Composition for improving eye absorption of medicine as well as preparation method and application of composition

Abstract

The invention discloses a composition for improving eye absorption of a medicine as well as a preparation method and application of the composition, belongs to the technical field of pharmaceutical preparations, and relates to an ophthalmic medicine. The composition for improving the eye absorption of the medicine is an oil-in-water type nanoemulsion, the particle size of oil drops of the nanoemulsion is not greater than 600 nm, and the composition comprises the following components in parts by mass: 0.01-2.0% of an active ingredient photosensitizer, 0.5-6.0% of an oil phase, 0.01-3.0% of an emulsifier and the balance of water, the composition comprises the following components in percentage by mass: 0.1-4.0% of an emulsion aid, 0.01-2.0% of a pH regulator, 0.01-1.0% of a pH buffering agent, and the balance of water and an osmotic pressure regulator, wherein the mass of the emulsion aid accounts for 0.1-4.0% of the total mass of the composition, and the mass of the pH regulator accounts for 0.01-2.0% of the total mass of the composition. The biological adhesion is high, the retention time on the ocular surface is long, the corneal epithelium penetrating capacity is high, and the medication compliance of a patient is good.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, relates to ophthalmic drugs, and specifically relates to an emulsion composition for improving ocular absorption of drugs, and a preparation method and application thereof. Background Art

[0002] Corneal collagen cross-linking (CXL) is a treatment method to prevent the progression of keratoconus from a pathological perspective. After the photosensitizer (riboflavin) enters the corneal stroma, it is stimulated by ultraviolet A with a wavelength of 370 nm to produce reactive oxygen species, which in turn promotes amino cross-linking between collagen fibers, thereby increasing corneal hardness and biomechanical stability of the corneal stroma, and ultimately preventing the gradual and irregular changes in corneal shape. In addition, studies have shown that when the riboflavin concentration in the corneal stroma is 15 μg / g, the absorption rate of ultraviolet rays by corneal tissue can be increased from 32% to 95%, thereby attenuating the energy of ultraviolet rays when passing through the cornea, preventing it from causing damage to the corneal endothelium and intraocular tissues. Therefore, the riboflavin concentration in the corneal stroma must reach a sufficient level to safely and effectively carry out CXL treatment.

[0003] Riboflavin phosphate is an essential vitamin for the human body. As a negatively charged water-soluble macromolecule, it is often formulated into water-soluble eye drops for use in the treatment of ophthalmic diseases (topical administration). After the eye drops are instilled into the ocular surface, they need to pass through two barriers, the tear film and the corneal epithelium, before riboflavin can successfully reach the corneal stroma. However, the lipid layer on the outside of the tear film is hydrophobic, which will create a restrictive barrier for hydrophilic drugs such as riboflavin phosphate; secondly, the mucin layer on the inner layer of the tear film is negatively charged, which will hinder riboflavin phosphate from penetrating the mucin layer of the tear film through electrostatic repulsion; thirdly, the corneal epithelium is composed of tightly connected squamous cells with a high lipid content, which will also limit the passage of hydrophilic riboflavin phosphate. Therefore, the current CXL treatment process first requires the removal of epithelial tissue in the central 5-9 mm area of ​​the cornea under anesthesia (in Europe, epithelial removal has become the surgical standard and is approved for use in CXL treatment) to facilitate the penetration of riboflavin sodium phosphate into the corneal stroma; next, 0.1% riboflavin sodium phosphate (dissolved in 20% dextran) solution is continuously applied for 30 minutes (once every 3 minutes) to make the riboflavin concentration in the corneal stroma reach 15 μg / g; then ultraviolet irradiation surgery is performed. After the treatment, antibiotic eye ointment is needed to prevent eye infection caused by corneal defects, and contact lenses soaked in fluoroxacin are worn until the corneal epithelium heals. Although this treatment can effectively prevent the development of keratoconus, the operation is time-consuming, and pain is inevitably caused when removing the corneal epithelium, causing discomfort to the patient. There are also problems such as long postoperative recovery time and possible postoperative complications related to corneal abrasion (such as corneal opacity, corneal infection, corneal melting, and corneal edema). In addition, to avoid ultraviolet radiation damage to the corneal endothelium and lens, the thickness of the corneal stroma after epithelial removal is greater than 400 microns, which is the basic requirement for CXL treatment. For patients with corneal thickness between 350 and 400 microns, either hypotonic riboflavin solution is applied before surgery to make the corneal stroma edema thickness reach more than 400 microns; or contact lens-assisted collagen cross-linking (CACXL) is used. This method temporarily increases corneal thickness by placing a contact lens on the cornea to reduce ultraviolet radiation during surgery. Although hypotonic drug application before surgery can temporarily increase corneal thickness, this method has two significant disadvantages. First, when using hypotonic solution for drug application, the increase in chemical gradient pressure may cause damage to the tight junction of the corneal epithelium; second, this effect is short-lived, and corneal thickness needs to be monitored during surgery. Its safety and effectiveness after surgery need to be further explored.CACXL is safe and effective for patients with thinner keratoconus, but the thickness of soft contact lenses cannot be customized, and the hydration state of different contact lens materials is different. The UV transmittance of contact lenses and corneal stroma is also different. Riboflavin membranes and soaked contact lenses also affect the absorption of UV rays, reducing the surface irradiance at the level of the corneal stroma by 40-50%. In addition, there is a certain demand for oxygen in the CXL reaction. The diffusion of oxygen in the CACXL treatment regimen is hindered by the corneal contact lens, and the effect of cross-linking is also affected. Therefore, more extensive clinical data is needed to verify the safety of this technology and determine its treatment parameters. Even with the above methods, it is generally believed that patients with too thin keratoconus with a corneal thickness of less than 300 microns cannot undergo CXL treatment.

