CN120732828A - AR-15512-containing composition and preparation method and application thereof - Google Patents

Abstract

Translated fromChinese

本发明提供了一种含有AR‑15512的组合物及其制备方法，及其在干眼症、睑板腺功能障碍、过敏性结膜炎、眼部疼痛等眼部疾病中的应用。

The present invention provides a composition containing AR-15512, a preparation method thereof, and applications thereof in treating eye diseases such as dry eye, meibomian gland dysfunction, allergic conjunctivitis, and eye pain.

Description

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

Technical Field

The invention relates to the field of pharmacy, in particular to a composition containing AR-15512, and a preparation method and application thereof.

Background

Dry eye is a complex multifactorial disease caused by a deficiency of natural tears, whether due to decreased tear secretion or increased tear evaporation. At present, the existing xerophthalmia treatment scheme mainly takes anti-inflammatory and antioxidant effects, and has larger limitations, including low medication satisfaction and poor medication compliance of patients caused by factors such as slow onset of action, eye irritation after eye drops, burning sensation and the like. In the investigation of dry eye patients, only 13% of the patients consider that their dry eye is well controlled.

Tears may be produced by nerve activation, which coordinates the innervation of lacrimal glands, meibomian glands and goblet cells to promote tear formation and secretion. The transient receptor potential melatonin 8 (TRANSIENT RECEPTOR POTENTIAL MELASTATIN, trpm 8) is a receptor that has been shown to be cold activated and is distributed across the cornea and lid margin of the human eye. TRPM8 agonists have been shown to stimulate the trigeminal nerve through nerve conduction, promoting basal tear production, and formula I (AR-15512, used by WS-12) is a TRPM8 calcium channel agonist, which has been demonstrated by several clinical studies to rapidly increase natural tear production in dry eye patients.

Tryptyr (acoltremon eye drops with AR-15512 as active ingredient) 0.003% was approved by the FDA at 5.28 of 2025 for the treatment of signs and symptoms of Dry Eye (DED). In two phase III clinical COMET-2 and COMET-3 studies, 930 dry eye patients were evaluated for their therapeutic effect (randomly assigned to either the treatment or control group at a 1:1 ratio), and the proportion of patients with at least a 10 mm increase in natural tear secretion on day 14 in the COMET-2 study compared to the control group was 42.6% and 8.2% and 53.2% and 14.4% in the COMET-3 study (p < 0.0001), and the results indicated that about half of the patients were improved in this index. Tryptyr shows statistically significant increases in natural tear secretion on day 1, which is the most effective drug for treating dry eye in the current market, but still has room for improvement in the proportion of patients whose tear secretion increases by at least 10 mm.

The solubility of AR-15512 in water is very low and the prior art WO2023/114986 discloses compositions of AR-15512 which achieve a formulation specification of only 0.0091% for the highest solubility in the composition with the solubiliser, thus limiting the development of formulations of higher drug concentration. In addition, the bioavailability of the drug is generally lower than 5% due to the special physiological barrier of human eyes after the conventional aqueous eye drops are administered, and the maximum therapeutic effect can be hopefully exerted if the limit of the solubility of AR-15512 in the aqueous solution is broken through or the higher tissue exposure and bioavailability of the target part are realized under the same concentration.

Therefore, the development of a new preparation of AR-15512 has great practical significance and clinical value.

Disclosure of Invention

The present invention provides an AR-15512 composition comprising AR-15512 and a medium chain triglyceride.

In some embodiments of the invention, the composition further comprises a surfactant.

In some embodiments of the invention, the weight ratio of medium chain triglycerides to surfactant in the composition is 1:1 to 1:20.

In some embodiments of the invention, the weight ratio of medium chain triglycerides to surfactant of the composition is preferably 1:4 to 1:10.

In some embodiments of the invention, the weight ratio of medium chain triglycerides to surfactant of the composition is further preferably 1:4, 1:6 or 1:10.

In some embodiments of the invention, the AR-15512 is present in an amount of 0.001% w/w to 0.05% w/w based on the weight of the composition.

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

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

In some embodiments of the invention, the amount of AR-15512 is most preferably 0.003%, 0.005%, 0.006%, 0.01%, 0.015%, 0.03% or 0.032% w/w based on the amount of the composition. As exemplary illustrations, 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、0.027％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 are possible.

In some embodiments of the invention, the medium chain triglycerides are present in an amount of 0.01% w/w to 2% w/w based on the weight of the composition.

In some embodiments of the invention, the medium chain triglycerides are preferably present in an amount of 0.05% w/w to 1.7% w/w based on the weight of the composition.

In some embodiments of the invention, the medium chain triglycerides are more preferably present in an amount of 0.1% w/w to 1.5% w/w based on the weight of the composition.

