Cyclosporine eye drops as well as preparation method and application thereof

Abstract

The invention provides cyclosporine eye drops as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The cyclosporin eye drops contain cyclosporin and plant flavonoid compounds, the mass ratio of the cyclosporin to the plant flavonoid compounds is (4-6): (2-4), and the addition amount of the cyclosporin and the plant flavonoid compounds in the cyclosporin eye drops is 0.5-1.2%. According to the cyclosporin eye drops, cyclosporin and plant flavonoid compounds are combined to be used for preparing the cyclosporin eye drops, and the added plant flavonoid compounds can obviously reduce irritation of cyclosporin to eyes and further promote secretion of tears. Therefore, the cyclosporine eye drops provided by the invention can improve the safety and the effectiveness at the same time, and can be used for preparing the medicine for relieving or treating the xerophthalmia.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to cyclosporine eye drops and a preparation method and application thereof. Background Art

[0002] Dry eye, also known as keratoconjunctivitis sicca, is a chronic ocular surface disease caused by insufficient tear secretion, excessive evaporation or abnormal tear composition, which leads to unstable tear film and ocular surface damage, resulting in ocular discomfort. The clinical symptoms of dry eye are usually manifested as eye fatigue, dryness, foreign body sensation, pain, burning sensation, blurred vision, photophobia, tearing, etc.

[0003] The pathogenesis of dry eye is relatively complex, and more and more studies have confirmed that inflammation plays an important role in the occurrence and development of dry eye. Cyclosporine eye drops have a certain therapeutic effect on dry eye. They can relieve inflammation of the lacrimal glands and the surface of the eye by preventing the release of inflammatory factors and promote tear secretion. However, due to the strong irritation of cyclosporine and its poor corneal permeability, it is easy to cause eye pain, foreign body sensation in the eye, blurred vision and conjunctival congestion.

[0004] Therefore, it is necessary to provide a cyclosporine eye drops that can reduce the irritation of cyclosporine and improve corneal permeability, so as to improve the effectiveness and safety of cyclosporine eye drops. Summary of the invention

[0005] The purpose of the present invention is to provide a cyclosporine eye drops and a preparation method and application thereof, so as to improve the effectiveness and safety of the cyclosporine eye drops.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The invention provides a cyclosporine eye drops, which contain cyclosporine and plant flavonoids, wherein the mass ratio of cyclosporine to the plant flavonoids is 4-6:2-4, and the total addition amount of cyclosporine and the plant flavonoids in the cyclosporine eye drops is 0.5-1.2% (w / v).

[0008] Preferably, the plant flavonoids include ginkgo flavonoids or baicalin.

[0009] Preferably, the cyclosporine eye drops further contain pharmaceutically acceptable excipients.

[0010] Preferably, the pharmaceutically acceptable excipients include a surfactant, a suspending agent, an osmotic pressure regulator and a pH regulator; the added amount of the surfactant is 0.8-1.2%, the added amount of the suspending agent is 0.8-1.2%, the added amount of the osmotic pressure regulator is 1.3-1.7%, and the added amount of the pH regulator is 0.5-5%.

[0011] Preferably, the surfactant is any one or more of sodium dodecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, sodium dodecylbenzene sulfonate, Span, and Tween; the suspending agent is any one or more of gum arabic, sodium alginate, methylcellulose, sodium carboxymethyl cellulose, and hydroxypropyl cellulose; the osmotic pressure regulator is any one or more of glucose, sodium chloride, and mannitol; and the pH regulator is any one or more of boric acid, citric acid, and sodium bicarbonate.

[0012] The present invention provides a method for preparing the cyclosporine eye drops, comprising the following steps:

[0013] (1) mixing cyclosporine with a portion of a surfactant and a vegetable oil to obtain a solution 1;

[0014] (2) mixing the plant flavonoid compound with the remaining portion of the surfactant and the dilute alkaline aqueous solution to obtain a second solution;

[0015] (3) Solution 1 and Solution 2 are mixed with a suspending agent and an osmotic pressure regulator, the pH is adjusted to 5.0 to 9.0 using a pH regulator, and water for injection is added to obtain cyclosporine eye drops.

[0016] Preferably, the vegetable oil in step (1) is corn oil; the temperature during the mixing is 80-100° C., the speed is 800-1200 rpm, and the time is 8-12 min.

[0017] Preferably, the dilute alkali aqueous solution in step (2) is a dilute sodium hydroxide aqueous solution or a dilute sodium carbonate aqueous solution, the concentration of the dilute sodium hydroxide aqueous solution is 0.8-1.2%, and the concentration of the dilute sodium carbonate aqueous solution is 4-6%;

[0018] The temperature during the mixing is 40-80° C., the speed is 150-250 rpm, and the time is 25-35 min.