[0004] The integrity of the corneal epithelium is very important for maintaining the health of the ocular surface and can effectively resist the invasion of harmful substances or microorganisms. If the epithelium can be preserved, the corneal thickness limit of the treatment can be relaxed while reducing the pain of the patient and the complications. Therefore, transepithelial CXL treatment is a current research hotspot. Among them, improving the transepithelial permeability of riboflavin phosphate is the key. Currently, the commonly used strategies are to use penetration enhancers, ultrasonic introduction, needle injection, iontophoresis and other methods. Benzalkonium chloride, tromethamine, EDTA and its salts can all be used as penetration enhancers to improve the penetration of riboflavin into the corneal epithelium. Patent WO2010 / 023705 reported the use of EDTA or its salts as a penetration enhancer to improve the transepithelial permeability of riboflavin phosphate, but compared with the traditional epithelial CXL treatment, the biomechanical properties of the cornea of ​​patients treated with the penetration enhancer method after surgery were only about 1 / 5 of those of the traditional epithelial CXL. The literature Invest Ophthalmol Vis Sci. 2013, 54(8): 5908-5912 reported the use of ultrasound to promote transepithelial penetration of riboflavin, but the riboflavin concentration in the corneal stroma was only about 30% of that in traditional epithelial CXL treatment. The literature Am J Ophthalmol. 2011, 152(1): 22-27 reported the use of needle injection to increase the concentration of riboflavin in the corneal stroma. Although this method has a clear efficacy, it needs to be combined with stroma ring implantation or refractive surgery during the operation, and riboflavin is injected through a corneal tunnel micro-incision, which is delicate and complicated. Patent CN 103384514 A and Patent CN 104023706 B disclose the use of iontophoresis to promote transepithelial permeation of riboflavin. This method can make the riboflavin concentration of the corneal stroma reach the surgical requirements while keeping the corneal epithelium intact. However, the amount of drug ion introduction is greatly affected by the solution concentration, solvent parasitic ions, current intensity, current time, etc. In order to increase the riboflavin concentration in the stroma, Patent CN103384514 A adopts a method of reducing the initial pH of the composition to 5.5; Patent CN 104023706 B adopts a method of reducing the osmotic pressure of the composition to 90-100 mOsm / l. These compositions inevitably cause discomfort to patients when applying the medicine, and their safety and effectiveness still need longer follow-up and more clinical bases to evaluate.

[0005] In order to solve the above-mentioned defects of the prior art, it is a major challenge currently to develop a safe, effective and non-invasive photosensitizer ocular drug delivery composition and use it for transepithelial CXL treatment.

[0006] Adv Mater. 2022, 34(21): 2109865 reported that riboflavin was loaded into positively charged, hydrophobic ZIF-8 nanoparticles to prepare riboflavin composite nanomaterials. The corneal permeability of riboflavin was significantly improved while retaining the epithelium. This technology is expected to provide a new solution for transepithelial CXL treatment. However, this technology is still in the laboratory research and development stage, and further optimization and verification of the effects of ZIF-8 particle size, morphology, and dispersibility on its release kinetics, as well as more clinical experimental data, are needed to ensure the safety and effectiveness of this technology. In addition, a large number of studies have shown that ZIF-8 will slowly hydrolyze in aqueous solution. The smaller the particle size and the lower the concentration, the faster the hydrolysis rate. Eye drops made with this nanomaterial as a carrier also need to solve the storage stability during the shelf life. At the same time, the Zn2+ and organic ligand 2-methylimidazole produced by the hydrolysis of ZIF-8 may be irritating and sensitizing to the eyes. These are problems that need to be solved but have not yet been solved. In addition, although the above-mentioned literature confirms its advantages in CXL treatment, the literature ACS Materials Lett. 2021, 3(2):255–260 reported that in the presence of water, ZIF-8 can absorb UVA photon energy and accelerate its decomposition process. This decomposition is different from the above-mentioned hydrolysis process. Therefore, a large number of experiments are needed to determine the UVA irradiance and total energy parameters in this treatment regimen, as well as more clinical bases to determine the impact of the decomposition products on patients.

