AR-15512-containing composition as well as preparation method and application thereof

Abstract

The invention provides a composition containing AR-15512, a preparation method of the composition and application of the composition in eye diseases such as xerophthalmia, meibomian gland dysfunction, allergic conjunctivitis and eye pain.

Description

Technical Field

[0001] The present invention relates to the pharmaceutical field, and in particular to a composition containing AR-15512, a preparation method thereof, and an application thereof. Background Art

[0002] Dry eye is a complex, multifactorial disease caused by a deficiency in natural tear production, either due to decreased tear production or increased tear evaporation. Currently, existing treatment options for dry eye primarily focus on anti-inflammatory and antioxidant therapies, which have significant limitations, including slow onset of action, eye irritation, and burning sensations after use, leading to low patient satisfaction and poor medication compliance. In a survey of dry eye patients, only 13% believed their dry eye was well controlled.

[0003] Tears can be produced through neural activation. Activating the trigeminal nerve coordinates the innervation of the lacrimal glands, meibomian glands, and goblet cells to promote tear formation and secretion. Transient receptor potential melatonin inhibitor 8 (TRPM8) is a receptor that has been shown to be activated by cold and is distributed in the cornea and eyelid margins of the human eye. TRPM8 agonists have been shown to stimulate the trigeminal nerve through neural conduction and promote basal tear production. Formula I (AR-15512, formerly known as WS-12) is a TRPM8 calcium channel agonist that has been shown in multiple clinical studies to rapidly increase natural tear production in patients with dry eye.

[0004]

[0005] On May 28, 2025, the FDA approved Tryptyr (acoltremon eye drops, active ingredient AR-15512) 0.003% for the treatment of signs and symptoms of dry eye disease (DED). In the two Phase III clinical trials, COMET-2 and COMET-3, which evaluated the efficacy of Tryptyr in over 930 patients with dry eye (randomly assigned in a 1:1 ratio to either the treatment group or the control group), the proportion of patients achieving an increase of at least 10 mm of natural tear production at day 14 was 42.6% in the COMET-2 study and 8.2% in the control group, while 53.2% and 14.4% in the COMET-3 study (p<0.0001). The results showed that approximately half of the patients experienced an improvement in this metric. Tryptyr demonstrated a statistically significant increase in natural tear production on day 1, making it the fastest-acting drug currently approved for the treatment of dry eye, but there is still room for improvement in the proportion of patients achieving an increase of at least 10 mm of tear production.

[0006] AR-15512 has extremely low solubility in water. Prior art WO2023 / 114986 discloses a composition of AR-15512, but its maximum solubility in a composition with a solubilizer is only 0.0091%, limiting the development of formulations with higher drug concentrations. Furthermore, conventional aqueous eye drops typically have a bioavailability of less than 5% due to the unique physiological barriers of the human eye. By overcoming the solubility limitations of AR-15512 in aqueous solution, or by achieving higher tissue exposure and bioavailability at the target site at the same concentration, it is hoped that its therapeutic effect will be maximized.

[0007] Therefore, the development of new formulations of AR-15512 is of great practical significance and clinical value. Summary of the Invention

[0008] The present invention provides an AR-15512 composition, comprising AR-15512 and medium-chain triglycerides.

[0009] In some embodiments of the present invention, the composition further comprises a surfactant.

[0010] In some embodiments of the present invention, the weight ratio of medium-chain triglycerides to surfactants in the composition is 1:1 to 1:20.

[0011] In some embodiments of the present invention, the weight ratio of medium-chain triglycerides to surfactants in the composition is preferably 1:4 to 1:10.

[0012] In some embodiments of the present invention, the weight ratio of medium-chain triglycerides to surfactants in the composition is further preferably 1:4, 1:6 or 1:10.

[0013] In some embodiments of the present invention, the amount of AR-15512 is 0.001% w / w to 0.05% w / w, based on the amount of the composition.

[0014] In some embodiments of the present invention, the amount of AR-15512 is preferably 0.0015% w / w to 0.045% w / w based on the amount of the composition.

[0015] In some embodiments of the present invention, the amount of AR-15512 is more preferably 0.003% w / w to 0.035% w / w based on the amount of the composition.

[0016] In some embodiments of the present invention, the amount of AR-15512 is most preferably 0.003% w / w, 0.005% w / w, 0.006% w / w, 0.01% w / w, 0.015% w / w, 0.03% w / w or 0.032% w / w based on the amount of the composition. As an example, it can be 0.003% w / w, 0.004% w / w, 0.005% w / w, 0.006% w / w, 0.007% w / w, 0.008% w / w, 0.009% w / w, 0. 01% w / w, 0.011% w / w, 0.012% w / w, 0.013% w / w, 0.014% w / w, 0.015% w / w, 0.016% w / w, 0.017% w / w, 0.018% w / w, 0.019% w / w, 0.02w / w, 0.021% w / w, 0.022% w / w, 0.023% w / w, 0.024% w / w, 0.025% w / w, 0.026% w / w, 0.02 7% w / w, 0.028% w / w, 0.029% w / w, 0.03% w / w, 0.031% w / w, 0.032% w / w, 0.033% w / w, 0.034% w / w or 0.035% w / w.

[0017] In some embodiments of the present invention, the amount of the medium chain triglyceride is 0.01% w / w to 2% w / w, based on the amount of the composition.

[0018] In some embodiments of the present invention, the amount of the medium chain triglyceride is preferably 0.05% w / w to 1.7% w / w, based on the amount of the composition.

[0019] In some embodiments of the present invention, the amount of the medium chain triglyceride is more preferably 0.1% w / w to 1.5% w / w, based on the amount of the composition.

