A low-aggregate ophthalmic nanoformulation and its preparation method and use

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a low-aggregate ophthalmic nanoformulation for efficient drug delivery, a preparation method and use thereof, and its use mainly relates to the treatment of eye diseases. The low-aggregate ophthalmic nanoformulation of the present invention is made of drug molecules, phospholipids or their derivatives and amphipathic surfactants, and the concentration of phospholipids or their derivatives is 0.05%-60% by weight, and the concentration of amphipathic surfactants is 0.05%-25%. The low-aggregate nanoformulation ophthalmic delivery system prepared by the present invention has the advantages of particle size less than 10nm, good tissue permeability, good stability and low irritation, which greatly improves the bioavailability of drug ophthalmic administration.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a low-aggregate ophthalmic nanoformulation for efficient drug delivery, a preparation method and uses thereof, and the uses thereof mainly relate to the treatment of ocular diseases. Background Art

[0002] In recent years, with the change of living habits, the increase of work pressure and the frequency of eye use, the incidence of eye diseases has increased year by year. Local administration of drugs to the ocular surface is the most commonly used method of drug administration for the treatment of eye diseases, with the advantages of easy use and high patient acceptance. Due to the unique physiological characteristics of the eye, ophthalmic preparations administered in the form of eye drops are very easy to be lost from the eye. The bioavailability of local administration of drugs to the ocular surface is generally less than 5%, which greatly hinders the therapeutic effect of ophthalmic preparations. The main barriers to anterior segment diseases include: corneal barrier, conjunctival barrier, etc., and the main barriers to posterior segment diseases also include: vitreous barrier, scleral barrier, choroidal barrier, etc. Among them, the cornea is located in the front of the eyeball, composed of epithelial cell layer, anterior elastic layer, stroma layer, posterior elastic layer and endothelial cell layer, and is one of the most important barriers to ocular drug delivery. The corneal epithelial cell layer is composed of lipophilic epithelial cells, which is a barrier to the penetration of hydrophilic drug molecules. The matrix layer is composed of water, collagen, proteoglycans and corneal stromal cells, accounting for 90% of the thickness of the cornea, and is a barrier to the penetration of lipophilic drugs. Therefore, the penetration of eye drops into the cornea is very limited, and the permeability of the cornea is of great significance from the perspective of drug treatment.

[0003] With the development of nanoformulation technology, new topical ocular drug delivery systems represented by nanoemulsions, liposomes, and micelles provide technical means to improve the efficiency of ocular drug delivery. Nanoemulsions and liposomes help improve the permeability of drugs in the cornea and the bioavailability of ocular drugs. For example, the O / W cyclosporine A nanoemulsion developed by Allergan Although nanoemulsions and liposomes have improved the bioavailability of topical ocular administration of drugs, they still face some difficult-to-solve technical problems, such as: the particle size of nanoemulsions and liposomes is usually around 100-200nm, and their permeability in ocular tissues needs to be further improved. Compared with liposomes and fat emulsions, micelles have a smaller particle size, generally between 20-50nm, and have better permeability in ocular tissues. For example, a cyclosporine A nanomicelle developed by Sun Pharma It is the first ophthalmic micelle preparation approved by the FDA. However, in order to maintain the stability of ordinary micelle particles, the number of carrier molecules and drug molecules aggregated is relatively high, and the size of the micelle particles formed is generally greater than 20nm, and its permeability in eye tissues still needs to be improved.

[0004] Considering the physiological characteristics of ocular tissues, nanoparticles after administration mainly penetrate into ocular tissues by diffusion, and their diffusion behavior is significantly related to the particle size of nanoparticles. The smaller the particle size of nanoparticles, the more conducive it is to diffusion, and the better the permeability in ocular tissues. The molecular aggregation number of nanoparticles can significantly affect their particle size. The smaller the molecular aggregation number and the smaller the particle size, the more conducive it is to diffusion, penetration and release of drug molecules in ocular tissues. In the field of drug delivery technology, there are huge technical challenges in preparing nanoparticles with a particle size less than 10nm, because 10nm is only about the size of 30 water molecules aggregated. Generally, for organic molecules with a molecular weight between 300-1000Da, the size of a single molecule is about 1-1.5nm. Nanoparticles below 10nm mean a very low molecular aggregation number. If nanoparticles with a particle size less than 10nm can be designed, they will have a diffusion capacity close to that of drug molecules, which can significantly improve the permeability and bioavailability of ocular drug delivery.

