A lotilaner ophthalmic solution formulation and methods of making and using the same

Abstract

This invention provides a semi-fluorinated alkane eye drop containing loteranal and its preparation method, as well as its application in eye diseases such as Demodex blepharitis, ocular erythema acne, and meibomian gland dysfunction.

Description

Technical Field

[0001] This invention relates to the field of eye drop technology, and also to its application in Demodex blepharitis. Background Technology

[0002] Demodex blepharitis is a chronic inflammatory disease of the eyelid margin caused by Demodex mites, the most common ectoparasite in humans. It primarily affects the eyelid skin, eyelash follicles and glands, as well as the meibomian glands, causing significant damage to the eyelid margin. It is prone to recurrence, leading to reduced lipid secretion, decreased tear film stability, and consequently, dry eye. Clinical manifestations include itchy eyes, foreign body sensation, dry eyes, eyelid hyperemia, scaling, and cuff-like discharge at the base of the eyelashes. The pathogenesis of Demodex blepharitis is currently unclear, but it may be related to local mechanical irritation, bacterial carriers, inflammatory responses, and immune responses. Untreated, it can lead to serious ocular complications, including meibomian gland dysfunction, dry eye syndrome, keratoconjunctivitis, and corneal ulceration and perforation.

[0003] According to Frost & Sullivan, the number of people with Demodex blepharitis worldwide was approximately 468 million in 2021; this number is projected to reach approximately 506 million by 2030. In China, the number of Demodex blepharitis patients increased from 58.1 million in 2017 to 58.8 million in 2021, a compound annual growth rate of 0.3%. It is projected that the number of Demodex blepharitis patients in China will increase to 59.8 million by 2030. Demodex blepharitis is clinically common, accounting for more than two-thirds of all blepharitis cases.

[0004] Globally, research on Demodex blepharitis is limited, and currently, loteilana is the only approved treatment for it. Loteilana is a non-competitive γ-aminobutyric acid chloride channel (GABA-Cl) antagonist that selectively inhibits GABA-Cl channels in parasites, thereby paralyzing and killing them. In December 2019, the FDA approved loteilana (Credelio) for the treatment and prevention of flea infestations in cats. On July 24, 2023, the FDA approved Tarsus Pharmaceuticals' XDEMVY (loteilana eye drops) for the treatment of Demodex blepharitis.

[0005] Currently, there are no drugs available in my country specifically for Demodex blepharitis. Clinical treatment primarily focuses on local mite removal, with commercially available products mainly consisting of mite-removing wipes. However, the local mite-killing effect is short-lived and difficult to penetrate deep into the glands. Therefore, there is an urgent clinical need for a safe and effective treatment that is fast-acting and can directly target deep within the lesions. On March 29, 2021, LianBio (China) and Tarsus Pharmaceuticals, Inc. (USA) announced a strategic partnership to acquire the Greater China rights to loterana. On October 30, 2023, LianBio released topline data from its Phase III clinical trial (CTR20220726) evaluating loterana in Chinese patients with Demodex blepharitis. The results showed that, compared with the solvent group, loteprana treatment for Demodex blepharitis patients had a statistically significant mite eradication rate (p<0.001); the cure rate for cuff secretions also showed a positive but not statistically significant trend (p=0.15), failing to meet this co-primary endpoint. Clinical results of XDEMVY abroad showed that in the Saturn-1 study, only 44% of patients in the XDEMVY treatment group achieved improvement (the proportion of patients with a cuff secretion score of 0 on day 43 was cured), and similarly, in the Saturn-2 study, only 56% of patients in the XDEMVY treatment group achieved improvement. Therefore, 40%–50% of patients still did not reach the primary treatment endpoint after 43 days of treatment. XDEMVY is a solution-type eye drop. Due to the physiological characteristics of the eye and the eye barrier, the drug is quickly lost from the ocular surface after administration and has difficulty entering the ocular tissues, especially the deeper glandular areas of the eyelid sebaceous glands and meibomian glands where Demodex mites reside, as well as the deep hair follicles. This results in low drug bioavailability and poor efficacy.

