Emulsion containing nitrogenous heterocyclic compound and preparation method therefor

Abstract

An emulsion containing a nitrogenous heterocyclic compound and a preparation method therefor. The emulsion comprises an active ingredient, vegetable oil, an emulsifier, hydroxypropyl cellulose, and water. The emulsion not only exhibits good efficacy in alleviating xerophthalmia, but also has relatively good homogeneity and stability, which helps ensure the effectiveness and safety of the drug during storage and use. Moreover, the ophthalmic emulsion composition can increase the retention time of the active ingredient in the eyes, improve the bioavailability of the drug, and reduce cytotoxicity and eye irritation.

Description

An emulsion containing a nitrogen-containing heterocyclic compound and its preparation method Technical Field

[0001] This invention belongs to the field of pharmaceutical compositions, and specifically relates to an emulsion containing a nitrogen-containing heterocyclic compound and a method for preparing the same. Background Technology

[0002] Dry eye has a high global prevalence, and moderate to severe dry eye requires anti-inflammatory treatment. Current treatments include corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and immunosuppressants. Currently, the main dry eye medications available domestically and internationally are artificial tears, corticosteroids, and cyclosporine. However, these medications only relieve dry eye symptoms and have a slow onset of action, and they also have certain side effects, failing to meet the huge demand in the dry eye medication market.

[0003] Therefore, given the large patient population suffering from dry eye disease, it is urgent to develop dry eye products with new medication mechanisms, faster onset of action, and better efficacy.

[0004] WO2021169958A1 discloses a dual-target inhibitor of Syk and VEGFR2, and discloses compounds relating to the following formula (II) or their medically acceptable salts. WO2022166548A1 further discloses the salt form, crystal form, and preparation method of pyrazole-substituted imidazo[1,2-a]quinoxaline derivatives, and their application in the preparation of drugs related to dual-target inhibitors of Syk and VEGFR2, and discloses the crystal form of compounds relating to the following formula (I).

[0005] The aforementioned molecules exhibit excellent target specificity and significant therapeutic and anti-inflammatory effects in animal dry eye models, with low biotoxicity, demonstrating promising potential for drug application. However, their high molecular structural stability leads to poor solubility in aqueous solutions, increasing the difficulty of forming effective drug formulations. Therefore, there is an urgent need to develop a formulation that can increase the solubility of these drugs or enable them to exert their therapeutic effects.

[0006] Summary of the Invention

[0007] The present invention first provides an ophthalmic emulsion composition comprising: i) an active ingredient, said active ingredient being a compound of formula (I) or a pharmaceutically acceptable salt thereof; ii) 15 w / v% to 25 w / v% of a vegetable oil, said vegetable oil being selected from one or more of soybean oil, corn oil, peanut oil, olive oil, castor oil, palm oil, coconut oil, rapeseed oil, sesame oil, and cottonseed oil; iii) 4 w / v% to 8 w / v% of an emulsifier; iv) 0.2 w / v% to 0.6 w / v% of hydroxypropyl cellulose; and v) water.

[0008] The present invention also provides a method for preparing the ophthalmic emulsion composition, comprising: mixing the active ingredient, vegetable oil, emulsifier, hydroxypropyl cellulose and water to obtain the ophthalmic emulsion composition.

[0009] The present invention also provides the use of the ophthalmic emulsion composition described herein in the prevention, treatment or relief of dry eye syndrome.

[0010] The present invention also provides the use of the ophthalmic emulsion composition described herein in the preparation of medicaments for the prevention, treatment or relief of dry eye syndrome.

[0011] The present invention also provides a medicine box containing a therapeutically effective amount of the ophthalmic emulsion composition, and illustrative material regarding the application of the ophthalmic emulsion composition to a patient suffering from dry eye syndrome.

[0012] This invention provides an ophthalmic emulsion composition comprising dual-target inhibitors of Syk and VEGFR2. This ophthalmic emulsion composition not only exhibits good efficacy in relieving dry eye syndrome but also demonstrates superior uniformity and stability, which helps ensure the efficacy and safety of the drug during storage and use. Simultaneously, this ophthalmic emulsion composition can prolong the residence time of the active ingredient in the eye, improve drug bioavailability, and reduce cytotoxicity and ocular irritation. Attached Figure Description

[0013] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0014] Figure 1 shows the HE staining (100×) results of the right eye of model group A♂01 in the experimental example of this invention.

