Tacrolimus ophthalmic microemulsion preparation, tacrolimus ophthalmic in-situ gel preparation as well as preparation method and application of tacrolimus ophthalmic microemulsion preparation and tacrolimus ophthalmic in-situ gel preparation

Abstract

The invention discloses an ophthalmic micro-emulsion preparation of tacrolimus, an ophthalmic in-situ gel preparation of tacrolimus as well as a preparation method and application of the ophthalmic micro-emulsion preparation and the ophthalmic in-situ gel preparation of tacrolimus. The tacrolimus eye micro-emulsion preparation comprises tacrolimus, a solubilizer and water, and the solubilizer comprises stearic acid polyethylene glycol ester and caprylic / capric acid polyethylene glycol glyceride. The tacrolimus ophthalmic in-situ gel preparation is prepared from tacrolimus, a solubilizer, a gel matrix and water. The tacrolimus ophthalmic microemulsion preparation and the tacrolimus ophthalmic in-situ gel preparation both can improve the drug loading capacity of tacrolimus, so that the effective drug amount acting on an affected part is improved; according to the tacrolimus eye microemulsion preparation, the solubility of tacrolimus can be remarkably improved, and eye medicine absorption can be promoted; according to the tacrolimus ophthalmic in-situ gel preparation, the retention time of eyes can be prolonged, and the bioavailability can be effectively improved.

Description

Technical Field

[0001] The invention relates to a tacrolimus ophthalmic microemulsion preparation, a tacrolimus ophthalmic instant gel preparation, and a preparation method and application thereof. Background Art

[0002] Dry eye syndrome, also known as dry eye, is the second most common eye disease in clinical practice after myopia. The incidence of dry eye is about 25%. It is estimated that there are nearly 300 million patients in China, of which moderate to severe dry eye accounts for about 30%. In addition, the age of the patients is getting younger, which has become an important issue affecting eye health.

[0003] Dry eye is a common multifactorial ocular surface disease characterized by tear film disturbances due to tear deficiency and / or excessive evaporation. Dry eye can cause patients to experience dry eyes, visual fatigue, eye irritation, foreign body sensation, decreased visual quality, and other adverse sensations. In severe cases, it can cause acute lacrimal gland inflammation and Sjögren's syndrome. In addition, dry eye can cause patients to suffer from psychological disorders, and in severe cases, patients can suffer from anxiety and depression.

[0004] In addition, moderate dry eye syndrome is often accompanied by inflammation, and clinically requires the use of nonsteroidal anti-inflammatory drugs or glucocorticoids, as well as tear secretion promoting drugs and mucin secretion stimulating drugs; severe dry eye syndrome often presents with severe inflammatory reactions, with obvious redness and swelling of the eyes, and requires the use of immunosuppressants such as cyclosporine and tacrolimus, with a focus on anti-inflammatory treatment. Immunosuppressants such as cyclosporine and tacrolimus can inhibit immune-related inflammation of dry eye syndrome, allow the antibacterial part of the immune system to fight infection, promote tear secretion and directly increase mucin secretion, and are safer, more effective and suitable for long-term use compared to anti-inflammatory products such as nonsteroidal anti-inflammatory drugs and glucocorticoids.

[0005] Tacrolimus (FK506) is a new type of macrolide immunosuppressant, which is composed of a semi-keto group, α, β-diketo groups and 23 rings. Its molecular formula is C 44 H 69 NO 12 ·H2O, molecular weight is 822.03. It is white crystal or crystalline powder at room temperature, relatively stable in solid state, unstable under alkaline and high temperature conditions. Insoluble in water, soluble in polar solvents such as methanol, acetone, chloroform, ethanol, ethyl acetate, etc.

[0006] Immunosuppressants are the first-line treatment option for moderate to severe dry eye. (Cyclosporin ophthalmic emulsion) was approved for marketing by the US FDA in 2002. It is the world's first drug for the treatment of moderate to severe tear deficiency dry eye syndrome. As a blockbuster drug for the treatment of dry eye syndrome, it has been the top seller for many years. Tacrolimus is a potent immunosuppressant suitable for the treatment of severe immune-related dry eye (acute phase) and more severe inflammatory reactions. The anti-inflammatory efficacy of tacrolimus eye drops is significantly higher than that of cyclosporine, and it takes effect more quickly, so it can be used as a shock treatment for critically ill patients.

[0007] The marketed products of tacrolimus for ophthalmic use are ( Japan Senju Pharmaceutical Co., Ltd., specification is 0.1% (5mL: 5mg, calculated as tacrolimus), it is a suspension eye drop, the main indications are vernal keratoconjunctivitis and corneal transplant rejection. The drug of this product is dispersed in the solvent in the form of fine particles, which is a thermodynamically unstable system. The particles are prone to sedimentation for a long time, which may lead to inaccurate dosage.

[0008] Due to the limited area of ​​the anterior surface of the cornea, the volume of eye drops that can be used on the ocular surface is about 30μL. Tear dilution and blinking remove most of the added volume. When eye drops are given, the tear film renewal rate and tear secretion increase. After eye drops, only less than 5% of the drug molecules can enter the eye. By increasing the drug loading and increasing the retention time in the eye, the effective amount of drug acting on the affected area is increased, and the bioavailability is improved to achieve better results. It has important clinical significance and huge social benefits for the treatment of moderate to severe dry eye. Summary of the invention

[0009] The technical problem to be solved by the present invention is to overcome the defects of the prior art such as low drug loading of tacrolimus in aqueous solution and low effective drug dosage acting on the affected part, and to provide a tacrolimus ophthalmic microemulsion preparation, a tacrolimus ophthalmic instant gel preparation and a preparation method and application thereof.

[0010] The present invention can prepare a tacrolimus ophthalmic microemulsion preparation through a simple and low-energy preparation method, and can prepare a tacrolimus ophthalmic instant gel preparation by adding a gel matrix. The tacrolimus ophthalmic microemulsion preparation and the tacrolimus ophthalmic instant gel preparation of the present invention can both increase the drug loading of tacrolimus, thereby increasing the effective amount of the drug acting on the affected part; the tacrolimus ophthalmic microemulsion preparation can also significantly increase the solubility of tacrolimus and promote ocular drug absorption; the tacrolimus ophthalmic instant gel preparation can also prolong the ocular retention time and improve the bioavailability; further, both of them can be free of preservatives, will not damage the ocular surface goblet cells, are safer to use, and have high practical value.

[0011] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0012] The present invention provides a tacrolimus ophthalmic microemulsion preparation, which comprises tacrolimus, a solubilizer and water;

[0013] Wherein, the solubilizer comprises polyethylene glycol stearate and caprylic acid capric acid macrogol glyceride.

[0014] In the present invention, the content of tacrolimus may be 0.01%-0.5%, preferably 0.02%-0.2%, more preferably 0.03%-0.1%, for example 0.01%, 0.03%, 0.05%, 0.1%, 0.15%, 0.2% or 0.5%, where the percentage is the mass percentage of tacrolimus in the tacrolimus ophthalmic microemulsion preparation.

[0015] In the present invention, the content of the solubilizer may be 0.1% to 20%, preferably 0.2% to 16%, where the percentage is the mass percentage of the solubilizer in the tacrolimus ophthalmic microemulsion preparation.

[0016] In the present invention, the solubilizer may also include one or more of polyoxyethylene hydrogenated castor oil, polyvinyl pyrrolidone, polyoxyethylene castor oil, propylene glycol monocaprylate, polysorbate, oleoyl polyoxyethylene glyceride, octylphenol polyoxyethylene ether, vitamin E polyethylene glycol succinate and poloxamer. Among them, the polyoxyethylene castor oil is, for example, polyoxyethylene castor oil 35; the polysorbate is, for example, polysorbate-80; the poloxamer is, for example, poloxamer 188 and / or poloxamer 407.

[0017] In some specific embodiments, the solubilizing agent further comprises vitamin E polyethylene glycol succinate and poloxamer.

[0018] In the present invention, when the solubilizing agent includes poloxamer, the amount of the poloxamer is 0.1%-20%, where the percentage is the mass percentage of the poloxamer in the tacrolimus ophthalmic microemulsion preparation. Within this amount range, the poloxamer has a solubilizing effect and will not form an instant gel.

[0019] In the present invention, the content of the polyethylene glycol stearate is preferably 0.05%-10%, more preferably 0.4%-6%, for example 0.05%, 0.4%, 0.7%, 3%, 4%, 7.5% or 10%, where the percentage is the mass percentage of the polyethylene glycol stearate in the tacrolimus ophthalmic microemulsion preparation.

[0020] In the present invention, the polyethylene glycol stearate is preferably 15-hydroxystearate polyethylene glycol. The 15-hydroxystearate polyethylene glycol can be referred to as Solutol HS-15.

[0021] In the present invention, the caprylic acid capric acid macrogol glyceride can be recorded as Labrasol. The content of the caprylic acid capric acid macrogol glyceride is preferably 0.1%-6%, more preferably 0.3%-4%, such as 0.1%, 0.3%, 0.5%, 2%, 3%, 5% or 6%, and the percentage is the mass percentage of the caprylic acid capric acid macrogol glyceride in the tacrolimus ophthalmic microemulsion preparation.

[0022] In the present invention, the tacrolimus ophthalmic microemulsion preparation may further include an oil phase.

[0023] The oil phase can be selected from one or more of medium chain triglycerides, almond oil, castor oil, soybean oil, corn oil, mineral oil, peanut oil and lanolin oil, preferably medium chain triglycerides and castor oil. The medium chain triglycerides can be recorded as MCT; the lanolin oil can be recorded as Lanolin oil.

[0024] The content of the oil phase may be 0.05%-3%, preferably 0.2%-1%, where the percentage is the mass percentage of the oil phase in the tacrolimus ophthalmic microemulsion preparation.

[0025] In some preferred embodiments, the oil phase includes medium chain triglycerides, and the content of the medium chain triglycerides is 0.1% to 3%, for example 0.1%, 0.15%, 0.2%, 0.3%, 1.5% or 3%, where the percentage is the mass percentage of the medium chain triglycerides in the tacrolimus ophthalmic microemulsion preparation.

[0026] In some preferred embodiments, the oil phase includes castor oil, and the content of the castor oil is 0.5% to 2%, such as 0.5% or 2%, where the percentage is the mass percentage of the castor oil in the tacrolimus ophthalmic microemulsion preparation.

[0027] In the present invention, the tacrolimus ophthalmic microemulsion preparation may further include an osmotic pressure regulator.

[0028] The osmotic pressure regulator may be a conventional osmotic pressure regulator in the art, preferably glycerol, sodium chloride or mannitol, more preferably glycerol.

