An ophthalmic formulation for the treatment of macular edema, optic neuritis, and non-infectious endophthalmitis via eye drop administration.

Abstract

An ophthalmic formulation for treating macular edema, optic neuritis, and non-infectious endophthalmitis, comprising an active ingredient for treating an eye disease and a carrier or auxiliary material for the ophthalmic formulation, wherein the active ingredient for treating the eye disease is a glucocorticoid and / or nonsteroidal drug, and the carrier or auxiliary material for the ophthalmic formulation contains a surfactant, an ionic polymer, and a solvent, or the carrier or auxiliary material for the ophthalmic formulation contains low-degree-of-polymerization povidone, medium-degree-of-polymerization povidone, and a solvent. [Solution] This ophthalmic formulation, administered by eye drops, carries (encapsulates) glucocorticoid and / or nonsteroidal drugs, passes through the anterior segment of the eye, and is transported to the posterior segment to treat macular edema, optic neuritis, and non-infectious endophthalmitis. It has excellent clinical value and very positive social significance.

Description

Technical Field

[0001] The present invention belongs to the field of ophthalmic drugs, and specifically relates to an ophthalmic preparation for treating macular edema, optic neuritis and non-infectious uveitis by eye drop administration.

Background Art

[0002] There are many patients with fundus diseases, and the number of patients in China alone exceeds tens of millions. With the progress of aging and the popularization of electronic products, the incidence rate is expected to increase year by year. Common fundus diseases include diabetic macular edema, diabetic retinopathy, age-related macular degeneration, retinal vein occlusion, pathological myopia, geographic atrophy, ocular tumors, uveitis, etc. These can lead to vision loss and even blindness, which may seriously affect people's quality of life. For example, about 6.8% of diabetic patients suffer from diabetic macular edema (DME), which is the main cause of blindness in diabetic patients (Urias et al., Vision Research , V139:221-227, 2017; Mandal et al., Ocular delivery of proteins and peptides: Chall enges and novel formulation approaches, Advanced Drug Delivery Reviews, 126:67-9 5, 2018).

[0003] Drug therapy is a major part of the treatment methods and research trends for fundus diseases. However, due to the complex physiological structures and barriers in the eye, it is difficult for drugs to enter the eyeball, especially the posterior segment of the eye, and it is difficult to reach the effective dose, so it is not easy to achieve effective treatment Finding effective and safe formulations or methods for treating retinal diseases is a key area of ​​expertise in this field. This is a goal that researchers have consistently strived for and aimed for.

[0004] There are generally three routes of administration of ophthalmic medication in clinical practice: (1) Conjunctival sac administration (eye drops): The drug passes through the cornea and enters the aqueous humor in the anterior chamber, then diffuses and distributes to the iris and ciliary body. Although this is possible, the barrier effect of the lens and vitreous membrane prevents entry into the lens and vitreous humor. It is difficult. (2) Administration by intraocular injection: subconjunctival injection, anterior chamber injection, intravitreous injection, retrobulbar injection This includes injections and orbital injections. Injection allows the drug to reach the treatment site directly, however Injections are traumatic and carry potential risks. For example, anterior chamber injections can cause pain, photophobia, and blood loss. It can cause tearing, anterior chamber opacity, hemorrhage, corneal endothelial cell damage, traumatic cataracts, etc. Also, within the vitreous cavity Injections can cause lens opacity, vitreous organization, retinal / optic nerve damage, etc. (3) Oral administration, Systemic administration, including intravenous administration: Drugs generally accumulate in the liver, kidneys, or lungs within the body. , blocked by the blood-retinal barrier (BRB) As a result, the concentration reaching the eye tissue decreases, and at the same time, unnecessary toxic side effects are reduced throughout the body, especially in major organs. To produce an effect.

[0005] Currently, in clinical practice, to allow drugs to pass through the ocular barrier, intravitreal injection into the eye is generally performed. or using technical means such as intravitreal implants (insertion into the eyeball) to deliver drugs to the patient's vitreous humor. It is transported to the ophthalmos, thereby treating diseases of the posterior segment of the eye. (From "Ophthalmic Drugs and Pharmaceutical Formulations," edited by Ling Pei-Xue) China Light Industry Press, 2010, p. 3; Wang et.al., Mediators of Inflammation,Vol.2013,Article ID 7806 34;Luaces-Rodriguez et al.,Pharmaceutics (2018, 10, 66). Intravitreal injection of drugs or intravitreal implantation is invasive. This is an involuntary administration procedure and must be performed by a specially trained ophthalmologist in a sterile environment such as an operating room. Because the procedure is invasive, for example, in cases of high intraocular pressure, cataracts, iatrogenic infectious endophthalmitis, vitreous hemorrhage, and reticularis. It may cause complications such as membrane damage. The requirements for treatment conditions and the treatment environment are... It must be performed in a hospital with high standards and appropriate facilities. Biological drugs for ophthalmic injection are biological Production and usage costs are high, and the timing of treatment is delayed due to constraints on medical conditions. In some cases, it may be difficult to flexibly adjust the administration plan (M.HATA et al., RETINA, 37:1320-1328, 2017).

[0006] In fact, conventional wet age-related macular degeneration r Degeneration, wAMD) and diabetic macular edema (Diabetes-r Biological drugs for treating elated Macular Edema (DME), etc. All ophthalmic injections are administered by intravitreal injection, and according to the drug's instructions, 1 It requires injections once every three months and needs to be administered over a long period of time. Furthermore, the glucocorticoid dexamethasone is used to treat macular edema and other conditions caused by retinal vein occlusion. Intraocular implants for treating eye diseases It is also being developed under the name ertion, product name: Ozurdex(registered trademark)), and after transplantation The drug's effects last for 6 months. However, some patients after transplantation experience elevated intraocular pressure, and after 2 months... reaches its peak (Ozurdex (registered trademark) Patient Management Manual, Alagan, CN / 011 / 2018), there is a risk of side effects.

[0007] Conjunctival sac administration is the simplest and safest method of ocular administration. However, the cornea of the eye has a multi-layer structure. divided from the outside to the inside, it consists of an epithelial layer rich in liposomes, a stromal layer rich in aqueous components, and an endothelial layer rich in liposomes. When eye drops are instilled, they first come into contact with the surface tear layer of the eye, and then must pass through the epithelial layer, stromal layer, and endothelial layer in order to reach the posterior segment of the eye. In this process, due to dilution by tears, the ocular surface barrier of the cornea and conjunctiva, and the anatomical position of the lens and vitreous body, eye drops tend to be present at a high concentration in the tissues of the anterior segment of the eye, and it is difficult to enter the posterior segment of the eye and reach an effective therapeutic concentration. Therefore, the method of administration into the conjunctival sac is safe, but the drug transportability deteriorates, and it is difficult to achieve the purpose of effectively treating fundus diseases.