[0015] Figure 2 shows the HE staining (100×) results of the right eye of the emulsion group B♀03 in the experimental example of this invention. Detailed Implementation

[0016] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the invention. Those skilled in the art can make various modifications and variations to the invention without departing from its scope or spirit. For example, features described or illustrated as part of one embodiment can be used in another embodiment to produce further embodiments.

[0017] Terminology Explanation

[0018] Unless otherwise stated, all terms used to disclose this invention (including technical and scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Further guidance is provided below for a better understanding of the teachings of this invention. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0019] The terms "and / or," "or / and," and "and / or" as used herein include any one of two or more of the related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or," "or / and," and "and / or," it should be understood that in this application, the technical solution undoubtedly includes technical solutions connected by "logical AND," and also undoubtedly includes technical solutions connected by "logical OR." For example, "A and / or B" includes three parallel solutions: A, B, and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, a technical solution that is connected by "logical OR"), as well as any and all combinations of A, B, C, and D, that is, combinations of any two or three of A, B, C, and D, and also combinations of all four of A, B, C, and D (that is, a technical solution that is connected by "logical AND").

[0020] The terms “containing,” “comprising,” and “including” as used in this invention are synonyms and are inclusive or open-ended, not excluding additional, uncited members, elements, or method steps.

[0021] In this invention, the numerical range represented by endpoints includes all numerical values ​​and fractions contained within that range, as well as the endpoints mentioned.

[0022] This invention relates to concentration values, which include fluctuations within a certain range. For example, fluctuations are allowed within a corresponding precision range. For instance, 2% may fluctuate within ±0.1%. For larger values ​​or values ​​that do not require overly precise control, even greater fluctuations are permitted. For example, 100mM may fluctuate within ranges of ±1%, ±2%, ±5%, etc. Regarding molecular weight, fluctuations of ±10% are allowed.

[0023] In this invention, the terms "multiple" or "various" are used unless otherwise specified, referring to a quantity of 2 or more.

[0024] In this invention, the technical features described in an open-ended manner include both closed-ended technical solutions composed of the listed features and open-ended technical solutions that include the listed features.

[0025] In this invention, terms such as "preferred," "better," "more suitable," and "ideal" are merely descriptions of more effective implementation methods or embodiments, and should be understood not to limit the scope of protection of this invention.

[0026] In this invention, "optionally," "optionally," "optionally," "optionally," "optionally," and "optional" mean that they are optional, that is, they are selected from either "with" or "without." If multiple "optional" or "optional" terms appear in a technical solution, unless otherwise specified and there are no contradictions or mutual constraints, then each "optional" or "optional" term is independent.

[0027] In this invention, the term "emulsion" refers to a colloidal dispersion involving two or more liquid immiscible (or substantially immiscible) phases in the form of droplets. One of the liquid phases is typically the dispersed phase, and the other is the continuous phase, wherein the dispersed phase is dispersed as multiple droplets within the continuous phase. Depending on the droplet size, the emulsion may be in the form of a macroemulsion, a microemulsion, or a nanoemulsion. If the continuous phase is an aqueous solution, the emulsion is an oil-in-water (o / w) emulsion; if the continuous phase is an oil, the emulsion is a water-in-oil (o / w) emulsion. Other examples of emulsions include oil-in-water-in-oil (o / w / o) emulsions, wherein the o / w / o emulsion comprises oil droplets contained within aqueous droplets dispersed in a continuous oil phase.

[0028] In this invention, the term "dry eye syndrome," also known as keratoconjunctivitis sicca, is a chronic ocular surface disease caused by a variety of factors. It mainly involves abnormalities in the quality, quantity, and dynamics of tears. These abnormalities lead to tear film instability or imbalance of the ocular surface microenvironment, and may be accompanied by ocular surface inflammation, tissue damage, and nerve abnormalities, thereby causing a variety of ocular discomfort symptoms and / or visual dysfunction.

[0029] Ophthalmic emulsion composition

[0030] The compound shown in Formula (I) (or its pharmaceutically acceptable salt) is a small molecule drug targeting tyrosine protein kinase. This compound inhibits the phosphorylation of spleen tyrosine kinase (Syk) / vascular endothelial growth factor receptor 2 (VEGFR-2), thereby inhibiting the release of various inflammatory cytokines and immune cell-mediated signal transduction, blocking the inflammatory cascade caused by the immune response. The main preclinical characteristics of this compound are its more significant target activity and better selectivity. At well-tolerated doses, its efficacy and improvement in inflammation are both significant. Eye drops containing this compound as the active ingredient have a large safety window, good animal tolerability, and no significant local irritation, supporting its development for clinical treatment of dry eye. Furthermore, preparing this compound as an emulsion can prolong the drug's residence time, improve its bioavailability, and reduce cytotoxicity and ocular irritation.

