Stable cyclosporine ophthalmic ultra-micro emulsion and preparation method thereof

Abstract

The invention discloses a stable cyclosporine ophthalmic ultra-micro emulsion, which comprises 0.1% of cyclosporine, 1%-2% of medium chain triglyceride, 0.4%-0.8% of an emulsifier, 2%-3% of glycerol, 0.0005%-0.005% of sitaammonium chloride and sodium hydroxide with a required amount for adjusting the pH value of the emulsion to 6.1-7.9, and the emulsifier is a combination of teloxaben and poloxamer in a weight ratio of 3: 1. The cyclosporin ophthalmic ultra-micro emulsion provided by the invention is smaller in droplet particle size and higher in Zeta potential, is basically not changed after being placed for a long time, and has better stability and better expected drug effect.

Description

Technical Field

[0001] The invention belongs to the field of medicine and relates to a stable cyclosporine ophthalmic ultramicroemulsion and a preparation method thereof. Background Art

[0002] Cyclosporine is a cyclic peptide with immunosuppressive activity, primarily used to treat autoimmune diseases and organ transplant rejection. Cyclosporine, when applied to the eye, can inhibit the activity of T lymphocytes in the lacrimal gland, thereby enhancing or restoring lacrimal gland function.

[0003] CN101056615A discloses a cyclosporine ophthalmic emulsion that utilizes a nonionic surfactant, an amine cationic agent, and other ingredients in its formulation to produce a stable emulsion with minimal change in zeta potential over 14 days. Generally speaking, a minimal change in zeta potential after long-term storage indicates a more stable emulsion, while a higher zeta potential indicates a more stable system. However, a closer look revealed significant variability in the zeta potential of the cyclosporine emulsions with different formulations in this patent, indicating significant differences in stability. Furthermore, the droplet size of the different formulations also varied significantly.

[0004] Cyclosporine is highly lipid-soluble and practically insoluble in water. Therefore, a smaller droplet size is crucial for its optimal efficacy. Therefore, the development of ultramicroemulsions with improved stability is needed. Summary of the Invention

[0005] The object of the present invention is to provide a cyclosporine ultramicroemulsion with better stability. In order to achieve the object of the present invention, the technical solution adopted is:

[0006] An ophthalmic emulsion comprises 0.1% cyclosporine, 1%-2% medium-chain triglycerides, 0.4%-0.8% emulsifier, 2%-3% glycerol, 0.0005%-0.005% cetaxel chloride, and an amount of sodium hydroxide required to adjust the pH value of the emulsion to 6.1-7.9, wherein the emulsifier is a combination of tyloxapol and poloxamer in a weight ratio of 3:1.

[0007] The inventors discovered that prior art cyclosporine ophthalmic emulsions struggled to maintain both optimal zeta potential and droplet size. Through in-depth research, they unexpectedly discovered that, contrary to prior art understanding, using an extremely low dosage of the specific cationic agent cetaxel and adjusting the emulsion pH to 6.1-7.9 not only made the emulsion more stable (higher zeta potential) but also resulted in smaller droplet size, forming a more stable ultramicroemulsion.

[0008] Preferably, the average droplet size in the ophthalmic emulsion is less than 10 nm.

[0009] Preferably, the Zeta potential of the eye emulsion is greater than 300 mV.

[0010] Preferably, the remaining components in the eye emulsion are all water.

[0011] Preferably, the eye emulsion of the present application is composed of 0.1% cyclosporine, 1-2% medium chain triglyceride, 0.4-0.8% emulsifier, 2-3% glycerol, 0.0005-0.005% cetalkonium chloride, sodium hydroxide in an amount required to adjust the pH of the emulsion to 6.1-7.9, and the balance of water, and the emulsifier is a combination of tyloxapol and poloxamer in a weight ratio of 3:1.

[0012] Preferably, the amount of medium chain triglyceride is selected from 1%, 1.25%, 1.5%, or 2%.

[0013] Preferably, the amount of tyloxapol is selected from 0.3%, 0.45%, or 0.6%.

[0014] Preferably, the amount of poloxamer is selected from 0.1%, 0.15%, or 0.2%.