In some embodiments of the invention, the amount of 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 weight of the composition. As exemplary illustrations, 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、0.55％w/w、0.56％w/w、0.57％w/w、0.58％w/w、0.59％w/w、0.6％w/w、0.61％w/w、0.62％w/w、0.63％w/w、0.64％w/w、0.65％w/w、0.66％w/w、0.67％w/w、0.68％w/w、0.69％w/w、0.7％w/w、0.71％w/w、0.72％w/w、0.73％w/w、0.74％w/w、0.75％w/w、0.76％w/w、0.77％w/w、0.78％w/w、0.79％w/w、0.8％w/w、0.81％w/w、0.82％w/w、0.83％w/w、0.84％w/w、0.85％w/w、0.86％w/w、0.87％w/w、0.88％w/w、0.89％w/w、0.9％w/w、0.91％w/w、0.92％w/w、0.93％w/w、0.94％w/w、0.95％w/w、0.96％w/w、0.97％w/w、0.98％w/w、0.99％w/w、1％w/w、1.01％w/w、1.02％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 are possible.

In some embodiments of the invention, the surfactant of the composition is selected from polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, 15-hydroxystearic acid polyethylene glycol ester, 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.

In some embodiments of the invention, the amount of 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, 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 weight of the composition. As an exemplary illustration, 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、0.25％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 is possible.

In some embodiments of the invention, the composition may further comprise a cosurfactant, a thickener, a pH adjustor, an osmotic pressure adjustor, or water, or a combination of two, three, or more thereof.

In some embodiments of the 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, based on the weight of the composition.

In some embodiments of the invention, the amount of 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, 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 weight of the composition. As exemplary illustrations, 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 are possible.

In some embodiments of the invention, the thickener of the composition is selected from methylcellulose, hydroxyethylcellulose, chitosan, hydroxypropyl chitosan, glycerol, polyvinylpyrrolidone or hydroxypropyl methylcellulose, or a combination of two, three or more thereof, preferably hydroxypropyl methylcellulose.

In some embodiments of the invention, the thickener is present in an amount of 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, most preferably 0.5% w/w, based on the weight of the composition. As an exemplary illustration, it may 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.

In some embodiments of the invention, the pH adjusting agent 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.

In some embodiments of the invention, the pH adjuster is present in an amount of 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, most preferably 0.32% w/w, 0.72% w/w or 1.04% w/w, based on the weight of the composition.

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.

In some embodiments of the invention, the pH of the composition is from 6 to 8.

In some embodiments of the invention, the osmolality adjusting agent of the composition is selected from sodium chloride, glycerol, sorbitol or mannitol, or a combination of two, three or more thereof, preferably sodium chloride.

In some embodiments of the invention, the osmolality adjusting agent is present in an amount of 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, most preferably 0.35% w/w or 0.38% w/w, based on the weight of the composition. As an exemplary illustration, it may 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.

In some aspects of the invention, the composition comprises AR-155120.003% w/w to 0.035% w/w, medium chain triglycerides 0.1% w/w to 1.5% w/w, surfactant 0.05% w/w to 5% w/w, and water in balance.

In some aspects of the invention, the composition comprises AR-155120.003% 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 modifiers 0.3% w/w to 1.1% w/w, osmotic pressure modifiers 0.3% w/w to 0.4% w/w, and balance water, based on the weight of the composition.

In some embodiments of the invention, the composition comprises AR-155120.003% 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 water, based on the weight of the composition.

In some aspects of the invention, the composition comprises AR-155120.003% 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 modifiers 0.3% w/w to 1.1% w/w, osmotic pressure modifiers 0.3% w/w to 0.4% w/w, and water in balance.

In some embodiments of the invention, the composition comprises AR-155120.003% 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, the balance being water, or

Comprises AR-15512.006% w/w, medium chain triglyceride 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 water as the rest

Comprises AR-15512.015% w/w, medium chain triglyceride 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 water as the rest

Comprises AR-15512.015% w/w, medium chain triglyceride 0.5% w/w, polyoxyethylene 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 water for the rest.

In some aspects of the invention, the composition comprises AR-155120.003% w/w to 0.035% w/w, medium chain triglycerides 0.1% w/w to 1.5% w/w, surfactant 0.05% w/w to 5% w/w, co-surfactant 0.08% w/w to 1.5% w/w, thickener 0.25% w/w to 0.5% w/w, pH regulator 0.3% w/w to 1.1% w/w, osmotic pressure regulator 0.3% w/w to 0.4% w/w, and water in balance.

In some embodiments of the invention, the composition comprises AR-155120.003% w/w, medium chain triglycerides 0.265% w/w, polyoxyethylene 40 hydrogenated castor oil 0.53% w/w, PEG 400.088% 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 water, based on the weight of the composition.

In some embodiments of the invention, the compositions may be developed directly or in combination with other adjuvants or devices into the form of preparations, especially ophthalmic preparations, which can be carried out by the skilled person, such as eye drops, ophthalmic gels, eye ointments, ophthalmic eyelid wipes, nasal drops, nasal sprays, etc.