[0007] The literature PLoS ONE. 2013, 8(6): e66408 reported the use of a cationic nanoemulsion delivery system to achieve trans-corneal epithelial penetration of riboflavin and its phosphate. The emulsion formulation and components are as follows: propylene glycol dicaprylate / dicaprate (Captex) as the oil phase, with an amount of 5% w / w; surfactants are soybean phosphatidylcholine (SPC), with an amount of 12% w / w, polyoxyethylene sorbitan monolaurate (Tween), with an amount of 12% w / w, and ethylene oxide / propylene oxide block copolymer (Pluronic), with an amount of 2% w / w; stearylamine (0.3% w / w) as a cationic agent; riboflavin (0.5% or 0.1% w / w); and the balance is normal saline.

[0008] However, the U.S. FDA-approved drug inactive ingredient database stipulates the maximum usage per unit dose / maximum daily usage / exposure of various compounds, among which the maximum daily exposure of SPC is 6 mg, the maximum usage per unit of Tween for topical ocular administration is 0.25% w / v, and the maximum usage per unit of Pluronic is 0.2% w / v. The amount of surfactant in the above prescription far exceeds the maximum usage stipulated by the FDA and cannot be marketed for use.

[0009] Although the above method can improve the transepithelial permeability of riboflavin phosphate to a certain extent, there are still problems such as poor patient compliance, many postoperative complications, difficulty in reaching an effective therapeutic concentration of riboflavin in the corneal stroma, insufficient long-term clinical safety data, and the prescription has not yet met the requirements for marketing. Therefore, the art urgently needs to develop a safe and effective ophthalmic liquid preparation composition that can improve the bioavailability of photosensitizers. The successful development of this combination will be of great significance in clinical applications and has huge market prospects.

[0010] In order to solve the above-mentioned defects of existing photosensitizer ophthalmic preparations, the applicant has developed a composition for improving the ocular absorption of drugs. Summary of the invention

[0011] The object of the present invention is to provide a composition for improving the ocular absorption of drugs.

[0012] Another object of the present invention is to provide a method for preparing the above ophthalmic composition.

[0013] Another object of the present invention is to provide use of the above ophthalmic composition.

[0014] The purpose of the present invention can be achieved by the following technical solutions: A composition for improving ocular absorption of drugs, wherein the ophthalmic composition is an oil-in-water nanoemulsion, the oil droplet diameter of the nanoemulsion is not greater than 600 nm, and comprises the following components in parts by weight: 0.01 to 2.0% of the total mass of the composition is an active ingredient, a photosensitizer, 0.5-6.0% of the total mass of the composition is an oil phase, 0.01 to 3.0% of the total mass of the composition is an emulsifier, 0.1 to 4.0% of the total mass of the composition is an emulsifier, 0.01 to 2.0% of the total mass of the composition is a pH adjuster, 0.01 to 1.0% of the total mass of the composition is a pH buffer, The balance is water and osmotic pressure regulator.

[0015] Furthermore, the active ingredient photosensitizer is rose Bengal, bacterial chlorophyll, riboflavin-5-phosphate or its salt or its medically acceptable derivatives in various forms. In the present invention, they can be used alone or in any combination of any two or more in any proportion.

[0016] The oil phase is medium chain triglyceride, long chain triglyceride, olive oil, castor oil and its derivatives, corn oil, soybean oil, cottonseed oil, walnut oil, sunflower oil, peanut oil, palm oil, coconut oil, almond oil, sesame oil, mineral oil, modified propylene glycol, propylene glycol diester, tricaprylic acid capric acid glyceride, saffron oil. In the present invention, they can be used alone or any two or more of them can be mixed in any proportion.

[0017] The emulsifier is egg yolk lecithin, soybean lecithin, Tween, Span, polyoxyethylene, polyoxypropylene, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, sucrose monolaurate, monoglycerol fatty acid ester, triglycerol fatty acid ester, polyglycerol stearate, fatty acid sorbitan, polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether or polyoxyethylene polyoxypropylene copolymer, sodium lauryl sulfate, tyloxapol, poloxamer, octoxynol. In the present invention, they can be used alone or any two or more of them can be mixed in any proportion.

[0018] The emulsifier is ethanol, n-butanol, ethylene glycol, propylene glycol, glycerol, polyethylene glycol, polyglycerol ester, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, glyceryl monostearate, stearic acid or stearyl alcohol. In the present invention, they can be used alone or in any combination of any two or more in any proportion.

[0019] The pH value of the ophthalmic composition is 5.0-9.0.

[0020] The pH regulator is glacial acetic acid, citric acid, lactic acid, phosphoric acid, hydrochloric acid, boric acid, tromethamine, sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, sodium citrate and its hydrate, borax, EDTA and its various forms of salts, DTPA and its various forms of salts, amine ethanolamine, diethanolamine, triethanolamine. In the present invention, they can be used alone or any two or more of them can be mixed in any proportion.