[0008] As described above, in the main administration methods for treating conventional fundus diseases such as macular edema, it has been difficult to achieve both safety and efficacy.

Summary of the Invention

Problems to be Solved by the Invention

[0009] The method of administration by eye drops has an obvious advantage of being safer and more convenient compared to intravenous injection and intravitreal injection, and inventing an ophthalmic preparation that can transport the drug to the posterior segment of the eye to treat macular edema is a technical problem that needs to be solved urgently in clinical practice, and its value and social significance in clinical treatment are very great.

[0010] ​​The objective of this invention is to deliver an active ingredient for treating eye diseases to the posterior segment of the eye, thereby treating macular edema, To provide ophthalmic drugs for eye drop administration that can treat optic neuritis and non-infectious endophthalmitis. That is what it is.

[0011] The present invention provides an ophthalmic formulation for eye drop administration, the formulation for treating eye diseases A formulation comprising an active ingredient and a carrier or auxiliary material for an ophthalmic formulation, The active ingredient for treating the aforementioned eye disease is a glucocorticoid drug and / or non-glucocorticoid drug. It is a teroid drug, The carrier or auxiliary material of the ophthalmic preparation comprises a surfactant, an ionic polymer, and a solvent. Yes, Alternatively, the carrier or auxiliary material of the ophthalmic preparation may be low-molecular-weight povidone or medium-molecular-weight povidone. A formulation characterized by containing an and a solvent.

[0012] Furthermore, the surfactant and ionic polymer in the carrier or auxiliary material of the ophthalmic formulation The mass ratio is (1~100):(0.1~50), and the ratio of the surfactant to the solvent is, Each 100 mL of solvent contains 5 to 3000 mg of surfactant.

[0013] Furthermore, the surfactant and ionic polymer in the carrier or auxiliary material of the ophthalmic formulation The mass ratio of the surfactant to the solvent is (12-31):(2-7.5), and the ratio of the surfactant to the solvent is Each 100 mL of the medium contains 880 to 1240 mg of surfactant.

[0014] Furthermore, the surfactant is a nonionic surfactant, preferably the nonionic The surfactants are span-type, polysorbate, poloxamer, alkyl glucoside, and vitamin Polyethylene glycol succinic acid, sucrose stearate or laurocapra It is a polymer, preferably a spun polymer or polysorbate.

[0015] Furthermore, the ionic polymer may be carboxymethylcellulose and its salts, glyco Sodium starch phosphate, hyaluronic acid and its salts, xanthan gum, alginic acid and The salt is selected from at least one of the following: polyethylene glycol diacetate PEG-(COOH)2. It is also one type, preferably the ionic polymer is carboxymethylcellulose and It is at least one selected from the salts of hyaluronic acid and its salts.

[0016] Furthermore, the carrier or auxiliary material of the ophthalmic formulation contains low-molecular-weight povidone and medium-molecular-weight povidone. The mass ratio with povidone is (0.1~10):1, and the ratio of the low-molecular-weight povidone to the solvent is Each 100 mL of solvent contains 5 to 3000 mg of low-degree-of-polymerization povidone. Preferably, the mass ratio of the low-molecular-weight povidone to the medium-molecular-weight povidone is (0.24~0. The ratio is 8):1, and the ratio of low-degree-of-polymerization povidone to solvent is 100 mL of solvent It contains 240-840 mg of povidone.

[0017] Furthermore, the low degree of polymerization povidone is a povidone with a weight-average molecular weight of 2000 to 5000. Preferably, it is povidone PVP K12 with a weight-average molecular weight of 3500.

[0018] Furthermore, the aforementioned povidone with a moderate degree of polymerization is a povidone with a weight-average molecular weight of 20,000 to 60,000. Yes, preferably povidone PVP K30 with a weight-average molecular weight of 35,000 to 50,000. be.

[0019] Furthermore, the solvent in the carrier or auxiliary material of the ophthalmic formulation is preferably a polar solvent. Ku is water.

[0020] Furthermore, the carrier or auxiliary material of the ophthalmic formulation further contains a thickening agent and / or cosolvent. It contains, Furthermore, the thickening agent may be polyethylene glycol, carbomer, poloxamer, or povidone. hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, por Livinyl alcohol, xanthan gum, polyoxyethylene fatty alcohols, hyaluronic acid At least one of the following: nic acid and its salts, or hydroxypropyl methylcellulose. The cosolvent is propylene glycol, glycerol, liquid polyethylene glycol It is either oatmeal or castor oil, and a thickener and surfactant, or a thickener and low-molecular-weight povidone. The mass ratio is 1:(0.1~100), and the cosolvent is a surfactant, or a cosolvent is a low degree of polymerization. The mass ratio with povidone is (1-10):1. Preferably, the mass ratio of the thickener to the surfactant is 1:(1.2~30), and eutosolubilable The mass ratio of the medium to the surfactant is (2.56-9):1. Furthermore, the surfactant or low-molecular-weight povidone and an active ingredient for treating eye diseases. The mass ratio between them is (12-31):1.

[0021] Furthermore, the aforementioned glucocorticoid drugs include dexamethasone, hydrocortisone, and prednisolone. At least one of nisolone and betamethasone, and the nonsteroidal drug is Among clofenac, pranoprofen, indomethacin, and bromfenac sodium There is at least one type.

[0022] Furthermore, the carrier or auxiliary material of the ophthalmic preparation is The components include nanoparticles formed by the self-assembly of components, and the nanoparticles are used in eye diseases It contains active ingredients for treating [the condition].

[0023] Furthermore, the nanoparticles are spherical, and their particle size is 1 to 100 nm, preferably, The particle size of the aforementioned nanoparticles is 5 to 30 nm.

[0024] Furthermore, the above formulation contains spherical nanospheres with a particle size of 10 to 2000 nm. The nosphere is formed by the self-assembly of nanoparticles, preferably the aforementioned The nospheres have a particle size of 100-2000 nm.

[0025] The present invention also provides a method for preparing the above-mentioned formulation, the method being: (1) Prepare a solution by adding a surfactant and / or thickener to the solvent, The active ingredient and / or co-solvent for treating eye diseases is dissolved in the solution obtained in step (1). Disperse in a liquid, then add an ionic polymer or a solution thereof, and disperse and mix to create an initial suspension. Step (2) to obtain the liquid, Stir and disperse the initial suspension obtained in step (2), or homogenize it. This includes the step of distributing (3), or (a) A step of preparing a solution by adding a low degree of polymerization povidone and / or a thickener to the solvent. and, The active ingredient and / or co-solvent for treating eye diseases is dissolved in the solution obtained in step (a). Disperse in liquid, then add medium-molecular-weight povidone or a solution thereof, and disperse and mix to create an initial suspension. Step (b) to obtain the turbid liquid, Step (b) involves grinding or homogenizing the mixture obtained in step (b) and dispersing it. Includes pp(c) and .

