodium phosphate, 2-5% of behenic acid glyceryl, 3-5% of PEG-600, 4-7% of Tween 80, 0.2-0.5% of phospholipid, 0.05-0.15% of preservative, and the balance is sterile water.

2. The dexamethasone sodium phosphate eye drops according to claim 1, characterized in that The invention comprises the following components in percentage by weight: 0.1% of dexamethasone sodium phosphate, 3% of behenic acid glyceryl, 4% of PEG-600, 6% of Tween 80, 0.4% of phospholipids, 0.1% of preservatives, and the balance is sterile water.

3. The dexamethasone sodium phosphate eye drops according to claim 1 or 2, characterized in that The phospholipids are soybean lecithin and / or egg yolk lecithin.

4. The dexamethasone sodium phosphate eye drops according to claim 1 or 2, characterized in that The preservative is one or more of benzalkonium chloride, benzalkonium bromide and povidone iodine.

5. A method for preparing the dexamethasone sodium phosphate eye drops according to any one of claims 1 to 4, comprising the following steps: S1) Weighing the prescribed amount of raw materials and sterilizing each raw material; S2) under sterile conditions, adding behenic acid glyceryl and PEG-600 to a reaction container, heating and stirring, adding dexamethasone sodium phosphate to the reaction container, and stirring until the dexamethasone sodium phosphate is completely dissolved and no solid components are visible in the mixture; S3) taking another reaction container, heating Tween 80, phospholipids, and sterilized water, and stirring evenly to prepare the aqueous phase; S4) adding the mixture obtained in S2 to the aqueous phase obtained in S3, stirring at high speed to form a pre-emulsion; S5) high-pressure homogenizing the pre-emulsion obtained in S4, cooling it to room temperature, and adding a preservative to obtain the dexamethasone sodium phosphate eye drops.

6. The preparation method according to claim 5, characterized in that: In step S2, glyceryl behenate and PEG-600 are heated to 75° C. and stirred at 200 rpm.

7. The preparation method according to claim 5, characterized in that: In step S3, Tween 80, phospholipids and sterilized water are heated to 75° C. and stirred at a speed of 200 rpm.

8. The preparation method according to claim 5, characterized in that: In step S4, the stirring speed is 8000 rpm and the stirring time is 10 minutes.

9. The preparation method according to claim 5, characterized in that: In step S5, the high-pressure homogenization pressure is 1200 bar, and the cycle is repeated 3 to 5 times.

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