[0019] Preferably, the mixing method in step (3) is high-pressure homogenous mixing, the pressure during mixing is 500 to 700 bar, and the mixing time is 5 to 15 minutes.

[0020] The present invention also provides a use of the cyclosporine eye drops or the cyclosporine eye drops prepared according to the method in preparing a medicine for relieving or treating dry eye.

[0021] The present invention combines cyclosporine with plant flavonoids to prepare cyclosporine eye drops, and the added plant flavonoids can significantly reduce the irritation of cyclosporine to the eyes and further promote the secretion of tears. It can be seen that the present invention provides a cyclosporine eye drop that can improve both safety and effectiveness, and can be used to prepare a drug for relieving or treating dry eye. DETAILED DESCRIPTION

[0022] The invention provides a cyclosporine eye drops, which contain cyclosporine and plant flavonoids, wherein the mass ratio of cyclosporine to the plant flavonoids is 4-6:2-4, and the total addition amount of cyclosporine and the plant flavonoids in the cyclosporine eye drops is 0.5-1.2% (w / v).

[0023] In the present invention, the plant flavonoids include ginkgo flavonoids or baicalin.

[0024] In the present invention, the mass ratio of cyclosporine to plant flavonoids is preferably 4.5-5.5:2.5-3.5, and more preferably 5:3.

[0025] In the present invention, the total amount of cyclosporine and plant flavonoids added to the cyclosporine eye drops is preferably 0.6-1.0% (w / v), more preferably 0.7-0.9% (w / v), and even more preferably 0.8% (w / v).

[0026] In the present invention, the cyclosporine eye drops further contain pharmaceutically acceptable excipients.

[0027] In the present invention, the pharmaceutically acceptable excipients include surfactants, suspending agents, osmotic pressure regulators and pH regulators; the added amount of the surfactant is 0.8-1.2%, preferably 0.9-1.1%, and more preferably 1%; the added amount of the suspending agent is 0.8-1.2%, preferably 0.9-1.1%, and more preferably 1%; the added amount of the osmotic pressure regulator is 1.3-1.7%, preferably 0.4-1.6%, and more preferably 1.5%; the added amount of the pH regulator is 0.5-5%, preferably 1-4%, and more preferably 2-3%.

[0028] In the present invention, the surfactant is any one or more of sodium dodecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, sodium dodecylbenzene sulfonate, Span, and Tween; the suspending agent is any one or more of gum arabic, sodium alginate, methylcellulose, sodium carboxymethyl cellulose, and hydroxypropyl cellulose; the osmotic pressure regulator is any one or more of glucose, sodium chloride, and mannitol; and the pH regulator is any one or more of boric acid, citric acid, and sodium bicarbonate.

[0029] The present invention provides a method for preparing the cyclosporine eye drops, comprising the following steps:

[0030] (1) mixing cyclosporine with a portion of a surfactant and a vegetable oil to obtain a solution 1;

[0031] (2) mixing the plant flavonoid compound with the remaining portion of the surfactant and the dilute alkaline aqueous solution to obtain a second solution;

[0032] (3) Solution 1 and Solution 2 are mixed with a suspending agent and an osmotic pressure regulator, the pH is adjusted to 5.0 to 9.0 using a pH regulator, and water for injection is added to obtain cyclosporine eye drops.

[0033] In the present invention, the vegetable oil in step (1) is corn oil; the temperature during the mixing is 80-100°C, preferably 85-95°C, more preferably 90°C, the speed is 800-1200rpm, preferably 900-1100rpm, more preferably 1000rpm, and the time is 8-12min, preferably 9-11min, more preferably 10min.

[0034] In the present invention, the dilute alkali aqueous solution in step (2) is a dilute sodium hydroxide aqueous solution or a dilute sodium carbonate aqueous solution, the concentration of the dilute sodium hydroxide aqueous solution is 0.8-1.2%, preferably 0.9-1.1%, more preferably 1%, and the concentration of the dilute sodium carbonate aqueous solution is 4-6%, preferably 4.5-5.5%, more preferably 5%;

[0035] The mixing temperature is 40-80°C, preferably 50-70°C, more preferably 55-65°C, more preferably 60°C, the mixing speed is 150-250rpm, preferably 180-220rpm, more preferably 200rpm, and the mixing time is 25-35min, preferably 28-32min, more preferably 30min.

[0036] In the present invention, the mixing method in step (3) is high-pressure homogenous mixing, the pressure during mixing is 500-700 bar, preferably 550-650 bar, more preferably 600 bar, and the time is 5-15 min, preferably 8-12 min, more preferably 10 min.

