W / O / W ophthalmic composite emulsion composition and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a W / O / W ophthalmic composite emulsion composition and a preparation method thereof. The raw material components comprise atropine sulfate, cyclosporin, sodium hyaluronate, castor oil, Tween 80, hydroxypropyl methylcellulose, sodium chloride, sodium oxide, hydrogen chloride and distilled water. The atropine sulfate is encapsulated in the W / O / W type composite emulsion droplet, the pH value of an internal water layer of the composite emulsion droplet is adjusted to 3.8-4.5 so as to improve the stability of the atropine sulfate, and the pH value of an external water layer of the composite emulsion droplet is adjusted to 6.5-7.5 so as to improve the comfort of eye medication. The prepared composite emulsion has the advantages of being fast in absorption, high in bioavailability, capable of improving drug stability and the like.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and more specifically relates to a W / O / W ophthalmic composite emulsion composition and a preparation method thereof. Background Art

[0002] Myopia is a type of refractive error, which refers to a type of eye disease in which vision is reduced, distant objects are blurred, and near objects are clear. Wearing glasses for correction can improve distant vision. Years of research by experts and scholars have confirmed that atropine-type drugs are currently the most effective drugs for preventing myopia in adolescents and children. Through the use of atropine-type drugs for treatment, the originally tense ciliary muscles of adolescents and children can be quickly restored, and their regulatory function can be further restored during sleep.

[0003] Atropine is a non-specific muscarinic acetylcholine receptor antagonist that can block the M receptors on the ciliary muscle, produce accommodative paralysis and relax the ciliary muscle, relieve accommodative tension, and inhibit the development of myopia. In addition, literature shows that atropine can affect scleral remodeling and inhibit axial elongation through the M receptor pathway on the sclera and the M receptor regulation on the retina. So far, atropine is the only drug that has been proven by a large number of studies to be able to continuously control the progression of myopia for a long time. However, atropine is a non-specific acetylcholine receptor antagonist, so it can also act on other parts such as the pupillary sphincter, which can cause adverse side effects such as photophobia, high intraocular pressure, and headaches.

[0004] Patent CN11366.2915A discloses an ophthalmic pharmaceutical composition, which contains 0.01-1wt% atropine sulfate, and its pH value is limited to the range of 3.5-4.0, which can inhibit the generation of related substances. However, eye drops with a pH value of 3.5-4.0 have a greater irritation to the eyes, and the most comfortable pH range for the eyes is 6.5-7.5. Therefore, the most common adverse reactions of atropine sulfate eye drops in clinical trials are eye pain, photophobia and dry eyes.

[0005] Many people with myopia suffer from dry eyes due to improper use of eyes and eye fatigue. The main symptoms of dry eyes include insufficient tear secretion from the aqueous layer of the lacrimal gland, secretion of the oil layer, secretion of the mucin layer, excessive tear evaporation, uneven distribution of the tear film, and inflammation. Cyclosporine emulsion eye drops are effective drugs for the treatment of dry eyes. They can effectively treat various types of dry eyes by suppressing the immune system, reducing inflammatory responses, increasing goblet cell density and mucin secretion levels, and increasing tear flow.

[0006] At present, there are no patents or literature reports on the development of therapeutic drugs for myopia accompanied by dry eyes. Because the solubility of the two is different, atropine sulfate is a hydrophilic drug and cyclosporine is an oil-soluble drug. When preparing an o / w emulsion, cyclosporine is dispersed in the oil phase and atropine sulfate is dispersed in the aqueous phase. However, in order to ensure the stability of atropine sulfate, the pH value range of the aqueous phase should be controlled at 3.5-4.0, which is more irritating to the eyes. Therefore, the present invention provides a W / O / W ophthalmic composite emulsion composition comprising atropine sulfate and cyclosporine, by first preparing a w / o type emulsion to encapsulate atropine sulfate and cyclosporine, and then mixing with a suitable aqueous phase to prepare a W / O / W type composite emulsion, and finally achieving the pH value range of the emulsion to be controlled at 6.5-7.5 while improving the stability of atropine sulfate to meet the needs of myopia treatment accompanied by dry eyes. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a W / O / W ophthalmic composite emulsion composition and a preparation method thereof, which has the advantages of rapid absorption, high bioavailability, improved drug stability, etc., and is suitable for drug treatment of myopic people with dry eye.