[0020] In some embodiments of the present invention, in terms of the amount of the composition, the amount of the medium-chain triglyceride is most preferably 0.1% w / w, 0.265% w / w, 0.3% w / w, 0.5% w / w, 0.7% w / w, 0.75% w / w, 0.8% w / w, 0.9% w / w, 1% w / w, 1.2% w / w or 1.5% w / w. As an illustrative example, it can be 0.1% w / w, 0.11% w / w, 0.12% w / w, 0.13% w / w, 0.14% w / w, 0.15% w / w, 0.16% w / w, 0.17% w / w, 0.18% w / w, 0.19% w / w, 0.2% w / w, 0.21% w / w, 0.22% w / w, 0.23% w / w, 0.24% w / w, 0.25% w / w, 0.255% w / w, 0.26% w / w, 0.265% w / w, 0.27% w / w, 0.275% w / w, 0.28% w / w, 0.285% w / w, 0.29% w / w, 0.295% w / w, 0.3% w / w, 0.31% w / w, 0.32% w / w, 0.33% w / w, 0.34% w / w, 0.35% w / w, 0.36% w / w, 0.37% w / w, 0.38% w / w, 0.39% w / w, 0.4% w / w, 0.41% w / w, 0.42% w / w, 0.43% w / w, 0.44% w / w, 0.45% w / w, 0.46% w / w, 0.47% w / w, 0.48% w / w, 0.49% w / w, 0.5% w / w, 0.51% w / w, 0.52% w / w, 0.53% w / w, 0.54% w / w, 0.02% w / w, 1.03% w / w, 1.04% w / w, 1.05% w / w, 1.06% w / w, 1.07% w / w, 1.08% w / w, 1.09% w / w, 1.1% w / w, 1.11% w / w, 1.12% w / w, 1.13% w / w, 1.14 % w / w, 1.15% w / w, 1.16% w / w, 1.17% w / w, 1.18% w / w, 1.19% w / w, 1.2% w / w, 1.25% w / w, 1.3% w / w, 1.35% w / w, 1.4% w / w, 1.45% w / w or 1.5% w / w. .

[0021] In some embodiments of the present invention, the surfactant of the composition is selected from polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyethylene glycol 15-hydroxystearate, polysorbate 80, polysorbate 20, nonoxynol-9, poloxamer 188, polyvinyl alcohol, or carbomer TR-1, or a combination of two, three, or more thereof. Polyoxyl 35 castor oil or polyoxyl 40 hydrogenated castor oil is preferred.

[0022] In some embodiments of the present invention, the amount of the surfactant is 0.01% w / w to 6% w / w, preferably 0.03% w / w to 5.5% w / w, more preferably 0.05% w / w to 5% w / w, and most preferably 0.05% w / w, 0.1% w / w, 0.13% w / w, 0.25% w / w, 0.5% w / w, 0.53% w / w, 1% w / w, 1.4% w / w, 2% w / w, 3% w / w, 4% w / w or 5% w / w, based on the amount of the composition. As an example, it can be 0.05% w / w, 0.1% w / w, 0.11% w / w, 0.12% w / w, 0.13% w / w, 0.14% w / w, 0.15% w / w, 0.2% w / w, 0.2 5% w / w, 0.3% w / w, 0.35% w / w, 0.4% w / w, 0.45% w / w, 0.5% w / w, 0.51% w / w, 0.52% w / w, 0.53% w / w, 0.54% w / w, 0 .55% w / w, 0.6% w / w, 0.65% w / w, 0.7% w / w, 0.75% w / w, 0.8% w / w, 0.85% w / w, 0.9% w / w, 0.95% w / w, 1% w / w, 1.1 % w / w, 1.2% w / w, 1.3% w / w, 1.4% w / w, 1.5% w / w, 2% w / w, 2.5% w / w, 3% w / w, 3.5% w / w, 4% w / w, 4.5% w / w or 5% w / w.

[0023] In some embodiments of the present invention, the composition may further comprise a co-surfactant, a thickener, a pH regulator, an osmotic pressure regulator or water, or a combination of two, three or more thereof.

[0024] In some embodiments of the present invention, the co-surfactant of the composition is ethanol, PEG200, PEG300, PEG400, PEG600 or propylene glycol, or a combination of two, three or more thereof, preferably PEG400 or a combination of PEG400 and propylene glycol, calculated on the amount of the composition.

[0025] In some embodiments of the present invention, the amount of the co-surfactant is 0.05% w / w to 2% w / w, preferably 0.06% w / w to 1.6% w / w, more preferably 0.08% w / w to 1.5% w / w, and most preferably 0.088% w / w, 0.167% w / w, 0.5% w / w, 1% w / w or 1.5% w / w, based on the amount of the composition. As an example, it can be 0.088% w / w, 0.1% w / w, 0.15% w / w, 0.16% w / w, 0.167% w / w, 0.2% w / w, 0.25%w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1% w / w or 1.5% w / w.

[0026] In some embodiments of the present invention, the thickener of the composition is selected from methylcellulose, hydroxyethylcellulose, chitosan, hydroxypropylchitosan, glycerol, polyvinylpyrrolidone or hydroxypropylmethylcellulose, or a combination of two, three or more thereof, preferably hydroxypropylmethylcellulose.

[0027] In some embodiments of the present invention, the amount of the thickener is 0.1% w / w to 0.6% w / w, preferably 0.15% w / w to 0.55% w / w, more preferably 0.25% w / w to 0.5% w / w, and most preferably 0.5% w / w, based on the amount of the composition. As an exemplary illustration, it can be 0.25% w / w, 0.3% w / w, 0.35% w / w, 0.4% w / w, 0.45% w / w, or 0.5% w / w.

[0028] In some embodiments of the present invention, the pH adjuster of the composition is selected from sodium hydroxide, anhydrous disodium hydrogen phosphate or sodium dihydrogen phosphate monohydrate, or a combination of two or three thereof, preferably a combination of anhydrous disodium hydrogen phosphate and sodium dihydrogen phosphate monohydrate.

[0029] In some embodiments of the present invention, the amount of the pH adjuster is 0.2% w / w to 1.5% w / w, preferably 0.25% w / w to 1.3% w / w, more preferably 0.3% w / w to 1.1% w / w, and most preferably 0.32% w / w, 0.72% w / w or 1.04% w / w, based on the amount of the composition.

[0030] As an exemplary illustration, it may be 0.3% w / w, 0.32% w / w, 0.35% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.72% w / w, 0.75% w / w or 1.04% w / w.

[0031] In some embodiments of the present invention, the pH of the composition is 6-8.

[0032] In some embodiments of the present invention, the osmotic pressure regulator of the composition is selected from sodium chloride, glycerol, sorbitol or mannitol, or a combination of two, three or more thereof, preferably sodium chloride.

[0033] In some embodiments of the present invention, the amount of the osmotic pressure regulator is 0.2% w / w to 0.5% w / w, preferably 0.25% w / w to 0.45% w / w, more preferably 0.3% w / w to 0.4% w / w, and most preferably 0.35% w / w or 0.38% w / w, based on the amount of the composition. As an exemplary illustration, it can be 0.3% w / w, 0.31% w / w, 0.32% w / w, 0.33% w / w, 0.34% w / w, 0.35% w / w, 0.36% w / w, 0.37% w / w, 0.38% w / w, 0.39% w / w or 0.4% w / w.