[0006] Therefore, it is crucial to develop a loteranal eye drop with a longer duration of action, strong permeability, and the ability to reach deep into the glands, which is expected to meet the unmet clinical needs of a large number of patients with Demodex blepharitis. Summary of the Invention

[0007] The present invention provides an ophthalmic composition for treating eye diseases, the ophthalmic composition comprising a pharmaceutically active ingredient, a solvent, and a cosolvent.

[0008] The active ingredient of the drug is loteranal;

[0009] The cosolvent includes one or both of cosolvent A and cosolvent B;

[0010] The cosolvent A is selected from one or more fatty acid glycerides;

[0011] The cosolvent B is selected from one or more of C2-C6 monohydric alcohols, polyhydric alcohols, and polyethylene glycols with an average molecular weight of 200 to 900.

[0012] In one embodiment of the present invention, the co-solvent is selected as self-solvent A;

[0013] In one embodiment of the present invention, the co-solvent is selected from a combination of co-solvent A and co-solvent B.

[0014] In some embodiments of the present invention, the content of the active ingredient loteranal, based on the weight of the composition, is 0.2% w / w to 0.7% w / w, preferably 0.21% w / w to 0.6% w / w, more preferably 0.22% w / w to 0.55% w / w, and most preferably 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.

[0015] In some embodiments of the present invention, the solvent is a semi-fluorinated alkane, wherein the semi-fluorinated alkane is selected from one or more of the general formula FnHm, wherein n is selected from 4 to 6 and m is selected from an integer in the range of 5 to 10.

[0016] In some embodiments of the present invention, the semi-fluorinated alkane is preferably one or more of F4H5, F4H6, F4H8, F6H6, F6H8, and F8H8, and more preferably one or more of F4H5 and F6H8.

[0017] In some embodiments of the present invention, the solvent content, based on the weight of the composition, is 0.1% to 99%, preferably 49.5% w / w to 99% w / w, more preferably 45% w / w to 90% w / w, more preferably 60% w / w to 85% w / w, and most preferably 49.5% w / w, 64.5% w / w, 68.05% w / w, 71.6% w / w, 75.15% w / w, 78.7% w / w, 82.25% w / w, or 84.25% w / w.

[0018] In some embodiments of the present invention, the cosolvent A is selected from one or more fatty acid glycerides, preferably one or more medium-chain fatty acid glycerides. More preferably, medium-chain diglycerides and medium-chain triglycerides are used, and even more preferably, medium-chain triglycerides are used.

[0019] In some embodiments of the present invention, the content of the cosolvent A, based on the weight of the composition, is 0.1% w / w to 50% w / w, preferably 12.5% ​​w / w to 35% w / w, and most preferably 15% w / w, 17.5% w / w, 21.00% w / w, 24.5% w / w, 28% w / w, 31.5% w / w, 35% w / w, or 50% w / w.

[0020] In some embodiments of the present invention, the cosolvent B is selected from one or more of C2-C6 monohydric alcohols, polyhydric alcohols, and polyethylene glycols with an average molecular weight of 200 to 900, preferably one or more of ethanol, isopropanol, propylene glycol, glycerol, and polyethylene glycols with an average molecular weight of 400, with ethanol being the most preferred.

[0021] In some embodiments of the present invention, the content of the cosolvent B, based on the weight of the composition, is 0.1% w / w to 1% w / w, preferably 0.15% w / w to 0.8% w / w, more preferably 0.2% w / w to 0.6% w / w, and most preferably 0.5% w / w.

[0022] In some embodiments of the present invention, the mass ratio of the solvent to the co-solvent A is 9.5:0.5 to 4.9:5.0, preferably 9.5:0.5 to 5:5, and more preferably 8.5:1.5 to 6.5:3.5.