[0026] Furthermore, the dispersion in step (2) or step (b) is due to mechanical stirring. Dispersion, dispersion by magnetic stirring, dispersion by vortex shaking, dispersion by shear, homogenization It is at least one of the following: dispersion by pulverization, dispersion by grinding, and dispersion by ultrasound. .

[0027] The present invention further proposes the use of the formulation in the preparation of drugs for treating retinal diseases. Preferably, a drug for treating the aforementioned retinal disease is used to treat macular edema and / or visual impairment. It is a drug used to treat neuritis and / or non-infectious endophthalmitis.

[0028] Furthermore, the drugs used to treat the aforementioned macular edema may also be used for macular edema caused by retinal vascular disease, and retinal edema. Central vein occlusive macular edema, retinal vein branch occlusive macular edema, diabetic macular edema, pathological myopia A drug for treating macular edema and / or macular edema due to exudative age-related macular degeneration. be.

[0029] The present invention also provides a method for treating retinal diseases, namely, the use of the preparation on a patient. To provide a service.

[0030] Furthermore, the aforementioned fundus disease may be macular edema and / or optic neuritis and / or non-infectious. It is endophthalmos.

[0031] Furthermore, the aforementioned macular edema can be classified as macular edema due to retinal vascular disease or macular edema due to central retinal vein occlusion. Macular edema, retinal vein branch occlusion macular edema, diabetic macular edema, pathological myopic macular edema, and / or macular edema. This is macular edema due to exudative age-related macular degeneration.

[0032] Furthermore, the method of use is administration by eye drops.

[0033] As is clear from the experimental results, the ophthalmic formulation for eye drop administration prepared in the present invention is sexual It has a stable consistency, is easy to store, and effectively delivers the active ingredient for treating eye diseases to the posterior segment of the eye. It can be delivered, reach an effective (expected) concentration in the fundus, and treat fundus diseases such as macular edema. This treatment enables conventional intravitreal injection, intravitreal injection implants, oral administration, and systemic administration. To overcome the challenges of injectable administration and resolve the problems of serious complications such as intraocular hemorrhage and pain, To significantly reduce the suffering of patients with this disease, improve medical convenience, and enhance the lives of patients and their families. The aim is to improve quality or avoid systemic toxic side effects from systemic administration.

[0034] This invention can avoid complications from local injections or implants in the eye.

[0035] The formulation developed in this invention is suitable as a therapeutic drug because it is administered in small doses and has few toxic side effects. Not only can it do this, but it can also prevent and control eye diseases.

[0036] The formulation of the present invention can meet the needs for long-term administration in clinical settings.

[0037] The eye drop therapy system of the present invention has already been used clinically as an active ingredient and It is possible to use small molecule drugs with a clear mechanism of action, and quality can be controlled. It is easy to use as a product, patients adapt well to it, and physicians can flexibly adjust the administration plan according to the patient's condition. It can be adjusted to be soft.

[0038] The nanoparticles described in this invention refer to components of carriers or auxiliary materials of ophthalmic formulations that self-contain in the solvent. These are nanoscale spherical aggregates that are formed through organized processes.

[0039] The nanospheres described in this invention are spherical shapes formed by the self-assembly of nanoparticles in a solvent. It refers to a self-organizing structure.

[0040] The solvent described in this invention is capable of dissolving the components of the carrier or auxiliary material of an ophthalmic formulation. It refers to the resulting liquid.

[0041] The surfactant described in this invention is a substance that can significantly reduce the surface tension of a liquid. This refers to a nonionic surfactant described in this invention, which is a surfactant that does not dissociate in water. That is the matter.

[0042] The ionic polymer described in this invention is a polymer polymer having a cation or anion. That is the case.

[0043] The low degree of polymerization povidone described in this invention refers to povidone with a molecular weight of 10,000 Daltons or less. Povidone with a moderate degree of polymerization has a molecular weight of 10,000 Daltons or more, or 100,000 Daltons. This refers to povidone below the Alton level.

[0044] The "active ingredient for treating eye diseases" as described in this invention refers to an active ingredient used for treating eye diseases. It is an active substance that can do so, that is, it is already being used as an ophthalmic medicine. The active substance, as well as its mechanism of action and target, suggests that it may be capable of treating eye diseases. However, at present, it is not used as an ophthalmic medicine (Active This refers to a Pharmaceutical Ingredient (API).

[0045] The eye drop administration described in this invention is a method of administering a drug solution by dropping it into the eye, and belongs to the corneal administration route. It is what it is.

[0046] Naturally, based on the above-mentioned content of this invention, general technical knowledge and conventional means of the art may be used. In light of the above-mentioned basic technical concept of the present invention, and on the premise that it does not deviate from the present invention, various other The form can be modified, replaced, or altered.

[0047] The above-mentioned content of the present invention will be explained in more detail below through specific embodiments in the form of examples. This is to clarify. However, this does not mean that the scope of the subject matter of the present invention is limited to the following embodiments. It must not be misinterpreted. Any technology realized based on the above content of the present invention falls within the scope of the present invention. It belongs to the enclosure. [Brief explanation of the drawing]

[0048] [Figure 1] Figure 1 shows (A) a transmission electron microscope image (scale bar at 200 nm) of the sample obtained in Example 1, and (B) a transmission electron microscope image (scale bar at 1 μm) after staining with a staining agent. [Figure 2] Figure 2 shows the total retinal thickness at approximately 750 μm and 1500 μm points on both the left and right sides of the occluded vein at different examination times for each group of animals. The horizontal axis represents the vertical distance (μm) between the measurement point and the center of the optic nerve head in the OCT image, and the vertical axis represents the total retinal thickness (μm). Data are shown as mean ± standard deviation (where 2A is the total retinal thickness for each group before modeling, N=8, and 2B is the total retinal thickness at D2). The total retinal thickness of each group was N=6 for the solvent control group and low-dose group, N=8 for the intermediate and high-dose group and aflibercept group, and N=7 for the dexamethasone group. 2C is the total retinal thickness of each group at D4, N=6 for the solvent control group, N=7 for the test dose group, and N=8 for the intermediate and high-dose group, aflibercept group, and dexamethasone group. Compared to the solvent control group at the same time, *p ≤ 0.05. [Figure 3] Figure 3 shows examples of color photographs of the fundus and images from angiography. [Figure 4]Figure 4 shows an example of an optical coherence tomography image (measurement of the total retinal thickness). [Modes for carrying out the invention]

[0049] The reagents or equipment used in this invention can be obtained by purchasing commercially available products. Unless otherwise specified, follow the conventional conditions or the conditions recommended by the manufacturer. It will be used.