[0021] The pH buffer is acetate buffer, citrate buffer, tris buffer, phosphate buffer, carbonate buffer, borate buffer, 6-aminocaproic acid, amino acid salts. In the present invention, they can be used alone or in any combination of two or more in any proportion.

[0022] The ophthalmic composition is an oil-in-water nanoemulsion, and the oil droplet diameter of the nanoemulsion is no greater than 600 nm, preferably no greater than 200 nm.

[0023] The present invention also provides a method for preparing the above-mentioned composition for improving ocular absorption of drugs, comprising the following steps: 1) Weigh the oil phase, emulsifier (oily) and other oil phase components in proportion, stir, heat and dissolve them to form the emulsion oil phase; 2) Take a certain amount of water, add the emulsifier (water-based), emulsifier, pH buffer, and water-soluble macromolecular drug component weighed in proportion, stir to dissolve, and use as the emulsion water phase; If it is a multi-dose product, one or more preservatives may be added when preparing the emulsion oil phase or water phase, and the amount of the preservative added is 0.001 to 6.7% of the total mass of the product; 3) Add the emulsion oil phase to the water phase under rapid stirring, and after the addition, perform high shear emulsification to minimize the oil droplets, and then perform high-pressure homogenization at a pressure of not less than 8000 psi until the particle size of the emulsion oil droplets meets the formulation requirements to obtain a crude emulsion, and finally add an osmotic pressure regulator and the remaining amount of water to adjust the emulsion pH to 5.0-9.0; 4) The product is obtained after sterilization and packaging.

[0024] The present invention also provides the use of the above-mentioned ophthalmic pharmaceutical composition in the preparation of drugs for preventing or treating corneal and conjunctival damage, glaucoma, scleral thinning, choroidal thinning, axial myopia progression, and relieving visual fatigue.

[0025] The inventive concept of the present invention is to prepare the photosensitive drug into an oil-in-water nanoemulsion, and to achieve the transepithelial absorption of such drug by non-invasive local administration to the eye, and to promote the absorption of the drug by the eye while reducing the side effects of the drug and the administration route, so as to improve its intraocular bioavailability, and at the same time, increase the patient's medication compliance.

[0026] During implementation, the composition of the present invention is an oil-in-water nanoemulsion, which can improve the ability of the photosensitizer to penetrate the corneal epithelial barrier, and can also improve the solubility of lipophilic compounds, thereby improving the bioavailability of these compounds; by selecting a suitable oil phase, emulsifier and co-emulsifier to prepare an emulsion, water-soluble macromolecules and lipophilic compounds will be tightly wrapped by the lipophilic part of the emulsifier and co-emulsifier and the oil phase, so as to achieve the ability to increase the amount of ocular absorption of the photosensitizer and the solubility of the lipophilic compound, and at the same time, the drug is prepared into a nanoemulsion, and its local concentration is high, the specific surface area is large, the dispersion speed on the ocular surface is fast, and the bioadhesion is strong, etc., to increase the solubility of the drug and the ability of trans-corneal epithelial absorption, and finally, to improve the bioavailability of such drugs and the medication compliance of patients.

[0027] Compared with the prior art, the present invention has the following advantages: (1) Riboflavin phosphate in commonly used preparations is negatively charged, and the tear film mucin layer and corneal cells are also negatively charged, which repel each other. The nanoemulsion of the present invention is positively charged / has a low Zeta potential. After application, the bioadhesion of the emulsion is greatly improved, and it can remain on the ocular surface for a long time; (2) The lipophilic part of the emulsifier and the oil phase tightly encapsulate the water-soluble macromolecular drug, enhancing its ability to penetrate the fat-soluble corneal epithelium; (3) The concentration of the drug in the discontinuous phase emulsion droplets (oil phase) is higher (compared with the aqueous preparation of the same concentration), which can form a larger concentration gradient difference and enhance the permeability of the drug; (4) Nanoemulsions have a small particle size, which facilitates penetration of the corneal epithelium; (5) The emulsion has good dispersibility and will quickly and evenly disperse on the ocular surface after application; (6) Compared with the marketed preparation Photrexa Viscous, the viscosity is lower, which is conducive to drug diffusion; (7) The emulsion formula is close to the composition of human tears, and patients have good medication compliance.