[0005] However, there are no reports on low-aggregate ophthalmic nanoformulations with a particle size less than 10 nm. Summary of the invention

[0006] In order to overcome the defects in the prior art, the inventors unexpectedly discovered that phospholipids and their derivatives can change their molecular self-assembly behavior under the induction of certain amphiphilic surfactant molecules to form low-aggregate nanoparticles with a particle size of less than 10 nm.

[0007] On this basis, the object of the present invention is to provide a low aggregate nanoformulation for eye use and its preparation method and use. The low aggregate nanoformulation for eye use of the present invention is made of drug molecules, phospholipids or their derivatives and amphiphilic surfactants. The low aggregate nanoformulation eye delivery system prepared by the present invention has the advantages of particle size less than 10nm, good tissue permeability, good stability and low irritation, which greatly improves the bioavailability of drug ocular administration.

[0008] In order to achieve the above object, the present invention adopts the following technical solutions:

[0009] In a first aspect, the present invention provides an oligoaggregate ophthalmic nanoformulation for efficient ocular drug delivery, the ophthalmic nanoformulation comprising a drug molecule, a phospholipid or a derivative thereof, and an amphiphilic surfactant.

[0010] As an optional mode, in the above-mentioned ophthalmic nanoformulation, the drug molecules participate in the self-assembly process of the carrier molecules to form a stable drug-loaded low-aggregate nanoformulation.

[0011] Preferably, the drug molecule is a hydrophobic drug molecule.

[0012] More preferably, the drug molecule is selected from one or more of the following: immunosuppressive drugs (e.g., cyclosporine A, tacrolimus, etc.), steroid drugs (e.g., loteprednol, dexamethasone, fluorometholone, prednisone acetate, etc.), prostaglandins (e.g., latanoprost, travoprost, bimatoprost, tafluprost, etc.), non-steroidal anti-inflammatory drugs (e.g., diclofenac, pranoprofen and bromfenac, etc.), antibiotics (e.g., levofloxacin, moxifloxacin, gatifloxacin, azithromycin, etc.), antiviral drugs (e.g., acyclovir, ganciclovir, ribavirin, etc.), antifungal drugs (e.g., natamycin, amphotericin B, etc.), antihistamines (e.g., olopatadine, azelastine, levocabastine, etc.), or atropine or rebamipide.

[0013] As an optional mode, in the above-mentioned ophthalmic nanoformulation, the phospholipid or its pharmaceutically acceptable derivative comprises a class of phospholipid molecules or their derivatives widely existing in organisms, which are molecules with an amphiphilic chemical structure.

