Cyclosporin ophthalmic formulations, methods of making and use thereof

Abstract

The application relates to the field of pharmaceutical preparations, in particular to a cyclosporine ophthalmic preparation, a preparation method and application thereof. The preparation comprises cyclosporine, an oil phase, a surfactant, a co-surfactant, a thickening agent, an osmotic pressure regulator and water for injection. The application realizes controllable, stable and feasible quality of the ophthalmic preparation containing high-concentration cyclosporine by controlling the peroxide value ratio of the oil phase and the co-surfactant or the pH value of the co-surfactant.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical preparations, specifically to a cyclosporine ophthalmic preparation, its preparation method, and its application. Background Technology

[0002] Cyclosporine is a potent immunosuppressant, highly effective and low in toxicity. It inhibits the proliferation of T and B lymphocytes and selectively affects the immune system, achieving immunosuppression. It also possesses anti-inflammatory, anti-infective, antifungal, and antiparasitic activities. It is a cyclic polypeptide composed of 11 amino acid residues, exhibiting strong hydrophobicity and a large molecular weight (1202.6), making it the most potent immunosuppressant currently available with the fewest side effects. Cyclosporine is suitable for ophthalmic preparations, increasing tear secretion in patients with dry eye syndrome, especially for dry eye syndrome caused by corneal and conjunctival inflammation. Marketed cyclosporine ophthalmic preparations are primarily used for the treatment of dry eye syndrome. Recent studies have found that cyclosporine ophthalmic preparations, while relieving dry eye syndrome, also have some efficacy against vernal keratoconjunctivitis (VKC).

[0003] VKC is a seasonal allergic ocular surface disease, most common in children and adolescents, associated with an abnormal immune system response. Typical symptoms include itchy eyes, redness, and thick discharge, which often worsen in spring or warmer seasons. Current common treatments for acute cases include: 1. First-line treatment with a dual-action drug of antihistamines and mast cell stabilizers (such as olopatadine); 2. Short-term use of corticosteroids (such as fluorometholone eye drops) for severe cases, but long-term use may cause glaucoma and cataracts, requiring regular monitoring of intraocular pressure. Immunosuppressants (such as cyclosporine A) are suitable for steroid-dependent patients, providing good long-term control of VKC and are safer to treat because they do not cause increased intraocular pressure or steroid-related complications.

[0004] Currently, the only commercially available cyclosporine product for treating VKC is Santen Oy Pharmaceuticals' cyclosporine eye drops (III), marketed under the brand name VERKAZIA. ®The cyclosporine concentration is 0.10%, and it is a cationic emulsion. Currently, there are no nonionic emulsion or microemulsion cyclosporine products for treating VKC. Due to the extremely high lipid solubility of cyclosporine, the cyclosporine ophthalmic preparations already on the market in China are mainly divided into two categories: one is to directly dissolve it in vegetable oil to prepare oil-soluble eye drops (such as patent CN101130058B). Although the formulation process is simple and can increase the cyclosporine concentration, it has drawbacks such as the drug needing to dissolve in the tear film aqueous phase to penetrate the cornea, resulting in insufficient absorption; high-viscosity carriers causing blurred vision and a strong foreign body sensation; and poor clinical tolerability. The other approach is to use microemulsion technology or ordinary emulsions to prepare water-soluble eye drops. Patent CN103656617A (microemulsion technology) solves the problem of poor water solubility of cyclosporine, has higher patient acceptance than oil-soluble preparations, and exhibits less eye irritation and better stability, but still contains certain impurities and its comfort needs improvement. Patent CN110237233B... While optimizing the formulation based on this approach has controlled impurities, improved comfort, and offered many advantages of microemulsions (such as simple preparation, small and uniform particle size, thermodynamic stability, and fewer adverse reactions), it has not fully utilized the pharmacological effects of cyclosporine, nor has it disclosed its therapeutic effects on VKC. Furthermore, the issue of impurities, especially at high concentrations, still needs improvement. Although patent CN101056615B (a cationic surfactant oil-in-water emulsion) has increased the concentration of cyclosporine, it suffers from complex processes requiring physical external forces and reliance on high-shear and microfluidic equipment, which are not conducive to large-scale production. Moreover, quaternary ammonium cationic surfactants may cause ocular surface toxicity and damage to tear film stability, and long-term use may also pose a risk of cumulative damage to the ocular surface.

[0005] Further research by pharmaceutical scientists has revealed that cyclosporine ophthalmic preparations, while relieving dry eye syndrome, also have some efficacy in treating vulvovaginal carcinoma (VKC) and post-transplant immune rejection. However, the concentration of cyclosporine required for treating VKC is typically higher than that for treating dry eye, making it crucial to note that high-concentration cyclosporine preparations often involve increased impurity levels. High-concentration cyclosporine preparations have already been found to contain substandard impurities. Therefore, ensuring formulation stability and effectively controlling impurity levels are critical requirements when preparing high-concentration cyclosporine preparations suitable for VKC treatment. Summary of the Invention

[0006] To address the above problems, one aspect of the present invention provides an ophthalmic preparation comprising:

[0007] Cyclosporine;

[0008] oil phase;

[0009] Surfactants;

[0010] Co-surfactants;

[0011] Thickener;

[0012] Osmotic pressure regulator;

[0013] Water for injection.

[0014] In some embodiments, the oil phase and / or co-surfactant used in this invention have a specific peroxide value.

[0015] In some embodiments, the co-surfactant used in this invention has a specific acidity or alkalinity (pH value).

[0016] In some implementations, the peroxide value ratio of the oil phase to the co-surfactant is less than or equal to 1:7.

[0017] In some implementations, the peroxide value of the oil phase used is less than 3.

[0018] In some implementations, the peroxide value of the co-surfactant used is less than 1.5.

[0019] In some implementations, the pH value of the co-surfactant used is 5.7 to 6.3.

[0020] In some implementations, the mass-to-volume ratio of cyclosporine is 0.08% to 0.20%.

[0021] In some implementations, the mass-to-volume ratio of cyclosporine is 0.08% to 0.15%.

[0022] In some embodiments, the mass-to-volume ratio of cyclosporine is 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, or 0.15%.

[0023] In some implementations, the mass-to-volume ratio of cyclosporine is 0.08%, 0.10%, 0.12%, or 0.15%.

[0024] In some implementations, the mass-to-volume ratio of cyclosporine is 0.10%.