[0031] However, the compound exhibits poor solubility and stability in emulsions. Therefore, this invention further investigates this issue and first provides an ophthalmic emulsion composition comprising: i) an active ingredient, said active ingredient being a compound of formula (I) or a pharmaceutically acceptable salt thereof; ii) 15 w / v% to 25 w / v% of a vegetable oil selected from one or more of soybean oil, corn oil, peanut oil, olive oil, castor oil, palm oil, coconut oil, rapeseed oil, sesame oil, and cottonseed oil; iii) 4 w / v% to 8 w / v% of an emulsifier; iv) 0.2 w / v% to 0.6 w / v% of hydroxypropyl cellulose (HPMC); and v) water.

[0032] The present invention has found that the above-mentioned ophthalmic emulsion formulation can effectively dissolve the active ingredients, while also effectively increasing the electrostatic charge between molecules and on the surface of the emulsion droplets, and possessing appropriate surface tension. As a result, the stability and uniformity of the emulsion are significantly improved, and the obtained ophthalmic emulsion composition has good efficacy in treating dry eye syndrome.

[0033] In some preferred embodiments, the vegetable oil is present in the ophthalmic emulsion composition at a concentration of 18 w / v to 22 w / v.

[0034] As an example, in some specific embodiments, the content of the vegetable oil in the ophthalmic emulsion composition may be 15 w / v%, 16 w / v%, 17 w / v%, 18 w / v%, 19 w / v%, 20 w / v%, 21 w / v%, 22 w / v%, 23 w / v%, 24 w / v%, 25 w / v%, or any value in the range of 15 w / v% to 25 w / v%.

[0035] In some preferred embodiments, the emulsifier is present in the ophthalmic emulsion composition at a concentration of 6 w / v to 8 w / v.

[0036] As an example, in some specific embodiments, the content of the emulsifier in the ophthalmic emulsion composition may be 4.0 w / v%, 4.5 w / v%, 5.0 w / v%, 5.5 w / v%, 6.0 w / v%, 6.5 w / v%, 7.0 w / v%, 7.5 w / v%, 8 w / v%, or any value in the range of 4 w / v% to 8 w / v%.

[0037] In some preferred embodiments, the hydroxypropyl cellulose content in the ophthalmic emulsion composition is 0.3 w / v% to 0.5 w / v.

[0038] As an example, in some specific embodiments, the content of hydroxypropyl cellulose in the ophthalmic emulsion composition may be 0.2 w / v%, 0.3 w / v%, 0.4 w / v%, 0.5 w / v%, 0.6 w / v%, or any value in the range of 0.2 w / v% to 0.6 w / v%.

[0039] In specific implementations, the active ingredient mentioned in this invention may be the compound shown in formula (I), or a pharmaceutically acceptable salt thereof (such as hydrochloride, or the hydrate, maleate, or gentianate disclosed in WO2022166548A1, etc.). Furthermore, the compound mentioned in this invention or its pharmaceutically acceptable salt may also include different crystal forms (such as crystal forms A, B, C, D, and E disclosed in WO2022166548A1). As an example, in some specific embodiments, the active ingredient is crystal form A of the compound shown in formula (I) disclosed in WO2022166548A1.

[0040] In some embodiments, the content of the active ingredient is 0.1 w / v% to 2.0 w / v, more preferably 0.3 w / v% to 1.0 w / v.

[0041] As an example, in some specific embodiments, the content of the active ingredient in the ophthalmic emulsion composition may be 0.1 w / v%, 0.3 w / v%, 0.5 w / v%, 0.7 w / v%, 1.0 w / v%, 1.5 w / v%, 2.0 w / v%, or any value in the range of 0.1 w / v% to 2.0 w / v%.

[0042] In some preferred embodiments, the vegetable oil is castor oil. The present invention further discovers that the active ingredient exhibits superior solubility and stability in castor oil.

[0043] In some preferred embodiments, the emulsifier is selected from one or both of Span-80 and Tween-80. The present invention further discovers that, for the active ingredient, stable emulsions are more readily formed when Span-80 and Tween-80 are used.

[0044] In some further preferred embodiments, the emulsifier is a mixture of Span 80 and Tween 80 in a mass ratio of 2:2.5 to 3.5. This makes it easier to form an emulsion with better stability.