In some embodiments of the invention, the compositions are used to treat ocular disorders such as dry eye, meibomian gland dysfunction, allergic conjunctivitis, ocular pain, and the like.

Definition and description

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

Drawings

FIG. 1 is a graph of drug concentration versus time for eyelid margin tissue;

FIG. 2 is a graph of corneal drug concentration versus time;

FIG. 3 shows tear secretion in scopolamine-induced mouse dry eye model;

FIG. 4 Scopolamine-induced mouse dry eye model corneal fluorescent staining score.

Detailed Description

The invention relates to a composition containing AR-15512, which is used for treating eye diseases, wherein the composition can be developed into preparation types which can be realized by technicians such as eye drops, eye gel, eye ointment, eye eyelid wipes, nasal drops, nasal spray and the like directly or in combination with other auxiliary materials or devices, and the diseases are selected from xerophthalmia, ocular pain, meibomian gland dysfunction, allergic conjunctivitis and the like, and especially xerophthalmia.

The invention relates to a special oil-in-water microemulsion preparation, which comprises an oil phase, one or more surfactants and a water phase, wherein the oil phase and the surfactants or cosurfactants together play a role in dissolving medicines, and simultaneously form a stable preparation system with other components so as to improve the physical stability of the preparation. Once the special microemulsion preparation is formed, the special microemulsion preparation has transparent or semitransparent appearance, small and uniform particle size and stable thermodynamic performance, and can obviously improve the solubility of AR-15512 and the stability of the preparation. Furthermore, the applicant has surprisingly found that the particular oil-in-water microemulsion eye drops prepared according to the invention have a higher exposure in the anterior ocular segment to the absorption of the ophthalmic active ingredient, in particular in the blepharum tissue (target site of TRPM8 receptor), and that the composition has been found to increase the bioavailability of AR-15512 in the blepharum tissue of the eye.

The microemulsion is used as a novel nano drug-carrying system, and the optical performance of the microemulsion can be visually verified through the Tyndall effect. When the incident light passes through the microemulsion system, the nano liquid drops in the disperse phase can cause the Rayleigh scattering phenomenon of the light, and obvious light paths are formed in the vertical observation direction.

The structural characteristics of the microemulsion are shown to be small in particle size, excellent in dispersion uniformity and outstanding in thermodynamic stability. These properties can be precisely characterized by Dynamic Light Scattering (DLS), where the particle size distribution index (PDI) is a key parameter for evaluating the monodispersity of the system. The invention uses Zetasizer Nano Zen3700 to carry out particle size measurement on the prepared examples under the condition of 25 ℃.

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

Experimental example 1 equilibrium solubility of AR-15512 in different solvents

The equilibrium solubility of AR-15512 in different solvents was examined. The solubility detection method comprises adding excessive AR-15512 into different solvents, standing at room temperature in constant temperature oscillation, centrifuging after 3d to obtain supernatant, and detecting AR-15512 content by high performance liquid chromatography. The equilibrium solubility of AR-15512 in different solvents and the results are shown in Table 1.

TABLE 1 equilibrium solubility of AR-15512 in different solvents

Solvent(s)	Solubility (mg/g)
		Medium chain triglycerides	1.59
Castor oil	0.53
		5% Polyoxyethylene 35 castor oil water solution	0.14
Polyethylene glycol 400	1.67
		Propylene glycol	1.66
Tween 80	0.48

Examples 1 to 9

The effect of different surfactant types on microemulsion formation was studied by selecting medium chain triglycerides as the oil phase, and polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, 15-hydroxystearic acid polyethylene glycol ester, tween 80, tween 20, nonoxynol-9, poloxamer 188, polyvinyl alcohol, carbomer TR-1 as the surfactants, respectively, prepared according to the weight ratio (w/w) of the prescription listed in table 2, by the following specific preparation methods:

(1) Respectively weighing AR-15512, medium chain triglyceride and different kinds of surfactants according to the prescription amount, and stirring at 55 ℃ to dissolve the medicine;

(2) Heating water for injection to the same temperature to obtain a water phase;

(3) Adding the prescribed amount of water for injection into the step (1), stirring and mixing uniformly, cooling to room temperature, and observing the appearance of the sample.

TABLE 2 surfactant species screening

The results of the various surfactant studies are shown in Table 2. It can be seen that clear light blue liquid can be formed when the oil phase is medium chain triglyceride and the surfactant is polyoxyethylene 35 castor oil, and other attempted surfactants can be layered or formed into milky liquid when prepared according to the conventional dosage of the preparation, so that stable preparation is difficult to form, and the polyoxyethylene 35 castor oil has better potential for forming stable microemulsion compared with other surfactants.