[0029] In the present invention, the dosage of the osmotic pressure regulator generally makes the osmotic pressure of the tacrolimus ophthalmic microemulsion preparation be 200-400 mOsmol / kg.

[0030] In the present invention, the pH value of the tacrolimus ophthalmic microemulsion preparation is preferably 5-8, more preferably 6-8, for example, 7.

[0031] In the present invention, the pH value of the tacrolimus ophthalmic microemulsion preparation can be achieved by adding a pH adjuster, that is, the tacrolimus ophthalmic microemulsion preparation can also include a pH adjuster. The pH adjuster can be a conventional inorganic acid, inorganic base, organic base or buffer in the art.

[0032] The inorganic acid is, for example, hydrochloric acid, phosphoric acid or boric acid. The hydrochloric acid may be 1 mol / L hydrochloric acid; the phosphoric acid may be 5% phosphoric acid.

[0033] The inorganic base is, for example, sodium hydroxide, which is preferably added in the form of a 1 mol / L sodium hydroxide aqueous solution.

[0034] The organic base is, for example, triethanolamine, triethylamine or tromethamine. The tromethamine is preferably added in the form of a 2% (w / v) tromethamine aqueous solution.

[0035] The buffer is, for example, sodium phosphate buffer, potassium phosphate buffer, sodium citrate buffer or boric acid buffer.

[0036] In the present invention, the amount of the pH regulator is determined to achieve the above pH value of the tacrolimus ophthalmic microemulsion preparation. In order to finally adjust the pH value of the tacrolimus ophthalmic microemulsion preparation to 5-8, one or more of the above pH regulators can be reasonably selected according to the acidity and alkalinity of the tacrolimus ophthalmic microemulsion preparation.

[0037] In the present invention, the water is preferably water for injection.

[0038] In the present invention, the amount of water used is generally sufficient to make up the sum of the mass fractions of the components in the composition to 100%.

[0039] In the present invention, preferably, the tacrolimus ophthalmic microemulsion preparation does not include a preservative.

[0040] In a preferred embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: tacrolimus, 15-hydroxystearate polyethylene glycol ester, caprylic acid capric acid polyethylene glycol glyceride, castor oil and glycerin, and the balance is water.

[0041] In a preferred embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.05%-0.15% tacrolimus, 3%-10% 15-hydroxystearate polyethylene glycol ester, 2%-6% caprylic capric acid polyethylene glycol glyceride, 0.5%-2% castor oil and 0.5%-2% glycerol, the balance being water, and the percentages are the mass percentages of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7.

[0042] In a specific embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.15% tacrolimus, 10% 15-hydroxystearate polyethylene glycol ester, 6% caprylic capric acid polyethylene glycol glyceride, 2% castor oil and 0.5% glycerol, the balance being water, and the percentages are the mass percentages of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7.

[0043] In a specific embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.05% tacrolimus, 3% 15-hydroxystearate polyethylene glycol ester, 2% caprylic capric acid polyethylene glycol glyceride, 0.5% castor oil and 2% glycerol, the balance being water, and the percentages are the mass percentages of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7.

[0044] In a preferred embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: tacrolimus, 15-hydroxystearate polyethylene glycol ester, caprylic capric macrogol glyceride, medium chain triglyceride and glycerol, and the balance is water.

[0045] In a preferred embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.03%-0.5% tacrolimus, 0.4%-7.5% 15-hydroxystearate polyethylene glycol ester, 0.3%-5% caprylic capric acid polyethylene glycol glyceride, 0.15%-3% medium chain triglyceride and 0.5%-2.5% glycerol, the balance is water, and the percentage is the mass percentage of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7.

[0046] In a specific embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.1% tacrolimus, 0.7% 15-hydroxystearate polyethylene glycol ester, 0.5% caprylic capric acid polyethylene glycol glyceride, 0.2% medium chain triglyceride and 2.2% glycerol, the balance being water, and the percentages are the mass percentages of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7.

[0047] In a specific embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.5% tacrolimus, 7.5% 15-hydroxystearate polyethylene glycol ester, 5% caprylic capric acid polyethylene glycol glyceride, 3% medium chain triglycerides and 0.5% glycerol, and the balance is water, and the percentage is the mass percentage of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7.

[0048] In a specific embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.03% tacrolimus, 0.4% 15-hydroxystearate polyethylene glycol ester, 0.3% caprylic capric acid polyethylene glycol glyceride, 0.15% medium chain triglyceride and 2.5% glycerol, the balance being water, and the percentages are the mass percentages of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7.

[0049] In a specific embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.05% tacrolimus, 3% 15-hydroxystearate polyethylene glycol ester, 2% caprylic capric acid polyethylene glycol glyceride, 0.3% medium chain triglyceride and 1.5% glycerol, the balance being water, and the percentages are the mass percentages of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7.

[0050] In a specific embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.2% tacrolimus, 4% 15-hydroxystearate polyethylene glycol ester, 6% caprylic capric acid polyethylene glycol glyceride, 1.5% medium chain triglycerides and 2% glycerol, the remainder being water, and the percentages are the mass percentages of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7.

[0051] In a preferred embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: tacrolimus, 15-hydroxystearate polyethylene glycol ester, caprylic capric macrogol glyceride, medium chain triglyceride and sodium chloride, and the balance is water.

[0052] In a preferred embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.01%-0.05% tacrolimus, 0.05%-0.3% 15-hydroxystearate polyethylene glycol ester, 0.1%-0.5% caprylic capric acid polyethylene glycol glyceride, 0.1%-0.3% medium chain triglyceride and 0.8%-1.5% sodium chloride, the balance being water, and the percentages are the mass percentages of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7.

[0053] In a specific embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.01% tacrolimus, 0.05% 15-hydroxystearate polyethylene glycol ester, 0.1% caprylic capric acid polyethylene glycol glyceride, 0.1% medium chain triglyceride and 0.8% sodium chloride, the balance being water, and the percentages are the mass percentages of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7.

[0054] In a preferred embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: tacrolimus, 15-hydroxystearate polyethylene glycol ester, caprylic acid capric acid polyethylene glycol glyceride and glycerol, and the balance is water.

[0055] In a preferred embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.1%-0.5% tacrolimus, 2%-6% 15-hydroxystearate polyethylene glycol ester, 2%-6% caprylic capric acid polyethylene glycol glyceride and 2%-2.5% glycerol, the balance being water, and the percentages are the mass percentages of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7.

[0056] In a specific embodiment of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.1% tacrolimus, 3% 15-hydroxystearate polyethylene glycol ester, 3% caprylic capric acid polyethylene glycol glyceride and 2.2% glycerol, the balance being water, and the percentages are the mass percentages of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7.

[0057] It should be noted that, in the above specific embodiments, "the balance is water" does not exclude the addition of a pH adjuster due to the need to adjust the pH value.

[0058] In the present invention, the average particle size of the tacrolimus ophthalmic microemulsion preparation is preferably not more than 300 nm.

[0059] The present invention also provides a method for preparing the tacrolimus ophthalmic microemulsion preparation, which comprises the following steps:

[0060] The components of the tacrolimus ophthalmic microemulsion preparation are mixed to obtain a uniform system, and the system is sterilized by filtering through a filter membrane to obtain the tacrolimus ophthalmic microemulsion preparation.

[0061] In the present invention, the mixing may be performed by conventional operations in the art, such as stirring.

[0062] In some preferred embodiments of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises tacrolimus, a solubilizer, an oil phase, an osmotic pressure regulator, a pH regulator and water, and the mixing comprises the following steps:

[0063] a) stirring and mixing the tacrolimus, the oil phase and the solubilizing agent to dissolve;

[0064] b) mixing and dissolving the osmotic pressure regulator, the pH regulator and the water;

[0065] c) stirring and mixing the solution obtained in a) and the solution obtained in b).

[0066] In the above scheme, the pH adjuster is preferably a buffer solution.

[0067] In some preferred embodiments of the present invention, the tacrolimus ophthalmic microemulsion preparation comprises tacrolimus, a solubilizer, an oil phase, an osmotic pressure regulator, a pH regulator and water, and the mixing comprises the following steps:

[0068] a) stirring and mixing the tacrolimus, the oil phase and the solubilizing agent to dissolve;

[0069] b) mixing the osmotic pressure regulator and the water to dissolve;

[0070] c) stirring and mixing the solution obtained in a) and the solution obtained in b) and adding the pH adjuster to adjust the pH to 7, and then adding the water to a sufficient amount.

[0071] In the above scheme, the pH adjuster is preferably an inorganic acid, an inorganic base and / or an organic base.

[0072] In the present invention, the filter membrane may be a conventional filter membrane in the art. The pore size of the filter membrane is preferably no more than 0.22 μm, for example 0.22 μm. The material of the filter membrane may be PVDF or PES. The filter membrane is, for example, a 0.22 μm PVDF filter membrane or a 0.22 μm PES filter membrane.

[0073] The present invention also provides an application of a tacrolimus ophthalmic microemulsion preparation in preparing a drug for treating dry eye.

[0074] The present invention also provides a tacrolimus ophthalmic instant gel preparation, which comprises tacrolimus, a solubilizer, a gel matrix and water.

[0075] In the present invention, the content of tacrolimus may be 0.01%-0.5%, preferably 0.02%-0.2%, more preferably 0.03%-0.1%, such as 0.03% or 0.05%, where the percentage is the mass percentage of tacrolimus in the tacrolimus instant ophthalmic gel preparation.

[0076] In the present invention, the content of the solubilizer may be 0.1% to 20%, preferably 0.3% to 16%, where the percentage is the mass percentage of the solubilizer in the tacrolimus ophthalmic instant gel preparation.

[0077] In the present invention, the solubilizer may include one or more of polyoxyethylene hydrogenated castor oil, polyvinyl pyrrolidone, polyoxyethylene castor oil, propylene glycol monocaprylate, polysorbate, oleoyl polyoxyethylene glyceride, octylphenol polyoxyethylene ether, stearic acid polyethylene glycol ester, caprylic acid capric acid polyethylene glycol glyceride, vitamin E polyethylene glycol succinate and poloxamer. Among them, the polyoxyethylene castor oil is, for example, polyoxyethylene castor oil 35; the polysorbate is, for example, polysorbate-80; the stearic acid polyethylene glycol ester is, for example, 15-hydroxystearate polyethylene glycol ester; the poloxamer is, for example, poloxamer 188 and / or poloxamer 407.

[0078] In the present invention, the content of the 15-hydroxystearate polyethylene glycol ester may be 0.1%-10%, preferably 0.4%-6%, more preferably 0.4%-3%, for example 0.4%, 1% or 3%, where the percentage is the mass percentage of the 15-hydroxystearate polyethylene glycol ester in the tacrolimus ophthalmic instant gel preparation.