[0014] Further, the phospholipid or its pharmaceutically acceptable derivative is selected from one or more of natural phospholipids, semi-synthetic phospholipids, and synthetic phospholipids. The natural phospholipid is selected from natural glycerophospholipids or natural sphingomyelin, and the natural glycerophospholipid includes one or more of soybean lecithin, egg yolk lecithin, cardiolipin, phosphatidylethanolamine, phosphatidylglycerol, and phosphatidylinositol. The semi-synthetic phospholipid is selected from one or more of hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, and hydrogenated sunflower phospholipid. The synthetic phospholipid is selected from one or more of synthetic glycerophospholipids, synthetic sphingomyelin, and polyethylene glycol phospholipid derivatives, and the synthetic glycerophospholipid is selected from at least one glycerophospholipid whose polar group is choline, ethanolamine, serine, glycerol, and inositol, wherein the fatty acid esterified at the sn-1 and sn-2 positions is a straight chain or branched chain, saturated or unsaturated C4-C24 fatty acid. The glycerophospholipids with choline as the polar group can be selected from distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dilauroylphosphatidylcholine, and dioctanoylphosphatidylcholine; the glycerophospholipids with glycerol as the polar group can be selected from distearoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, dimyristoylphosphatidylglycerol, dilauroylphosphatidylglycerol, and dioctanoylphosphatidylglycerol and their derivatives. Salt; glycerophospholipids with ethanolamine as polar group can be selected from distearoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine, dilauroylphosphatidylethanolamine; glycerophospholipids with inositol as polar group can be selected from one or more of distearoylphosphatidylinositol, dipalmitoylphosphatidylinositol, dioleoylphosphatidylinositol, dimyristoylphosphatidylinositol, and dilauroylphosphatidylinositol. Polyethylene glycol phospholipid derivatives can be selected from dimyristoylglycerol polyethylene glycol, distearoylglycerol polyethylene glycol, distearoylphosphatidylethanolamine polyethylene glycol, dimyristoylphosphatidylethanolamine polyethylene glycol, dipalmitoylphosphatidylethanolamine polyethylene glycol, and phosphatidylethanolamine polyethylene glycol.

[0015] Preferably, the phospholipid or a pharmaceutically acceptable derivative thereof is selected from one or more of soybean lecithin, egg yolk lecithin, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, sn-1 and sn-2 stearoylation, palmitoylation, oleoylated choline, sn-1 and sn-2 stearoylation, palmitoylation, oleoylated glycerol, sn-1 and sn-2 stearoylation, palmitoylation, oleoylated ethanolamine, sn-1 and sn-2 stearoylation, palmitoylation, oleoylated inositol, dimyristoylglycerol polyethylene glycol, distearoylglycerol polyethylene glycol, dipalmitoylphosphatidylacetamide polyethylene glycol, distearoylphosphatidylacetamide polyethylene glycol, and phosphatidylethanolamine polyethylene glycol.

[0016] Phospholipids are one of the main components of biological membranes and are amphiphilic. It is well known that phospholipids and their derivative molecules can preferentially form liposomes in aqueous media. The present invention unexpectedly found that certain amphiphilic surfactants can induce the self-assembly behavior of phospholipid molecules to form low-aggregate nanoparticles with non-liposome structures, and the most significant physicochemical feature is that the particle size is less than 10nm. In addition, surfactant molecules can also interact with biological membranes or reduce the efflux of drug molecules caused by P-glycoprotein, effectively promote the penetration of drug molecules in ocular tissues, and increase the bioavailability of drugs.

[0017] As an optional mode, in the above-mentioned ophthalmic nanoformulation, one or more of the amphiphilic surfactant polyoxyethylene surfactant and steroidal surfactant in the present invention are used. The polyoxyethylene surfactant is preferably a polyoxyethylene castor oil surfactant, polyoxyethylene 15-hydroxystearate ( HS 15) is more preferably polyoxyethylene 15 hydroxystearate ( HS 15). The steroidal surfactant is preferably selected from cholesteric acid and salts thereof, cholesteric acid-amino acid conjugates and salts thereof, more preferably deoxycholic acid, chenodeoxycholic acid salt, cholesteric acid-glycine conjugates and salts thereof, cholesteric acid-taurine conjugates and salts thereof. Also more preferably selected are glycocholic acid and salts thereof, deoxycholic acid and salts thereof, glycodeoxycholic acid and salts thereof, taurocholic acid and salts thereof, and taurodeoxycholic acid and salts thereof.

[0018] As an optional mode, the above-mentioned ophthalmic nano preparation also includes other commonly used excipients for ophthalmic preparations.

[0019] Other commonly used excipients of the ophthalmic preparations include, but are not limited to, buffers, lubricants, osmotic pressure regulators, antibacterial agents, antioxidants, bioadhesives, thickeners, wetting agents, and preservatives.