Examples 10 to 13

The influence of different oil phase types on the formation of the microemulsion was studied, namely, polyoxyethylene 35 castor oil was selected as a surfactant, medium chain triglyceride, castor oil, soybean oil, olive oil and propylene glycol laurate type 1 were respectively selected as oil phases, the microemulsion preparation was carried out according to the prescribed weight ratio (w/w) in table 3, and the oil phase types were screened. The preparation method comprises the following steps:

(1) Respectively weighing AR-15512, different oil phases and polyoxyethylene 35 castor oil according to the prescription amount, and stirring at 55 ℃ to dissolve the medicine;

(2) Heating water for injection to the same temperature to obtain a water phase;

(3) Adding the prescribed amount of water for injection into the step (1), stirring and mixing uniformly, cooling to room temperature, and observing the appearance of the sample.

Table 3 investigation of oil phase species

The results of the different oil phase investigation are shown in Table 3. It can be seen that when the oil phase is medium chain triglycerides or castor oil and the surfactant is polyoxyethylated 35 castor oil, a clear pale blue liquid is formed, while none of the other tested oil phases formed stable formulations under the same conditions. From the solubility data, it is clear that medium chain triglycerides have better solubility for AR-15512 than castor oil, so medium chain triglycerides are preferred as the oil phase.

Examples 14 to 20

The effect of different oil phase amounts on the formation of the microemulsion was examined, the specification of the immobilized AR-15512 was 0.003%, the amount of the surfactant polyoxyethylene 35 castor oil was 2%, and the amount of chain triglycerides in the oil phase was examined, according to the weight ratio (w/w) of the formulation shown in Table 4, the preparation method was as follows:

(1) Weighing AR-15512, medium chain triglyceride and polyoxyethylene 35 castor oil according to the prescription, and stirring at 55deg.C to dissolve the medicine;

(2) Weighing anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate and sodium chloride with prescription amount, adding appropriate amount of water for injection, stirring to dissolve, and heating to the same temperature;

(3) Weighing a prescription amount of hypromellose, adding a proper amount of water for injection, heating and stirring until the hypromellose is dissolved, and cooling to room temperature to obtain a hypromellose solution;

(4) Adding the components (2) into the components (1), stirring and mixing uniformly, cooling to room temperature, adding the components (3), supplementing the components to the whole volume by using water for injection, stirring and mixing uniformly, and filtering and sterilizing by using a microporous filter membrane with the thickness of 0.22 mu m.

Table 4 oil phase usage investigation

As shown in Table 4, the medium chain triglycerides were used in an amount of 0.1% to 1.2% to form stable microemulsions, whereas the medium chain triglycerides were used in an amount of 1.5% to give a larger PDI value and a non-uniform particle size distribution.

Examples 21 to 26

Investigation of the amount of surfactant, wherein the fixed AR-15512 specification is 0.003%, the medium chain triglyceride amount is 0.50%, the amount of polyoxyethylene 35 castor oil as a surfactant is selected, and the medicines and auxiliary materials are weighed according to the weight ratio (w/w) of the prescription in Table 5, and examples 21-26 are prepared by adopting the same preparation method as examples 14-20.

TABLE 5 examination of surfactant usage

As is clear from the results of Table 5, examples 21 to 26 show that the clear and transparent microemulsion can be prepared when the fixed AR-15512 specification is 0.003%, the medium chain triglyceride is 0.50% and the polyoxyethylene 35 castor oil is 0.50% -5.00%, the larger the ratio of the polyoxyethylene 35 castor oil to the medium chain triglyceride is, the smaller the obtained particle size is, but the amount of the polyoxyethylene 35 castor oil is required to be controlled within the safe application range of auxiliary materials, and the more preferable polyoxyethylene 35 castor oil is 2.00% -3.00% in consideration of the safety of the auxiliary materials and the particle size control.

Examples 27 to 31

The effect of different thickeners on microemulsion formation was examined and the specific formulation composition is shown in table 6.

TABLE 6 class selection of thickeners

As can be seen from the results in Table 6, the prescription prepared from sodium carboxymethylcellulose with the prescription amount has excessive viscosity, the solution is relatively viscous, the PDI value of the particle size detection is larger, which indicates that the sodium carboxymethylcellulose is used as a thickener to easily cause aggregation among particles, thus causing uneven particle size distribution, and the PDI value of the particle size detection of the embodiment prepared from hydroxypropyl methylcellulose (viscosity 4000 mpa.s), hydroxypropyl chitosan, glycerol and polyvinylpyrrolidone used as the thickener is smaller, thus showing even particle size distribution, wherein the prescription prepared from the hydroxypropyl methylcellulose used as the thickener has moderate viscosity, and is beneficial to prolonging the retention time of the medicament on the ocular surface.

Comparative examples 1 to 5

The stability of formulations made with reduced formulation components was examined. As shown in table 7, the following formulations were prepared with reduced surfactant, oil phase, and single co-surfactant co-solvents, respectively.