[0034] In some embodiments of the present invention, the composition comprises, based on the amount of the composition, 0.003% w / w to 0.035% w / w of AR-15512, 0.1% w / w to 1.5% w / w of medium chain triglycerides, 0.05% w / w to 5% w / w of surfactants, and the balance being water.

[0035] In some embodiments of the present invention, the composition comprises, by weight, AR-15512 0.003% w / w to 0.035% w / w, medium chain triglycerides 0.1% w / w to 1.5% w / w, surfactants 0.05% w / w to 5% w / w, pH regulators 0.3% w / w to 1.1% w / w, osmotic pressure regulators 0.3% w / w to 0.4% w / w, and the balance is water.

[0036] In some embodiments of the present invention, the composition comprises, by weight, AR-15512 0.003% w / w, medium chain triglycerides 0.5% w / w, polyoxyethylene 35 castor oil 2% w / w, anhydrous disodium hydrogen phosphate 0.72% w / w, sodium dihydrogen phosphate monohydrate 0.32% w / w, sodium chloride 0.38% w / w, and the balance being water.

[0037] In some embodiments of the present invention, the composition comprises, by weight of the composition, AR-15512 0.003% w / w to 0.035% w / w, medium chain triglycerides 0.1% w / w to 1.5% w / w, surfactants 0.05% w / w to 5% w / w, thickeners 0.25% w / w to 0.5% w / w, pH adjusters 0.3% w / w to 1.1% w / w, osmotic pressure regulators 0.3% w / w to 0.4% w / w, and the balance being water.

[0038] In some embodiments of the present invention, the composition comprises, by weight, AR-15512 0.003% w / w, medium chain triglycerides 0.5% w / w, polyoxyethylene 35 castor oil 2% w / w, hydroxypropyl methylcellulose 0.5% w / w, anhydrous disodium hydrogen phosphate 0.72% w / w, sodium dihydrogen phosphate monohydrate 0.32% w / w, sodium chloride 0.35% w / w, and the balance is water, or

[0039] Contains AR-15512 0.006% w / w, medium chain triglycerides 0.5% w / w, polyoxyethylene 35 castor oil 2% w / w, hydroxypropyl methylcellulose 0.5% w / w, anhydrous disodium hydrogen phosphate 0.72% w / w, sodium dihydrogen phosphate monohydrate 0.32% w / w, sodium chloride 0.35% w / w, and the balance is water, or

[0040] Contains AR-15512 0.015% w / w, medium chain triglycerides 0.5% w / w, polyoxyethylene 35 castor oil 2% w / w, hydroxypropyl methylcellulose 0.5% w / w, anhydrous disodium hydrogen phosphate 0.72% w / w, sodium dihydrogen phosphate monohydrate 0.32% w / w, sodium chloride 0.35% w / w, and the balance is water, or

[0041] The product comprises AR-15512 0.015% w / w, medium chain triglycerides 0.5% w / w, polyoxyl 35 castor oil 5% w / w, hydroxypropyl methylcellulose 0.5% w / w, anhydrous disodium hydrogen phosphate 0.72% w / w, sodium dihydrogen phosphate monohydrate 0.32% w / w, sodium chloride 0.35% w / w, and the balance is water.

[0042] In some embodiments of the present invention, the composition comprises, by amount of the composition, AR-15512 0.003% w / w to 0.035% w / w, medium chain triglycerides 0.1% w / w to 1.5% w / w, surfactants 0.05% w / w to 5% w / w, co-surfactants 0.08% w / w to 1.5% w / w, thickeners 0.25% w / w to 0.5% w / w, pH adjusters 0.3% w / w to 1.1% w / w, osmotic pressure regulators 0.3% w / w to 0.4% w / w, and the balance is water.

[0043] In some embodiments of the present invention, the composition comprises, based on the amount of the composition, AR-15512 0.003% w / w, medium chain triglycerides 0.265% w / w, polyoxyethylene 40 hydrogenated castor oil 0.53% w / w, PEG400 0.088% w / w, hydroxypropyl methylcellulose 0.5% w / w, anhydrous disodium hydrogen phosphate 0.72% w / w, sodium dihydrogen phosphate monohydrate 0.32% w / w, sodium chloride 0.38% w / w, and the balance is water.

[0044] In some embodiments of the present invention, the composition can be developed directly or in combination with other excipients or devices into eye drops, eye gels, eye ointments, ophthalmic eyelid wipes, nasal drops, nasal sprays and other preparation types that can be realized by technicians, especially ophthalmic preparations.

[0045] In some embodiments of the present invention, the composition is used to treat eye diseases such as dry eye, meibomian gland dysfunction, allergic conjunctivitis, and eye pain.

[0046] Definition and Explanation

[0047] The term "medium-chain triglycerides" refers to the definition in the national standard "YBH03422008": a triglyceride mixture obtained by esterifying caprylic acid, capric acid and glycerol separated from the fatty oil extracted from the hard dry part of the endosperm of coconut (Cocos nucifera L), or the fatty oil extracted from the dry endosperm of oil palm (Elaeis guineensis Jacq), wherein the content of saturated fatty acids with 8 and 10 carbon atoms should be not less than 95%. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 : Eyelid margin tissue drug concentration-time graph;

[0049] Figure 2 : Corneal drug concentration-time diagram;

[0050] Figure 3 : Tear secretion in scopolamine-induced dry eye model in mice;

[0051] Figure 4 : Scoring of corneal fluorescence staining in scopolamine-induced dry eye model in mice. DETAILED DESCRIPTION

[0052] The present invention relates to a composition containing AR-15512 for treating eye diseases, wherein the composition can be developed directly or in combination with other excipients or devices into eye drops, ophthalmic gels, eye ointments, ophthalmic eyelid wipes, nasal drops, nasal sprays, and other formulation types that can be realized by technicians; the diseases are selected from dry eye, eye pain, meibomian gland dysfunction, allergic conjunctivitis, etc., and the diseases are particularly dry eye.

[0053] The present invention relates to a special oil-in-water microemulsion preparation: an oil phase, one or more surfactants, and an aqueous phase constitute a microemulsion system, wherein the oil phase and the surfactant or co-surfactant jointly dissolve the drug and also form a stable preparation system with other components to improve the physical stability of the preparation; in the special microemulsion system, the drug is distributed in the oil phase or the oil-water interface layer, and may also be distributed in the hydrophobic region in the form of micelles or solubilization, ultimately forming a stable and uniform solution system, which can be sterilized by filtration sterilization. Once formed, the special microemulsion preparation involved in the present invention has a transparent or translucent appearance, a small and uniform particle size, and stable thermodynamic properties. It can significantly improve the solubility and preparation stability of AR-15512. In addition, the applicant surprisingly found that the special oil-in-water microemulsion eye drops prepared by the present invention absorb the ophthalmic active ingredient in the anterior segment of the eye, especially in the eyelid margin tissue (the target site of the TRPM8 receptor), and found that the composition can improve the bioavailability of AR-15512 in the eyelid margin tissue.