[0020] The ophthalmic nanoformulation is preferably prepared under the condition of pH 4-8, and the pH of the preparation can be adjusted by adding buffer salts. The buffer includes but is not limited to phosphates, borates, acetates, citrates, carbonates and mixtures thereof.

[0021] The osmotic pressure regulator includes but is not limited to mannitol, glucose, sodium chloride, glycerol, propylene glycol, xylitol and mixtures thereof. These osmotic pressure regulators can be used to adjust the molar osmotic pressure of the ophthalmic nanoformulation of the present invention.

[0022] The preservative includes but is not limited to benzyl alcohol, benzalkonium bromide, benzalkonium chloride, chlorhexidine, parabens such as methylparaben, ethylparaben, propylparaben, benzoic acid and the above mixtures thereof. It should be noted that the preservative does not necessarily need to be added. If the ophthalmic nano preparation of the present invention adopts a single-dose packaging form, the preparation may not contain a preservative.

[0023] The low-aggregate ophthalmic nanoformulation for efficient drug delivery to the eye also contains one or more pharmaceutically acceptable bioadhesives to increase the viscosity of the preparation and further increase the retention time of the preparation of the present invention in the eye. The bioadhesives of the present invention include carboxyl polymers such as carbomer, polycarbophil, etc.; cellulose derivatives include alkyl and hydroxyalkyl celluloses such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, etc.; gums such as xanthan gum, carrageenan, etc.; and other pharmaceutically acceptable polymers, including but not limited to polyvinyl alcohol, polyvinyl pyrrolidone, poloxamer and its derivatives, hyaluronic acid and its salts, alginate and its salts, etc. Such polymers can be used alone or in combination.

[0024] As an optional mode, in the above-mentioned nano preparation for eye use, the particle size range of the nano preparation for eye use is less than 10 nm. Preferably, the particle size range of the nano preparation for eye use is 1 nm-10 nm. The encapsulation efficiency of the nano preparation for eye use is greater than 90%.

[0025] As an optional method, in the above-mentioned ophthalmic nanopreparation, the concentration of phospholipids or their derivatives is 0.05%-60%, preferably 1%-50%, and more preferably 2%-40% by weight; the concentration of amphiphilic surfactant is 0.05%-25%, preferably 0.1%-20%, and more preferably 0.5%-15%.

[0026] In a second aspect, the present invention provides a method for preparing the ophthalmic nanoformulation described in the first aspect, comprising the following steps: dissolving or dispersing the drug component and the amphiphilic carrier in an appropriate amount of an organic solvent or a mixed solution of organic solvents, removing the solvent by evaporation under reduced pressure, and then uniformly mixing with a solution containing a water-soluble auxiliary component, filtering the solution through a microporous filter membrane, and sterilizing to obtain a drug-containing ophthalmic nanoformulation solution. The prepared drug-containing ophthalmic nanoformulation solution is aseptically packaged and filled into a multi-dose or single-dose packaging container.

[0027] Preferably, the organic solvent may be selected from one or more of the following: methanol, ethanol, isopropanol, dichloromethane or chloroform.

[0028] In addition, those skilled in the art know that other methods known in the field of pharmaceutical preparations can also be used to prepare the ophthalmic nanoformulation described in the first aspect.

[0029] In a third aspect, the present invention provides use of the ophthalmic nanoformulation described in the first aspect in the preparation of an ophthalmic drug.

[0030] As an optional mode, in the above-mentioned use, the ophthalmic drug is used for the prevention, treatment or auxiliary treatment of eye diseases.