[0045] As an example, in some specific embodiments, the mass ratio of Span 80 to Tween 80 in the emulsifier can be 2:2.5; 2:2.8; 2:3.0; 2:3.2; 2:3.5; or any ratio within the range of 2:2.5 to 3.5.

[0046] In some specific embodiments, the water is selected from one or more of purified water, water for injection, deionized water, sterile water, distilled water, and reverse osmosis water.

[0047] In some preferred embodiments, the ophthalmic emulsion composition contains: i) 0.1 w / v% to 2.0 w / v% of an active ingredient, said active ingredient being a compound of formula (I) or a pharmaceutically acceptable salt thereof; ii) 15 w / v% to 25 w / v% of castor oil; iii) 4 w / v% to 8 w / v% of an emulsifier, said emulsifier being a mixture of Span 80 and Tween 80 in a mass ratio of 2:2.5 to 3.5; iv) 0.2 w / v% to 0.6 w / v% of hydroxypropyl cellulose; and v) water.

[0048] In some specific embodiments, the ophthalmic emulsion composition may also contain one or more of the following reagents: 1) Osmotic pressure regulators: such as glycerol, propylene glycol, sorbitol, mannitol, etc., to help maintain intraocular osmotic pressure balance; 2) pH regulators: such as lactic acid, acetic acid, citric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, or sodium bicarbonate, etc., to maintain a suitable pH value to ensure drug stability and reduce eye irritation; 3) Chelating agents: such as disodium edetate, to remove metal ions in the solution that may affect drug stability; 4) Antioxidants: such as ascorbic acid, isoascorbic acid, etc., to prevent the formulation from deteriorating due to oxidation caused by the presence of oxygen free radicals or free metals in the composition.

[0049] Those skilled in the art can combine the above-mentioned embodiments with common sense to obtain more embodiments of the ophthalmic emulsion composition of the present invention.

[0050] Preparation method

[0051] The present invention also provides a method for preparing the ophthalmic emulsion composition, comprising: mixing the active ingredient, vegetable oil, emulsifier, hydroxypropyl cellulose and water to obtain the ophthalmic emulsion composition.

[0052] In some embodiments, the mixing is performed using one or more methods selected from high-pressure homogenization, high-shear homogenization, and microfluidics.

[0053] In some embodiments, the preparation method includes: mixing the active ingredient, Span 80, hydroxypropyl cellulose and the vegetable oil at 60-80°C (more preferably 70±5°C) to obtain an oil phase; mixing Tween 80 and water at 60-80°C (more preferably 70±5°C) to obtain an aqueous phase; slowly adding the oil phase to the aqueous phase while stirring the mixture at 12000-14000 r / min, and bringing the volume to a final volume to obtain a pre-emulsion; and homogenizing the pre-emulsion under high pressure at 800-1200 bar to obtain the ophthalmic emulsion composition.

[0054] In some specific embodiments, the colostrum is homogenized under high pressure of 800-1200 bar 3-5 times to obtain the ophthalmic emulsion composition.

[0055] In some specific embodiments, the colostrum is first homogenized at 800-900 bar 1-3 times, and then homogenized at 1100-1200 bar 1-3 times to obtain the ophthalmic emulsion composition.

[0056] In some specific embodiments, the preparation method further includes: sterilizing the homogenized product after high-pressure homogenization to obtain the ophthalmic emulsion composition.

[0057] application

[0058] The present invention also provides the use of the ophthalmic emulsion composition in the prevention, treatment, or relief of dry eye syndrome. In other words, the present invention also provides a method for the prevention, treatment, or relief of dry eye syndrome, the method comprising: administering a therapeutically effective amount of the ophthalmic emulsion composition to a subject.

[0059] The present invention also provides the use of the ophthalmic emulsion composition described herein in the preparation of medicaments for the prevention, treatment or relief of dry eye syndrome.

[0060] In some embodiments, the ophthalmic emulsion composition is used for at least one of the following aspects: 1) prolonging tear film breakup time; 2) increasing tear secretion; 3) reducing conjunctivitis cell infiltration; and 4) promoting goblet cell repair.

[0061] In some embodiments, the ophthalmic emulsion composition is suitable for topical application to the eye of a subject.

[0062] In this invention, "topical application" means applying something locally to the surface of a tissue, such as the eye, particularly any external aspect of the eye that is usually accessible between the eyelids. Topical application to the eye is typically done via eye drops, ointments, or sprays.