[0023] In some embodiments of the present invention, the ophthalmic composition comprises loteranal 0.2% w / w to 0.7% w / w, solvent 0.1% w / w to 99% w / w, cosolvent A 0.1% w / w to 50% w / w, and cosolvent B 0.1% w / w to 1% w / w.

[0024] In some embodiments of the present invention, the content of loteranal is preferably 0.21% w / w to 0.6% w / w, more preferably 0.22% w / w to 0.55% w / w, and most preferably 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.

[0025] In some embodiments of the present invention, the solvent is a semi-fluorinated alkane, wherein the semi-fluorinated alkane is selected from one or more of the general formula FnHm, wherein n is selected from 4 to 6 and m is selected from an integer in the range of 5 to 10.

[0026] In some embodiments of the present invention, the semi-fluorinated alkane is preferably one or more of F4H5, F4H6, F4H8, F6H6, F6H8, and F8H8, and more preferably one or more of F4H5 and F6H8.

[0027] In some embodiments of the present invention, the content of the semi-fluorinated alkane, based on the weight of the composition, is preferably 45% w / w to 90% w / w, more preferably 60% w / w to 85% w / w, and most preferably 49.5% w / w, 64.5% w / w, 68.05% w / w, 71.6% w / w, 75.15% w / w, 78.7% w / w, 82.25% w / w, or 84.25% w / w.

[0028] In some embodiments of the present invention, the cosolvent A is selected from one or more fatty acid glycerides, preferably one or more medium-chain fatty acid glycerides. More preferably, medium-chain diglycerides and medium-chain triglycerides are used, and even more preferably, medium-chain triglycerides are used.

[0029] In some embodiments of the present invention, the content of the cosolvent A, based on the weight of the composition, is 0.1% w / w to 50% w / w, preferably 12.5% ​​w / w to 35% w / w, and most preferably 15% w / w, 17.5% w / w, 21.00% w / w, 24.5% w / w, 28% w / w, 31.5% w / w, 35% w / w, or 50% w / w.

[0030] In some embodiments of the present invention, the cosolvent B is selected from one or more of C2-C6 monohydric alcohols, polyhydric alcohols, or polyethylene glycols with an average molecular weight of 200 to 900, preferably one or more of ethanol, isopropanol, propylene glycol, glycerol, and polyethylene glycols with an average molecular weight of 400, with ethanol being the most preferred.

[0031] In some embodiments of the invention, the content of the cosolvent B, based on the weight of the composition, is preferably 0.15 to 0.8% w / w. More preferably, it is 0.2% w / w to 0.6% w / w, and most preferably, it is 0.5% w / w.

[0032] In some embodiments of the present invention, the mass ratio of the solvent to the co-solvent A is 9.5:0.5 to 4.9:5.0, preferably 9.5:0.5 to 5:5, and more preferably 8.5:1.5 to 6.5:3.5.

[0033] In some embodiments of the present invention, the ophthalmic composition comprises loteranal 0.2% w / w to 0.7% w / w, F4H5 0.1% w / w to 99% w / w, medium-chain triglyceride 0.1% w / w to 50% w / w, and ethanol 0.1% w / w to 1% w / w.

[0034] In some embodiments of the present invention, the ophthalmic composition comprises loteranal 0.2% w / w to 0.7% w / w, F6H8 0.1% w / w to 99% w / w, medium-chain triglyceride 0.1% w / w to 50% w / w, and ethanol 0.1% w / w to 1% w / w.

[0035] In some embodiments of the present invention, the ophthalmic composition comprises loteranal 0.2% w / w to 0.7% w / w, F4H5 0.1% w / w to 99% w / w, and medium-chain triglycerides 0.1% w / w to 50% w / w.

[0036] In some embodiments of the present invention, the ophthalmic composition comprises loteranal 0.2% w / w to 0.7% w / w, F6H8 0.1% w / w to 99% w / w, and medium-chain triglycerides 0.1% w / w to 50% w / w.