Table 7 comparative examples 1-5 recipe composition and preparation

Comparative examples 1 and 2 show that the oil phase of the prescription dose alone cannot dissolve the medicine at room temperature, the surfactant of the prescription dose alone, and the medicine is separated out after the placement, and the preparation results of comparative examples 3-5 show that the cosurfactants of the prescription dose alone or in combination cannot dissolve the medicine and cannot obtain clear and transparent preparations. Only when the oil phase and the surfactant are mixed for use, a clear and transparent preparation can be prepared under the dosage of the prescription.

Examples 32 to 39

The solubilization capacity of the microemulsion system formed by medium chain triglycerides and polyoxyethylated 35 castor oil on AR-15512 was examined. As shown in table 8, the formulation was composed as follows in weight percent. The preparation methods of examples 32 to 39 are the same as examples 14 to 20.

Table 8 AR-15512 formulations of different specifications

As shown in Table 8, the formulation of different drug carrying capacities can be obtained by adjusting the ratio of medium chain triglycerides to polyoxyethylene 35 castor oil, and when the AR-15512 specification is lower than 0.015%, 2% polyoxyethylene 35 castor oil and 0.5% medium chain triglycerides can ensure the dissolution state of the drug in the whole microemulsion system, and when the AR-15512 specification reaches 0.030%, the formulation ratio of medium chain triglycerides needs to be increased, and a cosurfactant needs to be added to maintain the stable state of the microemulsion. When the specification reaches 0.030%, the case that the drug is precipitated in the room temperature standing process under the condition that no cosurfactant is added in the embodiment 37, and the solubility data of the drug show that the oil phase or the surfactant or the cosurfactant with the single prescription dose can not support the dissolution of the drug, and the embodiment 38 shows that when the specification reaches 0.030%, the dissolution of the drug needs to be realized by the oil phase, the surfactant and the cosurfactant together, and the drug is simultaneously distributed in the oil phase and the oil-water interface layer of the microemulsion and can be distributed in a hydrophobic area in a micelle-like or similar dissolution-assisting form, so that a special stable and uniform solution system is formed. By combining examples 14-26 and examples 32-39, it is found that a stable microemulsion formula can be obtained by combining the formula weight ratio of medium chain triglycerides to polyoxyethylene 35 castor oil between 1:1-1:20, and the formula weight ratio of medium chain triglycerides to polyoxyethylene 35 castor oil is preferably 1:4-1:10, more preferably 1:4, 1:6 and 1:10, based on factors such as drug solubility, particle size and safe and reasonable usage of auxiliary materials.

Examples 40 to 44

An AR-15512 preparation based on polyoxyethylene 40 hydrogenated castor oil, the prescription composition of which is shown in Table 9, and a preparation method of the AR-15512 composition, comprising the following steps:

(1) Weighing AR-15512, medium chain triglyceride, polyoxyethylene 40 hydrogenated castor oil and PEG400 according to the prescription amount, and stirring at 55 ℃ to dissolve the medicine;

(2) Weighing anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate and sodium chloride with a prescription amount, adding a proper amount of water for injection, stirring until the anhydrous disodium hydrogen phosphate, the sodium dihydrogen phosphate and the sodium chloride are dissolved, and heating the mixture to the same temperature;

(3) Adding the component (2) into the component (1), stirring and mixing uniformly, supplementing the mixture to the whole volume by using water for injection with the same temperature, cooling the mixture to room temperature, and filtering and sterilizing the mixture by using a microporous filter membrane with the thickness of 0.22 mu m.

TABLE 9 AR-15512 compositions based on polyoxyethylene 40 hydrogenated castor oil

As is clear from the results in Table 9, stable AR-15512 compositions were also prepared using polyoxyethylene 40 hydrogenated castor oil as a surfactant, and the prepared microemulsions were satisfactory in particle size and particle size distribution. However, the maximum safe dosage of the auxiliary materials is limited, and the maximum safe dosage of the polyoxyethylene 40 hydrogenated castor oil is lower than that of the polyoxyethylene 35 castor oil.

Experimental example 2 investigation of stability of AR-15512 microemulsion formulations

The stability of the AR-15512 microemulsion was examined based on the efficacy of the drug, as shown in Table 10, using examples 24, 27 and examples 40 to 42 as examples.

Temperature test, sampling at 60 deg.C for 0 and 30d, and examining various indexes of the preparation.

And (3) light test, namely placing the sample in a light stability test box, sampling at 0 and 10d under the condition that the illuminance is 4500 lx+/-500 lx, and examining each index of the preparation.

The investigation indexes comprise appearance, pH, osmotic pressure, content and particle size of the preparation.

TABLE 10 stability test results

The stability experiment result shows that the prepared microemulsion can keep stable under the conditions of high temperature of 60 ℃ and illumination, and the microemulsion formed by the microemulsion, which is prepared by taking polyoxyethylene 35 castor oil or polyoxyethylene 40 hydrogenated castor oil as a surfactant, has the characteristic of thermodynamic stability.