[0031] Preferably, the ophthalmic drug has higher drug permeability and bioavailability.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] The low-aggregate ophthalmic nanoparticles for efficient drug delivery to the eye of the present invention work in the following way: drug components, phospholipids and their derivatives and amphiphilic surfactants self-assemble to form low-aggregate nanoparticles for delivery of active drug molecules. Surprisingly, the active drug components, phospholipids and their derivatives and amphiphilic surfactants can form particles with a particle size of 1nm-10nm, which is much smaller than that of ordinary amphiphilic polymer micelles and commercially available The most significant advantage of the low-aggregate ophthalmic nanoformulation for efficient drug delivery to the eye of the present invention is its good permeability to ocular tissues. Since the size of low-aggregate nanoparticles is close to the size of ordinary drug molecules, phospholipids and their derivatives have good cell affinity with the components of cell membranes, and amphiphilic surfactants can promote the permeation behavior of drug components in ocular tissues, its permeability in ocular tissues is much stronger than other ordinary nano drug delivery systems. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is a representative particle size measurement result of Sample 3 of Example 1 described in the present invention.

[0035] Figure 2 This is the in vitro release curve of the low-aggregate nanoparticles of Example 3 of the present invention.

[0036] Figure 3 This is the corneal fluorescein sodium staining result of Example 4 of the present invention.

[0037] Figure 4 It is the tear film breakup time of Example 4 described in the present invention.

[0038] Figure 5 This is the level of change in the concentration of inflammatory factors in Example 4 of the present invention.

[0039] Figure 6 This is the distribution curve in ocular tissue and plasma of Example 5 described in the present invention. DETAILED DESCRIPTION

[0040] The present invention will be further described with reference to specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the scope of the present invention.

[0041] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0042] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified.

[0043] Example 1: Preparation of drug-loaded oligoaggregate nanoparticles and determination of pharmaceutical properties

[0044] Weigh the required phospholipids or their derivatives, amphiphilic surfactants, and active drugs according to the proportions in Table 1, add about 10 mL of ethanol solution or other organic solution, stir until a clear solution is obtained, heat and evaporate the solvent under vacuum conditions, add water or buffered saline solution, mix, and stir evenly to obtain a drug-loaded oligoaggregate nanoparticle solution.

[0045] Table 1 Formulation composition of low-aggregate nanoparticles encapsulating active drugs

[0046]

[0047] The preparation method of Comparative Example 1 is the same as that of Example 1.

[0048] Table 2 Nanoparticle formulation composition of Comparative Example 1

[0049]

[0050] Table 3 Main pharmaceutical properties of samples 1-9

[0051]

[0052]

[0053] Figure 1 The representative particle size measurement results of sample 3 in Example 1. The results in Table 3 show that the average light intensity particle size of the low-aggregate nanoparticles prepared by the present invention is less than 10 nm, which is much smaller than that of commercially available Product (20.32nm).

[0054] Example 2: Low-aggregate nanoparticle preparation containing water-soluble excipients

[0055] Weigh the required phospholipids or their derivatives, amphiphilic surfactants, and active drugs according to the proportions in Table 4, add about 10 mL of ethanol solution or other organic solution, stir until a clear solution is obtained, heat under vacuum conditions to evaporate the solvent, add the solution of water-soluble excipients, mix, and stir evenly. Adjust the pH to about 6.8 with NaOH or HCl, add NaCl to adjust the osmotic pressure to within the range of 280-300 mOSmol / kg, add deionized water to make the volume to 100 mL, filter and sterilize or sterilize by hot pressure, and fill to obtain the product.

[0056] Table 4 Composition of low aggregate nanoparticle preparations

[0057] Element 1 2 3 Cyclosporine A 0.09g Sodium glycocholesterol 5g Soybean lecithin 15g Tafluprost 0.0015g Soybean lecithin 5g Polyoxyethylene 40 Hydrogenated Castor Oil 2g Loteprednol 0.5g Phosphatidylglycerol 35g Sodium taurodeoxycholesterol 15g

[0058] Table 5 Composition of water-soluble excipient solution

[0059]

[0060]

[0061] Example 3: In vitro release of cyclosporine A low-aggregate nanoparticles

[0062] Take 2 mL of sample 3 solution in Example 1, place it in a dialysis bag (MW = 3500), tie both ends tightly and place it in 10 mL of PBS buffer (pH = 7.4) containing 1% SDS (w / w), place it in a constant temperature oscillator, oscillate at a constant temperature of 37 degrees, and the speed is 100 rpm. Take out 1 mL of release medium after 1, 2, 4, 6, 8, 10, 24, and 48 hours, and add 1 mL of release medium. After the sample passes through a 0.22 micron filter membrane, it is appropriately diluted with methanol, and the drug content in the medium is determined by HPLC and its cumulative release rate is calculated.