[0063] In some embodiments, the ophthalmic emulsion composition is in the form of an eye drop solution. For example, the emulsion composition may be present in a rigid and / or squeeze-type bottle equipped with a fitting cap configured to function as a dropper. Human subjects may receive between 1 and 10 drops per day (e.g., 5 or 8 drops per day), and the dose may be repeated, for example, twice daily. The eye drops may be dispensed, for example, in 12 mL or 20 mL volumes per bottle.

[0064] In some embodiments, the ophthalmic emulsion composition may also be applied via a carrier medium, such as liquid drops, liquid lotion, gel, ointment, and spray, or a combination thereof.

[0065] In some embodiments, the topical application may also occur by injecting the ophthalmic emulsion composition via a device (such as a pump-catheter system / continuous or selective release device, contact lens, or a combination thereof). The ophthalmic emulsion composition may also be administered in an injectable form, for example, such that injecting the ophthalmic emulsion composition retro-orbital and / or where application involves intravitreal injection.

[0066] In this invention, the term "subject" refers to mammals such as humans, domestic animals (such as felines or canines), farm animals (e.g., cattle, horses, goats, sheep, and pigs), wild animals, or research animals (e.g., mice, rats, rabbits, goats, sheep, pigs, dogs, and cats, and bird species (such as chickens, turkeys, and songbirds)).

[0067] In some implementations, the subjects are humans.

[0068] The present invention also provides a medicine box containing a therapeutically effective amount of the ophthalmic emulsion composition, and illustrative material regarding the application of the ophthalmic emulsion composition to a patient suffering from dry eye syndrome.

[0069] In some embodiments, the illustrative material may include publications, charts, or any other medium of expression that can be used to convey the usefulness of the composition and its application. In some embodiments, the illustrative material may be attached to a container containing the emulsion composition of the present invention, or may otherwise be provided together with the container containing the composition. In some embodiments, the illustrative material may be provided separately, for example, by electronic transmission, such as by means of a computer (e.g., via email, or downloaded from a website).

[0070] In some embodiments, the kit also includes at least one adjuvant that can be used to prevent, treat or relieve dry eye syndrome.

[0071] Example

[0072] The embodiments of the present invention will be described in detail below with reference to examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. For experimental methods in the following embodiments where specific conditions are not specified, please refer to the guidelines given in this invention, or follow experimental manuals or conventional conditions in the art, or other experimental methods known in the art, or follow the conditions recommended by the manufacturer.

[0073] In the specific embodiments described below, the measurement parameters involving raw material components may have slight deviations within the weighing accuracy range unless otherwise specified. Temperature and time parameters are subject to acceptable deviations due to instrument testing accuracy or operational precision.

[0074] For ease of comparison, equal amounts of one active ingredient, the structure of which is shown in formula (I), are used in the following examples and comparative examples. This active ingredient and its dosage do not constitute a limitation on the scope of protection of this invention. Active ingredients within the scope defined by this invention, when applied to the ophthalmic emulsion composition, all exhibit the technical effects described above.

[0075] Example 1

[0076] This embodiment first provides an ophthalmic emulsion composition containing: 0.5 w / v% of the active ingredient, 20 w / v% of castor oil, 3.2 w / v% of Span 80, 4.8 w / v% of Tween 80, and 0.4 w / v% of hydroxypropyl cellulose, with the balance being water for injection.

[0077] This embodiment further provides a method for preparing the above-mentioned ophthalmic emulsion composition, specifically as follows: The active ingredient, Span 80, and hydroxypropyl cellulose are added to castor oil in the above-mentioned amounts, and stirred at high speed under heating at 70°C to uniformly disperse the drugs in the castor oil to form an oil phase. Tween 80 is added to water for injection and dissolved at 70°C to form an aqueous phase, which is then stirred on a thermostatic magnetic stirrer. Finally, the oil phase is slowly added dropwise to the aqueous phase while simultaneously stirring at a high speed of 13000 r / min, and the volume is brought to a final volume to obtain the colostrum. The colostrum is homogenized under high pressure, first twice at 800–900 bar, and then twice at 1100–1200 bar, followed by sterilization.

[0078] Example 2

[0079] This embodiment provides an ophthalmic emulsion composition containing: 0.5 w / v% of the active ingredient, 15 w / v% of castor oil, 3.2 w / v% of Span 80, 4.8 w / v% of Tween 80, and 0.4 w / v% of hydroxypropyl cellulose, with the balance being water for injection.

[0080] The preparation method is the same as in Example 1.

[0081] Example 3

[0082] This embodiment provides an ophthalmic emulsion composition containing: 0.5 w / v% of the active ingredient, 25 w / v% of castor oil, 3.2 w / v% of Span 80, 4.8 w / v% of Tween 80, and 0.4 w / v% of hydroxypropyl cellulose, with the balance being water for injection.