[0079] In the present invention, the content of the caprylic acid capric acid macrogol glyceride can be 0.1%-6%, preferably 0.3%-4%, more preferably 0.3%-2%, for example 0.3%, 1.5% or 2%, where the percentage is the mass percentage of the caprylic acid capric acid macrogol glyceride in the tacrolimus ophthalmic instant gel preparation.

[0080] In the present invention, the gel matrix may include one or more of carbomer, poloxamer, xanthan gum, gellan gum, sodium carboxymethylcellulose, polycarbophil and sodium alginate. The gellan gum is, for example, low acyl gellan gum, the poloxamer is, for example, poloxamer 188 and / or poloxamer 407, and the gel matrix is ​​preferably poloxamer or low acyl gellan gum.

[0081] In the present invention, the content of the gel matrix can be 0.1% to 30%, preferably 0.2% to 20%, where the percentage is the mass percentage of the gel matrix in the tacrolimus ophthalmic instant gel preparation.

[0082] In the present invention, when the gel matrix includes poloxamer, the amount of the poloxamer can be 20-30%, preferably 22%-26%, where the percentage is the mass percentage of the poloxamer in the tacrolimus instant ophthalmic gel preparation. Within this amount range, the poloxamer acts as a gel matrix and forms an instant gel.

[0083] In some preferred embodiments, the gel matrix includes poloxamer 188, and the amount of poloxamer 188 is 2% to 10%, for example, 5%, where the percentage is the mass percentage of poloxamer 188 in the tacrolimus ophthalmic instant gel preparation.

[0084] In some preferred embodiments, the gel matrix includes poloxamer 407, and the amount of poloxamer 407 is 18% to 30%, for example, 20%, where the percentage is the mass percentage of poloxamer 407 in the tacrolimus ophthalmic instant gel preparation.

[0085] In some preferred embodiments, the gel matrix includes low acyl gellan gum, and the amount of the low acyl gellan gum is 0.1% to 2%, for example, 0.5%, where the percentage is the mass percentage of the low acyl gellan gum in the tacrolimus ophthalmic instant gel preparation.

[0086] In the present invention, the instant tacrolimus ophthalmic gel preparation may further include an oil phase.

[0087] The oil phase can be selected from one or more of medium chain triglycerides, almond oil, castor oil, soybean oil, corn oil, mineral oil, peanut oil and sheep oil, preferably medium chain triglycerides and castor oil.

[0088] The content of the oil phase may be 0.05%-3%, preferably 0.2%-1%, where the percentage is the mass percentage of the oil phase in the tacrolimus ophthalmic instant gel preparation.

[0089] In some preferred embodiments, the oil phase comprises medium chain triglycerides, and the content of the medium chain triglycerides is 0.1%-1%, such as 0.15% or 0.3%, where the percentage is the mass percentage of the medium chain triglycerides in the tacrolimus ophthalmic instant gel preparation.

[0090] In some preferred embodiments, the oil phase includes castor oil, and the content of the castor oil is 0.1%-1%, such as 0.5%, where the percentage is the mass percentage of the castor oil in the tacrolimus ophthalmic instant gel preparation.

[0091] In the present invention, the instant tacrolimus ophthalmic gel preparation may further include an osmotic pressure regulator.

[0092] The osmotic pressure regulator may be a conventional osmotic pressure regulator in the art, preferably glycerol, sodium chloride or mannitol, more preferably glycerol.

[0093] In the present invention, the dosage of the osmotic pressure regulator is generally such that the osmotic pressure of the instant tacrolimus ophthalmic gel preparation is 200-400 mOsmol / kg.

[0094] In the present invention, the pH value of the tacrolimus instant ophthalmic gel preparation is preferably 5-8, more preferably 6-8, for example, 7.

[0095] In the present invention, the pH value of the tacrolimus ophthalmic instant gel preparation can be achieved by adding a pH adjuster, that is, the tacrolimus ophthalmic microemulsion preparation can also include a pH adjuster. The pH adjuster can be a conventional inorganic acid, inorganic base, organic base or buffer in the art.

[0096] The inorganic acid is, for example, hydrochloric acid, phosphoric acid or boric acid. The hydrochloric acid may be 1 mol / L hydrochloric acid; the phosphoric acid may be 5% phosphoric acid.

[0097] The inorganic base is, for example, sodium hydroxide, which is preferably added in the form of a 1 mol / L sodium hydroxide aqueous solution.

[0098] The organic base is, for example, triethanolamine, triethylamine or tromethamine, and is more preferably added in the form of a 2% (w / v) tromethamine aqueous solution.

[0099] The buffer is, for example, sodium phosphate buffer, potassium phosphate buffer, sodium citrate buffer or boric acid buffer.

[0100] In the present invention, the amount of the pH regulator is determined to achieve the above pH value of the tacrolimus instant ophthalmic gel preparation. In order to finally adjust the pH value of the tacrolimus instant ophthalmic gel preparation to 5 to 8, one or more of the above pH regulators can be reasonably selected according to the acidity and alkalinity of the tacrolimus instant ophthalmic gel preparation.

[0101] In the present invention, the water is preferably water for injection.

[0102] In the present invention, the amount of water used is generally sufficient to make up the sum of the mass fractions of the components in the composition to 100%.

[0103] In the present invention, preferably, the tacrolimus ophthalmic instant gel preparation does not include a preservative.

[0104] In a preferred embodiment of the present invention, the instant tacrolimus ophthalmic gel preparation comprises the following components: tacrolimus, 15-hydroxystearate polyethylene glycol ester, caprylic capric macrogol glyceride, poloxamer 188, poloxamer 407 and medium chain triglycerides, and the balance is water.

[0105] In a preferred embodiment of the present invention, the tacrolimus instant ophthalmic gel preparation comprises the following components: 0.01%-0.5% tacrolimus, 0.1%-1% 15-hydroxystearate polyethylene glycol ester, 0.1%-1% caprylic capric acid polyethylene glycol glyceride, 2%-8% poloxamer 188, 18%-25% poloxamer 407 and 0.1%-0.5% medium chain triglyceride, the balance is water, and the percentage is the mass percentage of each component in the tacrolimus instant ophthalmic gel preparation; the pH value of the tacrolimus instant ophthalmic gel preparation is 7.

[0106] In a specific embodiment of the present invention, the tacrolimus instant ophthalmic gel preparation comprises the following components: 0.03% tacrolimus, 0.4% 15-hydroxystearate polyethylene glycol ester, 0.3% caprylic capric acid polyethylene glycol glyceride, 5% poloxamer 188, 20% poloxamer 407 and 0.15% medium chain triglyceride, the remainder is water, and the percentage is the mass percentage of each component in the tacrolimus instant ophthalmic gel preparation; the pH value of the tacrolimus instant ophthalmic gel preparation is 7.

[0107] In a preferred embodiment of the present invention, the instant tacrolimus ophthalmic gel preparation comprises the following components: tacrolimus, 15-hydroxystearate polyethylene glycol, caprylic acid capric acid polyethylene glycol glycerol, low acyl gellan gum, medium chain triglycerides and mannitol, with the balance being water.

[0108] In a preferred embodiment of the present invention, the tacrolimus instant gel preparation for eye use comprises the following components: 0.01%-0.1% tacrolimus, 0.4%-3% 15-hydroxystearate polyethylene glycol ester, 0.5%-3% caprylic capric acid polyethylene glycol glyceride, 0.1%-2% low acyl gellan gum, 0.1%-1% medium chain triglyceride and 2.5%-3.5% mannitol, and the balance is water, and the percentage is the mass percentage of each component in the tacrolimus instant gel preparation for eye use; the pH value of the tacrolimus instant gel preparation for eye use is 7.

[0109] In a specific embodiment of the present invention, the tacrolimus instant gel preparation for eye use comprises the following components: 0.05% tacrolimus, 1% 15-hydroxystearate polyethylene glycol ester, 1.5% caprylic capric acid polyethylene glycol glyceride, 0.5% low acyl gellan gum, 0.3% medium chain triglyceride and 3% mannitol, and the balance is water, and the percentage is the mass percentage of each component in the tacrolimus instant gel preparation for eye use; the pH value of the tacrolimus instant gel preparation for eye use is 7.

[0110] In a preferred embodiment of the present invention, the instant tacrolimus ophthalmic gel preparation comprises the following components: tacrolimus, 15-hydroxystearate polyethylene glycol ester, caprylic acid capric acid macrogol glyceride, poloxamer 188, poloxamer 407, castor oil, and the balance is water.

[0111] In a preferred embodiment of the present invention, the tacrolimus instant ophthalmic gel preparation comprises the following components: 0.01%-0.1% tacrolimus, 0.4%-5% 15-hydroxystearate polyethylene glycol ester, 0.3%-4% caprylic capric acid polyethylene glycol glyceride, 2%-8% poloxamer 188, 18%-25% poloxamer 407, 0.1%-1% castor oil, and the balance is water, and the percentage is the mass percentage of each component in the tacrolimus instant ophthalmic gel preparation; the pH value of the tacrolimus instant ophthalmic gel preparation is 7.

[0112] In a specific embodiment of the present invention, the tacrolimus instant ophthalmic gel preparation comprises the following components: 0.05% tacrolimus, 3% 15-hydroxystearate polyethylene glycol ester, 2% caprylic capric acid polyethylene glycol glyceride, 5% poloxamer 188, 20% poloxamer 407, 0.5% castor oil, and the balance is water, and the percentage is the mass percentage of each component in the tacrolimus instant ophthalmic gel preparation; the pH value of the tacrolimus instant ophthalmic gel preparation is 7.

[0113] It should be noted that, in the above specific embodiments, "the balance is water" does not exclude the addition of a pH adjuster for adjusting the pH value.

[0114] In the present invention, the average particle size of the tacrolimus instant ophthalmic gel preparation is preferably not more than 300 nm.

[0115] The present invention also provides a method for preparing the tacrolimus instant ophthalmic gel preparation, which comprises the following steps:

[0116] The components of the tacrolimus instant ophthalmic gel preparation are mixed to obtain a uniform system, and the system is sterilized by filtering through a filter membrane to obtain the tacrolimus instant ophthalmic gel preparation.

[0117] In the present invention, the mixing may be performed by conventional operations in the art, such as stirring.