Comparative example 6

An AR-15512 ophthalmic composition having the prescription composition as shown in table 11, a method of preparing the AR-15512 ophthalmic composition comprising the steps of:

(1) Weighing AR-15512 and polyoxyethylene 35 castor oil according to the prescription, and stirring to dissolve the medicine under the condition of heating to 55 ℃;

(2) Weighing sodium dihydrogen phosphate monohydrate and sodium chloride with a prescription amount, adding a proper amount of water for injection, stirring until the sodium dihydrogen phosphate monohydrate and the sodium chloride are dissolved, and heating to the same temperature;

(3) Weighing a prescription amount of hypromellose, adding a proper amount of water for injection, heating and stirring until the hypromellose is dissolved, and cooling to room temperature to obtain a hypromellose solution;

(4) Adding the component (2) into the component (1), stirring and mixing uniformly, adding the prescription residual amount of water for injection at the same temperature, cooling to room temperature, adding the component (3), stirring and mixing uniformly, and filtering and sterilizing by using a microporous filter membrane with the thickness of 0.22 mu m.

Table 11 comparative example 6 recipe composition

Experimental example 3 pharmacokinetic study of rabbit eye tissue

1. Test purpose:

eye drop administration of the formulations of the invention was studied in rabbits with New Zealand rabbits as the subject animals, and PK study in the upper and lower eyelid rims and cornea of the rabbits.

2. The test process comprises the following steps:

20 healthy New Zealand rabbits, 2-4kg, were randomly divided into 2 groups, comparative example 6 group, example 27 group, each 10. After combination anesthesia of dexmedetomidine hydrochloride and sultai 50, the upper and lower eyelid margins and the cornea were collected at 0.25h, 1h, 2h, 6h and 12h after administration, respectively. The surface of the tissue at each time point is cleaned by normal saline before tissue collection, then the upper eyelid margin, the lower eyelid margin and the cornea of the left eye and the right eye are respectively collected, and the tissue is cleaned by normal saline for 1 time after collection. And stored in an ultra-low temperature refrigerator as soon as possible until the sample is analyzed.

3. Sample detection and analysis

An LC-MS/MS analysis method for measuring the drug original concentration in the eyelid margin and cornea of the rabbit is established and is used for measuring the concentration of the biological sample obtained in the experiment, and the pretreatment process of the biological sample is required to be carried out on an ice-water bath. The results were calculated using non-compartmental model using Winnolin software.

4. Test results:

TABLE 12 pharmacokinetic parameters of different formulations on upper and lower blepharos of rabbits

Grouping	Concentration of	Tmax(h)	Cmax(ng/g)	AUC0-12h(h*ng/g)
					Comparative example 6	0.003%	1	107	695
Example 27	0.003%	2	131	889

TABLE 13 pharmacokinetic parameters of different formulations on rabbit cornea

Grouping	Concentration of	Tmax(h)	Cmax(ng/g)	AUC0-12h(h*ng/g)
					Comparative example 6	0.003%	0.25	93.4	189
Example 27	0.003%	0.25	89.1	195

5. Conclusion of the test:

The study showed (as shown in table 12, fig. 1) that the example 27 set was able to increase the drug exposure concentration in the upper and lower eyelid margins while delaying the peak time by 1h later compared to the comparative example 6 set, demonstrating that the microemulsion formulation of the example 27 set had a longer residence time in the ocular eyelid margin tissue. The 1.28-fold increase in lid tissue AUC_0-12h over the comparative example 6 group demonstrates that the composition of the invention can increase bioavailability in AR-15512 ocular lid tissue.

Pharmacokinetic parameters of the cornea indicated (as shown in table 13, fig. 2), the exposure of example 27 group at cornea was comparable to that of the ratio 6 group. In general, group 27 enhances the bioavailability of AR-15512 at TRPM8 receptor target tissues, especially at blephar tissues.

Experimental example 4 pharmacodynamic evaluation of scopolamine-induced mouse Dry eye model

1. Test purpose:

The present study investigated the therapeutic effect of different formulations on the model of C57BL/6 (J) mouse dry eye induced by the hind limb subcutaneous injection of scopolamine hydrobromide.

2. The test process comprises the following steps:

(1) Molding, namely, injecting scopolamine hydrobromide solution 5mg/mL subcutaneously on the hind limbs of the two sides of the D1 in an alternating manner, injecting sodium chloride injection 0.9% in equal volume subcutaneously on the hind limbs of the two sides of the negative control group, wherein the interval between each injection is about 3 hours, and the interval between each injection is 0.1 mL/time, and the injection is continuous for 17 days. Multiple sequential injections at the same injection site are to be avoided.