[0050] Some of the equipment and facilities are as follows:

[0051] ES225SM-DR(E) Electronic Analytical Balance, Precisa GmbH (Switzerland) DF-101S heat collecting type constant temperature heating magnetic stirrer, Yingyu High Technology Equipment Factory, Gunyi City (Henan, China) WH-2 Microvortex Mixer, Shanghai West Analytical Instruments Factory Co., Ltd. (Shanghai, China) country) Disperser: T25 EasyClean Digital, IKA GmbH (Germany) KQ-500 type ultrasonic cleaner, Kunshan Ultrasonic Instrument Co., Ltd. (Kunshan, China) JP-010T type ultrasonic cleaner, Shenzhen Jieming Cleaning Equipment Co., Ltd. AH-NANO Plus high pressure homogenizer, Antao Sina Rice Technology (Suzhou) Co., Ltd. country) PM-DK2 Planetary Ball Mill, manufactured by Zhuodei Instruments & Equipment (Shanghai) Co., Ltd. (Shanghai, China) Mettler-Toledo FE20 pH meter, Mettler-Toledo (Switzerland) NS-90 nanoparticle size analyzer, Zhuhai Oumei Equipment Co., Ltd. (Zhuhai, China) Agilent 1100 HPLC High-Performance Liquid Chromatography, Agilent Technologies, Inc. US) API 4000 Triple Quadrupole Mass Spectrometer (Applied Biosystems, Inc., USA) STY-1A osmotic pressure meter, Tianjin Tianda Tianfa Science and Technology Co., Ltd. (Tianjin, China).

[0052] The method for measuring the properties of the formulation of the present invention is as follows.

[0053] Particle size measurement method Transfer 1 mL of the sample prepared in the example or comparative example to the sample cell and set the measurement temperature to 40°C. The temperature was set to °C, the sample cell was placed in the NS-90 nanoparticle size analyzer, and the measurement was started. The sample is measured three times, and the average of the three measurement results is taken to determine the measurement result of the sample. Particle size (light intensity distribution, and %) and polydispersity index (PdI, Polydispersi It was shown as tyIndex.

[0054] Osmotic pressure measurement method The freezing point depression of the solution was measured, and the osmotic pressure molar concentration was determined. Procedure: STY-1A osmotic pressure analyzer Washing the probe of the instrument: Add 100 μL each of distilled water to three sample tubes, preheat the instrument, and Afterward, screw a sample tube containing 100 μL of distilled water onto the instrument probe and wash it three times. Select and click "Clean," repeating three times. Measurement: Sample in the instrument information table. I entered the information and clicked "Test". I then used a pipette gun to dispense 100 μL of the sample into the sun. I transferred the sample to the pull tube, lightly screwed it into the device, and clicked "Start" for measurement. I repeated the measurement three times. In return, the average of the three measurement results was used as the measurement result.

[0055] Method for measuring pH value The FE20 pH meter was tested with pH buffer solutions (pH 4.00 and 6.86 respectively). After calibrating according to 9.18), wash the electrodes with pure water, then absorb any excess moisture with fiberless paper. The liquid sample to be measured was immersed in the immersion The data obtained after stabilization was used as the pH value of the sample.

[0056] If the pH of the measured solution is <5 or >9, adjust the pH to 6-8 with an acid or alkali. pH adjustments are necessary, and common pH adjusters include NaOH and HCl, and phosphoric acid and phosphoric acid. Salts (e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate), citric acid and citric acid These are salts (e.g., sodium citrate), boric acid, and borax. The osmotic pressure of the measured liquid. If the solution is not isotonic, add an appropriate amount of sodium chloride to make it isotonic or I got closer to that.

[0057] Method for verifying the effectiveness of delivering drugs to the posterior segment of the eye The test equipment and facilities are as follows: High-performance liquid chromatography, model number: LC- 20AD (Shimadzu Japan). Mass spectrometer, model number: API4000 Triple Quadrupole Mass Spectrometer (Applied Biosystems, Inc., USA). Column: Fortis Pace C18 5μM 2.1 x 30 mm (Fortis, UK).

[0058] Healthy adult Sprague Dawley (SD) rats were selected, and a test group and a control group were compared. The subjects were divided into groups of six eyes each. The test group received the ophthalmic formulation prepared according to the examples of the present invention, while the control group received the ophthalmic formulation prepared according to the examples of the present invention. The solution contains a suspension of 2 mg of drug / 5 mL of physiological saline (shake with a vortex mixer before use to ensure uniformity). 20 μL of the substance was administered to each eye. The animals were euthanized 0.5 hours or 1 hour after administration. The vitreous humor was then quickly collected, the vitreous sample was homogenized, and then heated to -80°C. It was stored. Take 10 μL of vitreous homogenate and add 90 μL of 95% ethanol, 2 The solution was sonicated for 1 minute and vortex-mixed for 1 minute to obtain a vitreous homogenate solution. Take 50 μL of modinate solution, add 175 μL of methanol, and vortex mix for 3 minutes. Combine the contents, centrifuge at 4°C and 12000 rpm for 10 minutes, and remove the supernatant liquid to a thickness of 0.45 μm. Filter the filtrate using a syringe filter, and then perform LC / MS / MS (positive ion mode, MRM S) analysis. Used in CAN analysis.

[0059] Example 1: Preparation of the ophthalmic formulation of the present invention According to Table 1, 0.24 g of CMC-Na (carboxymethylcellulose sodium, Weigh the ionic polymer and add it to a glass Erlenmeyer flask containing 40 mL of pure water, then add a magnetic field. Stirring was started and continued for 2 hours to obtain Solution 1. 1.0 g of polysorbate 80 (surfactant) (The agent) and 0.24g HPMC (hydroxypropyl methylcellulose, thickener) are each Weigh the water and add it to a glass Erlenmeyer flask containing 60 mL of pure water, then start magnetic stirring. Solution 2 was obtained by heating in a bath at approximately 40°C for 1.5 hours. 40 mg of dexamethasone and Weigh out 4 mL of PEG400 (i.e., 4.3 times the amount of surfactant used (w / w)) Add to solution 2, continue heating and stirring for 30 minutes, then add solution 1 and stir for 30 minutes. A mixture was obtained. The mixture was dispersed using a disperser at a rotation speed of 9500 rpm for 5 minutes, and the machine was then removed. After stopping the process and allowing the bubbles to disappear, the dispersion was obtained by vacuum filtration using a Buchner funnel. Transfer to a pressure homogenizer, control the temperature to 15±5℃, and homogenize at a pressure of approximately 400 Bar for 3 minutes. Homogenize in between, then increase the pressure to >800 Bar and homogenize for 25 minutes, 30 Reduce the pressure to 0 Bar, homogenize for 2 minutes, then drain to obtain a colorless, transparent solution, and further... The solution was then filtered under reduced pressure to sterilize it and remove mechanical impurities, resulting in a colorless, transparent solution after impurity removal. .

[0060] pH and osmotic pressure adjustment: Add 700 mg of NaH2PO4 and 400 mg of Na2HPO4. Then, adjust the pH to 6.3, add sodium chloride, and bring the osmotic pressure to 282 mOsmol. It was adjusted to / kg.