[0118] In some preferred embodiments of the present invention, the instant tacrolimus ophthalmic gel preparation comprises tacrolimus, a solubilizer, a gel matrix, an oil phase, an osmotic pressure regulator, a pH regulator and water, and the mixing comprises the following steps:

[0119] a) stirring and mixing the tacrolimus, the oil phase and the solubilizing agent to dissolve;

[0120] b) mixing and dissolving the osmotic pressure regulator, the pH regulator and the water;

[0121] c) stirring and mixing the solution obtained in a) and the solution obtained in b);

[0122] d) adding the gel matrix to c), stirring to make it uniformly dispersed, stirring or leaving at 2° C. to 8° C. until the gel matrix is ​​completely swollen, and stirring to mix;

[0123] e) Add the water to a sufficient amount.

[0124] In the above scheme, the pH adjuster is preferably a buffer solution.

[0125] In some preferred embodiments of the present invention, the instant tacrolimus ophthalmic gel preparation comprises tacrolimus, a solubilizer, a gel matrix, an oil phase, an osmotic pressure regulator, a pH regulator and water, and the mixing comprises the following steps:

[0126] a) stirring and mixing the tacrolimus, the oil phase and the solubilizing agent to dissolve;

[0127] b) adding the solution obtained in a) into the water and stirring evenly;

[0128] c) slowly adding the gel matrix to the solution obtained in b) while stirring, stirring to make it uniformly dispersed, stirring or leaving at 2° C. to 8° C. until the gel matrix is ​​completely swollen, and stirring to mix;

[0129] d) adding the pH adjuster to adjust the pH to 7, and then adding the water to a sufficient amount.

[0130] In the above scheme, the pH adjuster is preferably an inorganic acid, an inorganic base and / or an organic base.

[0131] In the present invention, the filter membrane may be a conventional filter membrane in the art. The pore size of the filter membrane is preferably no more than 0.22 μm, for example 0.22 μm. The material of the filter membrane may be PVDF or PES. The filter membrane is, for example, a 0.22 μm PVDF filter membrane or a 0.22 μm PES filter membrane.

[0132] The present invention also provides an application of a tacrolimus instant gel preparation for eye use in preparing a drug for treating dry eye.

[0133] At present, all ophthalmic products on the market need to add preservatives to increase the stability of eye drops. Long-term use of eye drops containing preservatives will damage the goblet cells on the ocular surface, and may cause risks such as keratitis, conjunctivitis, and dry eyes. The preferred embodiments of the tacrolimus ophthalmic microemulsion preparation and the tacrolimus ophthalmic instant gel preparation provided by the present invention do not need to add preservatives, and are safer to use.

[0134] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0135] The reagents and raw materials used in the present invention are commercially available.

[0136] The positive and progressive effects of the present invention are:

[0137] (1) Both tacrolimus ophthalmic microemulsion preparations and tacrolimus ophthalmic instant gel preparations can increase the drug loading of tacrolimus, thereby increasing the effective amount of drug acting on the affected area.

[0138] (2) Tacrolimus ophthalmic microemulsion preparation can significantly improve the solubility of tacrolimus and promote ocular drug absorption.

[0139] (3) Tacrolimus ophthalmic instant gel preparation can prolong the retention time in the eye and effectively improve the bioavailability.

[0140] (4) The average particle size of the tacrolimus ophthalmic microemulsion preparation and the tacrolimus ophthalmic instant gel preparation is no more than 300 nm, the polydispersity coefficient is no more than 0.20, and the particle size stability is good.

[0141] (5) Tacrolimus ophthalmic microemulsion preparations and tacrolimus ophthalmic instant gel preparations can be prepared by direct stirring method and filtration sterilization method. The operation is simple and convenient, cost-saving and efficiency-enhancing, and they have high practical value. BRIEF DESCRIPTION OF THE DRAWINGS

[0142] Figure 1 : is the particle size distribution diagram of the tacrolimus ophthalmic microemulsion preparation prepared in Example 1;

[0143] Figure 2 : is the particle size distribution diagram of the tacrolimus instant ophthalmic gel preparation prepared in Example 8;

[0144] Figure 3 This is the corneal fluorescein sodium staining image after drug administration in Effect Example 4;

[0145] Figure 4 For the tear fern test crystal image after the drug administration intervention of effect example 5;

[0146] Figure 5 This is the drug-time curve of tacrolimus in rabbit tears of Effect Example 6 (n=5). DETAILED DESCRIPTION

[0147] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0148] In the embodiments and comparative examples of the present invention, the key reagents and instruments used are as follows:

[0149]

[0150]

[0151] (1) Specific method for determining the concentration of tacrolimus by high performance liquid chromatography:

[0152] Chromatographic column: Thermo scientific Acclaim TM 120 (C18 150mm×4.6mm, 5μm); mobile phase: mobile phase A: acetonitrile-methyl tert-butyl ether-6mM phosphoric acid aqueous solution (volume ratio of 335:55:600), mobile phase B: acetonitrile; the ratio of mobile phase A to mobile phase B is 60:40; flow rate: 1.0mL·min -1 ; Detection wavelength: 220nm; Column temperature: 60℃; Injection volume: 5μL.

[0153] (2) Specific method for determining tacrolimus concentration by LC-MS:

[0154] Liquid phase conditions: HPLC: Shimadzu LC-20A; Chromatographic column: Agilent ZORBAX 3.5μm SB-C84.6x 50mm; Mobile phase: Mobile phase A is 0.1% formic acid-water (containing 10mmol·L-1 ammonium acetate), mobile phase B is 0.1% formic acid-acetonitrile; Flow rate: 0.4L / min; Column temperature: 60℃; Injection volume: 10μL; Gradient elution program is as follows:

[0155]

[0156] Mass spectrometry conditions: analytical instrument: Shimadzu LCMS-8030; electrospray ion source, positive ion mode analysis; scanning mode: MRM; nebulizing gas flow rate: 3 L / min; drying gas flow rate: 15 L / min; DL temperature: 300°C; Heat block temperature: 400°C; dwell time: 100 ms.

[0157]

[0158] Example 1

[0159] A tacrolimus ophthalmic microemulsion preparation, the prescription composition of which is as follows by weight percentage:

[0160]

[0161] The percentage of "content" in the second column of the above table refers to the mass percentage of each component in the tacrolimus ophthalmic microemulsion preparation.

[0162] The third column "Content (mg / mL)" in the above table is calculated by converting the solution density to an approximate density of 1 g / mL.

[0163] The percentage content of each component involved in this embodiment is the mass percentage of the mass of the component relative to the total mass of the prescription composition.

[0164] Preparation method:

[0165] (1) Weigh the prescribed amount of tacrolimus, castor oil, Labrasol and Solutol HS-15, stir to mix and dissolve the drugs;

[0166] (2) Weigh the prescribed amount of glycerol and add an appropriate amount of water for injection and stir to mix;

[0167] (3) Add (1) to (2), stir and mix, then adjust the pH to 7 with 1 mol / L sodium hydroxide and / or 1 mol / L hydrochloric acid, add enough water for injection, filter and sterilize through a 0.22 μm PVDF filter membrane, and then prepare a tacrolimus ophthalmic microemulsion preparation.

[0168] The particle size of the prepared tacrolimus ophthalmic microemulsion was measured by a laser particle size analyzer (Z3000, NICOMP), with an average particle size of 68 nm and a polydispersity coefficient of 0.09. The drug loading is the mass percentage of the drug in the microemulsion (oil phase, solubilizer, drug, excluding other excipients), and the drug loading calculated from the above prescription is 0.8%. The particle size distribution diagram of the prepared tacrolimus ophthalmic microemulsion is as follows: Figure 1 shown.

[0169] Example 2

[0170] A tacrolimus ophthalmic microemulsion preparation, the prescription composition of which is as follows by weight percentage:

[0171]

[0172] The percentage content of each component involved in this embodiment is the mass percentage of the mass of the component relative to the total mass of the prescription composition.

[0173] Preparation method:

[0174] (1) Weigh the prescribed amount of tacrolimus, MCT, Labrasol and Solutol HS-15, stir to mix and dissolve the drugs;

[0175] (2) Weigh the prescribed amount of glycerol and add an appropriate amount of water for injection and stir to mix;

[0176] (3) Mix (1) and (2) by stirring, then adjust the pH to 7 with 1 mol / L sodium hydroxide and / or 1 mol / L hydrochloric acid, add enough water for injection, and filter through a 0.22 μm PVDF filter membrane for sterilization to obtain a tacrolimus ophthalmic microemulsion preparation.

[0177] The particle size of the prepared tacrolimus ophthalmic microemulsion preparation was measured by a laser particle size analyzer (Z3000, NICOMP), and the average particle size was 58 nm, and the polydispersity coefficient was 0.18. The drug loading was calculated in the same way as in Example 1, which was 6.7%.

[0178] Example 3

[0179] A tacrolimus ophthalmic microemulsion preparation, the prescription composition of which is as follows by weight percentage:

[0180]

[0181] The percentage content of each component involved in this embodiment is the mass percentage of the mass of the component relative to the total mass of the prescription composition.

[0182] Preparation method:

[0183] (1) Weigh the prescribed amount of tacrolimus, MCT, Labrasol and Solutol HS-15, stir to mix and dissolve the drugs;

[0184] (2) Weigh the prescribed amount of sodium chloride, add an appropriate amount of water for injection, stir to dissolve and mix well;

[0185] (3) Mix (1) and (2) by stirring, then adjust the pH to 7 with 1 mol / L sodium hydroxide and / or 1 mol / L hydrochloric acid, add enough water for injection, and filter through a 0.22 μm PES filter membrane for sterilization to obtain a tacrolimus ophthalmic microemulsion preparation.

[0186] The particle size of the prepared tacrolimus ophthalmic microemulsion preparation was measured by a laser particle size analyzer (Z3000, NICOMP), and the average particle size was 53 nm, and the polydispersity coefficient was 0.12. The drug loading was calculated in the same way as in Example 1, which was 3.8%.

[0187] Example 4

[0188] A tacrolimus ophthalmic microemulsion preparation, the prescription composition of which is as follows by weight percentage:

[0189]

[0190] The percentage content of each component involved in this embodiment is the mass percentage of the mass of the component relative to the total mass of the prescription composition.

[0191] Preparation method:

[0192] (1) Weigh the prescribed amount of tacrolimus, MCT, Labrasol and Solutol HS-15, stir to mix and dissolve the drugs;

[0193] (2) Weigh the prescribed amount of glycerol and add an appropriate amount of water for injection and stir to mix;

[0194] (3) Mix (1) and (2) by stirring, then adjust the pH to 7 with 1 mol / L sodium hydroxide and / or 1 mol / L hydrochloric acid, add enough water for injection, and filter through a 0.22 μm PES filter membrane for sterilization to obtain a tacrolimus ophthalmic microemulsion preparation.