[0028] In summary, the present invention improves the bioavailability of the drug by increasing the amount of drug absorbed by the eye. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is a photo of corneal yellowing in Example 1; Figure 2 This is a photo of corneal yellowing in Example 2; Figure 3 This is a photo of corneal yellowing in Example 3; Figure 4 This is a photo of corneal yellowing in Example 4; Figure 5 This is a photo of corneal yellowing in Example 5; Figure 6 This is a photo of corneal yellowing in Example 6; Figure 7 This is a photo of corneal yellowing in Example 7; Figure 8 This is a photo of corneal yellowing in Example 8; Fig. 9 This is a photo of corneal yellowing in Example 9; Fig.10 This is a photo of corneal yellowing in Example 10; Fig.11 This is a photo of corneal yellowing in Comparative Example 1; Fig.12 This is a photo of corneal yellowing in comparative example 2; Fig.13 This is a photo of corneal yellowing in the control group. Implementation

[0030] The specific implementation of the present invention is described in detail below in conjunction with the accompanying drawings. It should be understood that the specific implementation described here is only used to illustrate and explain the present invention, and is not used to limit the present invention.

[0031] The endpoints and any values ​​of the ranges disclosed in this specification are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed in this specification.

[0032] In the following examples and comparative examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used, if no manufacturer is specified, are all conventional products that can be purchased from the market and can be used for drug production. Example

[0033] 1) Preparation of oil phase: weigh the prescribed amount of light mineral oil (1.0%), heavy mineral oil (3.0%) and octoxynol-40 (0.25%), heat and stir to obtain the oil phase; 2) Preparation of aqueous phase: Measure 50 mL of water for injection, add the prescribed amount of glycerol (1.6%), polysorbate 80 (0.23%), disodium edetate (0.02%), borax (0.45%), boric acid (0.015%) and riboflavin-5'-(dihydrogen phosphate) monosodium salt (0.153%) and stir until a transparent solution is obtained to obtain the aqueous phase; 3) Preparation of emulsion: The oil phase was added to the water phase under rapid stirring. The resulting liquid was sheared and homogenized until the emulsion particle size was 183 nm to obtain a crude emulsion. The crude emulsion was diluted to 100 mL with the remaining amount of water in the prescription, and then the pH was adjusted to 7.0 to obtain riboflavin-5'-(dihydrogen phosphate) monosodium salt emulsion.

[0034] 4) Sterilization and packaging: Sterilize the emulsion prepared in step 3, take samples to check appearance, particle size, pH value, osmotic pressure, sterility, viscosity, content and impurities, and fill after passing the test. Example

[0035] 1) Preparation of oil phase: weigh the prescribed amount of medium chain triglycerides (2.0%) and tyloxapol (0.3%), heat and stir to obtain the oil phase; 2) Preparation of aqueous phase: Measure 50 mL of water for injection, add the prescribed amount of mannitol (2.0%), poloxamer-188 (0.2%), DTPA (0.01%), disodium hydrogen phosphate (0.015%), sodium dihydrogen phosphate (0.003%) and riboflavin-5'-(dihydrogen phosphate) monosodium salt (0.153%) and stir until a transparent solution is obtained to obtain the aqueous phase; 3) Preparation of emulsion: The oil phase was added to the water phase under rapid stirring. The resulting liquid was sheared and homogenized until the emulsion particle size was 95 nm to obtain a crude emulsion. The crude emulsion was diluted to 100 mL with the remaining amount of water in the prescription, and then the pH was adjusted to 7.0 to obtain riboflavin-5'-(dihydrogen phosphate) monosodium salt emulsion.

[0036] 4) Sterilization and packaging: Sterilize the emulsion prepared in step 3, take samples to check appearance, particle size, pH value, osmotic pressure, sterility, viscosity, content and impurities, and fill after passing the test. Example

[0037] 1) Preparation of oil phase: weigh castor oil (3.5%) and octoxynol-9 (0.3%) in the prescribed amount, heat and stir until a transparent solution is obtained to obtain the oil phase; 2) Preparation of aqueous phase: Measure 50 mL of water for injection, add the prescribed amount of mannitol (2.0%), polysorbate 80 (0.23%), citric acid (0.01%), tromethamine (0.1%) and riboflavin-5'-(dihydrogen phosphate) monosodium salt (0.153%) and stir until a transparent solution is obtained to obtain the aqueous phase; 3) Preparation of emulsion: The oil phase was added to the water phase under rapid stirring. The resulting liquid was sheared and homogenized until the emulsion particle size was 132 nm to obtain a crude emulsion. The crude emulsion was diluted to 100 mL with the remaining amount of water in the prescription, and then the pH was adjusted to 7.0 to obtain riboflavin-5'-(dihydrogen phosphate) monosodium salt emulsion.