[0054] As a novel nano-drug delivery system, the optical performance of microemulsions can be intuitively verified through the Tyndall effect. When incident light passes through a microemulsion system, the nanodroplets in the dispersed phase cause the light to undergo Rayleigh scattering, forming a distinct optical path perpendicular to the observation direction.

[0055] The structural characteristics of microemulsions are characterized by tiny particle size, excellent dispersion uniformity, and outstanding thermodynamic stability. These properties can be accurately characterized using dynamic light scattering (DLS), with the particle size distribution index (PDI) being a key parameter for evaluating the monodispersity of the system. The particle size of the prepared examples was measured using a Zetasizer Nano Zen 3700 at 25°C.

[0056] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are intended only to illustrate the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0057] Experimental Example 1 Equilibrium solubility of AR-15512 in different solvents

[0058] The equilibrium solubility of AR-15512 in various solvents was investigated. The solubility test method was as follows: an excess of AR-15512 was added to various solvents, the mixture was placed in a constant-temperature shaker at room temperature, and after 3 days, the supernatant was centrifuged and the AR-15512 content was determined by high-performance liquid chromatography. The equilibrium solubility of AR-15512 in various solvents is shown in Table 1.

[0059] Table 1 Equilibrium solubility of AR-15512 in different solvents

[0060] solvent Solubility (mg / g) Medium-chain triglycerides 1.59 castor oil 0.53 5% polyoxyethylene 35 castor oil aqueous solution 0.14 polyethylene glycol 400 1.67 Propylene glycol 1.66 Twain 80 0.48

[0061] Examples 1 to 9

[0062] The effects of different surfactant types on microemulsion formation were studied: medium-chain triglycerides were selected as the oil phase, and polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, 15-hydroxystearate polyethylene glycol, Tween 80, Tween 20, nonoxynol-9, poloxamer 188, polyvinyl alcohol, and carbomer TR-1 were selected as surfactants. The microemulsions were prepared according to the weight ratio (w / w) listed in Table 2. The specific preparation method is as follows:

[0063] (1) AR-15512, medium-chain triglycerides, and different types of surfactants were weighed separately and stirred at 55°C to dissolve the drugs;

[0064] (2) heating the water for injection to the same temperature to obtain an aqueous phase;

[0065] (3) Add the prescribed amount of water for injection to (1), stir and mix, cool to room temperature, and observe the appearance of the sample.

[0066] Table 2 Screening of surfactant types

[0067]

[0068] The results of the investigation of different surfactants are shown in Table 2. It can be seen that when the oil phase is medium-chain triglycerides and the surfactant is polyoxyethylene 35 castor oil, a clear light blue liquid is formed. However, the formulations prepared with other surfactants at conventional dosages exhibit stratification or form milky white liquids, making it difficult to form stable formulations. This indicates that compared with other surfactants, polyoxyethylene 35 castor oil has greater potential for forming stable microemulsions.

[0069] Examples 10 to 13

[0070] The effects of different oil phase types on microemulsion formation were studied: polyoxyethylene 35 castor oil was selected as the surfactant, and medium-chain triglycerides, castor oil, soybean oil, olive oil, and propylene glycol laurate type 1 were selected as the oil phase. Microemulsions were prepared according to the weight ratios (w / w) listed in Table 3, and the oil phase types were screened. The specific preparation method is as follows:

[0071] (1) AR-15512, different types of oil phases, and polyoxyethylene 35 castor oil were weighed in the prescribed amount and stirred at 55°C to dissolve the drug;

[0072] (2) heating the water for injection to the same temperature to obtain an aqueous phase;

[0073] (3) Add the prescribed amount of water for injection to (1), stir and mix, cool to room temperature, and observe the appearance of the sample.

[0074] Table 3 Investigation of oil phase types

[0075]

[0076] The results of the investigation of different oil phases are shown in Table 3. It can be seen that when the oil phase was medium-chain triglycerides or castor oil, and the surfactant was polyoxyethylene 35 castor oil, a clear, light blue liquid was formed; however, the other oil phases tested failed to form a stable formulation under the same conditions. The solubility data indicate that medium-chain triglycerides have a better solubility for AR-15512 than castor oil, making medium-chain triglycerides the preferred oil phase.

[0077] Examples 14 to 20

[0078] The effects of different oil phase amounts on microemulsion formation were investigated: the AR-15512 specification was fixed at 0.003%, the surfactant polyoxyethylene 35 castor oil was used at 2%, and the amount of medium-chain triglycerides in the oil phase was investigated. According to the weight ratio (w / w) shown in Table 4, the preparation method was as follows:

[0079] (1) Weigh the prescribed amount of AR-15512, medium-chain triglycerides, and polyoxyethylene 35 castor oil and stir at 55°C to dissolve the drugs;

[0080] (2) Weigh the prescribed amount of anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate, and sodium chloride, add appropriate amount of water for injection, stir until dissolved, and heat to the same temperature;

[0081] (3) Weigh the prescribed amount of HPMC, add an appropriate amount of water for injection, heat and stir until dissolved, and cool to room temperature to obtain a HPMC solution;

[0082] (4) Add (2) to (1), stir and mix, cool to room temperature, add (3), add injection water to the full amount, stir and mix, filter and sterilize with a 0.22 μm microporous filter membrane, and obtain the product.

[0083] Table 4 Investigation of oil phase dosage

[0084]

[0085] From the results in Table 4, it can be seen that a stable microemulsion can be formed when the amount of medium-chain triglycerides is between 0.1% and 1.2%, while when the amount of medium-chain triglycerides is 1.5%, the PDI value is large and the particle size distribution is uneven.

[0086] Examples 21 to 26

[0087] Investigation of the dosage of surfactant: The specification of AR-15512 was fixed at 0.003%, the dosage of medium-chain triglyceride was 0.50%, and the dosage of surfactant polyoxyethylene 35 castor oil was screened. The drugs and excipients were weighed according to the weight ratio (w / w) of the prescription in Table 5, and Examples 21 to 26 were prepared using the same preparation method as Examples 14 to 20.