[0195] The particle size of the prepared tacrolimus ophthalmic microemulsion preparation was measured by a laser particle size analyzer (Z3000, NICOMP), and the average particle size was 68 nm, and the polydispersity coefficient was 0.08. The drug loading was calculated in the same way as in Example 1, which was 3.1%.

[0196] Example 5

[0197] A tacrolimus ophthalmic microemulsion preparation, the prescription composition of which is as follows by weight percentage:

[0198]

[0199] The percentage content of each component involved in this embodiment is the mass percentage of the mass of the component relative to the total mass of the prescription composition.

[0200] Preparation method:

[0201] (1) Weigh the prescribed amount of tacrolimus, MCT, Labrasol and Solutol HS-15, stir to mix and dissolve the drugs;

[0202] (2) Weigh the prescribed amount of glycerol and add an appropriate amount of water for injection and stir to mix;

[0203] (3) Mix (1) and (2) by stirring, then adjust the pH to 7 with 1 mol / L sodium hydroxide and / or 1 mol / L hydrochloric acid, add enough water for injection, and filter through a 0.22 μm PVDF filter membrane for sterilization to obtain a tacrolimus ophthalmic microemulsion preparation.

[0204] The particle size of the prepared tacrolimus ophthalmic microemulsion preparation was measured by a laser particle size analyzer (Z3000, NICOMP), and the average particle size was 43 nm, and the polydispersity coefficient was 0.19. The drug loading was calculated in the same way as in Example 1, which was 3.4%.

[0205] Example 6

[0206] A tacrolimus ophthalmic microemulsion preparation, the prescription composition of which is as follows by weight percentage:

[0207]

[0208] The percentage content of each component involved in this embodiment is the mass percentage of the mass of the component relative to the total mass of the prescription composition.

[0209] Preparation method:

[0210] (1) Weigh the prescribed amount of tacrolimus, MCT, Labrasol and Solutol HS-15, stir to mix and dissolve the drugs;

[0211] (2) Weigh the prescribed amount of glycerol and add an appropriate amount of water for injection and stir to mix;

[0212] (3) Mix (1) and (2) by stirring, then adjust the pH to 7 with 1 mol / L sodium hydroxide and / or 1 mol / L hydrochloric acid, add enough water for injection, and filter through a 0.22 μm PVDF filter membrane for sterilization to obtain a tacrolimus ophthalmic microemulsion preparation.

[0213] The particle size of the prepared tacrolimus ophthalmic microemulsion preparation was measured by a laser particle size analyzer (Z3000, NICOMP), and the average particle size was 39 nm, and the polydispersity coefficient was 0.18. The drug loading was calculated in the same way as in Example 1, which was 0.9%.

[0214] Example 7

[0215] A tacrolimus ophthalmic microemulsion preparation, the prescription composition of which is as follows by weight percentage:

[0216]

[0217] The percentage content of each component involved in this embodiment is the mass percentage of the mass of the component relative to the total mass of the prescription composition.

[0218] Preparation method:

[0219] (1) Weigh the prescribed amount of tacrolimus, MCT, Labrasol and Solutol HS-15, stir to mix and dissolve the drugs;

[0220] (2) Weigh the prescribed amount of glycerol and add an appropriate amount of water for injection and stir to mix;

[0221] (3) Mix (1) and (2) by stirring, then adjust the pH to 7 with 1 mol / L sodium hydroxide and / or 1 mol / L hydrochloric acid, add enough water for injection, and filter through a 0.22 μm PES filter membrane for sterilization to obtain a tacrolimus ophthalmic microemulsion preparation.

[0222] The particle size of the prepared tacrolimus ophthalmic microemulsion preparation was measured by a laser particle size analyzer (Z3000, NICOMP), and the average particle size was 54 nm, and the polydispersity coefficient was 0.10. The drug loading was calculated in the same way as in Example 1, which was 1.7%.

[0223] Example 8

[0224] A tacrolimus instant gel preparation for eye use, the prescription composition of which is as follows by weight percentage:

[0225] Components content Tacrolimus 0.03％ 15-Hydroxystearate polyethylene glycol ester (Solutol HS-15) 0.4％ Caprylic / capric macrogol glycerides (Labrasol) 0.3％ Medium Chain Triglycerides (MCT) 0.15％ Poloxamer 188 5％ Poloxamer 407 20％ 1mol / L sodium hydroxide or 1mol / L hydrochloric acid Adjust to pH 7 Water for injection Add to 100%

[0226] The percentage content of each component involved in this embodiment is the mass percentage of the mass of the component relative to the total mass of the prescription composition.

[0227] Preparation method:

[0228] (1) Weigh the prescribed amount of tacrolimus, MCT, Labrasol and Solutol HS-15, stir to mix and dissolve the drugs;

[0229] (2) Add (1) into water for injection and stir to mix;

[0230] (3) Weigh the prescribed amount of poloxamer 188 and poloxamer 407, slowly add them to (2) while stirring, stir until they are evenly dispersed, and then stir in an ice water bath until they are completely swollen, thereby obtaining a tacrolimus ophthalmic instant gel preparation;

[0231] (4) Adjust the pH to 7 with 1 mol / L sodium hydroxide and / or 1 mol / L hydrochloric acid, make up the prescribed amount with water for injection, and filter through a 0.22 μm PES filter membrane for sterilization.

[0232] The particle size of the prepared tacrolimus instant ophthalmic gel preparation was measured by a laser particle size analyzer (Z3000, NICOMP), and the average particle size was 92 nm, and the polydispersity coefficient was 0.20. The drug loading was calculated in the same way as in Example 1, which was 3.4%. The particle size distribution of the prepared tacrolimus instant ophthalmic gel preparation is shown in FIG. Figure 2 shown.

[0233] Example 9

[0234] A tacrolimus instant gel preparation for eye use, the prescription composition of which is as follows by weight percentage:

[0235] Components content Tacrolimus 0.05％ 15-Hydroxystearate polyethylene glycol ester (Solutol HS-15) 1％ Caprylic / capric macrogol glycerides (Labrasol) 1.5％ Medium Chain Triglycerides (MCT) 0.3％ Mannitol 3％ Low Acyl Gellan Gum 0.5％ 2% (w / v) tromethamine or 1 mol / L hydrochloric acid Adjust to pH 7 Water for injection Add to 100%

[0236] The percentage content of each component involved in this embodiment is the mass percentage of the mass of the component relative to the total mass of the prescription composition.

[0237] Preparation method:

[0238] (1) Weigh the prescribed amount of tacrolimus, MCT, Labrasol and Solutol HS-15, stir to mix and dissolve the drugs;

[0239] (2) Weigh the prescribed amount of low acyl gellan gum and mannitol, add appropriate amount of water for injection, and stir to mix until swelling is complete;

[0240] (3) Add (1) to (2), then adjust the pH to 7 with 2% (w / v) tromethamine and / or 1 mol / L hydrochloric acid, add enough water for injection, and filter through a 0.22 μm PES filter membrane for sterilization to obtain a tacrolimus ophthalmic instant gel preparation.

[0241] The particle size of the prepared tacrolimus ophthalmic instant gel preparation was measured by a laser particle size analyzer (Z3000, NICOMP), and the average particle size was 205 nm, and the polydispersity coefficient was 0.19. The drug loading was calculated in the same way as in Example 1, which was 1.8%.

[0242] Example 10

[0243] A tacrolimus ophthalmic microemulsion preparation, the prescription composition of which is as follows by weight percentage:

[0244]

[0245] The percentage content of each component involved in this embodiment is the mass percentage of the mass of the component relative to the total mass of the prescription composition.

[0246] Preparation method:

[0247] (1) Weigh the prescribed amount of tacrolimus, Labrasol, and Solutol HS-15, stir to mix and dissolve the drugs;

[0248] (2) Weigh the prescribed amount of glycerol and add an appropriate amount of water for injection and stir to mix;

[0249] (3) Mix (1) and (2) by stirring, then adjust the pH to 7 with 1 mol / L sodium hydroxide and / or 1 mol / L hydrochloric acid, add enough water for injection, and filter through a 0.22 μm PES filter membrane for sterilization to obtain a tacrolimus ophthalmic microemulsion preparation.

[0250] The particle size of the prepared tacrolimus ophthalmic microemulsion preparation was measured by a laser particle size analyzer (Z3000, NICOMP), and the average particle size was 21 nm, and the polydispersity coefficient was 0.11. The drug loading was calculated in the same way as in Example 1, which was 1.6%.

[0251] Embodiment 11

[0252] A tacrolimus ophthalmic microemulsion preparation, the prescription composition of which is as follows by weight percentage:

[0253]

[0254] The percentage content of each component involved in this embodiment is the mass percentage of the mass of the component relative to the total mass of the prescription composition.

[0255] Preparation method:

[0256] (1) Weigh the prescribed amount of tacrolimus, castor oil, Labrasol and Solutol HS-15, stir to mix and dissolve the drugs;

[0257] (2) Weigh the prescribed amount of glycerol and add an appropriate amount of water for injection and stir to mix;

[0258] (3) Add (1) to (2), stir and mix, then adjust the pH to 7 with 1 mol / L sodium hydroxide and / or 1 mol / L hydrochloric acid, add enough water for injection, filter and sterilize through a 0.22 μm PVDF filter membrane, and then prepare a tacrolimus ophthalmic microemulsion preparation.

[0259] The particle size of the prepared tacrolimus ophthalmic microemulsion preparation was measured by a laser particle size analyzer (Z3000, NICOMP), and the average particle size was 65 nm, and the polydispersity coefficient was 0.15. The drug loading was calculated in the same way as in Example 1, which was 0.9%.

[0260] Example 12

[0261] A tacrolimus instant gel preparation for eye use, the prescription composition of which is as follows by weight percentage:

[0262] Components content Tacrolimus 0.05％ 15-Hydroxystearate polyethylene glycol ester (Solutol HS-15) 3％ Caprylic / capric macrogol glycerides (Labrasol) 2％ castor oil 0.5％ Poloxamer 188 5％ Poloxamer 407 20％ 1mol / L sodium hydroxide or 1mol / L hydrochloric acid Adjust to pH 7 Water for injection Add to 100%

[0263] The percentage content of each component involved in this embodiment is the mass percentage of the mass of the component relative to the total mass of the prescription composition.

[0264] Preparation method:

[0265] (1) Weigh the prescribed amount of tacrolimus, castor oil, Labrasol and Solutol HS-15, stir to mix and dissolve the drugs;

[0266] (2) Add (1) into water for injection and stir to mix;

[0267] (3) Weigh the prescribed amount of poloxamer 188 and poloxamer 407, slowly add them to (2) while stirring, stir until they are evenly dispersed, and then stir in an ice water bath until they are completely swollen, thereby obtaining a tacrolimus ophthalmic instant gel preparation;

[0268] (4) Adjust the pH to 7 with 1 mol / L sodium hydroxide and / or 1 mol / L hydrochloric acid, make up the prescribed amount with water for injection, and filter through a 0.22 μm PES filter membrane for sterilization.