[0038] 4) Sterilization and packaging: Sterilize the emulsion prepared in step 3, take samples to check appearance, particle size, pH value, osmotic pressure, sterility, viscosity, content and impurities, and fill after passing the test. Example

[0039] The emulsion formulation and dosage in reference PLoS ONE. 2013, 8(6): e66408 are different in that the dosage of the emulsifier Tween is 5% w / w. The emulsion preparation process is as follows: 1) Preparation of oil phase: weigh the prescribed amount of Captex (5%), Pluronic (2%), SPC (12%), Tween (5%) and stearylamine (0.3%), stir and dissolve to obtain the oil phase; 2) Preparation of aqueous phase: Measure 50 mL of water for injection, add the prescribed amount of riboflavin-5'-(dihydrogen phosphate) monosodium salt (0.153%) and stir until a transparent solution is obtained to obtain the aqueous phase; 3) Preparation of emulsion: The aqueous phase was added to the oil phase under vortex shaking. The resulting liquid was ultrasonically emulsified for 15 minutes (emulsification parameters: power 600 W; run for 1 minute, stop for 1 minute) to obtain a crude emulsion with an emulsion particle size of 276 nm. The crude emulsion was diluted to 100 mL with the remaining amount of water in the prescription, and then the pH was adjusted to 7.0 to obtain riboflavin-5'-(dihydrogen phosphate) monosodium salt emulsion.

[0040] 4) Sterilization and packaging: Sterilize the emulsion prepared in step 3, take samples to check appearance, particle size, pH value, osmotic pressure, sterility, viscosity, content and impurities, and fill after passing the test. Example

[0041] The emulsion formulation and dosage in reference PLoS ONE. 2013, 8(6): e66408 are different in that the dosage of the emulsifier SPC is 5% w / w. The emulsion preparation process is as follows: 1) Preparation of oil phase: weigh the prescribed amount of Captex (5%), Pluronic (2%), SPC (5%), Tween (12%) and stearylamine (0.3%) and stir to dissolve to obtain the oil phase; 2) Preparation of aqueous phase: Measure 50 mL of water for injection, add the prescribed amount of riboflavin-5'-(dihydrogen phosphate) monosodium salt (0.153%) and stir until a transparent solution is obtained to obtain the aqueous phase; 3) Preparation of emulsion: The aqueous phase was added to the oil phase under vortex shaking. The resulting liquid was ultrasonically emulsified for 15 minutes (emulsification parameters: power 600 W; run for 1 minute, stop for 1 minute) to obtain a crude emulsion with an emulsion particle size of 253 nm. The crude emulsion was diluted to 100 mL with the remaining amount of water in the prescription, and then the pH was adjusted to 7.0 to obtain riboflavin-5'-(dihydrogen phosphate) monosodium salt emulsion.

[0042] 4) Sterilization and packaging: Sterilize the emulsion prepared in step 3, take samples to check appearance, particle size, pH value, osmotic pressure, sterility, viscosity, content and impurities, and fill after passing the test. Example

[0043] The preparation method is basically the same as that of Example 2, except that in Example 6, the concentration of riboflavin-5'-(dihydrogen phosphate) monosodium salt is 0.076%. Example

[0044] The preparation method is basically the same as that of Example 2, except that in Example 7, the concentration of riboflavin-5'-(dihydrogen phosphate) monosodium salt is 0.765%. Example

[0045] The preparation method is basically the same as that in Example 2, except that 0.008% benzalkonium chloride is added in Example 8. Example

[0046] The preparation method is basically the same as that of Example 2, except that in Example 9, DTPA is not added.

[0047] The preparation method is basically the same as that of Example 2, except that in Example 10, the photosensitizer is 0.1% riboflavin.

[0048] 1) Preparation of oil phase: weigh the prescribed amount of medium chain triglycerides (2.0%) and tyloxapol (0.3%), heat and stir to obtain the oil phase; 2) Preparation of aqueous phase: Measure 50 mL of water for injection, add the prescribed amount of mannitol (2.0%), poloxamer-188 (0.2%), DTPA (0.01%), disodium hydrogen phosphate (0.015%), sodium dihydrogen phosphate (0.003%) and bacteriochlorophyll (0.27%), and stir until a transparent solution is obtained to obtain the aqueous phase; 3) Preparation of emulsion: The oil phase was added to the water phase under rapid stirring. The resulting liquid was sheared and homogenized until the emulsion particle size was 98 nm to obtain a crude emulsion. The crude emulsion was diluted to 100 mL with the remaining amount of water in the prescription, and then the pH was adjusted to 7.0 with disodium hydrogen phosphate to obtain a bacterial chlorophyll emulsion.

[0049] 4) Sterilization and packaging: Sterilize the emulsion prepared in step 3, take samples to check appearance, particle size, pH value, osmotic pressure, sterility, viscosity, content and impurities, and fill after passing the test.

[0050] 1) Preparation of oil phase: weigh the prescribed amount of light mineral oil (1.0%), heavy mineral oil (3.0%) and octoxynol-40 (0.25%), heat and stir to obtain the oil phase; 2) Preparation of aqueous phase: Measure 50 mL of water for injection, add the prescribed amount of glycerol (1.6%), polysorbate 80 (0.25%), disodium edetate (0.02%), borax (0.45%), boric acid (0.015%) and rose Bengal (0.3%), and stir until a transparent solution is obtained to obtain the aqueous phase; 3) Preparation of emulsion: The oil phase was added to the water phase under rapid stirring. The resulting liquid was sheared and homogenized until the emulsion particle size was 176 nm to obtain a crude emulsion. The crude emulsion was diluted to 100 mL with the remaining amount of water in the prescription, and then the pH was adjusted to 7.0 with boric acid to obtain Bengal rose red emulsion.