[0061] HPLC measurement: Measuring instrument: Agilent 1100 high-performance liquid chromatography, operating software T: OpenLab CDS c.01.10 (201) Chemstation Edition.

[0062] Chromatography conditions: Chromatography column is Waters XBridge C The column is 18.5 μm thick, 4.6 x 250 mm in size, with a column temperature of 35°C and a flow rate of 1.0 mL / min. Measurement wavelength: 240 nm, mobile phase: 0.1% phosphoric acid aqueous solution (72.0%)-acetonitrile Isocratic elution was performed using a 28.0% solution. The sample was diluted fivefold with the mobile phase. Later, 10 μL was taken and injected into a liquid chromatograph. Measurement result: 96.2%.

[0063] The particle size was 20.6 nm (85.6%), and PdI: 0.266. Stored at room temperature, away from light. After storage for one month, there was no change in the appearance or content of the sample.

[0064] Example 2: Preparation of the ophthalmic formulation of the present invention The preparation method is as shown in Example 1, and the raw materials and quantities used are as shown in Table 1. Impurity removal A colorless, transparent solution was obtained after removal.

[0065] pH adjustment: Adjust to pH 6.5 with 0.2N NaOH and / or 0.1N HCl. Ta.

[0066] The HPLC measurement method was the same as in Example 1, and the HPLC content measurement result was 95.1 The particle size was 12.9 nm (92.1%), and PdI was 0.509. Stability was relatively good. When left at room temperature, away from light, for one month, there were no significant changes in appearance or content. A small amount of precipitate formed after two months.

[0067] In rats, the vitreous API concentration was 13.9 ng / g and the RSD was 17.2% one hour after eye instillation. there were.

[0068] Example 3: Preparation of the ophthalmic formulation of the present invention For preparation methods and adjustments of pH and osmotic pressure, refer to Example 1. For materials and quantities, see Table 1. As shown, a yellowish, transparent solution was obtained after removing impurities.

[0069] HPLC measurement: Column: ZORBAX Eclipse Plus C18, 4.6 x100mm 3.5μm, Mobile phase A: 0.1% phosphoric acid, Mobile phase B: Methanol (80: 20) Isocratic elution, temperature: 35°C, measurement wavelength: 280nm, flow rate: 0.8ml / min, measurement result: 98.4%. Particle size 39.7nm (95.5%), PdI:0.31 The result was 8. After being left at room temperature, away from light, for one month, there was no change in appearance or content. .

[0070] The vitreous API concentration in rats 0.5 hours after eye instillation was 78.3 ng / g.

[0071] Example 4: Preparation of the ophthalmic formulation of the present invention Refer to Example 3 for the preparation method and adjustment of pH and osmotic pressure. The raw materials and quantities used are shown in Table 1. That is correct. A yellowish, transparent solution was obtained after removing impurities.

[0072] The HPLC measurement method was the same as in Example 3, and the measurement results were: 97.8%, particle size: 46.2. The result was nm (95.5%), PdI: 0.343. This was after leaving it at room temperature, away from light, for one month. Furthermore, there were no significant changes in appearance or content.

[0073] Example 5: Preparation of the ophthalmic formulation of the present invention The preparation method is as shown in Example 1, and the raw materials and quantities used are as shown in Table 1. Here, The amount of cosolvent PEG400 used was 5 times (w / w) that of the surfactant, and the colorless clear solution was obtained after impurity removal. We obtained a bright solution.

[0074] pH and osmotic pressure adjustment: Adjust the pH to 6.2 with a 1M Na2HPO4 solution, and sodium chloride The osmotic pressure was adjusted to 295 mOsmol / kg by adding mu.

[0075] The HPLC measurement method was the same as in Example 1, and the measurement results were 97.3% and a particle size of 22.4n. m(91.4%), PdI:0.293. After being left at room temperature, away from light for one month... There were no significant changes in appearance or content.

[0076] The vitreous API concentration in rats 0.5 hours after eye instillation was 42.7 ng / g.

[0077] Example 6: Preparation of the ophthalmic formulation of the present invention The preparation method is as shown in Example 1, and the raw materials and quantities used are as shown in Table 1. Here, The amount of cosolvent PEG400 used was 5 times (w / w) that of the surfactant, and the colorless clear solution was obtained after impurity removal. We obtained a bright solution.

[0078] The pH was 6.5, and no adjustment was necessary. Refer to Example 1 for osmotic pressure adjustment.

[0079] The HPLC measurement wavelength was 245 nm, the method was the same as in Example 1, and the measurement result was 98. It was 1%.

[0080] The particle size was 18.6 nm (96.9%), and PdI: 0.257. Stored at room temperature, away from light. After being left for several months, there were no significant changes in appearance or content.

[0081] The vitreous API concentration in rats 0.5 hours after eye instillation was 43.8 ng / g.

[0082] Example 7 Preparation of the ophthalmic formulation of the present invention Refer to Example 1 for the preparation method and adjustment of pH and osmotic pressure. The raw materials and quantities used are shown in Table 1. That is correct. A colorless, transparent solution was obtained after removing impurities.

[0083] The HPLC measurement method was the same as in Example 6, and the measurement result was 98.3%.

[0084] The particle size was 18.5 nm (97.6%), and PdI: 0.208. Stored at room temperature, away from light. After being left for several months, there were no significant changes in appearance or content.

[0085] Example 8: Preparation of the ophthalmic formulation of the present invention Refer to Example 1 for the preparation method and adjustment of pH and osmotic pressure. The raw materials and quantities used are shown in Table 1. That is correct. A colorless, transparent solution was obtained after removing impurities.

[0086] The HPLC measurement method was the same as in Example 1, and the measurement result was 96.8%.

[0087] The particle size was 18.7 nm (89.2%), and PdI: 0.255. Stored at room temperature, away from light. After being left for several months, there were no significant changes in appearance or content.

[0088] Example 9: Preparation of the ophthalmic formulation of the present invention Refer to Example 1 for the preparation method and adjustment of pH and osmotic pressure. The raw materials and quantities used are shown in Table 1. That is correct. Here, the amount of cosolvent PEG400 used is 1 mL, i.e., the amount of surfactant The dilution ratio was set to 8x (w / w). A colorless, transparent solution was obtained after removing impurities.

[0089] The HPLC measurement method was the same as in Example 1, and the measurement result was 97.2%.

[0090] The particle size was 19.6 nm (97.0%), and PdI: 0.289. Stored at room temperature, away from light. After being left for several months, there were no significant changes in appearance or content.

[0091] Comparative Example 1 The raw materials and amounts used are shown in Table 1, and the surfactant is activated with low-molecular-weight povidone PVP12. By replacing the actionant and substituting the ionic polymer with hydroxypropyl cellulose (HPC), The preparation method was as described in Example 1, and a milky white liquid was obtained using 1 mL of PEG400 as a co-solvent. .