[0037] In the present invention, the step (3) preferably uses a pH adjuster to adjust the pH to 6.0 to 8.0, and more preferably uses a pH adjuster to adjust the pH to 7.0.

[0038] The present invention also provides a use of the cyclosporine eye drops or the cyclosporine eye drops prepared according to the method in preparing a medicine for relieving or treating dry eye.

[0039] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0040] Example 1

[0041] A method for preparing cyclosporine eye drops, comprising the following steps:

[0042] (1) 5 g of cyclosporine, 5 g of sodium dodecyl sulfate and 20 mL of corn oil were mixed at 90° C. and 1000 rpm for 10 min to obtain solution 1;

[0043] (2) 3 g of ginkgo flavonoids, 5 g of sodium dodecyl sulfate and 50 mL of a 1% dilute sodium hydroxide aqueous solution were mixed at 60° C. and 200 rpm for 30 min to obtain Solution 2;

[0044] (3) Solution 1 and Solution 2 were mixed with 10 g of sodium carboxymethyl cellulose and 15 g of mannitol by high pressure homogenization at a pressure of 600 bar for 10 min, the pH was adjusted to 6.0 with boric acid, and water for injection was added to make the total volume 1 L to obtain cyclosporine eye drops.

[0045] Example 2

[0046] A method for preparing cyclosporine eye drops, comprising the following steps:

[0047] (1) 5 g of cyclosporine, 5 g of sodium dodecyl sulfate and 20 mL of corn oil were mixed at 90° C. and 1000 rpm for 10 min to obtain solution 1;

[0048] (2) 2.5 g of baicalin, 5 g of sodium dodecyl sulfate and 50 mL of a 5% aqueous sodium carbonate solution were mixed at 70° C. and 200 rpm for 30 min to obtain a solution 2;

[0049] (3) Solution 1 and Solution 2 were mixed with 10 g of sodium carboxymethyl cellulose and 15 g of mannitol by high pressure homogenization at a pressure of 600 bar for 10 min, the pH was adjusted to 6.0 with boric acid, and water for injection was added to make the total volume 1 L to obtain cyclosporine eye drops.

[0050] Comparative Example

[0051] A method for preparing cyclosporine eye drops, comprising the following steps:

[0052] (1) mixing 5 g of cyclosporine with 10 g of sodium dodecyl sulfate and 20 mL of corn oil at 90° C. and 1000 rpm for 10 min to obtain a cyclosporine solution;

[0053] (2) The cyclosporine solution was mixed with 10 g of sodium carboxymethyl cellulose and 15 g of mannitol by high pressure homogenization at a pressure of 600 bar for 10 min, the pH was adjusted to 6.0 with boric acid, and water for injection was added to make the total volume 1 L to obtain cyclosporine eye drops.

[0054] Test example

[0055] 1. Security testing

[0056] 9 healthy adult New Zealand white rabbits of similar weight were selected and divided into 3 groups. 0.1 mL of cyclosporine eye drops prepared in Examples 1 to 2 and the comparative example were dripped into the conjunctival sac of the left eye of the New Zealand white rabbits, and an equal amount of normal saline was dripped into the conjunctival sac of the right eye. After the dripping was completed, the rabbit eyes of the New Zealand white rabbits were closed for 10 seconds, and the state of the rabbit eyes was observed at 12h, 24h and 48h of dripping. The results showed that the left eyes of the New Zealand white rabbits in the Example 1 and Example 2 groups did not show redness and swelling, while the New Zealand white rabbits in the group of dripping the cyclosporine eye drops prepared in the comparative example showed redness around the left eyes. The results show that the cyclosporine eye drops prepared in Examples 1 and 2 are significantly less irritating than the cyclosporine eye drops prepared in the comparative example, and have good safety.

[0057] 2. Animal experiments

[0058] 50 New Zealand white rabbits were selected and randomly divided into 5 groups, 10 in each group. Except for the blank control group, the remaining groups (Example 1 group, Example 2 group, comparative example group, model group) were subcutaneously injected with 1mL of scopolamine at a concentration of 4mg / L, 4 times a day (8 o'clock, 12 o'clock, 16 o'clock, 20 o'clock), and injected for 14 days to obtain a rabbit dry eye model. The blank control group was injected with an equal volume of normal saline.

[0059] After the modeling was completed, 0.1 mL of 0.9% saline was dripped into the blank control group and the model group New Zealand white rabbits every day; 0.1 mL of cyclosporine eye drops prepared in Example 1, Example 2, and the comparative example were dripped into the New Zealand white rabbits in Example 1, Example 2, and the comparative example every day. After the dripping was completed in each group, the eyes of the New Zealand white rabbits were closed for 10 seconds, and the dripping was continued for a total of 14 days.