[0063] Figure 2 The results in the literature showed that the in vitro release rate of low-aggregate nanoparticles was slightly lower than that of the drug solution, showing certain sustained-release characteristics.

[0064] Example 4: Pharmacodynamics study of cyclosporine A low-aggregate nanoparticles

[0065] Healthy Japanese white rabbits were given 0.2% benzalkonium chloride solution to both eyes daily, once in the morning, noon and evening, for 7 consecutive days. The tear film breakup time (TBUT) and tear secretion were used to monitor the entire modeling and treatment process. TBUT was less than 10s and tear secretion was less than 5mm, proving that the dry eye modeling was successful. Each group of dry eye model rabbits was treated with physiological saline, comparative example 1 solution (Cequa) and example 1 sample 3 solution, and the treatment cycle was 2 weeks.

[0066] (1) Corneal fluorescein sodium staining

[0067] like Figure 3 As shown in the figure, the results of corneal fluorescein sodium staining showed that after 14 days of treatment, the fluorescence staining of the saline group did not improve, and the staining became more serious. Compared with the saline group, the fluorescein sodium staining of the preparation group was significantly improved. The degree of improvement in staining in the sample 3 preparation treatment group was significantly better than that in the comparative example 1 preparation treatment group.

[0068] (2) Tear film breakup time

[0069] like Figure 4 As shown, the TBUT of the saline group was basically unchanged, while the preparation groups were significantly improved. The tear film breakup time of Sample 3 and the TBUT value of the solution of Comparative Example 1 were both greater than 10s. The tear film breakup time of the sample 3 preparation treatment group was significantly greater than that of the comparative example 1 preparation treatment group.

[0070] (3) Tear inflammatory factors

[0071] After treatment with different eye drops, the changing trends of inflammatory factor concentrations in tears were determined. At designated time points, tears were collected using capillary tubes to measure the concentrations of IL-1, IL-2, IL-6, and TNF-α in tears.

[0072] like Figure 5 As shown, the concentration of each inflammatory factor rose to a very high level before treatment. After 14 days of treatment, each inflammatory factor showed a relatively obvious downward trend. The independent sample T test was used to statistically analyze the inflammatory factor levels of the sample 3 preparation group and the comparative example 1 group, and the sample 3 preparation group and the blank control group. The results showed that the inflammatory factor level of the sample 3 preparation group was significantly lower than that of the comparative example 1 preparation (Cequa) group (p<0.05) and the blank control group (p<0.001).

[0073] Example 5: Ocular tissue distribution and kinetics of cyclosporine A low-aggregate nanoparticles

[0074] Japanese big-eared white rabbits were randomly divided into 2 groups and given the solution of sample 3 of Example 1 (0.09%) and the solution of comparative example 1 (Cequa) (0.09%), respectively, with a dosage of 50 μL / eye, unilateral, single-dose administration. Blood was drawn at 0.25h, 1h and 6h after administration, and the animals were anesthetized and killed. The bulbar conjunctiva, palpebral conjunctiva, cornea, sclera and iris tissues were dissected and collected. About 0.1g of tissue sample was taken, accurately weighed, and an appropriate amount of 50% methanol was added. The sample was homogenized with a tissue homogenizer (8000rpm / time, 3 times) to prepare a 5% tissue homogenate. The homogenate was placed in a 2mL plastic polypropylene tube and stored at -60℃--90℃. The drug concentration of the samples after the above treatment was determined by LC / MS / MS. The ocular tissue distribution and pharmacokinetic curves of the homemade preparation (Sample 3 of Example 1) and the control preparation (Comparative Example 1) are shown in Figure 2. Figure 5 As shown. It can be seen from the results that the distribution concentration of the cyclosporine A low-aggregate nanoparticles of the present invention in the main tissues of the eye and the concentration in the plasma are significantly higher than those of the commercially available control preparation. The above results prove that compared with the commercially available comparative example 1 preparation, the low-aggregate nanoparticle preparation of the present invention has better eye tissue permeability and absorption behavior, and the bioavailability of ocular administration is higher.