[0092] Measurement results: particle size 899 nm (92.9%), PdI: 0.188. After leaving overnight... A white precipitate formed.

[0093] Comparative Example 2 The raw materials and quantities used are shown in Table 1, and the interfacial activity is activated with medium-polymerization povidone PVP30. A colorless, transparent liquid was obtained by substituting the herbicides and following the preparation method described in Example 1.

[0094] Measurement results: Particle size 241 nm (53.1%) and 89.4 nm (32.6%), PdI The value was 1.000. After one week, precipitation occurred.

[0095] Comparative Example 3 The raw materials and quantities used are shown in Table 1, and the interfacial activity is activated with medium-polymerization povidone PVP30. A colorless, transparent liquid was obtained by substituting the herbicides and following the preparation method described in Example 1.

[0096] Measurement results: Particle size 483nm (47.6%) and 117nm (33.9%), PdI: The value was 1.000. After one week, precipitation occurred.

[0097] Comparative Example 4 The raw materials and usage amounts are as shown in Table 1, and the amounts of HPMC and CMC-Na used have been changed. The preparation method was described in Example 1, and a white emulsion was obtained.

[0098] Measurement results: Particle size 26.9 nm (40.5%) and 2043 nm (31.8%), Pd The I ratio was 1.000. After being left overnight, a white precipitate formed.

[0099] Comparative Example 5 The raw materials and usage amounts are as shown in Table 1, and the amounts of HPMC and CMC-Na used have been changed. The preparation method is as described in Example 1, where 3 ml of PEG400 and 1 ml of ethanol are eutectic. It was added as a medium, and water was added until the total volume reached 100 mL to obtain a colorless solution. Sodium chloride In addition, the osmotic pressure was adjusted to 262 mOsmol / kg.

[0100] Measurement results: Particle size 416nm (80%) and 18.1nm (20%), PdI: 0.4 The result was 62. After being left at room temperature for two weeks, it turned into a white emulsion.

[0101] Example 10 Preparation of the ophthalmic formulation of the present invention The raw materials and amounts used are as shown in Table 2, including 0.52g of povidone (PVP) K30 Weigh the contents and add them to a 100 mL glass Erlenmeyer flask containing 25 mL of pure water, then magnetically filter for 2 hours. The mixture was stirred to obtain Solution 1. This solution contained 260 mg of HPMC and 420 mg of povidone (PVP) K1. 2 Weigh each component and add it to a 100 mL glass Erlenmeyer flask containing 25 mL of pure water, then add the magnetic compound. Stirring was initiated, and the solution was heated in a water bath at 40°C for 2 hours to obtain solution 2. 1 mL of PEG4 00 (cosolvent, amount used is equivalent to 2.56 times that of PVP K12) and 20 mg of dexamethasone Weigh the ingredients and add them to solution 2. Continue heating and stirring for 30 minutes, then add solution 1 and continue for 30 minutes. The mixture was stirred to obtain a mixed solution. High-speed dispersion, high-pressure homogenization, and membrane filtration were performed similarly to Example 1. The process was carried out to obtain a colorless, transparent solution after removing impurities.

[0102] pH and osmotic pressure adjustment: pH 6.5 does not require adjustment, and osmotic pressure can be controlled with sodium chloride. The pressure was adjusted to 293 mmol / kg.

[0103] The HPLC measurement method was the same as in Example 1, and the measurement result was 99.2%, particle size 575 nm. (92.6%), PdI: 0.211. After being left at room temperature and away from light for one month, There were no significant changes in appearance or content. After two months, precipitation occurred.

[0104] The vitreous API concentration in rats 0.5 hours after eye instillation was 5.1 ng / g.

[0105] Example 11: Preparation of the ophthalmic formulation of the present invention The raw materials and amounts used are shown in Table 2, and the amount of cosolvent PEG400 used is the surfactant The solution was diluted 8.9 times (w / w), and the preparation method and adjustment of pH and osmotic pressure were as shown in Example 15. A colorless, transparent solution was obtained after removing impurities.

[0106] The HPLC measurement method was the same as in Example 10, and the measurement result was 98.5%.

[0107] Particle size: 125.6 nm (63.5%) and 13.6 nm (33.1%), PdI: 0. The value was 255. After being left at room temperature, away from light for one month, there were no significant changes in appearance or content. There wasn't one.

[0108] Comparative Example 6 The raw materials and quantities used are shown in Table 2, and the preparation method is as shown in Example 15. A pale white emulsion was obtained by adding a polymer.

[0109] Measurement results: Particle size 1299 nm (92.4%), PdI: 0.175. After leaving overnight... A white precipitate formed.

[0110] Comparative Example 7 The raw materials and quantities used are as shown in Table 2. For the preparation method, refer to Example 15, and use 1 mL. Add PEG400 as a cosolvent (the amount used is 20 times the amount of surfactant (w / w)), and the solution is colorless. A solution was obtained.

[0111] Measurement results: Particle size 637 nm (85.9%), PdI: 0.258. Left overnight. A white precipitate formed.

[0112] Comparative Example 8 The raw materials and quantities used are shown in Table 2, and the preparation method is as shown in Example 15, povidone Without adding any ions, an ionic polymer was added to obtain a colorless solution.

[0113] Measurement results: pH5.2, particle size 46.2nm (96.9%), PdI:0.343, HP LC content measurement result: 98.9%. When stored in a refrigerator for two weeks, fine particles were found. Crystals precipitated.

[0114] Based on the measurement results of API concentrations in the rat vitreous humor after eye drop administration, the ophthalmic formulation of the present invention is effective in the eyes It can carry active ingredients for treating diseases and pass through the barrier of the eyeball structure, conjunctiva Because the effective dose of the drug can be delivered to the vitreous humor by the method of administration in a capsule (eye drop). This avoids invasive administration methods such as intravitreal injection, and also significantly reduces the total amount of drug administered. It has been shown that this reduces the absorption of drugs throughout the body and avoids the occurrence of toxic side effects. Ta.

[0115] Table 1 [Table 1] TIFF2026136339000002.tif177170

[0116] Table 2 [Table 2]

[0117] The beneficial effects of the eye drop drug formulation of the present invention will be demonstrated below through experimental examples.

[0118] Experimental Example 1: Transmission electron microscope observation results of the carrier of the present invention Transmission electron microscope (JEM-2100 Plus, JEOL Ltd.) One drop of the liquid sample prepared in Example 1 was drawn up and dropped onto a copper sample mesh. After letting it stand for 5 minutes and aspirating any excess liquid sample, allow it to air dry and then prepare the electron microscope sample. Measurements were taken in the room. Sample staining: One drop of liquid sample was drawn up and the copper material sample was stained. After dropping the sample onto a mesh and removing any excess sample from the mesh, add 2% phosphomolybdenum. Add one drop of dic acid, let stand for 5 minutes, then aspirate the excess liquid, let it air dry, and then sample the solution. The sample was placed under an electron microscope and measured. The results are shown in Figure 1. The drug prepared according to the present invention The supporting material forms spherical structures (nanoparticles, Figure 1A) with a particle size of 1 to 100 nm in the solvent. Furthermore, the nanoparticles are further formed into spheres (nanospheres, Figure 1B) with a particle size of 10-2000 nm. It becomes clear that it can be organized.