(2) Grouping the model animals were randomly and evenly divided into 5 groups, namely, model control group, vehicle control group, comparative example 6 group, example 33 group, example 36 group, 6 animals of each group, according to the tear secretion amount and cornea fluorescence staining score by performing binocular tear secretion amount measurement and cornea fluorescence staining score at D10.

(3) Administration to animals of each group was carried out by eye drop administration to eyes at D11, 3. Mu.L/eye/time, 4 times/day, about 3 hours at intervals, 7 days total, and 0.9% sodium chloride injection was administered to eyes of animals of the negative control group and the model control group in equal volumes, and the vehicle control group was a blank prescription of example 36 without AR-15512.

Note that the scopolamine hydrobromide solution was administered by eye drop immediately after daily subcutaneous injection.

(4) The index detection comprises measuring the two-eye tear secretion and scoring the cornea fluorescence staining of the animal at D0, wherein the interval between the two index detection is about 3 hours, measuring the two-eye tear secretion and scoring the cornea fluorescence staining after the first and second molding of D10, measuring the two-eye tear secretion about 30 minutes after the first administration of D14 and D17, and scoring the cornea fluorescence staining about 30 minutes after the second administration.

(5) Data statistics data were analyzed statistically using GraphPad prism8.0, and the data obtained were expressed in terms of means+ -SD or means+ -SEM, and comparisons between sets of data were made using One-way ANOVA, and comparisons between sets of data were made using t-test. Differences of P <0.05 were statistically significant (^*P<0.05,^** P <0.01, ns=no significance).

3. Test results

Table 14 Effect of the formulations on tear secretion in Dry eye model mice (mean+ -SD)

Note that^#P<0.05,^## P <0.01 compared to the negative control and^* P <0.05 compared to the vehicle control.

As shown in table 14, the data of D10 to D17 lacrimal secretion amounts showed that the model control group had a significant difference (^* P < 0.01) from the negative control group, indicating that the model modeling was successful. According to the results of each group at the administration end point D17 (FIG. 3), comparative example 6 showed an increase in the amount of lacrimal secretion compared to the model control group and the vehicle control group, indicating that AR-15512 has the effect of promoting lacrimal secretion. The tear secretion amounts of the group of example 33 and the group of example 36 are higher than those of the group of comparative example 6, which shows that the improvement of the AR-15512 specification can play a role in enhancing the effect of AR-15512 on promoting tear secretion, and the group of example 36 is remarkably different in statistical significance from the vehicle control group (^* P < 0.05).

Table 15 effect of formulation on the score of fluorescent staining of cornea of Dry eye model mice (mean+ -SD)

Note that^#P<0.05,^## P <0.01 compared to the negative control,^&P<0.05,^&& P <0.01 compared to the model control, and^*P<0.05,^** P <0.01 compared to the vehicle control.

As shown in table 15, the results of the corneal fluorescence staining scores D10 to D17 (fig. 4) showed that the score values of the model control group were significantly higher than those of the negative control group, and the model was successfully modeled as a result of significant difference (P < 0.01). From comparison of the data of each group at the end of dose D17, the scores of example 33 and example 36 were significantly reduced compared to the model control group and had a very significant difference (P < 0.01), while the scores of comparative example 6 were reduced to some extent compared to the model control group but were not significantly different, in addition, the scores of example 33 and example 36 were significantly reduced compared to the vehicle control group (P <0.01; P < 0.05), while the scores of comparative example 6 were not significantly different, indicating that the improvement of AR-15512 to 0.006% and 0.015% both improved the dry eye symptom index of the corneal fluorescent staining score.

The invention adopts a special microemulsion preparation to improve the solubility of AR-15512 in aqueous solution, and surprisingly discovers that AR-15512 can not only improve the tear secretion index of a scopolamine induced mouse xerophthalmia model, but also reduce the cornea fluorescence staining score of the model. And demonstrated a certain improvement in both tear secretion and corneal fluorescence staining scores compared to 0.003% when the AR-15512 gauge was increased to 0.006% and 0.015%.

It should be noted that the above embodiments are merely for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the above embodiments, it should be understood by those skilled in the art that the technical solution described in the above embodiments may be modified or some or all of the technical features may be equivalently replaced, and these modifications or substitutions do not make the essence of the corresponding technical solution deviate from the scope of the technical solution of the embodiments of the present invention.

Claims (34)

1. An AR-15512 composition, comprising AR-15512 and a medium chain triglyceride.

2. The composition of claim 1, wherein the composition further comprises a surfactant.

3. The composition according to claim 1 or 2, wherein the weight ratio of medium chain triglycerides to surfactant is 1:1 to 1:20.

4. A composition according to claim 3, wherein the weight ratio of medium chain triglycerides to surfactant of the composition is preferably 1:4 to 1:10.

5. The composition according to claim 4, characterized in that the weight ratio of medium chain triglycerides to surfactant of the composition is further preferably 1:4, 1:6 or 1:10.