[0088] Table 5 Investigation of surfactant dosage

[0089]

[0090] As shown in Table 5, Examples 21 to 26 show that clear and transparent microemulsion preparations can be prepared when the AR-15512 specification is fixed at 0.003%, the medium chain triglyceride dosage is 0.50%, and the polyoxyethylene 35 castor oil dosage is 0.50% to 5.00%. The larger the ratio of the polyoxyethylene 35 castor oil dosage to the medium chain triglyceride dosage, the smaller the obtained particle size. However, the dosage of polyoxyethylene 35 castor oil needs to be controlled within the safe application range of excipients. Considering the safety of the excipient dosage and the particle size control, the more preferred dosage of polyoxyethylene 35 castor oil is 2.00% to 3.00%.

[0091] Examples 27 to 31

[0092] The effects of different thickeners on microemulsion formation were investigated, and the specific formulation compositions are shown in Table 6.

[0093] Table 6 Thickener type screening

[0094]

[0095] As can be seen from the results in Table 6, the viscosity of the prescription prepared with the prescribed amount of sodium carboxymethyl cellulose is too large, the solution is relatively viscous, and the PDI value of the particle size detection is large, indicating that sodium carboxymethyl cellulose as a thickener easily causes aggregation between particles, resulting in uneven particle size distribution; the PDI values ​​of the examples prepared with hydroxypropyl methylcellulose (viscosity 4000 mPa·s), hydroxypropyl chitosan, glycerol, and polyvinyl pyrrolidone as thickeners are small, indicating a uniform particle size distribution. Among them, the prescription prepared with hydroxypropyl methylcellulose as a thickener has a moderate viscosity, which is beneficial to prolonging the retention time of the drug on the ocular surface.

[0096] Comparative Examples 1 to 5

[0097] The stability of the formulations obtained by reducing the formulation components was investigated. As shown in Table 7, the following formulations were prepared by reducing the surfactant and oil phase, and using a single co-surfactant solubilizer.

[0098] Table 7 Comparative Examples 1 to 5 Prescription Composition and Preparation

[0099]

[0100] Comparative Examples 1 and 2 also demonstrate that the prescribed amount of oil phase alone at room temperature cannot dissolve the drug, and that the prescribed amount of surfactant alone causes drug precipitation after standing. The preparation results of Comparative Examples 3-5 also demonstrate that the prescribed amount of co-surfactants alone or in combination cannot dissolve the drug, and a clear, transparent preparation cannot be obtained. Only when the oil phase and surfactant are used in combination can a clear, transparent preparation be produced at the prescribed amount.

[0101] Examples 32 to 39

[0102] The solubilization ability of AR-15512 in a microemulsion system formed by medium-chain triglycerides and polyoxyethylene 35 castor oil was investigated. The formulation composition, by weight percentage, is as follows, as shown in Table 8. The preparation methods for Examples 32-39 are the same as for Examples 14-20.

[0103] Table 8 AR-15512 preparations of different specifications

[0104]

[0105] The results in Table 8 show that by adjusting the ratio of medium-chain triglycerides to polyoxyethylene 35 castor oil, formulations with different drug loading capacities can be obtained. When the AR-15512 specification is lower than 0.015%, 2% polyoxyethylene 35 castor oil and 0.5% medium-chain triglycerides can ensure the solubility of the drug in the entire microemulsion system. When the AR-15512 specification reaches 0.030%, the prescription ratio of medium-chain triglycerides needs to be increased, and a cosurfactant needs to be added to maintain the stability of the microemulsion. When the specification reaches 0.030%, Example 37, without the addition of a cosurfactant, exhibits drug precipitation during room temperature storage. The drug solubility data indicate that the oil phase, surfactant, or cosurfactant alone cannot support drug dissolution. Example 38 demonstrates that when the specification reaches 0.030%, drug dissolution requires the combined efforts of the oil phase, surfactant, and cosurfactant. The drug is simultaneously distributed in the oil phase and oil-water interface of the microemulsion, and may also be distributed in the hydrophobic region in a micelle-like or solubilizing manner, forming a unique, stable, and uniform solution system. Combining Examples 14-26 and Examples 32-39, it was found that a medium-chain triglyceride to polyoxyethylene 35 castor oil weight ratio of 1:1 to 1:20 can produce a stable microemulsion formulation. Taking into account factors such as drug solubility, particle size, and the safe and reasonable dosage of excipients, the preferred medium-chain triglyceride to polyoxyethylene 35 castor oil weight ratio is 1:4 to 1:10, with 1:4, 1:6, and 1:10 being more preferred.

[0106] Examples 40 to 44

[0107] An AR-15512 preparation based on polyoxyethylene 40 hydrogenated castor oil, the composition of which by weight percentage is shown in Table 9. The preparation method of the AR-15512 composition comprises the following steps:

[0108] (1) Weigh the prescribed amount of AR-15512, medium-chain triglycerides, polyoxyethylene 40 hydrogenated castor oil, and PEG400 and stir at 55°C to dissolve the drugs;

[0109] (2) Weigh the prescribed amount of anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate, and sodium chloride, add an appropriate amount of water for injection, stir until dissolved, and heat to the same temperature;

[0110] (3) Add (2) to (1), stir and mix, then add water for injection at the same temperature to the full amount, cool to room temperature, and filter through a 0.22 μm microporous membrane for sterilization.

[0111] Table 9 AR-15512 composition based on polyoxyethylene 40 hydrogenated castor oil

[0112]

[0113]

[0114] The results in Table 9 show that using polyoxyethylene 40 hydrogenated castor oil as a surfactant can also produce a stable AR-15512 composition, and the resulting microemulsion particle size and particle size distribution meet the requirements. However, due to the maximum safe dosage of excipients, the maximum safe dosage of polyoxyethylene 40 hydrogenated castor oil is lower than that of polyoxyethylene 35 castor oil.

[0115] Experimental Example 2: Stability Study of AR-15512 Microemulsion Formulation

[0116] Stable performance is the basis for a drug to exert its efficacy. Taking Examples 24, 27, and Examples 40 to 42 as examples, as shown in Table 10, the stability of the AR-15512 microemulsion preparation was investigated.

[0117] Temperature test: Under the condition of 60℃, samples were taken at 0 and 30 days to examine various indicators of the preparation.

[0118] Light test: Place the sample in a light stability test box, under the condition of illumination of 4500lx±500lx, take samples at 0 and 10 days, and examine various indicators of the preparation.

[0119] Evaluation indicators include the appearance, pH, osmotic pressure, content, and particle size of the preparation.