[0119] Experimental Example 2: Measurement of particle size, content, and stability 1. Experimental Method Transfer 1 mL of the sample prepared in the examples and comparative examples to a sample cell and set the measurement temperature to 40°C. The temperature was set to °C, the sample cell was placed in the NS-90 nanoparticle size analyzer, and the measurement was started. The sample is measured three times, and the average of the three measurement results is taken to determine the measurement result of the sample. Furthermore, particle size (light intensity distribution, and %) and polydispersity index (PdI) are measured. The sample was shown as a sity index. After measurement, it was stored away from light, and changes in appearance were observed. At the same time, the particle size was measured again.

[0120] Using Agilent 1100 high-performance liquid chromatography, the ophthalmic preparations prepared in this invention The HPLC content of the formulation samples was measured.

[0121] 2. Experimental Results Please refer to Table 3.

[0122] Table 3 [Table 3] TIFF2026136339000005.tif220170

[0123] As can be seen from the above results, the drug formulation prepared in this invention has a small particle size, and measured by HPLC The content of the active ingredients is high, and both the form and content remain stable even after being stored for a long time. Therefore, the formulation of the present invention has a high encapsulation rate and excellent stability. On the other hand, the present invention Comparative formulations prepared using different auxiliary materials or raw materials showed poor stability and short duration. Phenomena such as precipitation or alteration may occur.

[0124] Experimental Example 3: Verification of the therapeutic effect of the eye drop administration method of the ophthalmic formulation of the present invention on macular edema. 1. Experimental Method 48 SD rats with no obvious abnormalities in either eye were randomly divided into 6 groups (8 rats per group, half male, half female). Divide into portions and administer the photosensitizer rose bengal (40 mg / mL, 40 mg / kg) to the D1 tail vein. Immediately after injecting the drug, laser photocoagulation was performed on one retinal vein in the right eye. Approximately 15 minutes after solidification was complete, we checked whether the target retinal vein was occluded. After confirming that the product was prepared, the drug administration process was carried out according to Table 4, and the test product was prepared in Example 1. A high-dose group was created using the agent, and the preparation prepared in Example 1 was diluted three times with medical physiological saline. The formulation was designated as the medium-dose group, and the formulation prepared in Example 1 was diluted 9 times with medical physiological saline to obtain a low-dose formulation. The dosage groups included the commercially available drug aflibercept intraocular injection (Bayer, Germany) and Dexamethoxazole. Samethasone sodium phosphate injection (Sinopharm Rongsheng Pharmaceutical Co., Ltd., China) was used as the control drug. D-1 (before modeling), D1 (immediately after modeling), D2 (2 days after modeling), D4 (modeling On the fourth day after denaturation, fundus photography (FP) and fluorescein angiography (FF) were performed on the right eye of all animals. A) Optical coherence tomography (OCT, not performed immediately after D1 modeling) was performed. Image analysis was performed on the FP and FFA images, and approximately 750 of the occluded veins on both the left and right sides were identified. The total retinal thickness at a 1500 μm point was measured using OCT scanning. For all animals, the left eye was measured. In this case, modeling, medication, and corresponding ophthalmic examinations were not performed.

[0125] Table 4: Medication Treatment Table by Animal Group [Table 4]

[0126] 2. Experimental Results As can be seen from Figure 2, a significant increase in the total retinal thickness after modeling was observed, demonstrating the effectiveness of the present invention. A significant decrease in the total retinal thickness was observed at D2 and D4 after administering the drug as eye drops, and further Since its effect is equivalent to that of commercially available pharmaceuticals administered by intravitreal injection, the formulation of the present invention is administered by eye drop injection. This method can be used to achieve a very good improvement in retinal edema.

[0127] As shown in Figure 3, after modeling (D1), compared to before modeling, the laser photocoagulation area In contrast to the case where significant intravenous thrombus formation and blood flow stagnation were observed, the formulation of the present invention After administering the eye drops, although some degree of retinal vein occlusion remained, the venous thrombosis clearly improved. It is being done well.

[0128] As shown in Figure 4, after administering the formulation of the present invention as eye drops, thickening of acute retinal edema occurs at D2. However, by D4, the edema gradually began to recover, approaching the normal state before modeling.

[0129] As can be seen from the above results, the medium-dose group (0.133 mg / mL) and the high-dose group (0 Repeated instillation of the test product (0.4 mg / mL) (20 μL / eye, 4 consecutive days, 4 times for the first 3 days) (Administered once on day 4) is a combination of laser photocoagulation and a photosensitizer that induces retinal irritation. It has a significant inhibitory / therapeutic effect on acute retinal edema in venous-occluded rats, and the dosage and There is a correlation, and the efficacy of the high-dose group is similar to that of aflibercept intraocular injection, a commercially available control product. Close. In this study, a single dose of the commercially available control product, dexamethasone sodium injection, was administered via glass. No clear inhibitory or therapeutic effect on acute retinal edema was observed even when administered intravenously.