[0083] The preparation method is the same as in Example 1.

[0084] Example 4

[0085] This embodiment provides an ophthalmic emulsion composition containing: 0.5 w / v% of the active ingredient, 20 w / v% of castor oil, 1.6 w / v% of Span 80, 2.4 w / v% of Tween 80, and 0.4 w / v% of hydroxypropyl cellulose, with the balance being water for injection.

[0086] The preparation method is the same as in Example 1.

[0087] Example 5

[0088] This embodiment provides an ophthalmic emulsion composition containing: 0.5 w / v% of the active ingredient, 20 w / v% of castor oil, 2.4 w / v% of Span 80, 3.6 w / v% of Tween 80, and 0.4 w / v% of hydroxypropyl cellulose, with the balance being water for injection.

[0089] The preparation method is the same as in Example 1.

[0090] Example 6

[0091] This embodiment provides an ophthalmic emulsion composition containing: 0.5 w / v% of the active ingredient, 20 w / v% of castor oil, 3.2 w / v% of Span 80, 4.8 w / v% of Tween 80, and 0.2 w / v% of hydroxypropyl cellulose, with the balance being water for injection.

[0092] The preparation method is the same as in Example 1.

[0093] Example 7

[0094] This embodiment provides an ophthalmic emulsion composition containing: 0.5 w / v% of the active ingredient, 20 w / v% of castor oil, 3.2 w / v% of Span 80, 4.8 w / v% of Tween 80, and 0.6 w / v% of hydroxypropyl cellulose, with the balance being water for injection.

[0095] The preparation method is the same as in Example 1.

[0096] Comparative Example 1

[0097] The only difference between this comparative example and Example 1 is that the hydroxypropyl cellulose was replaced with an equal amount of polyvinyl alcohol. The results showed that it could form a stable emulsion, but with high viscosity and poor flowability.

[0098] Comparative Example 2

[0099] The only difference between this comparative example and Example 1 is that hydroxypropyl cellulose was replaced with an equal amount of polyvinylpyrrolidone. The results showed that it was difficult to form a stable emulsion, and more sediment was produced.

[0100] Comparative Example 3

[0101] The only difference between this comparative example and Example 1 is that hydroxypropyl cellulose was replaced with an equal amount of magnesium aluminum silicate. The results showed that it was difficult to form a stable emulsion, and more sediment was produced.

[0102] Comparative Example 4

[0103] The only difference between this comparative example and Example 1 is that hydroxypropyl cellulose was replaced with an equal amount of xanthan gum. The results showed that it was difficult to form a stable emulsion and produced more sediment.

[0104] Comparative Example 5

[0105] The only difference between this comparative example and Example 1 is that the amount of castor oil used is changed to 10 w / v.

[0106] Comparative Example 6

[0107] The only difference between this comparative example and Example 1 is that the amount of Span 80 was changed to 0.8 w / v and the amount of Tween 80 was changed to 1.2 w / v.

[0108] Test Example 1: Performance Testing of Ophthalmic Emulsion Composition

[0109] 1. Centrifugal stability

[0110] The centrifugal stability of the ophthalmic emulsion compositions in each example and comparative examples 5-6 was tested. The specific testing method was as follows: the ophthalmic emulsion composition samples were centrifuged at 4000 r / min for 15 min, and then the appearance and separation of the emulsion were observed. The results are shown in Table 1 below.

[0111] Table 1

[0112] Experimental Example 2: Effect of Ophthalmic Emulsion Composition on Oval Albumin-Induced Dry Eye in Guinea Pigs

[0113] 1. Laboratory animals

[0114] See Table 2 below for details.

[0115] Table 2 Information on Experimental Animals

[0116] 2. Experimental grouping and drug administration

[0117] Ten Hartley guinea pigs that passed the adaptation observation were selected for the experiment. Four animals were randomly selected as the negative control group, and the remaining animals were sensitized by intraperitoneal injection of 0.5 mL of albumin solution with a concentration of 10 mg / mL per animal. Sensitization was repeated every other day for three consecutive days. Fourteen days after the last sensitization, 20 μL of 20 mg / mL albumin solution was pipetted into the conjunctival sac of the guinea pigs using a pipette to challenge the model. Tear secretion (phenol red cotton thread method) (both eyes) and tear film breakup time (both eyes) were measured. Animals that were too light or too heavy for the model were excluded. The animals were divided into two groups according to the tear film breakup time (both eyes) after the first challenge. The model animals were divided into two groups: the model group and the emulsion group, with 4 animals (8 eyes) in each group, half male and half female.