[0120] Table 10: Stability test results

[0121]

[0122]

[0123] The results of stability experiments show that the prepared microemulsion can remain stable at high temperature of 60°C and under light conditions. Whether polyoxyethylene 35 castor oil or polyoxyethylene 40 hydrogenated castor oil is used as the surfactant, the microemulsion formed with medium-chain triglycerides has the characteristics of thermodynamic stability.

[0124] Comparative Example 6

[0125] An AR-15512 ophthalmic composition, whose composition by weight percentage is shown in Table 11, and a method for preparing the AR-15512 ophthalmic composition comprises the following steps:

[0126] (1) Weigh the prescribed amount of AR-15512 and polyoxyethylene 35 castor oil, heat at 55°C, and stir to dissolve the drugs;

[0127] (2) Weigh the prescribed amount of sodium dihydrogen phosphate monohydrate and sodium chloride, add an appropriate amount of water for injection, stir until dissolved, and heat to the same temperature;

[0128] (3) Weigh the prescribed amount of HPMC, add an appropriate amount of water for injection, heat and stir until dissolved, and cool to room temperature to obtain a HPMC solution;

[0129] (4) Add (2) to (1), stir and mix, then add the remaining amount of water for injection at the same temperature, cool to room temperature and add (3), stir and mix, and filter with a 0.22μm microporous membrane to sterilize.

[0130] Table 11 Comparative Example 6 Prescription Composition

[0131]

[0132]

[0133] Experimental Example 3 Pharmacokinetic Study of Rabbit Eye Tissue

[0134] 1. Purpose of the test:

[0135] New Zealand rabbits were used as test animals to study the PK of the preparation of the present invention in the upper and lower eyelid margins and cornea of ​​the rabbits after eye drop administration.

[0136] 2. Test process:

[0137] 20 healthy New Zealand rabbits weighing 2-4 kg were randomly divided into 2 groups, namely comparative example 6 groups and embodiment 27 groups, 10 in each group. After anesthesia with a combination of dexmedetomidine hydrochloride and Shutai 50, the upper and lower eyelid margins and cornea were collected at 0.25 h, 1 h, 2 h, 6 h, and 12 h after administration. The surface was cleaned with normal saline before the tissue collection at each time point, and the upper and lower eyelid margins and cornea of ​​the left and right eyes were collected respectively. After collection, the upper and lower eyelid margins and cornea were cleaned with normal saline once. The tissue was stored in a cryogenic refrigerator as soon as possible until sample analysis.

[0138] 3. Sample testing and analysis

[0139] An LC-MS / MS method was established to determine unchanged drug concentrations in rabbit eyelid margins and corneas. This method was used to determine concentrations in biological samples obtained in this experiment. Sample pretreatment was performed in an ice-water bath. Pharmacokinetic parameters were calculated using Winnonlin software using a non-compartmental model.

[0140] 4. Test results:

[0141] Table 12 Pharmacokinetic parameters of different preparations at the upper and lower eyelid margins of rabbits

[0142] Grouping concentration Tmax(h) Cmax (ng / g) <![CDATA[AUC 0-12h (h*ng / g)]]> Comparative Example 6 0.003％ 1 107 695 Example 27 0.003％ 2 131 889

[0143] Table 13 Pharmacokinetic parameters of different preparations in rabbit cornea

[0144] Grouping concentration Tmax(h) Cmax (ng / g) <![CDATA[AUC 0-12h (h*ng / g)]]> Comparative Example 6 0.003％ 0.25 93.4 189 Example 27 0.003％ 0.25 89.1 195

[0145] 5. Test conclusion:

[0146] Studies have shown that (as shown in Table 12, Figure 1 As shown in Figure 2, compared with the comparative example 6 group, the Example 27 group was able to increase the drug exposure concentration in the upper and lower eyelid margins and delayed the peak time by 1 hour, indicating that the microemulsion formulation of the Example 27 group has a longer retention time in the eyelid margin tissue. 0-12h Compared with the control group 6, the bioavailability of AR-15512 in the eyelid margin tissue was increased by 1.28 times.

[0147] The pharmacokinetic parameters of cornea showed (Table 13, Figure 2 As shown in Figure 3 , the exposure of Group 27 in the cornea was comparable to that of Group 6. In general, Group 27 was able to increase the bioavailability of AR-15512 in TRPM8 receptor target tissues, especially in the eyelid margin tissue.

[0148] Experimental Example 4 Pharmacodynamic evaluation of scopolamine-induced dry eye model in mice

[0149] 1. Purpose of the test:

[0150] In this study, a dry eye model was induced in C57BL / 6(J) mice by subcutaneous injection of scopolamine hydrobromide solution into the hind limbs to investigate the therapeutic effects of different preparations on this model.

[0151] 2. Test process:

[0152] (1) Modeling: All animals in each group received alternating injections of 5 mg / mL scopolamine hydrobromide solution subcutaneously on both hind limbs at D1, 4 times a day, 0.1 mL / time, with an interval of approximately 3 hours between each injection, for 17 consecutive days. The negative control group received an equal volume of 0.9% sodium chloride injection subcutaneously on both hind limbs. Multiple injections at the same injection site should be avoided.

[0153] (2) Grouping: Tear secretion and corneal fluorescence staining scores were measured on both eyes at D10, and the modeling animals were randomly and evenly divided into 5 groups according to the tear secretion and corneal fluorescence staining scores, namely, model control group, vehicle control group, comparative example group 6, example 33 group, and example 36 group, with 6 animals in each group.

[0154] (3) Administration: On D11, each group of animals was administered eye drops in both eyes, 3 μL / eye / time, 4 times / day, with an interval of approximately 3 hours between administrations, for a total of 7 days. The negative control group and the model control group were given an equal volume of 0.9% sodium chloride injection in both eyes. The vehicle control group was given the blank formulation of Example 36 without AR-15512.

[0155] Note: Administer eye drops immediately after subcutaneous injection of scopolamine hydrobromide solution daily.

[0156] (4) Index detection: The tear secretion volume of the animals was measured and the corneal fluorescence staining score was scored on D0, with the interval between the two index detections being about 3 hours; the tear secretion volume of the animals was measured and the corneal fluorescence staining score was scored on D10 after the first and second modeling, respectively; the tear secretion volume of the animals was measured about 30 minutes after the first administration on D14 and D17, and the corneal fluorescence staining score was scored about 30 minutes after the second administration.

[0157] (5) Data statistics: GraphPad Prism 8.0 was used for statistical analysis. The obtained data were expressed as means ± SD or means ± SEM. One-way ANOVA was used to compare multiple groups of data, and Student's t test was used to compare two groups of data. P < 0.05 was considered statistically significant. * P<0.05, ** P < 0.01, ns = not significant).