[0025] In some implementations, the oil phase has a mass-volume ratio of 0.20% to 0.40%.

[0026] In some implementations, the oil phase has a mass-volume ratio of 0.20% to 0.25%.

[0027] In some embodiments, the mass-to-volume ratio of the oil phase is 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, and 0.40%.

[0028] In some implementations, the mass-to-volume ratio of the oil phase is 0.20%, 0.22%, 0.24%, 0.26%, 0.28%, 0.30%, 0.32%, 0.34%, 0.36%, 0.38%, or 0.40%.

[0029] In some implementations, the oil phase has a mass-to-volume ratio of 0.20%, 0.25%, 0.30%, 0.35%, and 0.40%.

[0030] In some implementations, the oil phase has a mass-to-volume ratio of 0.20%, 0.25%, or 0.40%.

[0031] In some implementations, the oil phase is selected from one or more of the following: medium-chain triglycerides, liquid paraffin, corn oil, soybean oil, castor oil, and olive oil.

[0032] In some implementations, the oil phase is a medium-chain triglyceride.

[0033] In some implementations, the surfactant has a mass-volume ratio of 0.80% to 1.60%.

[0034] In some implementations, the surfactant has a mass-volume ratio of 0.80% to 1.00%.

[0035] In some embodiments, the mass-volume ratio of the surfactant is 0.80%, 0.85%, 0.90%, 0.95%, 1.00%, 1.05%, 1.10%, 1.15%, 1.20%, 1.25%, 1.30%, 1.35%, 1.40%, 1.45%, 1.50%, 1.55%, or 1.60%.

[0036] In some embodiments, the mass-volume ratio of the surfactant is 0.80%, 0.90%, 1.00%, 1.10%, 1.20%, 1.30%, 1.40%, 1.50%, or 1.60%.

[0037] In some implementations, the mass-volume ratio of the surfactant is 0.80%, 1.00%, 1.20%, 1.40%, or 1.60%.

[0038] In some implementations, the surfactant is present in a mass-volume ratio of 0.80%, 1.00%, or 1.60%.

[0039] In some implementations, the surfactant is a nonionic surfactant.

[0040] In some embodiments, the surfactant is selected from one or more of the following: polyoxyethylene (40) hydrogenated castor oil, Tween 20, Tween 80, and poloxamer.

[0041] In some implementations, the surfactant is polyoxyethylene (40) hydrogenated castor oil.

[0042] In some implementations, the mass-volume ratio of the co-surfactant is 0.40% to 0.80%.

[0043] In some implementations, the mass-volume ratio of the co-surfactant is 0.40% to 0.50%.

[0044] In some embodiments, the mass-to-volume ratio of the co-surfactant is 0.40%, 0.42%, 0.44%, 0.46%, 0.48%, 0.50%, 0.52%, 0.54%, 0.56%, 0.58%, 0.60%, 0.62%, 0.64%, 0.66%, 0.68%, 0.70%, 0.72%, 0.74%, 0.76%, 0.78%, and 0.80%.

[0045] In some implementations, the mass-volume ratio of the co-surfactant is 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, or 0.80%.

[0046] In some implementations, the mass-volume ratio of the co-surfactant is 0.40%, 0.50%, 0.60%, 0.70%, or 0.80%.

[0047] In some implementations, the mass-volume ratio of the co-surfactant is 0.40%, 0.50%, or 0.80%.

[0048] In some implementations, the co-surfactant is a nonionic surfactant.

[0049] In some implementations, the co-surfactant is selected from one or more of ethanol, isopropanol, n-butanol, polyethylene glycol 400, and polyethylene glycol 300.

[0050] In some implementations, the co-surfactant is polyethylene glycol 400.

[0051] In some implementation schemes, the thickener has a mass-to-volume ratio of 1.20% to 1.90%.

[0052] In some embodiments, the mass-to-volume ratio of the thickener is 1.20%, 1.25%, 1.30%, 1.35%, 1.40%, 1.45%, 1.50%, 1.55%, 1.60%, 1.65%, 1.70%, 1.75%, 1.80%, 1.85%, and 1.90%.

[0053] In some implementations, the thickener has a mass-to-volume ratio of 1.20%, 1.30%, 1.40%, 1.50%, 1.60%, 1.70%, 1.80%, and 1.90%.

[0054] In some implementations, the thickener has a mass-to-volume ratio of 1.20%, 1.40%, or 1.90%.

[0055] In some implementations, the thickener is selected from one or more of carboxymethyl cellulose, glycerol, and poloxamer.

[0056] In some implementations, the thickener is glycerin.

[0057] In some implementations, the osmotic pressure regulator has a mass-to-volume ratio of 1.40% to 2.00%.

[0058] In some implementations, the mass-to-volume ratio of the osmotic pressure regulator is 1.40%, 1.45%, 1.50%, 1.55%, 1.60%, 1.65%, 1.70%, 1.75%, 1.80%, 1.85%, 1.90%, 1.95%, or 2.00%.

[0059] In some implementations, the mass-to-volume ratio of the osmotic pressure regulator is 1.40%, 1.50%, 1.60%, 1.70%, 1.80%, 1.90%, or 2.00%.

[0060] In some implementations, the mass-to-volume ratio of the osmotic pressure regulator is 1.40%, 1.60%, 1.80%, or 2.00%.

[0061] In some implementations, the osmotic pressure regulator has a mass-to-volume ratio of 1.40%, 1.60%, or 2.00%.

[0062] In some implementations, the osmotic pressure regulator is a nonionic osmotic pressure regulator.

[0063] In some implementations, the osmotic pressure regulator is selected from one or more of mannitol, sorbitol, and glycerol.

[0064] In some implementations, the osmotic pressure regulator is mannitol.

[0065] In some implementations, the peroxide value of the oil phase is less than 0.3, and the peroxide value of the co-surfactant is less than 1.5.

[0066] In some implementations, the peroxide value of the oil phase is less than or equal to 0.2.

[0067] In some implementations, the peroxide value of the co-surfactant is less than or equal to 1.4, 1.3, 1.2, 1.1, or 1.0.

[0068] In some implementations, the peroxide value ratio of the oil phase to the co-surfactant is less than or equal to 1:7.

[0069] In some embodiments, the present invention achieves control over the physicochemical stability of the formulation by employing an oil phase with a specific peroxide value and a co-surfactant, and ensures that although the active pharmaceutical ingredient increases, the concentration of impurities does not increase accordingly.