[0008] The invention discloses a W / O / W ophthalmic composite emulsion composition, whose raw material components include atropine sulfate, cyclosporine, sodium hyaluronate, and pharmaceutically acceptable excipients such as an oil phase matrix, a surfactant, a thickener, a pH regulator, and an osmotic pressure regulator.

[0009] The pharmaceutically acceptable excipients include castor oil as the oil phase matrix, Tween 80 as the surfactant, hydroxypropyl methylcellulose as the thickener, sodium chloride as the osmotic pressure regulator, and sodium oxychloride and hydrogen chloride as the pH regulator.

[0010] Furthermore, the raw material components include 0.01% of atropine sulfate,

[0011] 0.05% cyclosporine, 0.2%-0.4% sodium hyaluronate, 0.1%-0.2% hypromellose, 0.25-0.3% castor oil, 0.6%-1% Tween 80.

[0012] The present invention also provides a method for preparing the W / O / W ophthalmic compound emulsion composition, wherein the pH value of the inner water layer of the compound emulsion droplet is adjusted to 3.8-4.5, and the pH value of the outer water layer is adjusted to 6.5-7.5.

[0013] Furthermore, the preparation method comprises the following steps:

[0014] (1) mixing cyclosporine, castor oil and Tween 80 to prepare an oil phase;

[0015] (2) After fully swelling the hydroxypropyl methylcellulose with water, add atropine sulfate, stir to dissolve, and adjust the pH value to 3.8-4.5 with a pH adjuster to prepare an atropine sulfate aqueous solution;

[0016] (3) adding water to sodium hyaluronate to fully swell it, thereby obtaining a sodium hyaluronate aqueous solution;

[0017] (4) dissolving sodium chloride in water to obtain an osmotic pressure regulating solution;

[0018] (5) mixing (1) the oil phase and (2) the aqueous solution of atropine sulfate and homogenizing and emulsifying them to prepare colostrum;

[0019] (6) mixing (5) colostrum and (3) sodium hyaluronate aqueous solution and emulsifying them homogeneously to obtain a W / O / W drug composite emulsion;

[0020] (7) measuring the osmotic pressure of the solution obtained in (6), adding the osmotic pressure adjusting solution (4) to adjust the osmotic pressure value to 290-310 mosm / kg;

[0021] (8) Determine the pH value of the solution obtained in (7) and adjust the pH value to 6.5-7.5 using a pH adjuster.

[0022] The present invention has the following advantages:

[0023] The invention encapsulates atropine sulfate in W / O / W type composite emulsion droplets, adjusts the pH value of the water layer inside the composite emulsion droplets to 3.8-4.5 to improve the stability of atropine sulfate, and adjusts the pH value of the external water layer to 6.5-7.5 to improve the comfort of eye medication. The prepared composite emulsion has the advantages of fast absorption, high bioavailability, improved drug stability, etc. DETAILED DESCRIPTION

[0024] The technical scheme of the present invention will be described clearly and completely below in conjunction with specific embodiments. If no specific conditions are specified in the examples, the conditions are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0025] Example 1: Ophthalmic drug composite emulsion composition

[0026] Components

[0027] Atropine sulfate 0.1g

[0028] Cyclosporine 0.5 g

[0029] Sodium hyaluronate 2g

[0030] Hydroxypropyl methylcellulose 2g

[0031] Castor oil 2.5g

[0032] Tween 80 10g

[0033] Sodium chloride

[0034] Sodium hydroxide appropriate amount

[0035] Hydrogen chloride appropriate amount

[0036] Add water for injection to 1000ml

[0037] Mix cyclosporine, castor oil and Tween 80 to prepare the oil phase; After fully swelling hydroxypropyl methylcellulose with water, add atropine sulfate, stir and dissolve, adjust the pH value to 4.0 with sodium hyaluronate or hydrogen chloride to prepare an atropine sulfate aqueous solution; After fully swelling sodium hyaluronate with water, obtain a sodium hyaluronate aqueous solution; Mix the cyclosporine oil phase solution with the atropine sulfate aqueous solution and homogenize and emulsify to prepare colostrum; then mix the colostrum with the sodium hyaluronate aqueous solution and homogenize and emulsify to obtain a W / O / W drug composite emulsion. Then add sodium chloride solution to adjust the osmotic pressure to 290-310mosm / Kg; according to the specific situation, use sodium hyaluronate solution / hydrochloric acid solution to adjust the solution pH to 7.0.