[0037] In some embodiments of the invention, the loteranar is preferably 0.21% w / w to 0.6% w / w, more preferably 0.22% w / w to 0.55% w / w, and most preferably 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, based on the weight of the composition.

[0038] In some embodiments of the present invention, the F4H5, based on the weight of the composition, is preferably 45% w / w to 90% w / w, more preferably 60% w / w to 85% w / w, and most preferably 49.5% w / w, 64.5% w / w, 68.05% w / w, 71.6% w / w, 75.15% w / w, 78.7% w / w, 82.25% w / w, or 84.25% w / w.

[0039] In some embodiments of the present invention, the F6H8, based on the weight of the composition, is preferably 45% w / w to 90% w / w, more preferably 60% w / w to 85% w / w, and most preferably 49.5% w / w, 64.5% w / w, 68.05% w / w, 71.6% w / w, 75.15% w / w, 78.7% w / w, 82.25% w / w, or 84.25% w / w.

[0040] In some embodiments of the present invention, the medium-chain triglyceride, based on the weight of the composition, is preferably 10% w / w to 50% w / w, more preferably 12.5% ​​w / w to 50% w / w, and most preferably 15% w / w, 17.5% w / w, 21.00% w / w, 24.5% w / w, 28% w / w, 31.5% w / w, 35% w / w, or 50% w / w.

[0041] In some embodiments of the invention, the ethanol is preferably 0.15 to 0.8% w / w based on the weight of the composition. More preferably, it is 0.2% w / w to 0.6% w / w, and most preferably, it is 0.5% w / w.

[0042] In some embodiments of the present invention, the most preferred mass ratio of F4H5 to medium-chain triglycerides is 8.5:1.5 to 6.5:3.5.

[0043] In some embodiments of the present invention, the most preferred mass ratio of F6H8 to medium-chain triglycerides is 8.5:1.5 to 6.5:3.5.

[0044] In some embodiments of the present invention, the ophthalmic composition comprises 0.25% w / w loteranal, 82.25% w / w F6H8, and 17.5% w / w medium-chain triglycerides.

[0045] In some embodiments of the present invention, the ophthalmic composition comprises 0.25% w / w loteranal, 84.25% w / w F6H8, 15% w / w medium-chain triglyceride, and 0.5% w / w ethanol.

[0046] In some embodiments of the present invention, the ophthalmic composition comprises 0.25% w / w loteranal, 82.25% w / w F4H5, and 17.5% w / w medium-chain triglycerides.

[0047] In some embodiments of the present invention, the ophthalmic composition comprises 0.25% w / w loteranal, 84.25% w / w F4H5, 15% w / w medium-chain triglyceride, and 0.5% w / w ethanol.

[0048] The ophthalmic composition for treating eye diseases provided by the present invention is a drop, spray or injection, preferably a drop.

[0049] The ophthalmic composition for treating eye diseases provided by the present invention is preferably in the form of eye drops.

[0050] The ophthalmic composition for treating eye diseases provided by this invention can be used to treat, preferably Demodex blepharitis, ocular erythema, and meibomian gland dysfunction.

[0051] This invention utilizes semi-fluorinated alkanes as a solvent carrier for the drug, leveraging their advantages such as good biocompatibility, extremely low surface tension, and rapid diffusion ability to improve ocular bioavailability and prolong drug retention time. Furthermore, the semi-fluorinated alkane eye drops prepared by this invention are preservative-free, non-aqueous eye drops with smaller droplets and improved instillation comfort. Specifically, this invention combines semi-fluorinated alkanes with fatty acid glycerides or polyols in a specific ratio to obtain a clear, transparent, and stable loteranar non-aqueous eye drop. The fatty acid glycerides can interact with the lipid layer of the tear film, allowing the formulation to remain in the conjunctival sac for a longer period, acting as a drug reservoir. Combined with the rapid diffusion ability of semi-fluorinated alkanes, the drug can continuously diffuse into the eyelid margin tissue and deep glands, reaching the Demodex mite infestation area and achieving better therapeutic effects.