[0070] In some embodiments, the present invention also controls the physicochemical stability of the formulation and the concentration of impurities by confirming the peroxide value ratio of the oil phase and the co-surfactant used.

[0071] In some embodiments, the present invention achieves control over the physicochemical stability of the formulation by employing a co-surfactant with a specific pH, and ensures that although the active pharmaceutical ingredient increases, the concentration of impurities does not increase accordingly.

[0072] In some embodiments, “using” means that when formulating the ophthalmic formulation of the present invention, the peroxide value of the oil phase and / or the co-surfactant is confirmed or measured, and / or the pH of the co-surfactant is confirmed or measured.

[0073] In some embodiments, the formulation comprises:

[0074] Cyclosporine at a mass-to-volume ratio of 0.08% to 0.15%;

[0075] Medium-chain triglycerides, 0.20%~0.40% by mass-volume ratio;

[0076] 0.80%~1.60% by mass volume of polyoxyethylene (40) hydrogenated castor oil;

[0077] 0.40%~0.80% by mass / volume of polyethylene glycol 400;

[0078] Glycerin at a mass-to-volume ratio of 1.20% to 1.90%;

[0079] Mannitol at a mass-to-volume ratio of 1.40% to 2.00%;

[0080] The remainder is water for injection.

[0081] In some embodiments, the formulation comprises:

[0082] 0.10% cyclosporine by volume;

[0083] Medium-chain triglycerides, 0.20%~0.40% by mass-volume ratio;

[0084] 1.00% by weight (by volume) of hydrogenated castor oil (40) polyoxyethylene;

[0085] 0.50% by volume of polyethylene glycol 400;

[0086] 1.40% glycerol by mass / volume;

[0087] 1.60% mannitol by mass / volume;

[0088] The remainder is water for injection.

[0089] In some embodiments, the formulation comprises:

[0090] 0.10% cyclosporine by volume;

[0091] 0.25% by volume of medium-chain triglycerides;

[0092] 1.00% by weight (by volume) of hydrogenated castor oil (40) polyoxyethylene;

[0093] 0.40%~0.80% by mass / volume of polyethylene glycol 400;

[0094] 1.40% glycerol by mass / volume;

[0095] 1.60% mannitol by mass / volume;

[0096] The remainder is water for injection.

[0097] In some embodiments, the formulation comprises:

[0098] 0.10% cyclosporine by volume;

[0099] 0.25% by volume of medium-chain triglycerides;

[0100] 0.80%~1.60% by mass volume of polyoxyethylene (40) hydrogenated castor oil;

[0101] 0.50% by volume of polyethylene glycol 400;

[0102] 1.40% glycerol by mass / volume;

[0103] 1.60% mannitol by mass / volume;

[0104] The remainder is water for injection.

[0105] In some embodiments, the formulation comprises:

[0106] 0.10% cyclosporine by volume;

[0107] 0.25% by volume of medium-chain triglycerides;

[0108] 1.00% by weight (by volume) of hydrogenated castor oil (40) polyoxyethylene;

[0109] 0.50% by volume of polyethylene glycol 400;

[0110] Glycerin at a mass-to-volume ratio of 1.20% to 1.90%;

[0111] 1.60% mannitol by mass / volume;

[0112] The remainder is water for injection.

[0113] In some embodiments, the formulation comprises:

[0114] 0.10% cyclosporine by volume;

[0115] 0.25% by volume of medium-chain triglycerides;

[0116] 1.00% by weight (by volume) of hydrogenated castor oil (40) polyoxyethylene;

[0117] 0.50% by volume of polyethylene glycol 400;

[0118] 1.40% glycerol by mass / volume;

[0119] Mannitol at a mass-to-volume ratio of 1.40% to 2.00%;

[0120] The remainder is water for injection.

[0121] In some embodiments, the formulation comprises:

[0122] Cyclosporine at a mass-to-volume ratio of 0.08% to 0.15%;

[0123] 0.25% by volume of medium-chain triglycerides;

[0124] 1.00% by weight (by volume) of hydrogenated castor oil (40) polyoxyethylene;

[0125] 0.50% by volume of polyethylene glycol 400;

[0126] 1.40% glycerol by mass / volume;

[0127] 1.60% mannitol by mass / volume;

[0128] The remainder is water for injection.

[0129] In some embodiments, the formulation comprises:

[0130] 0.10% cyclosporine by volume;

[0131] 0.25% by volume of medium-chain triglycerides;

[0132] 1.00% by weight (by volume) of hydrogenated castor oil (40) polyoxyethylene;

[0133] 0.50% by volume of polyethylene glycol 400;

[0134] 1.40% glycerol by mass / volume;

[0135] 1.60% mannitol by mass / volume;

[0136] The remainder is water for injection.

[0137] In some embodiments, the viscosity of the formulation is less than or equal to 10 mPa·s.

[0138] In some embodiments, the osmotic pressure of the formulation is 250~320 mOsmol / Kg.

[0139] In another aspect, the present invention provides an ophthalmic preparation comprising the step of confirming or measuring the peroxide value of the oil phase.

[0140] In another aspect, the present invention provides an ophthalmic formulation, the preparation of which includes the step of confirming or measuring the peroxide value of a co-surfactant.

[0141] In another aspect, the present invention provides an ophthalmic formulation, the preparation of which includes the step of confirming or measuring the pH of a co-surfactant.

[0142] In another aspect, the present invention provides an ophthalmic formulation, the preparation of which includes the step of confirming or measuring the ratio of the peroxide value of the oil phase and the co-surfactant.

[0143] Another aspect of the present invention provides a method for preparing the aforementioned ophthalmic formulation, comprising the following steps:

[0144] Step 1: Mix the oil phase with the surfactant and co-surfactant until homogeneous to obtain the first product;

[0145] Step 2: Under stirring conditions, cyclosporine is dissolved in the first product to obtain the second product;

[0146] Step 3: Dissolve the thickener and osmotic pressure regulator in water to obtain the third product;

[0147] Step 4: Under stirring conditions, add the second product to the third product and mix thoroughly;

[0148] Step 5: Add water for injection to the full volume, and you have the product.

[0149] In some implementations, the temperature of the first product is not less than 80°C before step 2.

[0150] In some implementations, the temperature of the first product is 90°C to 100°C before step 2.