[0118] The administration regimen consisted of 7 consecutive days of drug administration, with each dose administered via pipette at a rate of 20 μL / eye / time, 4 times / day (only one dose was administered on the day of grouping and the last treatment day), with an interval of approximately 2–3 hours between doses, as detailed in Table 3 below. During the experiment, challenge was performed on days 4 and 7 of the administration period, followed by drug administration approximately 5 minutes after challenge, and observation of ocular symptoms was conducted approximately 20 minutes later. Tear secretion (both eyes) and / or tear film breakup time (both eyes) were measured on days 4 and 7 of the administration period. After the last administration and all indicator observations and tests were completed, the animals were euthanized, and the palpebral conjunctiva and conjunctival fornix were harvested, fixed with Davison's solution, routinely stained with hematoxylin and eosin (HE), and observed under a light microscope for histological changes in the bulbar conjunctiva, palpebral conjunctiva, and conjunctival fornix.

[0119] Table 3 Experimental Groups and Drug Administration

[0120] 3. Results Analysis

[0121] 3.1 Results of tear film breakup time in guinea pigs with dry eye syndrome

[0122] Table 4. Effects of the emulsion of the present invention on tear film breakup time in an OVA-induced guinea pig dry eye model.

[0123] Note: Compared with the model group, * indicates P<0.05, and ** indicates P<0.01.

[0124] Tear film breakup time is a commonly used indicator for diagnosing dry eye syndrome. When the tear film is unstable, its breakup time is shortened, which can lead to a dry feeling in the eyes and increase the frequency of blinking. The experimental results in Table 4 show: ① Before administration: Compared with the model group, there was no significant difference in tear film breakup time among the animals in the emulsion group. ② Day 4 after administration: Compared with the model group, there was no significant difference in tear film breakup time among the animals in the emulsion group (P>0.05); ③ Day 7 after administration: Compared with the model group, the tear film breakup time in the emulsion group was significantly prolonged, with statistically significant differences (P<0.05 or P<0.01). This indicates that the emulsion group can enhance tear film stability and prolong tear film breakup time.

[0125] 3.2 Results of tear secretion (length of phenol red cotton thread wetted) in guinea pigs with dry eye syndrome

[0126] Table 5. Effects of the emulsion of this invention on tear secretion in an OVA-induced guinea pig dry eye model.

[0127] Note: Compared with the model group, * indicates P<0.05, and ** indicates P<0.01.

[0128] Decreased tear secretion is also a significant cause of dry eye syndrome. Tear secretion was measured using the phenol red cotton thread test and the Schirmer I test. The results in Table 5 show that: ① Before administration: Compared with the model group, there was no significant difference in the wetted length of the phenol red cotton thread in the emulsion group. ② On day 4 after administration: Compared with the model group, the wetted length of the phenol red cotton thread in the animals in the emulsion group was significantly longer, with statistically significant differences (P<0.05 or P<0.01); ③ On day 7 after administration: Compared with the model group, the wetted length of the phenol red cotton thread in the animals in the emulsion group was significantly longer, with statistically significant differences (P<0.01). This indicates that the emulsion of the present invention can increase tear secretion.

[0129] 3.3 Pathological examination results

[0130] Table 6. Statistical table of eyelid histological examination results for various animals.

[0131] Note: The degree of histological changes is indicated by -, ±, +, ++, and +++ to represent normal, very mild, mild, moderate, and severe, respectively.

[0132] Model group: 7 eyes (A♂01 left, A♂01 right, A♂02 left, A♂02 right, A♀03 left, A♀03 right, A♀04 right; 7 / 8) showed moderate to severe inflammatory cell infiltration in the conjunctival layer, with very mild to slight reduction in goblet cells; 1 eye (A♀04 left; 1 / 8) showed severe inflammatory cell infiltration in the conjunctival layer. The HE staining (100×) results of the right eye of A♂01 in the model group are shown in Figure 1. As can be seen from the figure, the right eye of A♂01 showed severe inflammatory cell infiltration in the conjunctival layer, with a slight reduction in goblet cells.

[0133] In the OT202 emulsion group: 2 eyes (B♀04 left, B♀04 right; 2 / 8) showed mild to moderate inflammatory cell infiltration in the conjunctival layer and a very slight reduction in goblet cells; 6 eyes (B♂01 left, B♂01 right, B♂02 left, B♀02 right, B♀03 left, B♀03 right; 6 / 8) showed mild to moderate inflammatory cell infiltration in the conjunctival layer, with normal degrees of goblet cell reduction. The HE staining (100×) results of the right eye of B♀03 in the emulsion group are shown in Figure 2. As can be seen from the figure, the right eye of B♀03 showed mild inflammatory cell infiltration in the conjunctival layer.