[0075] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A low-aggregate ophthalmic nanoformulation, characterized in that: The ophthalmic nanoparticle preparation comprises drug molecules, phospholipids or their derivatives and amphiphilic surfactants, wherein the drug molecules, phospholipids and their derivatives and amphiphilic surfactants self-assemble to form low-aggregate nanoparticles, and the particle size of the ophthalmic nanoparticle preparation ranges from 1 nm to 10 nm. nm, the encapsulation rate of the ophthalmic nanoformulation is greater than 90%, the drug molecule is a hydrophobic drug molecule, and the drug molecule is selected from one or more of the following: cyclosporine A, dexamethasone or loteprednol; the phospholipid or its derivative is selected from one or more of the following: soybean lecithin, soybean lecithin, phosphatidylethanolamine, phosphatidylglycerol, polyethylene glycol phosphatidylethanolamine, dipalmitoylphosphatidylcholine or hydrogenated soybean lecithin; the amphiphilic surfactant is selected from one or more of the following: polyoxyethylene-15-hydroxystearate, polyoxyethylene 40 hydrogenated castor oil, sodium glycocholesterate, sodium glycodeoxycholesterate, sodium taurodeoxycholesterate, sodium deoxycholesterate, potassium glycocholesterate or sodium taurocholesterate; in terms of weight percentage, the concentration of the phospholipid or its derivative is 2.5%-60%, and the concentration of the amphiphilic surfactant is 1%-25%.

2. The ophthalmic nanoformulation according to claim 1, characterized in that: The ophthalmic nanoformulation further comprises other commonly used excipients for ophthalmic preparations, which are selected from one or more of the following: buffers, lubricants, osmotic pressure regulators, antibacterial agents, antioxidants, bioadhesives, thickeners, wetting agents or preservatives. The pH of the ophthalmic nanoformulation is 6-7.

5.

3. The ophthalmic nanoformulation according to claim 2, characterized in that: The buffer is selected from one or more of the following: phosphate, borate, acetate, citrate or carbonate; the osmotic pressure regulator is selected from one or more of the following: mannitol, glucose, sodium chloride, glycerol, propylene glycol or xylitol; the preservative is selected from one or more of the following: benzyl alcohol, benzalkonium bromide, benzalkonium chloride, chlorhexidine, methylparaben, ethylparaben, propylparaben or benzoic acid; the bioadhesive is selected from one or more of the following: carboxyl polymers, cellulose derivatives, gums, polyvinyl alcohol, polyvinyl pyrrolidone, poloxamer, hyaluronic acid or its salt or alginate or its salt.

4. The method for preparing the ophthalmic nanoformulation according to any one of claims 1 to 3, characterized in that: The preparation method comprises the following steps: S1: dissolving or dispersing the drug molecule, phospholipid or its derivative and amphiphilic surfactant in an appropriate amount of organic solvent or a mixed solution of organic solvents, removing the solvent by evaporation under reduced pressure, and then uniformly mixing with a solution containing water-soluble auxiliary ingredients, filtering the solution through a microporous filter membrane, and sterilizing to obtain a drug-containing ophthalmic nanoformulation solution; S2: Aseptically pack the prepared medicated ophthalmic nanoformulation solution and fill it into multi-dose or single-dose packaging containers.

5. Use of the ophthalmic nanoformulation according to any one of claims 1 to 3 or the ophthalmic nanoformulation prepared by the preparation method according to claim 4 in the preparation of ophthalmic drugs.

6. The use according to claim 5, characterized in that: The ophthalmic medicine is used for the prevention, treatment or auxiliary treatment of eye diseases.

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