[0151] In some embodiments, the aforementioned ophthalmic preparation, or the ophthalmic preparation obtained according to the aforementioned preparation method, is an eye drop.

[0152] In some embodiments, the eye drops are emulsion-type eye drops.

[0153] In another aspect of the present invention, the use of the aforementioned ophthalmic formulation, or the ophthalmic formulation obtained according to the aforementioned preparation method, in the preparation of a medicament for treating immunosuppression-related diseases, inflammatory diseases, infectious diseases, or dry eye syndrome is provided.

[0154] In another aspect of the present invention, the use of the aforementioned ophthalmic preparation, or the ophthalmic preparation obtained according to the aforementioned preparation method, in the preparation of a medicament for treating dry eye syndrome and keratoconjunctivitis is provided.

[0155] In some implementations, the dry eye syndrome is defined as meibomian gland dysfunction, decreased lacrimal gland secretion, or abnormal tear secretion / evaporation caused by Sjögren's syndrome.

[0156] In some implementations, the dry eye syndrome is dry eye syndrome caused by keratitis and / or conjunctivitis.

[0157] In some embodiments, the keratoconjunctivitis is caused by seasonal and / or allergic factors.

[0158] In some embodiments, the keratoconjunctivitis is selected from seasonal allergic keratoconjunctivitis, perennial allergic keratoconjunctivitis, vernal keratoconjunctivitis, and atopic keratoconjunctivitis.

[0159] (1) This application found through experiments that controlling the peroxide value ratio of medium chain triglycerides to polyethylene glycol 400 and / or the pH of polyethylene glycol 400 can improve the quality of the formulation, make the physicochemical properties of the formulation stable and prevent impurities from increasing with the increase of drug concentration.

[0160] (2) This application is applicable to different concentrations of cyclosporine, especially cyclosporine with higher content, which maximizes the pharmacological effect of cyclosporine and improves the selectivity of cyclosporine ophthalmic preparations.

[0161] (3) This application uses microemulsion technology, which improves the solubility and stability of cyclosporine in ophthalmic preparations, prolongs the retention time on the ocular surface, and enhances the bioavailability of cyclosporine;

[0162] (4) Cyclosporine is formulated into an ophthalmic preparation. The aqueous phase continuous layer buffers the irritation of the oil phase, which improves drug tolerance and treatment compliance.

[0163] (5) The formulation of this application does not contain quaternary ammonium cationic surfactants, so it will not cause ocular surface toxicity, will not damage tear film stability, and will have low eye irritation and will not accumulate and cause damage to the ocular surface. Detailed Implementation

[0164] I. Definition

[0165] The term "w / v" refers to a physical quantity that describes the proportional relationship between a specific component and the total volume of the ophthalmic formulation in this application. Specifically, it is defined as the ratio of the mass of a component in the ophthalmic formulation to the total volume of the ophthalmic formulation. For example, a w / v ratio of 0.08% to 0.20% for cyclosporine means that in the ophthalmic formulation described in this application, the mass of cyclosporine in every 100 ml of the ophthalmic formulation ranges from 0.08 g to 0.20 g. The total volume of the ophthalmic formulation is the total volume of all components in the formulation (including cyclosporine, oil phase, surfactant, co-surfactant, thickener, osmotic pressure regulator, and water for injection, etc.). Unless otherwise specified, "%" in the embodiments of this application represents the w / v ratio (i.e., g / 100 mL).

[0166] The term "peroxide value" is a key physicochemical indicator for measuring the initial degree of oxidative deterioration of oily substances (such as vegetable oils, animal fats, and medium-chain triglycerides). Under pharmacopoeia-compliant testing conditions, it refers to the amount of peroxides per kilogram of the sample being tested, whose oxidizing power is equivalent to a certain amount of oxygen.

[0167] The term "ophthalmic preparation" refers to a preparation used directly on the eye to treat or prevent eye diseases, relieve eye discomfort, or aid in eye diagnosis. Ophthalmic preparations described herein include, but are not limited to, eye drops, ophthalmic ointments, ophthalmic gels, ophthalmic creams, intraocular injections, ophthalmic films, and ophthalmic implants. Preferably, they are eye drops, and most preferably, emulsion-type eye drops.

[0168] The term "total impurities" refers to the total content of all impurities (including process impurities, degradation impurities, etc.) other than the active pharmaceutical ingredient (e.g., cyclosporine) in the ophthalmic formulation described in this application. The percentage (%) represents the ratio of the total mass of impurities to the mass of the active pharmaceutical ingredient in the formulation. The calculation formula is: Total impurities (%) = (Total mass of all impurities in the formulation / Mass of the active pharmaceutical ingredient in the formulation) × 100%. For example, total impurities (≤1.5%) means that this indicator limits the total content of all impurities in the formulation to no more than 1.5% of the mass of the active pharmaceutical ingredient.

[0169] II. Examples

[0170] The sources of materials involved in the experimental examples of this application are as follows:

[0171] Cyclosporine, Zhejiang Ruibang Pharmaceutical Co., Ltd.;

[0172] Medium-chain triglycerides (MCT), Liaoning Xinxing Pharmaceutical Co., Ltd.;

[0173] Polyoxyethylene (40) Hydrogenated Castor Oil (RH40), BASF;

[0174] Polyethylene Glycol 400 (PEG400): Nanjing Well Pharmaceutical Co., Ltd.;

[0175] Mannitol, Qingdao Mingyue Seaweed Group Co., Ltd.;

[0176] Glycerin, Hunan Ercon Pharmaceutical Co., Ltd.;

[0177] Water for injection, Shenyang Xingqi Pharmaceutical Co., Ltd.

[0178] Ovalbumin (OVA), Sigma;

[0179] Aluminum Salt Adjuvant (ALUM), Lianmai Biotechnology;

[0180] Phosphate-Buffered Saline (PBS), Sigma.

[0181] Example 1: The effect of specific parameters of excipients on formulation

[0182] Example 1.1: Investigation of the effect of peroxide value of MCT and PEG400 on the formulation

[0183] Preparations 1 to 7 were prepared according to the mass-to-volume ratios described in Table 1, and the preparation methods are as follows:

[0184] Step 1: Mix and dissolve MCT, RH40 and PEG400 to obtain the first product, and heat the first product to about 85°C for later use.

[0185] Step 2: Dissolve cyclosporine in the first product to obtain the second product;

[0186] Step 3: Dissolve glycerol and mannitol in water for injection to obtain the third product;

[0187] Step 4: While stirring, add the second product to the third product and mix well;

[0188] Step 5: Add water for injection to the full volume, and you have the product.