[0269] The particle size of the prepared tacrolimus instant ophthalmic gel preparation was measured by a laser particle size analyzer (Z3000, NICOMP), and the average particle size was 79 nm, and the polydispersity coefficient was 0.19. The drug loading was calculated in the same way as in Example 1, which was 0.9%.

[0270] Comparative Example 1

[0271] A tacrolimus ophthalmic microemulsion preparation, the prescription composition of which is as follows by weight percentage:

[0272]

[0273] The percentage content of each component involved in this embodiment is the mass percentage of the mass of the component relative to the total mass of the prescription composition.

[0274] Preparation method:

[0275] (1) Weigh the prescribed amount of tacrolimus, MCT and Solutol HS-15, stir to mix and dissolve the drugs;

[0276] (2) Weigh the prescribed amount of glycerol and add an appropriate amount of water for injection and stir to mix;

[0277] (3) Mix (1) and (2) by stirring, then adjust the pH to 7 with 1 mol / L sodium hydroxide and / or 1 mol / L hydrochloric acid, add enough water for injection, and filter through a 0.22 μm PVDF filter membrane for sterilization to obtain a tacrolimus ophthalmic microemulsion preparation. After standing, white insoluble matter precipitates.

[0278] The concentration of other tacrolimus determined by high performance liquid chromatography was 0.4 mg / ml, which was lower than the concentration of tacrolimus added in the formula. This indicates that when only 15-hydroxystearate polyethylene glycol ester is used as the solubilizing agent without adding caprylic acid capric acid polyethylene glycol glyceride, the solubilizing effect will be poor and the concentration of tacrolimus will be reduced.

[0279] Comparative Example 2

[0280] Comparative Example 2 provides a tacrolimus ophthalmic microemulsion preparation, in which the preparation method is the same as that of Example 2 except that the "medium chain triglyceride" in the prescription of Example 2 is replaced by "polyethylene glycol 400".

[0281] The tacrolimus ophthalmic microemulsion preparation is prepared according to the prescription shown in the following table, and its prescription composition is in weight percentage:

[0282] Components content Content (mg / ml) Tacrolimus 0.1％ 1.0 15-Hydroxystearate polyethylene glycol ester (Solutol HS-15) 0.7％ 7 PEG 400 0.5％ 5 Medium Chain Triglycerides (MCT) 0.2％ 2 glycerin 2.2％ 22 1mol / L sodium hydroxide and / or 1mol / L hydrochloric acid Adjust to pH 7 / Water for injection Add to 100% /

[0283] The percentage content of each component involved in this embodiment is the mass percentage of the mass of the component relative to the total mass of the prescription composition.

[0284] Preparation method:

[0285] (1) Weigh the prescribed amount of tacrolimus, MCT, PEG 400, and Solutol HS-15, stir and mix, and heat and stir to dissolve all the drugs;

[0286] (2) Weigh the prescribed amount of glycerol and add an appropriate amount of water for injection and stir to mix;

[0287] (3) Stir (1) and (2) to mix well, then adjust the pH to 7 with 1 mol / L sodium hydroxide and / or 1 mol / L hydrochloric acid, add enough water for injection, mix well, and white insoluble matter will precipitate. Filter and sterilize through a 0.22 μm PVDF filter membrane to obtain a drug-containing liquid. White precipitate will still appear after standing.

[0288] The tacrolimus concentration determined by HPLC was 0.3 mg / ml, indicating that when 15-hydroxystearate polyethylene glycol ester and PEG400 were used as solubilizers without adding caprylic / decanoic acid polyethylene glycol glyceride, the solubilization effect was poor and the tacrolimus concentration would decrease.

[0289] Effect Example 1 Ocular surface tolerance test

[0290] Forty healthy BALB / c mice (6-8 weeks old) were selected. Before the experiment, the ocular surface of the mice was examined to confirm that there was no inflammation or any damage. The mice were divided into four groups, with 10 mice in each group.

[0291] 5 μL of 0.9% NaCl, the microemulsion of Example 1, the microemulsion of Example 5, and the instant gel of Example 8 were respectively dripped into the right eyes of the three groups of mice, and the administration was repeated for 7 days to observe whether there was any irritation reaction on the ocular surface of the right eyes of the mice. After repeated administration for 7 days, the eyeballs of the three groups of mice were free of bloodshot and redness, and the tolerance was good. The results of the ocular surface tolerance test are shown in Table 1.

[0292] Table 1 Ocular surface tolerance test

[0293]

[0294] Effect Example 2 Tear Secretion Test (Schirmer Test)

[0295] 1. Animal grouping, pathological model establishment and drug administration method

[0296] Animal grouping: 42 BALB / c mice (6-8 weeks) were randomly divided into blank group, negative control group, Group (positive control group), microemulsion group (microemulsion preparation of Example 2), microemulsion group (microemulsion preparation of Example 5), microemulsion group (microemulsion preparation of Example 11), instant gel group (instant gel preparation of Example 8), 6 mice in each group. Except for the blank group, the other groups were used to prepare the dry eye syndrome model.

[0297] Pathological model establishment: A 0.2% benzalkonium chloride aqueous solution (filtered and sterilized through a 0.22 μm PVDF membrane) was prepared and administered to the right eye of each mouse twice a day (once in the morning and once in the evening), 5 μL each time, for a period of 1 week to establish the model.

[0298] Dosage method: Give the right eye of the negative control group mice 0.9% sodium chloride injection twice a day (once in the morning and once in the evening), 10 μL each time; The four groups of mice were administered with 10 μL of the drug twice a day (morning and evening) to the right eye of the mice for one week.

[0299] 2. Tear secretion test (Schirmer Test)

[0300] A whatman41 filter paper strip (size 1mm×40mm) was used, and the quantitative filter paper was folded and marked at 2mm. It was placed at the junction of the middle and outer 1 / 3 of the conjunctival sac of the inferior fornix of the mouse, and the rest of the part protruded out of the eye. After 2 minutes, it was taken out and the length of the filter paper wetted was measured, accurate to 0.1mm, and the average value was taken for each group. The experimental results showed that compared with the blank group, the tear secretion of each group was significantly reduced after 1 week of modeling (P<0.05), indicating that the benzalkonium chloride-induced mouse eye dryness model was effective. After 1 week of drug intervention, the tear secretion of the microemulsion group (microemulsion preparation in Example 2), microemulsion group (microemulsion preparation in Example 5), microemulsion group (microemulsion preparation in Example 11), instant gel group (instant gel preparation in Example 8) and the positive control group was significantly increased compared with the negative control group (P<0.05); and the four homemade preparations were also statistically different from the positive control group (P<0.05), indicating that these four homemade preparations can more effectively restore the tear secretion function of mice.

[0301] Effect Example 3 Tear Breakup Time (BUT)

[0302] 1. Animal grouping, pathological model establishment, homemade preparation and administration method are the same as those in Example 2.

[0303] 2. Tear breakup time (BUT)

[0304] 5 μL of 0.5% sodium fluorescein solution was dropped into the conjunctival sac of the lower eyelid, and the mouse eyes were opened with constant force after blinking 3 times manually. The cornea was observed with cobalt blue light of a slit lamp microscope, and the time point when the first tear film breakup black spot appeared on the cornea when the eyes were opened again after blinking was recorded, which was the BUT. The average value was taken for each group. Compared with the blank group, the tear film breakup time of each group was significantly shortened after 1 week of modeling (P < 0.01), indicating that the benzalkonium chloride-induced mouse eye dryness model is effective. After one week of drug intervention, the tear film breakup time of the microemulsion group (microemulsion preparation of Example 2), microemulsion group (microemulsion preparation of Example 5), microemulsion group (microemulsion preparation of Example 11), instant gel group (instant gel preparation of Example 8) and positive control group were significantly prolonged compared with the negative control group (P < 0.01); and there was a statistical difference compared with the positive control group (P < 0.05), indicating that these four homemade preparations can more effectively improve the tear film breakup time of mice with dry eye model and improve the tear film stability of dry eye.

[0305] Effect Example 4 Corneal fluorescein sodium staining (CFS)

[0306] 1. Animal grouping, pathological model establishment, homemade preparation and administration method are the same as those in Example 2.

[0307] 2. Corneal fluorescein sodium staining (CFS)

[0308] 5 μL of 0.5% sodium fluorescein solution was dripped into the conjunctival sac, and the excess sodium fluorescein was washed off with 0.9% sodium chloride solution. The cornea was observed under cobalt blue light of a slit lamp microscope 2 minutes after the instillation. There was no ocular surface damage and no sodium fluorescein staining in the blank group. After 1 week of benzalkonium chloride intervention, a large area of ​​corneal fluorescein staining was observed in each group, indicating that the benzalkonium chloride-induced mouse eye dryness model was effective. After 1 week of drug intervention, the experimental results are shown in the attached figure. Figure 3 It is shown that a represents the blank group, b represents the negative control group, c represents the positive control group, d represents the microemulsion group (microemulsion preparation of Example 2), e represents the microemulsion group (microemulsion preparation of Example 5), f represents the microemulsion group (microemulsion preparation of Example 11), and g represents the instant gel group (instant gel preparation of Example 8). There was no significant improvement in the negative control group, and corneal punctate coloration fusion and filaments appeared; in comparison, the staining of the positive control group, microemulsion group (microemulsion preparation of Example 2), microemulsion group (microemulsion preparation of Example 5), microemulsion group (microemulsion preparation of Example 11), and instant gel group (instant gel preparation of Example 8) all improved, with very little punctate coloration. This shows that the nanoemulsions of the present invention can improve the corneal state of the mouse eye dryness model, and the effect is comparable to that of the conventional nanoemulsions. quite.

[0309] Effect Example 5 Tear Fern Test (TFT)

[0310] 1. Animal grouping, pathological model establishment, homemade preparation and administration method are the same as those in Example 2.