[0130] As described above, the present invention provides a formulation for eye drop administration that can carry (encapsulate) glucocorticoid and / or nonsteroidal drugs, pass through the anterior segment of the eye, and be transported to the posterior segment to exert a therapeutic effect. This achieves the goal of treating retinal diseases such as macular edema by eye drop administration, solves an unresolved technical problem that has been urgently needed to be solved in this field for many years, and has extremely excellent clinical value and very positive social significance. In embodiments of the present invention, for example, the following items are provided. (Item 1) An ophthalmic preparation for eye drop administration, A formulation comprising an active ingredient for treating eye diseases, and a carrier or auxiliary material for ophthalmic formulations. The active ingredient for treating the aforementioned eye disease is a glucocorticoid drug and / or a nonsteroidal drug. The carrier or auxiliary material of the ophthalmic preparation contains a surfactant, an ionic polymer, and a solvent. Alternatively, the carrier or auxiliary material of the ophthalmic preparation contains low-molecular-weight povidone, medium-molecular-weight povidone, and a solvent. A pharmaceutical preparation characterized by the following features. (Item 2) The ophthalmic preparation according to item 1, characterized in that the mass ratio of surfactant to ionic polymer in the carrier or auxiliary material of the ophthalmic preparation is (1-100):(0.1-50), and the ratio of surfactant to solvent is such that 5 to 3000 mg of surfactant is contained per 100 mL of solvent. (Item 3) The ophthalmic preparation according to item 2, characterized in that the mass ratio of surfactant to ionic polymer in the carrier or auxiliary material of the ophthalmic preparation is (12-31):(2-7.5), and the ratio of surfactant to solvent is such that 880-1240 mg of surfactant is contained per 100 mL of solvent. (Item 4) The formulation according to any one of items 1 to 3, characterized in that the surfactant is a nonionic surfactant, preferably a span-type surfactant, polysorbate, poloxamer, alkyl glucoside, vitamin E polyethylene glycol succinic acid, sucrose stearate, or laurocaprum, and preferably a span-type surfactant or polysorbate. (Item 5) The formulation according to any one of items 1 to 3, wherein the ionic polymer is at least one selected from carboxymethylcellulose and its salts, sodium starch glycolate, hyaluronic acid and its salts, xanthan gum, alginic acid and its salts, and polyethylene glycol diacetate PEG-(COOH)2, and preferably, the ionic polymer is at least one selected from carboxymethylcellulose and its salts, hyaluronic acid and its salts. (Item 6) The mass ratio of low-degree-of-polymerization povidone to medium-degree-of-polymerization povidone in the carrier or auxiliary material of the ophthalmic preparation is (0.1-10):1, and the ratio of low-degree-of-polymerization povidone to solvent is such that 5-3000 mg of low-degree-of-polymerization povidone is contained per 100 mL of solvent. Preferably, the mass ratio of low-molecular-weight povidone to medium-molecular-weight povidone is (0.24-0.8):1, and the ratio of low-molecular-weight povidone to solvent is such that 240-840 mg of low-molecular-weight povidone is contained per 100 mL of solvent. The formulation described in item 1, characterized by the features described herein. (Item 7) The formulation according to item 6, characterized in that the low degree of polymerization povidone is povidone with a weight-average molecular weight of 2000 to 5000, and the medium degree of polymerization povidone is povidone with a weight-average molecular weight of 20000 to 60000. (Item 8) The formulation according to item 6, characterized in that the low degree of polymerization povidone is povidone PVP K12 with a weight-average molecular weight of 3500, and the medium degree of polymerization povidone is povidone PVP K30 with a weight-average molecular weight of 35000 to 50000. (Item 9) The formulation according to any one of items 1 to 8, characterized in that the solvent in the carrier or auxiliary material of the ophthalmic formulation is a polar solvent, preferably water. (Item 10) The carrier or auxiliary material of the ophthalmic preparation further contains a thickener and / or a cosolvent. Preferably, the thickener is at least one of polyethylene glycol, carbomer, poloxamer, povidone, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, xanthan gum, polyoxyethylene fatty alcohols, hyaluronic acid and its salts, or hydroxypropyl methylcellulose, the cosolvent is propylene glycol, glycerol, liquid polyethylene glycol, or castor oil, the mass ratio of the thickener to the surfactant is 1:(0.1~100), the mass ratio of the cosolvent to the surfactant is (1~10):1, the mass ratio of the thickener to low-molecular-weight povidone is 1:(0.1~100), and the mass ratio of the cosolvent to low-molecular-weight povidone is (1~10):1. More preferably, the mass ratio of the thickener to the surfactant is 1:(1.2~30), the mass ratio of the cosolvent to the surfactant is (2.56~9):1, the mass ratio of the thickener to the low degree of polymerization povidone is 1:(1.2~30), and the mass ratio of the cosolvent to the low degree of polymerization povidone is (2.56~9):1. A formulation according to any one of items 1 to 8, characterized by the above. (Item 11) The formulation according to item 1, characterized in that the mass ratio of the surfactant or low-degree-of-polymerization povidone to the active ingredient for treating eye diseases is (12-31):1. (Item 12) The preparation according to item 1, characterized in that the glucocorticoid drug is at least one of dexamethasone, hydrocortisone, prednisolone, and betamethasone, and the nonsteroidal drug is at least one of diclofenac, pranoprofen, indomethacin, and bromfenac sodium. (Item 13) The formulation according to any one of items 1 to 12, characterized in that the carrier or auxiliary material of the ophthalmic formulation includes nanoparticles formed by the self-assembly of components of the carrier or auxiliary material of the ophthalmic formulation, and the nanoparticles contain an active ingredient for treating an eye disease. (Item 14) The formulation according to item 13, characterized in that the nanoparticles are spherical, have a particle size of 1 to 100 nm, and preferably have a particle size of 5 to 30 nm. (Item 15) The formulation according to item 14, comprising spherical nanospheres with a particle size of 10 to 2000 nm, wherein the nanospheres are formed by the self-assembly of nanoparticles, and preferably the particle size of the nanospheres is 100 to 2000 nm. (Item 16) A method for preparing a preparation described in any one of items 1 to 15, wherein the method is (1) Prepare a solution by adding a surfactant and / or thickener to the solvent, Step (2) involves dispersing an active ingredient and / or co-solvent for treating eye diseases in the solution obtained in step (1), and then adding an ionic polymer or a solution thereof, dispersing and mixing to obtain an initial suspension. Step (3) includes stirring and dispersing the initial suspension obtained in step (2), or homogenizing and dispersing it. or (a) a step of preparing a solution by adding a low degree of polymerization povidone and / or a thickener to a solvent, Step (b) involves dispersing an active ingredient and / or co-solvent for treating eye diseases in the solution obtained in step (a), then adding a medium-degree polymerized povidone or a solution thereof, and dispersing and mixing to obtain an initial suspension. Step (c) involves grinding or homogenizing and dispersing the mixture obtained in step (b). A method characterized by the following features. (Item 17) The method according to item 16, characterized in that the dispersion in step (2) or step (b) is at least one selected from dispersion by mechanical stirring, dispersion by magnetic stirring, dispersion by vortex shaking, dispersion by shearing, dispersion by homogenization, dispersion by grinding, and dispersion by ultrasound. (Item 18) Use of any one of the preparations described in item 1 to 15 in the preparation of a drug for treating a retinal disease, preferably the drug for treating the retinal disease is a drug for treating macular edema and / or optic neuritis and / or non-infectious endophthalmitis. (Item 19) The use described in item 18, characterized in that the drug for treating the macular edema is a drug for treating macular edema due to retinal vascular disease, central retinal vein occlusion macular edema, branch retinal vein occlusion macular edema, diabetic macular edema, pathological myopic macular edema, and / or macular edema due to exudative age-related macular degeneration. (Item 20) A method for treating a retinal disease, characterized in that a patient is given a therapeutically effective amount of a preparation described in any one of items 1 to 15. (Item 21) The method according to item 20, characterized in that the retinal disease is macular edema and / or optic neuritis and / or non-infectious endophthalmitis. (Item 22) The method according to item 21, characterized in that the macular edema is macular edema due to retinal vascular disease, central retinal vein occlusion macular edema, branch retinal vein occlusion macular edema, diabetic macular edema, pathological myopic macular edema, and / or macular edema due to exudative age-related macular degeneration. (Item 23) The method according to item 20, characterized in that the method of use is administration by eye drops.

Claims

[Claim 1] The invention described herein.

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