[0038] Example 2: Ophthalmic drug composite emulsion composition

[0039] Components

[0040] Atropine sulfate 0.1g

[0041] Cyclosporine 0.5 g

[0042] Sodium hyaluronate 3g

[0043] Hydroxypropyl methylcellulose 1g

[0044] Castor oil 2.5g

[0045] Tween 80 8g

[0046] Sodium chloride

[0047] Sodium hydroxide appropriate amount

[0048] Hydrogen chloride appropriate amount

[0049] Add water for injection to 1000ml

[0050] Mix cyclosporine, castor oil and Tween 80 to prepare the oil phase; After fully swelling hydroxypropyl methylcellulose with water, add atropine sulfate, stir and dissolve, adjust the pH value to 4.5 with sodium hyaluronate or hydrogen chloride to prepare an atropine sulfate aqueous solution; After fully swelling sodium hyaluronate with water, obtain a sodium hyaluronate aqueous solution; Mix the cyclosporine oil phase solution with the atropine sulfate aqueous solution and homogenize and emulsify to prepare colostrum; Then mix the colostrum with the sodium hyaluronate aqueous solution and homogenize and emulsify to obtain a W / O / W drug composite emulsion. Then add sodium chloride solution to adjust the osmotic pressure to 290-310mosm / Kg; Use sodium hyaluronate solution / hydrochloric acid solution to adjust the pH value of the solution to 7.0 according to the specific situation.

[0051] Example 3: Ophthalmic drug composite emulsion composition

[0052] Components

[0053] Atropine sulfate 0.1g

[0054] Cyclosporine 0.5 g

[0055] Sodium hyaluronate 4g

[0056] Hydroxypropyl methylcellulose 1.5g

[0057] Castor oil 3g

[0058] Tween 80 6g

[0059] Sodium chloride

[0060] Sodium hydroxide appropriate amount

[0061] Hydrogen chloride appropriate amount

[0062] Add water for injection to 1000ml

[0063] Mix cyclosporine, castor oil and Tween 80 to prepare the oil phase; After fully swelling hydroxypropyl methylcellulose with water, add atropine sulfate, stir and dissolve, adjust the pH value to 3.8 with sodium hyaluronate or hydrogen chloride to prepare an atropine sulfate aqueous solution; After fully swelling sodium hyaluronate with water, obtain a sodium hyaluronate aqueous solution; Mix the cyclosporine oil phase solution with the atropine sulfate aqueous solution and homogenize and emulsify to prepare colostrum; then mix the colostrum with the sodium hyaluronate aqueous solution and homogenize and emulsify to obtain a W / O / W drug composite emulsion. Then add sodium chloride solution to adjust the osmotic pressure to 290-310mosm / Kg; according to the specific situation, use sodium hyaluronate solution / hydrochloric acid solution to adjust the solution pH to 7.0.

[0064] Comparative Example 4: 0.01% atropine sulfate eye drops

[0065] Components

[0066] Atropine sulfate 0.1g

[0067] Hydroxypropyl methylcellulose 2g

[0068] Sodium chloride

[0069] Sodium hydroxide appropriate amount

[0070] Hydrogen chloride appropriate amount

[0071] Add water for injection to 1000ml

[0072] Preparation method: After fully swelling the hydroxypropyl methylcellulose with water, add atropine sulfate, stir to dissolve, and then add sodium chloride solution to adjust the osmotic pressure to 290-310mosm / Kg; according to the specific situation, use sodium oxychloride solution / hydrochloric acid solution to adjust the solution pH to 7.0.