[0052] Definitions and Explanations

[0053] The abbreviations, trade names, and their meanings of some technical terms used in this invention are as follows:

[0054] Attached Figure Description

[0055] Figure 1 Figure 4 shows the change in drug concentration over time in the upper eyelid margin of New Zealand rabbits after administration of Loteranal aqueous solution eye drops, as described in Examples 4 and 16.

[0056] Figure 2 Figure 4 shows the change in drug concentration over time in the lower eyelid margin of New Zealand rabbits after administration of Loteranal aqueous solution eye drops, as described in Examples 4 and 16.

[0057] Figure 3 AUC of Loteranal aqueous solution administered as eye drops in the upper / lower eyelid margins of New Zealand rabbits in Examples 4 and 16 0-24h . Detailed Implementation

[0058] The present invention will be further described in detail through the following embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0059] Comparative Examples 1–8 Loteranar Solubility Test

[0060] Loteranal solubility test in various cosolvents: Loteranal active pharmaceutical ingredient was added to a certain amount of cosolvent at room temperature with stirring, and the dissolution state of loteranal was observed. The solubility results of loteranal in different types of cosolvents are shown in Table 1.

[0061] surface

[0062]

[0063] Preparation of loteranal solution: Weigh the prescribed amounts (w / w) of ethanol, diethyl sebacate, propylene glycol dioctanoate, isopropanol and perfluorohexyloctane according to Table 2, add loteranal active pharmaceutical ingredient under stirring at room temperature, and observe the dissolution state of loteranal.

[0064] surface

[0065]

[0066] Diethyl sebacate and isopropanol were the best co-solvents for loteranar among the tested solvents. Of the formulations shown in Table 2, only Comparative Example 3 could dissolve 0.25% loteranar, while the other tested formulations failed to dissolve it completely.

[0067] Examples 1-7

[0068] Using perfluorohexyloctane as the main solvent, the range of medium-chain triglycerides used as co-solvents was investigated.

[0069] Preparation of loteranal solution: Weigh the prescribed amount (w / w) of loteranal and medium-chain triglycerides according to Table 3, stir at room temperature or heat appropriately until the drug is completely dissolved, and then add the prescribed amount of perfluorohexyloctane and stir evenly.

[0070] surface

[0071]

[0072] Medium-chain triglycerides are miscible with perfluorohexyloctane. In Example 1, due to the low proportion of medium-chain triglycerides in the formulation, the solution became turbid after adding perfluorohexyloctane during the preparation process, indicating that the proportion of the co-solvent needs to be increased. In Example 2, the drug precipitated during overnight standing at room temperature, indicating that it is difficult to maintain the drug's solubility at this co-solvent ratio. In Examples 3-7, the solution remained clear and transparent after 30 days at room temperature, with no drug precipitation, indicating that at room temperature, a medium-chain triglyceride proportion greater than 15% can maintain the drug's solubility in the medium-chain triglyceride / perfluorohexyloctane mixed solvent system.

[0073] Examples 8-12

[0074] Using perfluorohexyloctane as the main solvent, the range of amounts of ethanol and medium-chain triglycerides as co-solvents was investigated.

[0075] Preparation of loteranal solution: Weigh the prescribed amount (w / w) of loteranal, ethanol and medium-chain triglycerides according to the examples in Table 4, stir at room temperature until the drug is completely dissolved, and then add the prescribed amount of perfluorohexyloctane and stir evenly.

[0076] surface

[0077]

[0078] Medium-chain triglycerides, ethanol, and perfluorohexyloctane are miscible in any proportion. In Example 8, the solution became turbid after adding perfluorohexyloctane in the prescribed proportion, indicating that the amount of the mixed cosolvent was insufficient to support drug dissolution. In Example 9, the drug precipitated during overnight storage at room temperature. Examples 10-12 remained clear and transparent without crystal precipitation after 30 days at room temperature, indicating that in the prescription proportions of Examples 10-12, the mixed cosolvent of medium-chain triglycerides and ethanol can maintain the drug's solubility in the mixed solvent system of medium-chain triglycerides / ethanol / perfluorohexyloctane at room temperature.