[0015] Preferably, the amount of cetalkonium chloride is selected from 0.0005%, 0.001%, 0.002%, or 0.005%.

[0016] Preferably, the amount of glycerol is selected from 2%, 2.25%, 2.5%, 2.75%, or 3%.

[0017] Preferably, the eye emulsion of the present application does not contain vitamin E.

[0018] The present application also provides a preparation method of the above-mentioned eye emulsion.

[0019] A preparation method of an eye emulsion, comprising the following steps:

[0020] 1) Dissolve cyclosporine in medium chain triglyceride, add emulsifier and cetalkonium chloride, mix uniformly to obtain an oil phase;

[0021] 2) Add water to the oil phase obtained in step 1), mix uniformly to obtain an emulsion;

[0022] 3) Add glycerol to the emulsion obtained in step 2), mix uniformly, add sodium hydroxide to adjust the pH to 6.1-7.9, dilute with water, filter with a 0.22 μm filter membrane, fill, and obtain the eye emulsion.

[0023] In the above preparation method, the amounts of the materials are the same as those of the aforementioned eye emulsion of the present application.

[0024] Note: The percentages in the present application are all weight percentages.

[0025] The cyclosporine ophthalmic nanoemulsion provided by the present invention not only has a smaller droplet size than the prior art, but also has a higher zeta potential. A higher zeta potential indicates better stability, and a smaller particle size helps the active ingredient exert better efficacy. Therefore, the ophthalmic nanoemulsion of the present invention has better stability and is expected to have better efficacy. DETAILED DESCRIPTION

[0026] The present invention is described in detail below with reference to examples, but the examples are not intended to limit the present invention in any way.

[0027] Example 1:

[0028] 0.1 g of cyclosporine was dissolved in 2 g of medium-chain triglycerides, and 0.3 g of tyloxapol, 0.1 g of poloxamer, and 0.005 g of cetaxel were added and mixed uniformly to obtain an oil phase; water was added to the oil phase and mixed uniformly to obtain an emulsion; 2.25 g of glycerol was added to the emulsion and mixed uniformly, and sodium hydroxide was added to adjust the pH value of the system to 6.1-7.9. Finally, water was added to make the volume to 100 mL, filtered through a 0.22 μm filter membrane, and filled to obtain an ophthalmic emulsion.

[0029] Example 2-8:

[0030] The ophthalmic emulsion was prepared by the same preparation method as in Example 1, and the prescription dosage is shown in Table 1. All examples were operated under the same environmental conditions, and the operating parameters and operation time of each step were basically the same.

[0031] Table 1 Prescription dosage of each embodiment

[0032]

[0033] Test Example 1:

[0034] The ophthalmic emulsions prepared according to Examples 1-8 were placed at 40° C. and 25% humidity for 6 months. The droplet size and zeta potential of each ophthalmic emulsion were measured at 0, 1, 3, and 6 months.

[0035] Droplet size and zeta potential were determined using conventional methods in the field. Zeta potential was determined using a zeta potential analyzer. The dispersion medium was water with a viscosity of 0.8872 cp and a refractive index of 1.33. 80 μL of the emulsion to be tested was precisely added to 19.92 mL of ultrapure water and mixed thoroughly before measurement. Particle size was determined using a dynamic light scattering particle size analyzer. The dispersion medium was water with a viscosity of 0.8872 cp and a refractive index of 1.33. 10 μL of the emulsion to be tested was precisely added to a cuvette and mixed thoroughly with 1 mL of ultrapure water before measurement.

[0036] Table 2-5 lists the test results.