[0073] Comparative Example 5: 0.01% atropine sulfate eye drops

[0074] Components

[0075] Atropine sulfate 0.1g

[0076] Cyclosporine 0.5 g

[0077] Sodium hyaluronate 2g

[0078] Hydroxypropyl methylcellulose 2g

[0079] Castor oil 2.5g

[0080] Tween 80 10g

[0081] Sodium chloride

[0082] Sodium hydroxide appropriate amount

[0083] Hydrogen chloride appropriate amount

[0084] Add water for injection to 1000ml

[0085] Preparation method: cyclosporine, castor oil and Tween 80 are mixed to prepare the oil phase; after the hydroxypropyl methylcellulose is fully swollen with water, atropine sulfate is added, stirred and dissolved, sodium hyaluronate or hydrogen chloride is used to adjust the pH value to 5.5 to prepare an atropine sulfate aqueous solution; sodium hyaluronate is fully swollen with water to obtain a sodium hyaluronate aqueous solution; the cyclosporine oil phase solution and the atropine sulfate aqueous solution are mixed and homogenized to prepare colostrum; the colostrum is then mixed and homogenized with the sodium hyaluronate aqueous solution to obtain a W / O / W drug composite emulsion. Sodium chloride solution is then added to adjust the osmotic pressure to 290-310mosm / Kg; sodium hyaluronate solution / hydrochloric acid solution is used to adjust the pH value of the solution to 7.0 according to the specific situation.

[0086] Test Example 5: Study on the stability of emulsion

[0087] Through the test tube static method and centrifugal stability test; static method: observe the stratification of different emulsions after 30 days; centrifugal method: through 4000r / min, 10min centrifugal test, observe the stratification of emulsions after centrifugation, as shown in Table 1.

[0088] Table 1: Results of emulsion stability study

[0089]

[0090] Test Example 6: Investigation of Tropicic Acid Impurities

[0091] The samples of implementation 1, implementation 2, implementation 3, comparative example 4 and comparative example 5 were subjected to accelerated test. Test conditions: temperature: 40°C ± 2°C, relative humidity: 75% ± 5%. After 6 months of storage, samples were taken at the 0th, 1st, 2nd, 3rd and 6th month of the test, and the HPLC method was used to detect the tropic acid impurity in the samples.

[0092] Table 2: Tropicic acid impurity investigation results

[0093]

[0094] As can be seen from Table 2, after 6 months of accelerated testing, the tropic acid impurity content of Comparative Examples 4 and 5 is greater than that of Example 1, Example 2, and Example 3, indicating that the pH value affects the stability of atropine sulfate.

[0095] Although the specific implementation modes of the present invention are described above, those skilled in the art should understand that the specific implementation modes described are only illustrative and are not intended to limit the scope of the present invention. Equivalent modifications and changes made by those skilled in the art in accordance with the spirit of the present invention should be included in the scope of protection of the claims of the present invention.

Claims

1. A W / O / W ophthalmic composite emulsion composition, characterized in that: The raw material components include atropine sulfate, cyclosporine, sodium hyaluronate, castor oil, Tween 80, hydroxypropyl methylcellulose, sodium chloride, sodium hydroxide, hydrogen chloride and distilled water.

2. The W / O / W ophthalmic composite emulsion composition according to claim 1, characterized in that: The raw material components include 0.01% atropine sulfate, 0.05% cyclosporine, 0.2%-0.4% sodium hyaluronate, 0.1%-0.2% hydroxypropyl methylcellulose, 0.25-0.3% castor oil, and 0.6%-1% Tween 80, accounting for 0.01% of the total weight of the composition.

3. The method for preparing the W / O / W ophthalmic composite emulsion composition according to claim 1 or 2, characterized in that: The pH value of the inner water layer of the composite emulsion droplets is adjusted to 3.8-4.5, and the pH value of the outer water layer is adjusted to 6.5-7.

5.

4. The preparation method according to claim 3, characterized in that: The preparation method comprises the following steps: (1) mixing cyclosporine, castor oil and Tween 80 to prepare an oil phase; (2) After fully swelling the hydroxypropyl methylcellulose with water, add atropine sulfate, stir to dissolve, and adjust the pH value to 3.8-4.5 with a pH adjuster to prepare an atropine sulfate aqueous solution; (3) Adding water to sodium hyaluronate to fully swell it, thereby obtaining a sodium hyaluronate aqueous solution; (4) Dissolve sodium chloride in water to obtain an osmotic pressure regulating solution; (5) mixing (1) the oil phase and (2) the aqueous solution of atropine sulfate and homogenizing and emulsifying them to prepare colostrum; (6) mixing (5) colostrum and (3) sodium hyaluronate aqueous solution and emulsifying them homogeneously to obtain a W / O / W drug composite emulsion; (7) Determine the osmotic pressure of the solution obtained in (6), add the osmotic pressure adjusting solution (4), and adjust the osmotic pressure value to 290-310 mosm / kg; (8) Determine the pH value of the solution obtained in (7) and adjust the pH value to 6.5-7.5 using a pH adjuster.

Images