[0158] 3. Test results

[0159] Table 14 Effects of the preparations on tear secretion in dry eye model mice (mean ± SD)

[0160]

[0161] Note: Compared with the negative control group, # P<0.05, ## P<0.01, compared with the vehicle control group * P<0.05.

[0162] As shown in Table 14, the tear secretion data from D10 to D17 show that the model control group has a significant difference compared with the negative control group ( * P<0.01, indicating that the model was successfully established. Figure 3), the tear secretion of Comparative Example 6 was increased compared with the model control group and the vehicle control group, indicating that AR-15512 has the effect of promoting tear secretion. The tear secretion of Example 33 and Example 36 groups was higher than that of Comparative Example 6 group, indicating that increasing the specification of AR-15512 can enhance the effect of AR-15512 in promoting tear secretion. More notably, there was a statistically significant difference between Example 36 group and the vehicle control group ( * P<0.05).

[0163] Table 15 Effects of the preparations on corneal fluorescence staining scores in dry eye model mice (mean ± SD)

[0164]

[0165] Note: Compared with the negative control group, # P<0.05, ## P<0.01; compared with the model control group, & P<0.05, && P<0.01; compared with the vehicle control group, * P<0.05, ** P<0.01.

[0166] As shown in Table 15, the corneal fluorescence staining scores from D10 to D17 showed that ( Figure 4 ), the score of the model control group was significantly higher than that of the negative control group, with a significant difference (P<0.01), indicating that the model was successfully established. According to the comparison of the data of each group at the dosing endpoint D17, the scores of Example 33 and Example 36 were significantly lower than those of the model control group, and there was a very significant difference (P<0.01), while the score of Comparative Example 6 was lowered to a certain extent compared with the model control group, but there was no significant difference; In addition, compared with the solvent control group, the scores of Example 33 and Example 36 were significantly lower (P<0.01; P<0.05), while there was no significant difference in Comparative Example 6, indicating that increasing the AR-15512 specification to 0.006% and 0.015% can improve the corneal fluorescence staining score, a dry eye symptom indicator.

[0167] The present invention utilizes a special microemulsion formulation to increase the solubility of AR-15512 in aqueous solution. The study unexpectedly found that AR-15512 not only improves tear secretion in a scopolamine-induced dry eye mouse model but also reduces corneal fluorescein staining scores. Furthermore, it was demonstrated that increasing the AR-15512 dosage to 0.006% and 0.015% significantly improved both tear secretion and corneal fluorescein staining scores compared to 0.003%.

[0168] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An AR-15512 composition, characterized in that The composition comprises AR-15512 and medium chain triglycerides.

2. The composition according to claim 1, characterized in that The composition further comprises a surfactant.

3. The composition according to claim 1 or 2, characterized in that The weight ratio of the medium chain triglyceride to the surfactant in the composition is 1:1 to 1:

20.

4. The composition according to claim 3, characterized in that The weight ratio of the medium chain triglyceride to the surfactant in the composition is preferably 1:4 to 1:

10.

5. The composition according to claim 4, characterized in that The weight ratio of the medium chain triglyceride to the surfactant in the composition is further preferably 1:4, 1:6 or 1:

10.

6. The composition according to claim 1, characterized in that In the composition, the amount of AR-15512 is 0.001% w / w to 0.05% w / w based on the amount of the composition.

7. The composition according to claim 6, characterized in that In the composition, the amount of AR-15512 is preferably 0.0015% w / w to 0.045% w / w based on the amount of the composition.

8. The composition according to claim 7, characterized in that In the composition, the amount of AR-15512 is more preferably 0.003% w / w to 0.035% w / w based on the amount of the composition.

9. The composition according to claim 8, characterized in that In the composition, the amount of AR-15512 is most preferably 0.003% w / w, 0.005% w / w, 0.006% w / w, 0.01% w / w, 0.015% w / w, 0.03% w / w or 0.032% w / w based on the amount of the composition.

10. The composition according to claim 1, characterized in that In the composition, the amount of the medium chain triglyceride is 0.01% w / w to 2% w / w based on the amount of the composition.

11. The composition according to claim 10, characterized in that In the composition, the amount of the medium chain triglyceride is preferably 0.05% w / w to 1.7% w / w based on the amount of the composition.

12. The composition according to claim 11, characterized in that In the composition, the amount of the medium chain triglyceride is more preferably 0.1% w / w to 1.5% w / w based on the amount of the composition.

13. The composition according to claim 12, characterized in that In the composition, the amount of the medium chain triglycerides is most preferably 0.1% w / w, 0.265% w / w, 0.3% w / w, 0.5% w / w, 0.7% w / w, 0.75% w / w, 0.8% w / w, 0.9% w / w, 1% w / w, 1.2% w / w or 1.5% w / w, based on the amount of the composition.

14. The composition according to claim 2, characterized in that The surfactant is selected from polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol 15-hydroxystearate, Tween 80, Tween 20, nonoxynol-9, poloxamer 188, polyvinyl alcohol or carbomer TR-1, or a combination of two, three or more thereof. Polyoxyethylene 35 castor oil or polyoxyethylene 40 hydrogenated castor oil is preferred.

15. The composition according to claim 2, characterized in that In the composition, the amount of the surfactant is 0.01% w / w to 6% w / w, preferably 0.03% w / w to 5.5% w / w, more preferably 0.05% w / w to 5% w / w, and most preferably 0.05% w / w, 0.1% w / w, 0.13% w / w, 0.25% w / w, 0.5% w / w, 0.53% w / w, 1% w / w, 1.4% w / w, 2% w / w, 3% w / w, 4% w / w or 5% w / w, based on the amount of the composition.

16. The composition according to claim 1 or 2, characterized in that The composition may further comprise a co-surfactant, a thickener, a pH regulator, an osmotic pressure regulator or water, or a combination of two, three or more thereof.

17. The composition according to claim 16, characterized in that The cosurfactant is ethanol, PEG200, PEG300, PEG400, PEG600 or propylene glycol, or a combination of two, three or more thereof, preferably PEG400 or a combination of PEG400 and propylene glycol.

18. The composition according to claim 16, characterized in that In the composition, the amount of the co-surfactant is 0.05% w / w to 2% w / w, preferably 0.06% w / w to 1.6% w / w, more preferably 0.08% w / w to 1.5% w / w, and most preferably 0.088% w / w, 0.167% w / w, 0.5% w / w, 1% w / w or 1.5% w / w, based on the amount of the composition.