[0051] 4) Sterilization and packaging: Sterilize the emulsion prepared in step 3, take samples to check appearance, particle size, pH value, osmotic pressure, sterility, viscosity, content and impurities, and fill after passing the test.

[0052] Riboflavin sodium phosphate balanced salt solution with a concentration of 0.153%.

[0053] Riboflavin sodium phosphate balanced salt solution with a concentration of 1.53%.

[0054] Experimental group: 60 healthy New Zealand white rabbits, half male and half female, weighing 2-2.5 kg, were randomly divided into 12 groups, 5 rabbits in each group. Among them, 11 groups retained the epithelium, and applied the prescriptions in the above-mentioned Examples 1 to 9 and Comparative Examples 1 to 2, once every 5 minutes for 40 minutes, and observed the degree of corneal yellowing after rinsing with 10 mL of balanced salt solution. Then, the central 8.5 mm corneal piece was taken, the corneal epithelium and corneal endothelium were removed, and the corneal epithelium and corneal endothelium were removed, and the corneal epithelium and corneal endothelium were weighed after rinsing with 10 mL of balanced salt solution, and tested.

[0055] Control group: After the epithelium was removed, 5 healthy New Zealand white rabbits (5 eyes) were treated with 0.153% riboflavin sodium phosphate balanced salt solution every 3 minutes for 30 minutes. The central 8.5 mm corneal piece was removed, the corneal epithelium and corneal endothelium were removed, and the corneal piece was washed with 10 mL of balanced salt solution and weighed for testing.

[0056] Detection of riboflavin concentration in corneal stroma: The corneal stroma sheet was placed in a phosphate buffer solution with a pH of 7.0, stirred to make a slurry, and the volume was adjusted to 1 mL; 1 mL of magnesium acetate solution (15 mmol / L) was added to the homogenate and incubated at 65°C for 15 min; then 0.5 mL of trichloroacetic acid solution (10%) was added and mixed; after centrifugation, the supernatant was collected and treated with a pre-activated C18-SPE adsorption column using methanol as the eluent, and the eluent was collected and diluted 10 times for HPLC quantification.

[0057] The experimental results are shown in Table 1. The experimental results show that no matter which emulsion of Examples 1 to 3 and Examples 6 to 9 listed in this specification is used, compared with the balanced salt solution of riboflavin sodium phosphate, the yellowing degree of the cornea and the concentration of riboflavin in the corneal stroma are significantly improved, especially, the smaller the particle size of the nanoemulsion (Example 2, emulsion particle size 95nm), the higher the riboflavin concentration in the corneal stroma (18.24±1.87 µg / g); under the same emulsion system, the higher the concentration of photosensitizer (Example 7, concentration 0.765%), the higher the concentration of riboflavin in the corneal stroma during the same drug application time.

[0058] Table 1 Riboflavin concentration in corneal stroma layer detected by HPLC after a certain period of time in the embodiment, comparative example and control group (µg / g, x±s) Table 1

[0059] a: Concentration 240 minutes after application.

[0060] It should be noted that from the data in Table 1, the following conclusion can be drawn: compared with the traditional de-epithelialized aqueous solution drug application system, the emulsion system listed in this specification can improve the ability of photosensitizer to be absorbed across the corneal epithelium, while reducing the frequency of drug administration during surgery and improving the bioavailability of the drug in the eye. The emulsions of Examples 4 and 5 (reference emulsion prescriptions in PLoSONE. 2013, 8(6): e66408) showed stratification after being placed at 30°C±2°C / 35%RH±5%RH for one week. In comparison, the emulsion system listed in this specification was placed at 40°C±2°C / 25%RH±5%RH for 6 months, and the emulsions were still stable, with no significant changes in various indicators.

[0061] It should be further explained that although CXL is an effective means to treat / alleviate the progression of keratoconus, this technology requires the use of specific instruments and equipment during the treatment process. Patients living in remote and underdeveloped areas are unable to or cannot receive timely treatment due to insufficient medical conditions. The literature Journal of Cataract & Refractive Surgery.2023, 49(10): 1049-1055 reported that the use of low-concentration riboflavin (de-epithelialization) combined with sunlight exposure can also enhance the biomechanical properties of corneal stromal fibers, which is for patients in underdeveloped medical areas and patients with too thin corneas (corneal thickness less than 350 cm) Micrometers) provides a new solution to alleviate the progression of keratoconus and other related diseases, wherein the effective concentration of riboflavin in the corneal stroma is the key to the successful implementation of the solution. Although no relevant experiments are conducted in this specification, the nanoemulsion composition reported in the present invention can effectively improve the eye absorption of photosensitizers such as riboflavin. Therefore, the photosensitizer nanoemulsion composition disclosed in the present invention can also be combined with sunlight irradiation to improve the strength of corneal stroma fibers without the aid of cross-linking equipment, thereby achieving the purpose of preventing / slowing down the progression of keratoconus and treating related diseases.