[0189] Before preparation, the peroxide values ​​of the oil phase, the co-surfactant, and the ratio of their peroxide values ​​must be confirmed.

[0190] Table 1

[0191]

[0192] This application improves formulation stability by controlling the peroxide value ratio of MCT and PEG400. Stability tests (40℃, 6 months) were conducted, and the total impurity test results for the above experimental examples are shown in Table 2.

[0193] Table 2

[0194]

[0195] As shown in Table 2, the total impurities in the cyclosporine eye drops of this application increase with the increase of the peroxide value ratio of MCT to PEG400. When the peroxide value ratio of MCT to PEG400 is 1:4, the total impurities of the cyclosporine eye drops exceed the limits specified in the quality standard during the stability study period. Therefore, the peroxide value ratio of MCT to PEG400 should be less than or equal to 1:7. Furthermore, the generation of total impurities in the cyclosporine eye drops can be further controlled when the MCT peroxide value is less than 0.3, preferably less than or equal to 0.2, and / or the PEG400 peroxide value is less than 1.5, preferably less than or equal to 1.4, 1.3, 1.2, 1.1, or 1.0.

[0196] Example 1.2: The effect of PEG400 pH on the formulation

[0197] Formulations 8 to 11 were prepared according to the mass-to-volume ratios described in Table 3, using the same preparation method as in Example 1.1:

[0198] Table 3

[0199]

[0200] The pH of PEG400 was determined according to the acidity test item in the PEG400 quality standard of the 2025 edition of the Chinese Pharmacopoeia, Part IV. The test method was General Rule 0631 of the 2025 edition of the Chinese Pharmacopoeia, and the test equipment was a pH meter, METTLER TOLEDO, model: FE28. The pH of the co-surfactant was confirmed before preparation.

[0201] The pH value and total impurities were examined during the formulation stability study, and the results are shown in Table 4.

[0202] Table 4

[0203]

[0204] According to the quality standard for cyclosporine eye drops (National Medical Products Administration Standard YBH01622020), the pH value of cyclosporine eye drops should be 4.8–6.2, and the total impurities limit should not exceed 1.5%. During the stability study, formulation 8 had a pH value below the quality standard limit; formulation 11 had total impurities above the quality standard limit during the stability study. Therefore, the total impurities in the cyclosporine eye drops of this application increase with increasing PEG400 pH; conversely, when the PEG400 pH is low, the pH value of the formulation will fall below the lower limit during the stability study. Experimental data show that the formulation has the best quality when the PEG400 pH range is 5.7–6.3.

[0205] In summary, specific parameters of excipients in a formulation have a significant impact on the quality of the formulation. Effectively controlling the various indicators of specific excipient parameters plays a decisive role in ensuring the quality of the formulation.

[0206] Example 2: Screening of the range of excipient dosage

[0207] Example 2.1: Determination of MCT Dosage

[0208] Formulations 12 and 13 were prepared according to the mass-to-volume ratios described in Table 5, using the same preparation method as in Example 1.1.

[0209] Table 5

[0210]

[0211] Note: The peroxide value of MCT used in this experiment was 0.04; the peroxide value of PEG400 was 0.4, and the pH was 6.0. The quality standard for MCT and PEG400 is the same as that in the 2025 edition of the Chinese Pharmacopoeia, Part IV. The test method for peroxide value is General Rule 0713 of the 2025 edition of the Chinese Pharmacopoeia. The test method for pH is Rule 0631 of the 2025 edition of the Chinese Pharmacopoeia.

[0212] Referring to the quality standard of cyclosporine eye drops (National Medical Products Administration standard YBH01622020), the total impurities and properties during the formulation stability study were investigated to examine the effect of different dosages of MCT on the formulation quality. The results are shown in Table 6.

[0213] The relevant substance testing equipment is: High Performance Liquid Chromatography (HPLC), Waters, model: e2695.

[0214] Table 6

[0215]

[0216] According to the quality standard for cyclosporine eye drops (National Medical Products Administration Standard YBH01622020), the limit for total impurities in cyclosporine eye drops is not more than 1.5%. The test results show that all quality indicators for formulations 12 and 13 meet the requirements. In summary, the dosage of MCT is within the range of 0.20% to 0.40%, and the quality of the formulations is stable.

[0217] Example 2.2: Determination of PEG400 dosage

[0218] Formulations 14 and 15 were prepared according to the mass-to-volume ratios described in Table 7, using the same method as in Example 1.1:

[0219] Table 7

[0220]

[0221] Note: The peroxide value of MCT used in this experiment was 0.04; the peroxide value of PEG400 was 0.4, and the pH was 6.0. The quality standard for MCT and PEG400 is the same as that in the 2025 edition of the Chinese Pharmacopoeia, Part IV. The test method for peroxide value is General Rule 0713 of the 2025 edition of the Chinese Pharmacopoeia. The test method for pH is Rule 0631 of the 2025 edition of the Chinese Pharmacopoeia.

[0222] Referring to the quality standard of cyclosporine eye drops (National Medical Products Administration standard YBH01622020), the total impurities, pH value, and properties during the formulation stability study were investigated to examine the effect of different amounts of PEG400 on the formulation quality. The results are shown in Table 8.

[0223] Table 8

[0224]

[0225] The test results show that all quality indicators of the cyclosporine eye drops prepared according to the above formulation meet the requirements. In summary, the formulation maintains stable quality when the dosage of PEG400 is between 0.40% and 0.80%.

[0226] Example 2.3: Determination of RH40 dosage

[0227] Formulations 16 and 17 were prepared according to the mass-volume ratios described in Table 9, using the same preparation method as in Example 1.1.

[0228] Table 9

[0229]

[0230] Note: The peroxide value of MCT used in this experiment was 0.04; the peroxide value of PEG400 was 0.4, and the pH was 6.0. The quality standard for MCT and PEG400 is the same as that in the 2025 edition of the Chinese Pharmacopoeia, Part IV. The test method for peroxide value is General Rule 0713 of the 2025 edition of the Chinese Pharmacopoeia. The test method for pH is Rule 0631 of the 2025 edition of the Chinese Pharmacopoeia.

[0231] Referring to the quality standard of cyclosporine eye drops (National Medical Products Administration standard YBH01622020), the total impurities and properties during the formulation stability study were investigated to examine the effect of different amounts of RH40 on the formulation quality. The results are shown in Table 10.