[0037] Table 2 Droplet size and zeta potential of each ophthalmic emulsion at 0 month

[0038]

[0039]

[0040] Table 3 Droplet size and zeta potential of each ophthalmic emulsion at 1 month

[0041] Droplet size (nm) Zeta potential (mV) Example 1 8.3 361 Example 2 26.2 312 Example 3 29.8 129 Example 4 9.1 338 Example 5 8.8 310 Example 6 8.6 337 Example 7 9.1 324 Example 8 42.3 285

[0042] Table 4 Droplet size and zeta potential of each ophthalmic emulsion at 3 months

[0043] Droplet size (nm) Zeta potential (mV) Example 1 8.0 352 Example 2 34.4 307 Example 3 35.7 110 Example 4 9.4 326 Example 5 8.6 323 Example 6 9.2 331 Example 7 8.9 318 Example 8 54.8 246

[0044] Table 5 Droplet size and zeta potential of each ophthalmic emulsion at 6 months

[0045] Droplet size (nm) Zeta potential (mV) Example 1 8.9 346 Example 2 51.5 264 Example 3 63.9 74 Example 4 9.1 314 Example 5 9.4 329 Example 6 8.8 320 Example 7 9.6 307 Example 8 76.7 183

[0046] The above results show that at 0 months, the droplet size of the ophthalmic emulsions of Examples 1, 4, 5, 6, and 7 was smaller, reaching ultrafine droplets below 10 nm, significantly superior to the ophthalmic emulsions of Examples 2, 3, and 8. The ophthalmic emulsions of Examples 1, 2, 4, 5, 6, 7, and 8 had a very high zeta potential, reaching over 300 mV, significantly superior to the ophthalmic emulsion of Example 3. The results suggest that in the formulation system selected by the present invention, the amount of cetylpyridinium chloride has a significant impact on droplet size. Formulations with more than 0.01% cetylpyridinium chloride cannot form ultrafine emulsions, while extremely low amounts of cetylpyridinium chloride help the system form droplets with smaller particle sizes. In the formulation system selected by the present invention, pH has a significant impact on zeta potential. A pH below 6.0 is not conducive to maintaining a high zeta potential, while a higher pH value helps the system form a higher zeta potential.

[0047] Comparing the results from October and June revealed that the ophthalmic emulsions of Examples 1, 4, 5, 6, and 7 exhibited excellent stability, essentially maintaining a small droplet size and high zeta potential after six months. However, the ophthalmic emulsions of Examples 2, 3, and 8 exhibited significant changes in both droplet size and zeta potential after six months, indicating poor stability. The specific formulation of the present invention can produce a cyclosporine ophthalmic nanoemulsion with excellent stability, a lower droplet size, and a higher zeta potential.

Claims

1. An ophthalmic emulsion comprising, by weight, 0.1% cyclosporine, 1%-2% medium-chain triglycerides, 0.4%-0.8% emulsifier, 2%-3% glycerol, 0.0005%-0.005% cetaxel chloride, and an amount of sodium hydroxide required to adjust the pH of the emulsion to 6.1-7.9, wherein the emulsifier is a combination of tyloxapol and poloxamer in a weight ratio of 3:

1.

2. The ophthalmic emulsion according to claim 1, wherein the remaining component of the emulsion is entirely water.

3. The ophthalmic emulsion according to claim 1, wherein the amount of the medium chain triglyceride is selected from 1%, 1.25%, 1.5% or 2%.

4. The ophthalmic emulsion according to claim 1, wherein the amount of tyloxapol is selected from 0.3%, 0.45% or 0.6%. The ophthalmic emulsion according to claim 1 , wherein the amount of the poloxamer is selected from 0.1%, 0.15% or 0.2%.

6. The ophthalmic emulsion according to claim 1, wherein the amount of cetabularium chloride is selected from 0.0005%, 0.001%, 0.002% or 0.005%.

7. The ophthalmic emulsion according to claim 1, wherein the amount of glycerol is selected from 2%, 2.25%, 2.5%, 2.75% or 3%.

8. A method for preparing the ophthalmic emulsion according to any one of claims 1 to 7, comprising the following steps: 1) dissolving cyclosporine in medium-chain triglycerides, adding an emulsifier and cephalosporin, and mixing uniformly to obtain an oil phase; 2) adding water to the oil phase obtained in step 1) and mixing uniformly to obtain an emulsion; 3) adding glycerol to the emulsion obtained in step 2) and mixing uniformly, and adding sodium hydroxide to adjust the pH to 6.1-7.9, making up to volume with water, filtering through a 0.22 μm filter membrane, and filling to obtain an ophthalmic emulsion.

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