[0062] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is impossible to list all the embodiments here. All obvious changes or modifications derived from the technical solution of the present invention are within the scope of protection covered by the present invention.

Claims

1. A composition for improving ocular absorption of a drug, characterized in that: The ophthalmic composition is an oil-in-water nanoemulsion, comprising the following components in parts by weight: 0.01 to 2.0% of the total mass of the composition is an active ingredient, a photosensitizer, 0.5-6.0% of the total mass of the composition is an oil phase, 0.01 to 3.0% of the total mass of the composition is an emulsifier, 0.1 to 4.0% of the total mass of the composition is an emulsifier, 0.01 to 2.0% of the total mass of the composition is a pH adjuster, 0.01 to 1.0% of the total mass of the composition is a pH buffer, The balance is water and osmotic pressure regulator.

2. The composition for improving drug ocular absorption according to claim 1, characterized in that: The oil droplet diameter of the nanoemulsion is no greater than 600 nm.

3. The composition for improving drug ocular absorption according to claim 1, characterized in that: The oil droplet diameter of the nanoemulsion is no greater than 200 nm.

4. The composition for improving ocular absorption of a drug according to claim 1, characterized in that: The active ingredient photosensitizer includes any one or more of Bengal rose red, bacterial chlorophyll, riboflavin-5-phosphate or its salt or its various medically acceptable derivatives.

5. The composition for improving ocular absorption of a drug according to claim 1, characterized in that: The oil phase includes any one or more of medium-chain triglycerides, long-chain triglycerides, olive oil, castor oil and its derivatives, corn oil, soybean oil, cottonseed oil, walnut oil, sunflower seed oil, peanut oil, palm oil, coconut oil, almond oil, sesame oil, mineral oil, modified propylene glycol, propylene glycol diester, tricaprylic capric glyceride, and saffron oil.

6. The composition for improving ocular absorption of a drug according to claim 1, characterized in that: The emulsifier includes any one or more of egg yolk lecithin, soybean lecithin, Tween, Span, polyoxyethylenes, polyoxypropylenes, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, sucrose monolaurate, monoglycerol fatty acid ester, triglycerol fatty acid ester, polyglycerol stearate, fatty acid sorbitan, polysorbate, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene polyoxypropylene copolymers, sodium lauryl sulfate, tyloxapol, poloxamer, and octoxynol.

7. The composition for improving ocular absorption of a drug according to claim 1, characterized in that: The emulsifier includes any one or more of ethanol, n-butanol, ethylene glycol, propylene glycol, glycerol, polyethylene glycol, polyglycerol ester, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, glyceryl monostearate, stearic acid, and stearyl alcohol.

8. The composition for improving ocular absorption of a drug according to claim 1, characterized in that: The pH value of the ophthalmic composition is 5.0 to 9.0; The pH regulator includes any one or more of glacial acetic acid, citric acid, lactic acid, phosphoric acid, hydrochloric acid, boric acid, tromethamine, sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, sodium citrate and its hydrate, borax, EDTA and its various forms of salts, DTPA and its various forms of salts, amine ethanolamine, diethanolamine, triethanolamine; The pH buffer includes any one or more of acetate buffer, citrate buffer, tris(hydroxymethylaminomethane) buffer, phosphate buffer, carbonate buffer, borate buffer, 6-aminocaproic acid, and amino acid salts.

9. A method for preparing the composition for improving ocular absorption of a drug according to any one of claims 1 to 8, comprising the steps of: 1) Weigh the oil phase and emulsifier in proportion, heat and dissolve them to form the oil phase of the emulsion; 2) Weigh the emulsifier, emulsifier aid, pH buffer, and active ingredient photosensitizer according to the proportion, add water, stir to dissolve, and use as the aqueous phase of the emulsion; 3) Add the emulsion oil phase to the emulsion water phase under rapid stirring, perform high shear emulsification to minimize the oil droplets, and then perform high pressure homogenization at a pressure of not less than 8000 psi until the particle size of the emulsion oil droplets meets the formulation requirements to obtain a crude emulsion; add an osmotic pressure regulator, and finally add the remaining amount of water to adjust the emulsion pH to 5.0-9.0; 4) After sterilization and packaging, it is ready.

10. Use of the composition for improving ocular absorption of a drug according to any one of claims 1 to 8 in the preparation of drugs for preventing or treating corneal and conjunctival damage, glaucoma, scleral thinning, choroidal thinning, axial myopia progression, and relieving visual fatigue.

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