[0060] After the dripping was completed, the tear secretion of each group of New Zealand white rabbits was measured. The specific method was as follows: the New Zealand white rabbits were placed in a room with medium brightness and humidity, and the Schirmer test paper (5mm×40mm×0.2mm) was folded back at 5mm from the head end and placed at the junction of the middle and rear 1 / 3 of the lower eyelid. The rabbits were asked to close their eyes for 5 minutes, and then the paper strip was taken out. After drying at room temperature for 30 seconds, the length of the test paper soaked with tears (mm) was measured, and the average value of the test results was taken, as shown in Table 1.

[0061] Table 1 The results of the tear secretion experiment of New Zealand white rabbits in each group

[0062] Length of test paper soaked by tear / mm Blank control group 21.38 Example 1 Group 20.17 Example 2 Group 18.04 Comparative group 14.19 Model Group 9.76

[0063] As can be seen from Table 1, the length of the test paper of the tear-wetted part of the New Zealand white rabbits in the model group is significantly lower than that in the blank control group, indicating that the dry eye model of the New Zealand white rabbits was successfully established; compared with the comparative example group, the length of the test paper of the tear-wetted part of the New Zealand white rabbits in Examples 1 to 2 can be significantly increased, indicating that the cyclosporine eye drops prepared by combining cyclosporine with plant flavonoids in the present invention can significantly promote the secretion of tears in New Zealand white rabbits compared with the eye drops in the comparative example in which only cyclosporine is added, and have a better effect of improving and treating dry eye.

[0064] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A cyclosporine eye drop, characterized in that: The cyclosporine eye drops contain cyclosporine and plant flavonoids, the mass ratio of cyclosporine to plant flavonoids is 4-6:2-4, and the total added amount of cyclosporine and plant flavonoids in the cyclosporine eye drops is 0.5-1.2% (w / v).

2. The cyclosporine eye drops according to claim 1, characterized in that The plant flavonoids include ginkgo flavonoids or baicalin.

3. The cyclosporine eye drops according to claim 2, characterized in that The cyclosporine eye drops also contain pharmaceutically acceptable excipients.

4. The cyclosporine eye drops according to claim 3, characterized in that The pharmaceutically acceptable excipients include surfactants, suspending agents, osmotic pressure regulators and pH regulators; the added amount of the surfactant is 0.8-1.2%, the added amount of the suspending agent is 0.8-1.2%, the added amount of the osmotic pressure regulator is 1.3-1.7%, and the added amount of the pH regulator is 0.5-5%.

5. The cyclosporine eye drops according to claim 4, characterized in that The surfactant is any one or more of sodium dodecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, sodium dodecylbenzene sulfonate, Span, and Tween; the suspending agent is any one or more of gum arabic, sodium alginate, methylcellulose, sodium carboxymethyl cellulose, and hydroxypropyl cellulose; the osmotic pressure regulator is any one or more of glucose, sodium chloride, and mannitol; and the pH regulator is any one or more of boric acid, citric acid, and sodium bicarbonate.

6. A method for preparing the cyclosporine eye drops according to any one of claims 1 to 5, characterized in that: The steps include: (1) mixing cyclosporine with a portion of a surfactant and a vegetable oil to obtain a solution 1; (2) mixing the plant flavonoid compound with the remaining portion of the surfactant and the dilute alkaline aqueous solution to obtain a second solution; (3) Solution 1 and Solution 2 are mixed with a suspending agent and an osmotic pressure regulator, the pH is adjusted to 5.0 to 9.0 using a pH regulator, and water for injection is added to obtain cyclosporine eye drops.

7. The method according to claim 6, characterized in that The vegetable oil in step (1) is corn oil; the temperature during the mixing is 80-100° C., the speed is 800-1200 rpm, and the time is 8-12 min.

8. The method according to claim 7, characterized in that The dilute alkali aqueous solution in step (2) is a dilute sodium hydroxide aqueous solution or a dilute sodium carbonate aqueous solution, the concentration of the dilute sodium hydroxide aqueous solution is 0.8-1.2%, and the concentration of the dilute sodium carbonate aqueous solution is 4-6%; The temperature during the mixing is 40-80° C., the speed is 150-250 rpm, and the time is 25-35 min.

9. The method according to claim 8, characterized in that The mixing method in step (3) is high-pressure homogenous mixing, the pressure during mixing is 500-700 bar, and the time is 5-15 minutes.

10. Use of the cyclosporine eye drops according to any one of claims 1 to 5 or the cyclosporine eye drops prepared according to the method according to any one of claims 6 to 9 in the preparation of a medicament for relieving or treating dry eye.