[0232] Table 10

[0233]

[0234] The test results show that all quality indicators of formulations 16 and 17 meet the requirements. In summary, as shown in Table 10, the dosage of RH40 is within the range of 0.80% to 1.60%, and the quality of the formulations is stable.

[0235] Example 2.4: Determination of Glycerin Dosage

[0236] Formulations 18 and 19 were prepared according to the mass-volume ratios described in Table 11, using the same method as in Example 1.1.

[0237] Table 11

[0238]

[0239] Note: The peroxide value of MCT used in this experiment was 0.04; the peroxide value of PEG400 was 0.4, and the pH was 6.0. The quality standard for MCT and PEG400 is the same as that in the 2025 edition of the Chinese Pharmacopoeia, Part IV. The test method for peroxide value is General Rule 0713 of the 2025 edition of the Chinese Pharmacopoeia. The test method for pH is Rule 0631 of the 2025 edition of the Chinese Pharmacopoeia.

[0240] Referring to the quality standard of cyclosporine eye drops (National Medical Products Administration standard YBH01622020), the viscosity and properties of the formulation were examined during the stability study to investigate the effect of different amounts of glycerin on the quality of the formulation. The results are shown in Table 12.

[0241] Table 12

[0242]

[0243] Using a rotational viscometer (Brookfield LV type or equivalent) and a No. 18 rotor, the viscosity was measured according to the prescribed method at a rotation speed of 200 rpm and a temperature of 25℃ ± 0.5℃. The test results show that all quality indicators of formulations 18 and 19 meet the requirements. In summary, as shown in Table 11, when the glycerol content is within the range of 1.20% to 1.90%, the viscosity of the formulations is not greater than 10 mPa·s.

[0244] Example 2.5: Determination of Mannitol Dosage

[0245] Formulations 20 and 21 were prepared according to the mass-volume ratios described in Table 13, using the same preparation method as in Example 1.1.

[0246] Table 13

[0247]

[0248] Note: The peroxide value of MCT used in this experiment was 0.04; the peroxide value of PEG400 was 0.4, and the pH was 6.0. The quality standard for MCT and PEG400 is the same as that in the 2025 edition of the Chinese Pharmacopoeia, Part IV. The test method for peroxide value is General Rule 0713 of the 2025 edition of the Chinese Pharmacopoeia. The test method for pH is Rule 0631 of the 2025 edition of the Chinese Pharmacopoeia.

[0249] Referring to the quality standard of cyclosporine eye drops (National Medical Products Administration standard YBH01622020), the osmotic pressure and properties during the stability study of the formulation were investigated to examine the effect of different amounts of mannitol on the quality of the formulation. The results are shown in Table 14.

[0250] Table 14

[0251]

[0252] The test results show that all quality indicators of formulations 20 and 21 meet the requirements. In summary, as shown in Table 13, the optimal comfort is achieved when the mannitol dosage is within the range of 1.40% to 2.00% and the osmolality of the formulation is within the range of 250 to 320 mOsmol / Kg.

[0253] Example 3: Concentration screening of cyclosporine

[0254] Example 3.1: Solubility test of cyclosporine

[0255] Based on the above excipient ratios, the concentration of the active pharmaceutical ingredient was screened, and formulations 22 to 26 were prepared according to the mass-volume ratios described in Table 15, using the same preparation method as in Example 1.1.

[0256] Table 15

[0257]

[0258] Note: The peroxide value of MCT used in this experiment was 0.04; the peroxide value of PEG400 was 0.4, and the pH was 6.0. The quality standard for MCT and PEG400 is the same as that in the 2025 edition of the Chinese Pharmacopoeia, Part IV. The test method for peroxide value is General Rule 0713 of the 2025 edition of the Chinese Pharmacopoeia. The test method for pH is Rule 0631 of the 2025 edition of the Chinese Pharmacopoeia.

[0259] Cyclosporine has extremely poor solubility. This application utilizes microemulsion technology to improve the solubility of cyclosporine in ophthalmic solutions. The amount of cyclosporine added is also one of the factors affecting the stability of the formulation. Referring to the National Medical Products Administration standard YBH01622020 for cyclosporine eye drops, the properties of the formulation during the stability study were examined to determine the impact of the amount of cyclosporine added on the quality of the emulsion. The results are shown in Table 16.

[0260] Table 16

[0261]

[0262] The results of the investigation show that the properties of formulation 25 changed during the stability study, and no related substances or pH tests were performed. Therefore, the concentration of cyclosporine in the cyclosporine eye drops of this application should be less than 0.20%, preferably not more than 0.15%.

[0263] Example 3.2: Effect of cyclosporine concentration on efficacy

[0264] The OVA (ovalbumin) model was used to simulate vernal keratoconjunctivitis (VKC) to investigate the efficacy of different concentrations of cyclosporine eye drops. The OVA model was a mouse model induced by OVA to explore the pharmacodynamic effects of different concentrations of cyclosporine eye drops. Xenogeneic protein—OVA—was used as an allergen, mixed with aluminum salt adjuvant to adsorb and carry OVA. Mice were sensitized by intraperitoneal injection twice a week. Seven days after the second sensitization, a high concentration of OVA was used to challenge the model. From the day before challenge until the end of the experiment, 5 µL was administered to the right eye four times a day. After challenge, slit-lamp photography was used to score ocular swelling, congestion, and secretion content to evaluate the efficacy of the test drug in treating allergic conjunctivitis in mice.

[0265] The equipment used in this experiment is as follows:

[0266] Slit lamp microscope, Wenzhou Gaoshi Raymond Optoelectronic Technology Co., Ltd., Model: TSL-5.

[0267] Test animals: Balb / c mice; weight: 18-22 g; sex: female

[0268] The scoring criteria are shown in Table 17.

[0269] Table 17

[0270]

[0271] Formulation 25 was not investigated because its stability did not meet the requirements. The results of the investigations of other groups are shown in Table 18.

[0272] Table 18

[0273]

[0274] Eight healthy Balb / c mice were used per group, and the experiment was conducted according to the above experimental protocol. The results are shown in Table 18. All drug groups with concentrations of 0.08% to 0.15% showed efficacy. The efficacy increased with increasing drug concentration, but the efficacy of the 0.10% to 0.15% concentrations was basically the same.