[0134] As shown in Table 6, after ovalbumin-induced dry eye in Hartley guinea pigs, the conjunctiva of the animals showed varying degrees of inflammatory cell infiltration and a reduction in goblet cells. The inflammatory cells were predominantly lymphocytes, indicating successful modeling. Compared with the model group, the emulsion-treated group showed a reduced degree of goblet cell reduction in the conjunctiva, suggesting a role in goblet cell repair.

[0135] In summary, the ophthalmic emulsion composition of the present invention has a certain restorative effect on ovalbumin-induced dry eye syndrome in Hartley guinea pigs.

[0136] The embodiments described above are merely examples of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

Claims

1. An ophthalmic emulsion composition comprising: i) An active ingredient, wherein the active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt thereof; ii) Vegetable oils of 15 w / v% to 25 w / v%; wherein the vegetable oils are selected from one or more of soybean oil, corn oil, peanut oil, olive oil, castor oil, palm oil, coconut oil, rapeseed oil, sesame oil, and cottonseed oil; iii) Emulsifiers ranging from 4 w / v% to 8 w / v%; iv) 0.2 w / v% to 0.6 w / v% hydroxypropyl cellulose; and v) Water.

2. The ophthalmic emulsion composition according to claim 1, wherein, The content of the active ingredient is 0.1 w / v% to 2.0 w / v%.

3. The ophthalmic emulsion composition according to claim 1 or 2, wherein, The vegetable oil is castor oil.

4. The ophthalmic emulsion composition according to any one of claims 1 to 3, wherein, The emulsifier is selected from one or both of Span 80 and Tween 80.

5. The ophthalmic emulsion composition according to claim 4, wherein, The emulsifier is a mixture of Span 80 and Tween 80 in a mass ratio of 2:2.5 to 3.

5.

6. The ophthalmic emulsion composition according to claim 1, wherein, The ophthalmic emulsion composition contains: i) 0.1 w / v% to 2.0 w / v% of the active ingredient, wherein the active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt thereof; ii) Castor oil of 15 w / v % to 25 w / v %; iii) 4 w / v% to 8 w / v% of emulsifier; said emulsifier is a mixture of Span 80 and Tween 80 in a mass ratio of 2:2.5 to 3.5; iv) 0.2 w / v% to 0.6 w / v% hydroxypropyl cellulose; and v) Water.

7. A method for preparing an ophthalmic emulsion composition according to any one of claims 1 to 6, comprising: The active ingredient, vegetable oil, emulsifier, hydroxypropyl cellulose, and water are mixed to obtain the ophthalmic emulsion composition.

8. The method for preparing the ophthalmic emulsion composition according to claim 7, wherein, The mixing is performed using one or more of the following methods: high-pressure homogenization, high-shear method, and microfluidic method.

9. A method for preparing an ophthalmic emulsion composition according to claim 7 or 8, comprising: The active ingredient, Span 80, hydroxypropyl cellulose and the vegetable oil are mixed at 60-80°C to obtain the oil phase; Tween 80 is mixed with water at 60–80°C to obtain an aqueous phase; The oil phase is slowly added to the aqueous phase while the mixture is stirred at a speed of 12000-14000 r / min, and the volume is adjusted to obtain the initial emulsion; The colostrum was homogenized under high pressure at 800–1200 bar to obtain the ophthalmic emulsion composition.

10. The use of the ophthalmic emulsion composition according to any one of claims 1 to 6 in any of the following aspects: I) Prevention, treatment, or relief of dry eye syndrome; II) Prepare drugs for the prevention, treatment or relief of dry eye syndrome.

11. The application according to claim 10, wherein, The ophthalmic emulsion composition is used in at least one of the following aspects: 1) Prolong tear film breakup time; 2) Increase tear production; 3) Reduces the degree of cell infiltration in conjunctivitis; 4) Promotes goblet cell repair.

12. The application according to claim 10 or 11, wherein, The ophthalmic emulsion composition is suitable for topical application to the eyes of a subject.

13. A medicine box comprising a therapeutically effective amount of any one of claims 1 to 6 of an ophthalmic emulsion composition, and illustrative material relating to the application of said ophthalmic emulsion composition to a patient suffering from dry eye syndrome.

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