[0311] 2. Tear Fern Test (TFT)

[0312] Use a capillary glass tube to collect 2-3 μL of tears from the lacrimal caruncle of the conjunctival sac of the lower eyelid, apply it on a clean glass slide, dry it at room temperature for 5-10 minutes, and then analyze the crystal image under an optical microscope and classify it into grades. Normal patients have good fern-like crystal formation, and the entire field of vision is covered with uniform fern-like branches. Patients with mucin deficiency, such as dry eye syndrome, have reduced or even disappeared fern-like crystals, and there are large areas without branches in the field of vision. Among them, grade III or IV indicates mucin deficiency. The grading standard is shown in Table 2, and the test results are shown in Table 3. Compared with the blank group (good fern-like crystals), after 1 week of benzalkonium chloride intervention, it can be clearly seen under a digital microscope that the branches of the crystal image after intervention are reduced and the spatial intervals are increased, indicating that the benzalkonium chloride-induced mouse dry eye model is effective. After 1 week of drug intervention, the experimental results are shown in the attached figure. Figure 4 The results show that a represents the blank group, b represents the negative control group, c represents the positive control group, d represents the microemulsion group (microemulsion preparation in Example 2), e represents the microemulsion group (microemulsion preparation in Example 5), f represents the microemulsion group (microemulsion preparation in Example 11), and g represents the instant gel group (instant gel preparation in Example 8). The crystallization of the negative control group did not improve significantly. In comparison, the crystallization of the positive control group, microemulsion group (microemulsion preparation in Example 2), microemulsion group (microemulsion preparation in Example 5), microemulsion group (microemulsion preparation in Example 11), and instant gel group (instant gel preparation in Example 8) increased, and the space between the branches became denser. This shows that the homemade preparation can improve the lack of mucin in the mouse eye dryness model, and the effect is similar to that of the conventional preparation. quite.

[0313] Table 2 Crystallization image classification

[0314]

[0315] Table 3 Tear fern test

[0316]

[0317]

[0318] Effect Example 6 Eye Retention Time

[0319] Fifteen healthy rabbits (3-6 months old) with a body weight range of 2.0kg-2.5kg were selected. Before the experiment, the ocular surface of the rabbits was checked to confirm that there was no inflammation or any damage. The rabbits were randomly divided into three groups: A, B, and C, with 5 rabbits in each group.

[0320] Rabbits in group A were given the tacrolimus ophthalmic microemulsion preparation of Example 11, rabbits in group B were given the tacrolimus ophthalmic instant gel preparation of Example 12, and rabbits in group C were given the tacrolimus ophthalmic instant gel preparation of Example 9. Dosage: 30 μL. Before administration, blank tears were collected. Tears were collected 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, and 12h after administration. The drug concentration in tears was determined by LC-MS. The average drug-time curve of rabbit tears is shown in Figure 2. Figure 5 It can be seen that the concentrations of tacrolimus in tears of the three preparations gradually decreased after administration, and the drug concentrations of the two groups of microemulsion instant gels were higher than those of the microemulsion group 2h to 12h after administration, which indicates that the instant gel preparation can prolong the drug retention time in the eye.

[0321] Effect Example 7 Stability Study

[0322] The contents and related substances of the homemade preparations of Example 1, Example 2 and Example 8 were determined, and the preparations were refrigerated at 2°C-8°C. The stability was investigated using content, total impurities, average particle size and polydispersity index (PDI) as indicators. The average particle size and polydispersity index (PDI) were determined by a laser particle size analyzer (Z3000, NICOMP).

[0323] “Content” refers to the tacrolimus concentration measured by high performance liquid chromatography / theoretical concentration calculated from the amount of tacrolimus actually added×100%.

[0324] The determination method of "total impurities" is as follows: Chromatographic column: 4.6x 150mm 3.5μm; mobile phase: phase A: 6mM phosphoric acid: [acetonitrile: tert-butyl methyl ether (81:19)] (4:1), phase B: 6mM phosphoric acid: [acetonitrile: tert-butyl methyl ether (81:19)] (1:4); flow rate: 1.5ml / min; detection wavelength: 290nm; column temperature: 60℃; injection volume: 40μL; gradient elution program is as follows:

[0325]

[0326] The above determination method of "total impurities" refers to the United States Pharmacopoeia Tacrolimus Raw Material Quality Standard.

[0327] Table 4 Stability study of homemade preparations

[0328]

[0329] Note: "0 month" refers to the preparation just made.

[0330] The results are shown in Table 4. It can be seen that the content, related substances, and particle size distribution of the homemade preparations were not significantly different from those of month 0, indicating that the homemade preparations had good stability.

Claims

1. A tacrolimus ophthalmic microemulsion preparation, characterized in that: It contains tacrolimus, a solubilizer, and water; Wherein, the solubilizer comprises polyethylene glycol stearate and caprylic acid capric acid macrogol glyceride.

2. The tacrolimus ophthalmic microemulsion preparation according to claim 1, characterized in that: The content of tacrolimus is 0.01%-0.5%, preferably 0.02%-0.2%, more preferably 0.03%-0.1%, for example 0.01%, 0.03%, 0.05%, 0.1%, 0.15%, 0.2% or 0.5%, where the percentage is the mass percentage of tacrolimus in the tacrolimus ophthalmic microemulsion preparation; And / or, the content of the solubilizer is 0.1% to 20%, preferably 0.2% to 16%, where the percentage is the mass percentage of the solubilizer in the tacrolimus ophthalmic microemulsion preparation; And / or, the solubilizer further comprises one or more of polyoxyethylene hydrogenated castor oil, polyvinyl pyrrolidone, polyoxyethylene castor oil, propylene glycol monocaprylate, polysorbate, oleoyl polyoxyethylene glyceride, octylphenol polyoxyethylene ether, vitamin E polyethylene glycol succinate and poloxamer, wherein the polyoxyethylene castor oil is, for example, polyoxyethylene castor oil 35; the polysorbate is, for example, polysorbate-80; the poloxamer is, for example, poloxamer 188 and / or poloxamer 407; preferably, the solubilizer further comprises vitamin E polyethylene glycol succinate and poloxamer; And / or, the content of the polyethylene glycol stearate is 0.05%-10%, preferably 0.4%-6%, for example 0.05%, 0.4%, 0.7%, 3%, 4%, 7.5% or 10%, where the percentage is the mass percentage of the polyethylene glycol stearate in the tacrolimus ophthalmic microemulsion preparation; And / or, the polyethylene glycol stearate is 15-hydroxystearate polyethylene glycol; And / or, the content of the caprylic acid capric acid macrogol glyceride is 0.1%-6%, preferably 0.3%-4%, for example 0.1%, 0.3%, 0.5%, 2%, 3%, 5% or 6%, where the percentage is the mass percentage of the caprylic acid capric acid macrogol glyceride in the tacrolimus ophthalmic microemulsion preparation; And / or, the water is water for injection; And / or, the amount of water used is to make up the sum of the mass fractions of the components in the composition to 100%; and / or, the tacrolimus ophthalmic microemulsion preparation does not include a preservative; And / or, the average particle size of the tacrolimus ophthalmic microemulsion preparation is no more than 300 nm.

3. The tacrolimus ophthalmic microemulsion preparation according to claim 1, characterized in that: The tacrolimus ophthalmic microemulsion preparation further comprises an oil phase; Preferably, the oil phase is selected from one or more of medium chain triglycerides, almond oil, castor oil, soybean oil, corn oil, mineral oil, peanut oil and sheep oil, preferably medium chain triglycerides and / or castor oil; Preferably, the content of the oil phase is 0.05%-3%, preferably 0.2%-1%, where the percentage is the mass percentage of the oil phase in the tacrolimus ophthalmic microemulsion preparation; Preferably, the oil phase comprises medium chain triglycerides, and the content of the medium chain triglycerides is 0.1% to 3%, for example, 0.1%, 0.15%, 0.2%, 0.3%, 1.5% or 3%, where the percentage is the mass percentage of the medium chain triglycerides in the tacrolimus ophthalmic microemulsion preparation; Preferably, the oil phase comprises castor oil, and the content of the castor oil is 0.5% to 2%, for example 0.5% or 2%, where the percentage is the mass percentage of the castor oil in the tacrolimus ophthalmic microemulsion preparation; And / or, the tacrolimus ophthalmic microemulsion preparation further comprises an osmotic pressure regulator; Preferably, the osmotic pressure regulator is glycerol, sodium chloride or mannitol, preferably glycerol; Preferably, the dosage of the osmotic pressure regulator is such that the osmotic pressure of the tacrolimus ophthalmic microemulsion preparation is 200 to 400 mOsmol / kg; And / or, the pH value of the tacrolimus ophthalmic microemulsion preparation is 5 to 8, preferably the pH value is 6 to 8, for example, the pH value is 7; And / or, the tacrolimus ophthalmic microemulsion preparation further comprises a pH regulator; Preferably, the pH adjuster is an inorganic acid, an inorganic base, an organic base or a buffer; Wherein, the inorganic acid is, for example, hydrochloric acid, phosphoric acid or boric acid, wherein the hydrochloric acid is preferably 1 mol / L hydrochloric acid; the phosphoric acid is preferably 5% phosphoric acid; Wherein, the inorganic base is, for example, sodium hydroxide, and the sodium hydroxide is preferably added in the form of a 1 mol / L sodium hydroxide aqueous solution; Wherein, the organic base is, for example, triethanolamine, triethylamine or tromethamine, wherein the tromethamine is preferably added in the form of a 2% (w / v) tromethamine aqueous solution; The buffer is, for example, sodium phosphate buffer, potassium phosphate buffer, sodium citrate buffer or boric acid buffer.

4. The tacrolimus ophthalmic microemulsion preparation according to claim 1, characterized in that: The tacrolimus ophthalmic microemulsion preparation comprises the following components: tacrolimus, 15-hydroxystearate polyethylene glycol ester, caprylic acid capric acid polyethylene glycol glyceride, castor oil and glycerin, and the balance is water; Preferably, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.05%-0.15% tacrolimus, 3%-10% 15-hydroxystearate polyethylene glycol ester, 2%-6% caprylic acid capric acid polyethylene glycol glyceride, 0.5%-2% castor oil and 0.5%-2% glycerol, the balance being water, and the percentages are the mass percentages of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7; Or, the tacrolimus ophthalmic microemulsion preparation comprises the following components: tacrolimus, 15-hydroxystearate polyethylene glycol ester, caprylic acid capric acid polyethylene glycol glyceride, medium chain triglyceride and glycerol, and the balance is water; Preferably, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.03%-0.5% tacrolimus, 0.4%-7.5% 15-hydroxystearate polyethylene glycol ester, 0.3%-5% caprylic capric acid polyethylene glycol glyceride, 0.15%-3% medium chain triglyceride and 0.5%-2.5% glycerol, the balance is water, and the percentage is the mass percentage of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7; Or, the tacrolimus ophthalmic microemulsion preparation comprises the following components: tacrolimus, 15-hydroxystearate polyethylene glycol ester, caprylic acid capric acid polyethylene glycol glyceride, medium chain triglyceride and sodium chloride, and the balance is water; Preferably, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.01%-0.05% tacrolimus, 0.05%-0.3% 15-hydroxystearate polyethylene glycol ester, 0.1%-0.5% caprylic capric acid polyethylene glycol glyceride, 0.1%-0.3% medium chain triglyceride and 0.8%-1.5% sodium chloride, the balance being water, and the percentages are the mass percentages of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7; Or, the tacrolimus ophthalmic microemulsion preparation comprises the following components: tacrolimus, 15-hydroxystearate polyethylene glycol, caprylic acid capric acid polyethylene glycol glyceride and glycerol, and the balance is water; Preferably, the tacrolimus ophthalmic microemulsion preparation comprises the following components: 0.1%-0.5% tacrolimus, 2%-6% 15-hydroxystearate polyethylene glycol ester, 2%-6% caprylic capric acid polyethylene glycol glyceride and 2%-2.5% glycerol, the balance being water, and the percentages are the mass percentages of each component in the tacrolimus ophthalmic microemulsion preparation; the pH value of the tacrolimus ophthalmic microemulsion preparation is 7.