[0275] Example 3.3: Effect of cyclosporine concentration on eye irritation

[0276] Test formulations: Formulation 22, Formulation 23, Formulation 2, Formulation 24.

[0277] Blank control: Prepared according to the formulation of Formulation 2 without cyclosporine.

[0278] Test animals: Japanese white rabbits, weighing 2.3-2.5 kg, both male and female.

[0279] Experimental method: Single-dose eye irritation test.

[0280] The scoring criteria for eye irritation response are shown in Table 19.

[0281] Table 19

[0282]

[0283] The judgment criteria are shown in Table 20.

[0284] Table 20

[0285]

[0286] Single-dose eye irritation test: Four healthy rabbits (male and female, weighing 2.2-2.8 kg) were used. 0.1 ml of cyclosporine eye drops was instilled into the left eye of each rabbit, and 0.1 ml was given to the right eye as a corresponding blank control. All drops were instilled into the conjunctival sac. The upper and lower eyelids were passively closed for approximately 10 seconds. Local reactions of the cornea, iris, and conjunctiva were observed at 6, 24, 48, and 72 hours after administration, and the total score was calculated. The irritation score for the blank control was 0. The scores for the administered groups are shown in Table 21.

[0287] Note: Formulation 25 was not investigated because its stability did not meet the requirements.

[0288] Table 21

[0289]

[0290] The results show that the eye irritation score increased slightly with increasing drug concentration, but no eye irritation was observed.

[0291] In summary, the analysis of the results of quality, efficacy, and eye irritation studies of cyclosporine eye drops at different concentrations shows that when the concentration of cyclosporine is 0.08%~0.15%, the preparation has stable quality, definite efficacy, and no eye irritation.

[0292] Example 3.4: Process Screening

[0293] According to the formulation ratio of Formulation 2, the final temperature of the first product in the first step of the preparation process was controlled at 70℃, 80℃, 90℃, and 100℃ respectively to investigate the solubility of cyclosporine at different temperatures and its impact on the product. The process is as follows:

[0294] Note: The peroxide value of MCT used in this experiment was 0.04; the peroxide value of PEG400 was 0.4, and the pH was 6.0. The quality standard for MCT and PEG400 is the same as that in the 2025 edition of the Chinese Pharmacopoeia, Part IV. The test method for peroxide value is General Rule 0713 of the 2025 edition of the Chinese Pharmacopoeia. The test method for pH is Rule 0631 of the 2025 edition of the Chinese Pharmacopoeia.

[0295] Formulation 26:

[0296] Step 1: Mix and dissolve MCT, RH40 and PEG400 to obtain the first product, and heat the first product to about 70°C for later use; Steps 2-5 are the same as in Example 1.1.

[0297] Formulation 27:

[0298] Step 1: Mix and dissolve MCT, RH40 and PEG400 to obtain the first product, and heat the first product to about 80°C for later use; Steps 2-5 are the same as in Example 1.1.

[0299] Formulation 28:

[0300] Step 1: Mix and dissolve MCT, RH40 and PEG400 to obtain the first product, and heat the first product to about 90°C for later use; Steps 2-5 are the same as in Example 1.1.

[0301] Formulation 29:

[0302] Step 1: Mix and dissolve MCT, RH40 and PEG400 to obtain the first product, and heat the first product to about 100°C for later use; Steps 2-5 are the same as in Example 1.1.

[0303] The test results are shown in Table 22.

[0304] Table 22

[0305]

[0306] In summary, based on the above experimental results, the temperature of the first product affects the dissolution time and state of cyclosporine. To ensure product quality and improve production efficiency, the temperature of the first product should not be less than 80℃, and preferably 90℃~100℃ is more conducive to product quality and production operation.

Claims

1. Ophthalmic preparations, comprising: Cyclosporine; oil phase; Surfactants; Co-surfactants; Thickener; Osmotic pressure regulator; Water for injection; in, The peroxide value ratio of the oil phase to the co-surfactant is less than or equal to 1:7; the peroxide value of the oil phase is less than 0.3; the pH value of the co-surfactant is 5.7~6.3; and the peroxide value of the co-surfactant is less than 1.

5. The mass-to-volume ratio of cyclosporine is 0.08%~0.15%; The oil phase has a mass-to-volume ratio of 0.20% to 0.40%; The mass-volume ratio of the surfactant is 0.80%~1.60%; The mass-volume ratio of the co-surfactant is 0.40%~0.80%; The thickener has a mass-to-volume ratio of 1.20% to 1.90%; The osmotic pressure regulator has a mass-to-volume ratio of 1.40% to 2.00%. The oil phase is a medium-chain triglyceride; The surfactant is polyoxyethylene 40 hydrogenated castor oil; The co-surfactant is polyethylene glycol 400; The thickener is glycerin; the osmotic pressure regulator is mannitol.

2. The ophthalmic preparation according to claim 1, wherein, The mass-to-volume ratios of cyclosporine were 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, and 0.15%.

3. The ophthalmic preparation according to claim 1, wherein, The oil phase has a mass-to-volume ratio of 0.20% to 0.25%.

4. The ophthalmic preparation according to claim 1, wherein, The mass-to-volume ratios of the oil phase were 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, and 0.40%.

5. The ophthalmic preparation according to claim 1, wherein, The mass-volume ratio of the surfactant is 0.80%~1.00%.

6. The ophthalmic preparation according to claim 1, wherein, The mass-volume ratios of the surfactants were 0.80%, 0.85%, 0.90%, 0.95%, 1.00%, 1.05%, 1.10%, 1.15%, 1.20%, 1.25%, 1.30%, 1.35%, 1.40%, 1.45%, 1.50%, 1.55%, and 1.60%.

7. The ophthalmic preparation according to claim 1, wherein, The mass-volume ratio of the co-surfactant is 0.40%~0.50%.

8. The ophthalmic preparation according to claim 1, wherein, The mass-volume ratios of the co-surfactants were 0.40%, 0.42%, 0.44%, 0.46%, 0.48%, 0.50%, 0.52%, 0.54%, 0.56%, 0.58%, 0.60%, 0.62%, 0.64%, 0.66%, 0.68%, 0.70%, 0.72%, 0.74%, 0.76%, 0.78%, and 0.80%.

9. The ophthalmic preparation according to claim 1, wherein, The mass-volume ratios of the thickeners are 1.20%, 1.25%, 1.30%, 1.35%, 1.40%, 1.45%, 1.50%, 1.55%, 1.60%, 1.65%, 1.70%, 1.75%, 1.80%, 1.85%, and 1.90%.