19. The composition according to claim 16, characterized in that The thickener is selected from methylcellulose, hydroxyethylcellulose, chitosan, hydroxypropylchitosan, glycerol, polyvinylpyrrolidone or hydroxypropylmethylcellulose, or a combination of two, three or more thereof, preferably hydroxypropylmethylcellulose.

20. The composition according to claim 16, characterized in that In the composition, based on the amount of the composition, the amount of the thickener is 0.1% w / w to 0.6% w / w, preferably 0.15% w / w to 0.55% w / w, more preferably 0.25% w / w to 0.5% w / w, and most preferably 0.5% w / w.

21. The composition according to claim 16, characterized in that The pH regulator is selected from sodium hydroxide, anhydrous disodium hydrogen phosphate or sodium dihydrogen phosphate monohydrate, or a combination of two or three thereof; preferably a combination of anhydrous disodium hydrogen phosphate and sodium dihydrogen phosphate monohydrate.

22. The composition according to claim 16, characterized in that The amount of the pH adjuster is 0.2% w / w to 1.5% w / w, preferably 0.25% w / w to 1.3% w / w, more preferably 0.3% w / w to 1.1% w / w, and most preferably 0.32% w / w, 0.72% w / w or 1.04% w / w.

23. The composition according to claim 16, characterized in that The pH of the composition is 6-8.

24. The composition according to claim 16, characterized in that The osmotic pressure regulator is selected from sodium chloride, glycerol, sorbitol or mannitol, or a combination of two, three or more thereof, preferably sodium chloride.

25. The composition according to claim 16, characterized in that In the composition, the amount of the osmotic pressure regulator is 0.2% w / w to 0.5% w / w, preferably 0.25% w / w to 0.45% w / w, more preferably 0.3% w / w to 0.4% w / w, and most preferably 0.35% w / w or 0.38% w / w, based on the amount of the composition.

26. The composition according to any one of claims 1 to 25, characterized in that Based on the amount of the composition, the composition comprises 0.003% w / w to 0.035% w / w of AR-15512, 0.1% w / w to 1.5% w / w of medium chain triglycerides, 0.05% w / w to 5% w / w of surfactants, and the balance is water.

27. The composition according to any one of claims 1 to 25, characterized in that Calculated by the amount of the composition, the composition comprises 0.003% w / w to 0.035% w / w of AR-15512, 0.1% w / w to 1.5% w / w of medium-chain triglycerides, 0.05% w / w to 5% w / w of surfactants, 0.3% w / w to 1.1% w / w of pH regulators, 0.3% w / w to 0.4% w / w of osmotic pressure regulators, and the balance being water.

28. The composition according to claim 27, characterized in that Based on the amount of the composition, the composition comprises 0.003% w / w of AR-15512, 0.5% w / w of medium chain triglycerides, 2% w / w of polyoxyethylene 35 castor oil, 0.72% w / w of anhydrous disodium hydrogen phosphate, 0.32% w / w of sodium dihydrogen phosphate monohydrate, 0.38% w / w of sodium chloride, and the balance being water.

29. The composition according to any one of claims 1 to 25, characterized in that Calculated by the amount of the composition, the composition comprises 0.003% w / w to 0.035% w / w of AR-15512, 0.1% w / w to 1.5% w / w of medium-chain triglycerides, 0.05% w / w to 5% w / w of surfactants, 0.25% w / w to 0.5% w / w of thickeners, 0.3% w / w to 1.1% w / w of pH regulators, 0.3% w / w to 0.4% w / w of osmotic pressure regulators, and the balance being water.

30. The composition according to claim 29, characterized in that Calculated by the amount of the composition, the composition comprises AR-15512 0.003% w / w, medium chain triglycerides 0.5% w / w, polyoxyl 35 castor oil 2% w / w, hydroxypropyl methylcellulose 0.5% w / w, anhydrous disodium hydrogen phosphate 0.72% w / w, sodium dihydrogen phosphate monohydrate 0.32% w / w, sodium chloride 0.35% w / w, and the balance is water; or Containing AR-15512 0.006% w / w, medium chain triglycerides 0.5% w / w, polyoxyl 35 castor oil 2% w / w, hydroxypropyl methylcellulose 0.5% w / w, anhydrous disodium hydrogen phosphate 0.72% w / w, sodium dihydrogen phosphate monohydrate 0.32% w / w, sodium chloride 0.35% w / w, and the balance is water; or Containing AR-15512 0.015% w / w, medium chain triglycerides 0.5% w / w, polyoxyl 35 castor oil 2% w / w, hydroxypropyl methylcellulose 0.5% w / w, anhydrous disodium hydrogen phosphate 0.72% w / w, sodium dihydrogen phosphate monohydrate 0.32% w / w, sodium chloride 0.35% w / w, and the balance is water; or The product comprises AR-15512 0.015% w / w, medium chain triglycerides 0.5% w / w, polyoxyl 35 castor oil 5% w / w, hydroxypropyl methylcellulose 0.5% w / w, anhydrous disodium hydrogen phosphate 0.72% w / w, sodium dihydrogen phosphate monohydrate 0.32% w / w, sodium chloride 0.35% w / w, and the balance is water.

31. The composition according to any one of claims 1 to 25, characterized in that Calculated by the amount of the composition, the composition comprises 0.003% w / w to 0.035% w / w of AR-15512, 0.1% w / w to 1.5% w / w of medium chain triglycerides, 0.05% w / w to 5% w / w of surfactants, 0.08% w / w to 1.5% w / w of co-surfactants, 0.25% w / w to 0.5% w / w of thickeners, 0.3% w / w to 1.1% w / w of pH adjusters, 0.3% w / w to 0.4% w / w of osmotic pressure regulators, and the balance being water.

32. The composition according to claim 31, characterized in that Based on the amount of the composition, the composition includes AR-15512 0.003% w / w, medium chain triglycerides 0.265% w / w, polyoxyethylene 40 hydrogenated castor oil 0.53% w / w, PEG400 0.088% w / w, hydroxypropyl methylcellulose 0.5% w / w, anhydrous disodium hydrogen phosphate 0.72% w / w, sodium dihydrogen phosphate monohydrate 0.32% w / w, sodium chloride 0.38% w / w, and the balance is water.

33. The composition according to any one of claims 1 to 32, characterized in that The composition is in the form of eye drops, eye gel, eye ointment, ophthalmic eyelid wipes, nose drops or nasal spray.

34. The composition according to any one of claims 1 to 33, characterized in that The composition is used in preparing medicines for treating eye diseases such as dry eye, meibomian gland dysfunction, allergic conjunctivitis, eye pain, etc.

Images