5. A method for preparing the tacrolimus ophthalmic microemulsion preparation according to any one of claims 1 to 4, characterized in that: It includes the following steps: The components of the tacrolimus ophthalmic microemulsion preparation are mixed to obtain a uniform system, and the system is sterilized by filtering through a filter membrane to obtain the tacrolimus ophthalmic microemulsion preparation.

6. A tacrolimus instant gel preparation for ophthalmology, characterized in that: It contains tacrolimus, a solubilizer, a gel base and water.

7. The instant tacrolimus ophthalmic gel preparation according to claim 6, characterized in that: The content of tacrolimus is 0.01%-0.5%, preferably 0.02%-0.2%, more preferably 0.03%-0.1%, such as 0.03% or 0.05%, where the percentage is the mass percentage of tacrolimus in the tacrolimus instant ophthalmic gel preparation; And / or, the content of the solubilizer is 0.1% to 20%, preferably 0.3% to 16%, where the percentage is the mass percentage of the solubilizer in the tacrolimus ophthalmic instant gel preparation; And / or, the solubilizer includes one or more of polyoxyethylene hydrogenated castor oil, polyvinyl pyrrolidone, polyoxyethylene castor oil, propylene glycol monocaprylate, polysorbate, oleoyl polyoxyethylene glyceride, octylphenol polyoxyethylene ether, stearic acid polyethylene glycol ester, caprylic acid capric acid polyethylene glycol glyceride, vitamin E polyethylene glycol succinate and poloxamer; wherein the polyoxyethylene castor oil is, for example, polyoxyethylene castor oil 35; the polysorbate is, for example, polysorbate-80; the stearic acid polyethylene glycol ester is, for example, 15-hydroxystearate polyethylene glycol ester; the poloxamer is, for example, poloxamer 188 and / or poloxamer 407; Preferably, the solubilizer comprises 15-hydroxystearate polyethylene glycol, and the content of the 15-hydroxystearate polyethylene glycol is 0.1%-10%, preferably 0.4%-6%, more preferably 0.4%-3%, for example 0.4%, 1% or 3%, where the percentage is the mass percentage of the 15-hydroxystearate polyethylene glycol in the tacrolimus ophthalmic instant gel preparation; Preferably, the solubilizer comprises caprylic acid capric acid macrogol glyceride, and the content of the caprylic acid capric acid macrogol glyceride is 0.1%-6%, preferably 0.3%-4%, more preferably 0.3%-2%, for example 0.3%, 1.5% or 2%, where the percentage is the mass percentage of the caprylic acid capric acid macrogol glyceride in the tacrolimus ophthalmic instant gel preparation; And / or, the gel matrix comprises one or more of carbomer, poloxamer, xanthan gum, gellan gum, sodium carboxymethyl cellulose, polycarbophil and sodium alginate; wherein the gellan gum is, for example, low acyl gellan gum, the poloxamer is, for example, poloxamer 188 and / or poloxamer 407, and the gel matrix is ​​preferably poloxamer or low acyl gellan gum; And / or, the content of the gel matrix is ​​0.1% to 30%, preferably 0.2% to 20%, where the percentage is the mass percentage of the gel matrix in the tacrolimus instant ophthalmic gel preparation; Preferably, the gel matrix includes poloxamer 188, and the amount of poloxamer 188 is 2% to 10%, for example, 5%, where the percentage is the mass percentage of poloxamer 188 in the tacrolimus instant ophthalmic gel preparation; Preferably, the gel matrix includes poloxamer 407, and the amount of poloxamer 407 is 18% to 30%, for example, 20%, where the percentage is the mass percentage of the poloxamer 407 in the tacrolimus ophthalmic instant gel preparation; Preferably, the gel matrix comprises low acyl gellan gum, and the amount of the low acyl gellan gum is 0.1% to 2%, for example, 0.5%, where the percentage is the mass percentage of the low acyl gellan gum in the tacrolimus ophthalmic instant gel preparation; And / or, the instant tacrolimus ophthalmic gel preparation further comprises an oil phase; Preferably, the oil phase is selected from one or more of medium chain triglycerides, almond oil, castor oil, soybean oil, corn oil, mineral oil, peanut oil and sheep oil, preferably medium chain triglycerides and castor oil; Preferably, the content of the oil phase is 0.05%-3%, preferably 0.2%-1%, where the percentage is the mass percentage of the oil phase in the tacrolimus ophthalmic instant gel preparation; Preferably, the oil phase comprises medium chain triglycerides, and the content of the medium chain triglycerides is 0.1%-1%, such as 0.15% or 0.3%, and the percentage is the mass percentage of the medium chain triglycerides in the tacrolimus ophthalmic instant gel preparation; Preferably, the oil phase comprises castor oil, and the content of the castor oil is 0.1%-1%, such as 0.5%, where the percentage is the mass percentage of the castor oil in the tacrolimus instant ophthalmic gel preparation; And / or, the instant tacrolimus ophthalmic gel preparation further comprises an osmotic pressure regulator; Preferably, the osmotic pressure regulator is glycerol, sodium chloride or mannitol, more preferably glycerol; Preferably, the dosage of the osmotic pressure regulator is such that the osmotic pressure of the instant tacrolimus ophthalmic gel preparation is 200-400 mOsmol / kg; And / or, the pH value of the tacrolimus instant ophthalmic gel preparation is 5 to 8, preferably 6 to 8, for example, 7; And / or, the tacrolimus ophthalmic microemulsion preparation further comprises a pH regulator; Preferably, the pH adjuster is an inorganic acid, an inorganic base, an organic base or a buffer; Wherein, the inorganic acid is, for example, hydrochloric acid, phosphoric acid or boric acid, wherein the hydrochloric acid is preferably 1 mol / L hydrochloric acid; the phosphoric acid is preferably 5% phosphoric acid; Wherein, the inorganic base is, for example, sodium hydroxide, and the sodium hydroxide is preferably added in the form of a 1 mol / L sodium hydroxide aqueous solution; Wherein, the organic base is, for example, triethanolamine, triethylamine or tromethamine, wherein the tromethamine is preferably added in the form of a 2% (w / v) tromethamine aqueous solution; Wherein, the buffer is, for example, sodium phosphate buffer, potassium phosphate buffer, sodium citrate buffer or boric acid buffer; And / or, the water is water for injection; And / or, the amount of water used is to make up the sum of the mass fractions of the components in the composition to 100%; And / or, the tacrolimus ophthalmic instant gel preparation does not include a preservative; And / or, the average particle size of the tacrolimus instant ophthalmic gel preparation is no more than 300 nm.

8. The instant tacrolimus ophthalmic gel preparation according to claim 6, characterized in that: The instant tacrolimus ophthalmic gel preparation comprises the following components: tacrolimus, 15-hydroxystearate polyethylene glycol, caprylic acid capric acid polyethylene glycol glyceride, poloxamer 188, poloxamer 407 and medium chain triglyceride, and the balance is water; Preferably, the tacrolimus instant ophthalmic gel preparation comprises the following components: 0.01%-0.5% tacrolimus, 0.1%-1% 15-hydroxystearate polyethylene glycol ester, 0.1%-1% caprylic capric acid polyethylene glycol glyceride, 2%-8% poloxamer 188, 18%-25% poloxamer 407 and 0.1%-0.5% medium chain triglyceride, the remainder is water, and the percentage is the mass percentage of each component in the tacrolimus instant ophthalmic gel preparation; the pH value of the tacrolimus instant ophthalmic gel preparation is 7; Or, the instant tacrolimus ophthalmic gel preparation comprises the following components: tacrolimus, 15-hydroxystearate polyethylene glycol, caprylic acid capric acid polyethylene glycol glycerol, low acyl gellan gum, medium chain triglyceride and mannitol, and the balance is water; Preferably, the tacrolimus instant ophthalmic gel preparation comprises the following components: 0.01%-0.1% tacrolimus, 0.4%-3% 15-hydroxystearate polyethylene glycol, 0.5%-3% caprylic capric acid polyethylene glycol glyceride, 0.1%-2% low acyl gellan gum, 0.1%-1% medium chain triglyceride and 2.5%-3.5% mannitol, the balance being water, and the percentages are the mass percentages of each component in the tacrolimus instant ophthalmic gel preparation; the pH value of the tacrolimus instant ophthalmic gel preparation is 7; Or, the instant tacrolimus ophthalmic gel preparation comprises the following components: tacrolimus, 15-hydroxystearate polyethylene glycol, caprylic acid capric acid polyethylene glycol glyceride, poloxamer 188, poloxamer 407, castor oil, and the balance is water; Preferably, the tacrolimus instant ophthalmic gel preparation comprises the following components: 0.01%-0.1% tacrolimus, 0.4%-5% 15-hydroxystearate polyethylene glycol ester, 0.3%-4% caprylic capric acid polyethylene glycol glyceride, 2%-8% poloxamer 188, 18%-25% poloxamer 407, 0.1%-1% castor oil, and the balance is water, and the percentage is the mass percentage of each component in the tacrolimus instant ophthalmic gel preparation; the pH value of the tacrolimus instant ophthalmic gel preparation is 7.

9. A method for preparing the instant tacrolimus ophthalmic gel preparation according to any one of claims 6 to 8, characterized in that: It includes the following steps: The components of the tacrolimus instant ophthalmic gel preparation are mixed to obtain a uniform system, and the system is sterilized by filtering through a filter membrane to obtain the tacrolimus instant ophthalmic gel preparation.

10. Use of the tacrolimus ophthalmic microemulsion preparation according to any one of claims 1 to 4 and the tacrolimus ophthalmic instant gel preparation according to any one of claims 6 to 8 in the preparation of a drug for treating dry eye.

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