10. The ophthalmic preparation according to claim 1, wherein, The mass-volume ratios of the osmotic pressure regulators are 1.40%, 1.45%, 1.50%, 1.55%, 1.60%, 1.65%, 1.70%, 1.75%, 1.80%, 1.85%, 1.90%, 1.95%, and 2.00%.

11. The ophthalmic preparation according to claim 1, wherein, The formulation comprises: Cyclosporine at a mass-to-volume ratio of 0.08% to 0.15%; Medium-chain triglycerides, 0.20%~0.40% by mass-volume ratio; 0.80%~1.60% by mass volume of 40-hydrogenated castor oil with polyoxyethylene; 0.40%~0.80% by mass / volume of polyethylene glycol 400; Glycerin at a mass-to-volume ratio of 1.20% to 1.90%; Mannitol at a mass-to-volume ratio of 1.40% to 2.00%; The remainder is water for injection.

12. The ophthalmic preparation according to claim 1, wherein, The formulation comprises: 0.10% cyclosporine (by mass); Medium-chain triglycerides, 0.20%~0.40% by mass; 1.00% by mass of polyoxyethylene 40 hydrogenated castor oil; 0.50% by mass of polyethylene glycol 400; 1.40% by mass of glycerol; 1.60% mannitol by mass; The remainder is water for injection.

13. The ophthalmic preparation according to claim 1, wherein, The formulation comprises: 0.10% cyclosporine (by mass); 0.25% by mass of medium-chain triglycerides; 1.00% by mass of polyoxyethylene 40 hydrogenated castor oil; 0.40%~0.80% by mass of polyethylene glycol 400; 1.40% by mass of glycerol; 1.60% mannitol by mass; The remainder is water for injection.

14. The ophthalmic preparation according to claim 1, wherein, The formulation comprises: 0.10% cyclosporine (by mass); 0.25% by mass of medium-chain triglycerides; 0.80%~1.60% by mass of polyoxyethylene 40 hydrogenated castor oil; 0.50% by mass of polyethylene glycol 400; 1.40% by mass of glycerol; 1.60% mannitol by mass; The remainder is water for injection.

15. The ophthalmic preparation according to claim 1, wherein, The formulation comprises: 0.10% cyclosporine (by mass); 0.25% by mass of medium-chain triglycerides; 1.00% by mass of polyoxyethylene 40 hydrogenated castor oil; 0.50% by mass of polyethylene glycol 400; 1.20%~1.90% glycerol by mass; 1.60% mannitol by mass; The remainder is water for injection.

16. The ophthalmic preparation according to claim 1, wherein, The formulation comprises: 0.10% cyclosporine (by mass); 0.25% by mass of medium-chain triglycerides; 1.00% by mass of polyoxyethylene 40 hydrogenated castor oil; 0.50% by mass of polyethylene glycol 400; 1.40% by mass of glycerol; Mannitol with a mass fraction of 1.40% to 2.00%; The remainder is water for injection.

17. The ophthalmic preparation according to claim 1, wherein, The formulation comprises: Cyclosporine at a mass fraction of 0.08% to 0.15%; 0.25% by mass of medium-chain triglycerides; 1.00% by mass of polyoxyethylene 40 hydrogenated castor oil; 0.50% by mass of polyethylene glycol 400; 1.40% by mass of glycerol; 1.60% mannitol by mass; The remainder is water for injection.

18. The ophthalmic preparation according to claim 1, wherein, The formulation comprises: 0.10% cyclosporine (by mass); 0.25% by mass of medium-chain triglycerides; 1.00% by mass of polyoxyethylene 40 hydrogenated castor oil; 0.50% by mass of polyethylene glycol 400; 1.40% by mass of glycerol; 1.60% mannitol by mass; The remainder is water for injection.

19. The ophthalmic preparation according to claim 1, wherein, The peroxide value of the oil phase is less than or equal to 0.2, and / or the peroxide value of the co-surfactant is less than or equal to 1.

4.

20. The ophthalmic preparation according to claim 1, wherein, The peroxide value of the oil phase is less than or equal to 0.2, and / or the peroxide value of the co-surfactant is less than or equal to 1.

3.

21. The ophthalmic preparation according to claim 1, wherein, The peroxide value of the oil phase is less than or equal to 0.2, and / or the peroxide value of the co-surfactant is less than or equal to 1.

2.

22. The ophthalmic preparation according to claim 1, wherein, The peroxide value of the oil phase is less than or equal to 0.2, and / or the peroxide value of the co-surfactant is less than or equal to 1.

1.

23. The ophthalmic preparation according to claim 1, wherein, The peroxide value of the oil phase is less than or equal to 0.2, and / or the peroxide value of the co-surfactant is less than or equal to 1.

0.

24. The ophthalmic preparation according to claim 1, wherein, The viscosity of the formulation is less than or equal to 10 mPa·s; And / or, the osmotic pressure of the formulation is 250~320 mOsmol / Kg.

25. A method for preparing an ophthalmic formulation according to any one of claims 1-24, comprising the following steps: Step 1: Mix the oil phase with the surfactant and co-surfactant until homogeneous to obtain the first product; Step 2: Under stirring conditions, cyclosporine is dissolved in the first product to obtain the second product; Step 3: Dissolve the thickener and osmotic pressure regulator in water to obtain the third product; Step 4: Under stirring conditions, add the second product to the third product and mix thoroughly; Step 5: Add water for injection to the full volume; Before step 3, the temperature of the first product is 90℃~100℃.

26. The ophthalmic preparation according to any one of claims 1-24, or the ophthalmic preparation obtained by the preparation method according to claim 25, wherein, The ophthalmic preparation is an eye drop.

27. The ophthalmic preparation according to any one of claims 1-24, 26, or the ophthalmic preparation obtained by the preparation method according to claim 25, for use in the preparation of a medicament for treating dry eye syndrome and keratoconjunctivitis; The dry eye syndrome is caused by keratitis and / or conjunctivitis; The keratoconjunctivitis mentioned is caused by seasonal and / or allergic factors; The keratoconjunctivitis mentioned is selected from seasonal allergic keratoconjunctivitis, perennial allergic keratoconjunctivitis, vernal keratoconjunctivitis, and atopic keratoconjunctivitis.

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