6. The composition of claim 1, wherein the amount of AR-15512 is 0.001% w/w to 0.05% w/w based on the amount of composition.

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

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

9. The composition according to claim 8, wherein 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 composition.

10. The composition of claim 1, wherein the amount of medium chain triglycerides in the composition is 0.01% w/w to 2% w/w based on the amount of composition.

11. Composition according to claim 10, wherein the amount of medium chain triglycerides is preferably 0.05% w/w to 1.7% w/w based on the amount of composition.

12. Composition according to claim 11, wherein the amount of medium chain triglycerides in the composition is more preferably 0.1% w/w to 1.5% w/w based on the amount of composition.

13. The composition according to claim 12, wherein the amount of medium chain triglycerides in the composition 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 composition.

14. The composition of claim 2, wherein the surfactant is selected from polyoxyl 35 castor oil, polyoxyl 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, wherein the amount of surfactant in the composition 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, 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 of claim 1 or 2, wherein the composition further comprises a cosurfactant, a thickener, a pH adjuster, an osmotic pressure adjuster, or water, or a combination of two, three, or more thereof.

17. The composition of claim 16, wherein the co-surfactant 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, wherein the amount of co-surfactant in the composition 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, 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 composition.

19. The composition according to claim 16, wherein the thickener is selected from methylcellulose, hydroxyethylcellulose, chitosan, hydroxypropyl chitosan, glycerol, polyvinylpyrrolidone or hydroxypropyl methylcellulose, or a combination of two, three or more thereof, preferably hydroxypropyl methylcellulose.

20. Composition according to claim 16, wherein the thickener is present in the composition in an amount of 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, most preferably 0.5% w/w, based on the weight of the composition.

21. The composition according to claim 16, wherein the pH adjustor 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, wherein the amount of pH modifier 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, most preferably 0.32% w/w, 0.72% w/w or 1.04% w/w.

23. The composition of claim 16, wherein the pH of the composition is from 6 to 8.

24. The composition according to claim 16, wherein the osmolality adjusting agent 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, wherein the amount of osmolality adjusting agent 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, most preferably 0.35% w/w or 0.38% w/w, based on the amount of composition.

26. The composition of any one of claims 1-25, wherein the composition comprises AR-15512 0.003% w/w to 0.035% w/w, medium chain triglycerides 0.1% w/w to 1.5% w/w, surfactant 0.05% w/w to 5% w/w, and water as the remainder, based on the weight of the composition.

27. The composition of any one of claims 1-25, wherein the composition comprises 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 modifiers 0.3% w/w to 1.1% w/w, osmotic pressure modifiers 0.3% w/w to 0.4% w/w, and balance water, based on the weight of the composition.

28. The composition of claim 27, wherein the composition comprises AR-15512.003% 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 balance water, based on the weight of the composition.

29. The composition of any one of claims 1-25, wherein the composition comprises 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 modifiers 0.3% w/w to 1.1% w/w, osmotic pressure modifiers 0.3% w/w to 0.4% w/w, and balance water, based on the weight of the composition.

30. The composition of claim 29, wherein the composition comprises AR-15512.003% 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, the balance being water, or

Comprises AR-15512.006% w/w, medium chain triglyceride 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 water as the rest

Comprises AR-15512.015% w/w, medium chain triglyceride 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 water as the rest

Comprises AR-15512.015% w/w, medium chain triglyceride 0.5% w/w, polyoxyethylene 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 water for the rest.

31. The composition of any one of claims 1-25, wherein the composition comprises AR-15512 0.003% w/w to 0.035% w/w, medium chain triglycerides 0.1% w/w to 1.5% w/w, surfactant 0.05% w/w to 5% w/w, co-surfactant 0.08% w/w to 1.5% w/w, thickener 0.25% w/w to 0.5% w/w, pH adjuster 0.3% w/w to 1.1% w/w, osmotic pressure adjuster 0.3% w/w to 0.4% w/w, and balance water, based on the weight of the composition.

32. The composition of claim 31, wherein the composition comprises AR-15512.003% w/w, medium chain triglycerides 0.265% w/w, polyoxyethylene 40 hydrogenated castor oil 0.53% w/w, PEG 400.088% w/w, hydroxypropyl methylcellulose 0.5% w/w, anhydrous disodium phosphate 0.72% w/w, sodium dihydrogen phosphate monohydrate 0.32% w/w, sodium chloride 0.38% w/w, and the balance water, based on the weight of the composition.

33. The composition of any one of claims 1-32, wherein the composition is an eye drop, an ophthalmic gel, an eye cream, an ophthalmic eyelid wipe, a nasal drop, or a nasal spray.

34. The composition according to any one of claims 1 to 33, wherein the composition is used for the preparation of a medicament for the treatment of ocular diseases such as dry eye, meibomian gland dysfunction, allergic conjunctivitis, ocular pain, etc.