[0079] Examples 13-19

[0080] Using perfluorobutylpentane as the main solvent, the range of amounts of medium-chain triglycerides used as co-solvents was investigated.

[0081] Preparation of loteranal solution: Weigh the prescribed amount (w / w) of loteranal and medium-chain triglycerides according to Table 5, stir at room temperature or heat appropriately until the drug is completely dissolved, and then add the prescribed amount of perfluorobutylpentane and stir evenly.

[0082] surface

[0083]

[0084] Medium-chain triglycerides are miscible with perfluorobutylpentane in any proportion. In Example 13, it was found that the solution became turbid after adding the prescribed amount of perfluorobutylpentane. In Example 14, the drug precipitated during overnight storage at room temperature, indicating that the proportion of solubilizer in the formulation of Examples 13 / 14 was insufficient to support the dissolution of the drug in the perfluorobutylpentane mixed solvent system. Examples 15-19 remained clear and transparent with no drug precipitation after 30 days of storage at room temperature, suggesting that when the proportion of medium-chain triglycerides is greater than 15%, the drug can maintain its solubility in the medium-chain triglyceride / perfluorobutylpentane mixed solvent system at room temperature.

[0085] Examples 20-24

[0086] Using perfluorobutylpentane as the main solvent, the range of amounts of ethanol and medium-chain triglycerides as co-solvents was investigated.

[0087] Preparation of loteranal solution: Weigh the prescribed amount (w / w) of loteranal, ethanol and medium-chain triglycerides according to the examples in Table 6, stir at room temperature until the drug is completely dissolved, and then add the prescribed amount of perfluorobutylpentane and stir evenly.

[0088] surface

[0089]

[0090] Medium-chain triglycerides, ethanol, and perfluorobutylpentane are miscible in any proportion. In Example 20, it was found that the solution became turbid after adding the prescribed amount of perfluorobutylpentane during the preparation process. In Example 21, the drug precipitated during overnight storage at room temperature. In Examples 22-24, the solution remained clear and transparent after 30 days of storage at room temperature, suggesting that at the formulation proportions of Examples 22-24, the mixed co-solvent of medium-chain triglycerides and ethanol can maintain the solubility of the drug in the mixed solvent system of medium-chain triglycerides / ethanol / perfluorobutylpentane at room temperature.

[0091] Examples 25-30

[0092] Loteranar solutions of different specifications were prepared using perfluorohexyloctane as the main solvent and medium-chain triglycerides as co-solvents.

[0093] Preparation of loteranal solution: Weigh the prescribed amount (w / w) of loteranal and medium-chain triglycerides according to the examples in Table 7, stir at room temperature until the drug is completely dissolved, and then add the prescribed amount of perfluorohexyloctane and stir evenly.

[0094] surface

[0095]

[0096] The experimental results show that Examples 25-30 can all form clear and transparent solutions.

[0097] Examples 31-36

[0098] Loteranar solutions of different specifications were prepared using perfluorobutylpentane as the main solvent and medium-chain triglycerides as co-solvents.

[0099] Preparation of loteranal solution: Weigh the prescribed amount (w / w) of loteranal and medium-chain triglycerides according to the examples in Table 8, stir at room temperature until the drug is completely dissolved, and then add the prescribed amount of perfluorobutylpentane and stir evenly.

[0100] surface

[0101]

[0102] The experimental results show that all of Examples 31 to 36 can form clear and transparent solutions.

[0103] Experimental Example 1: Stability Study of Examples 3, 10, 15, and 22

[0104] The formulations of Examples 3, 10, 15, and 22 were prepared for stability studies.

[0105] High temperature 60℃: Samples were taken at 0, 5d, 10d, and 15d under 60℃ conditions to observe the appearance of the formulations in Examples 3, 10, 15, and 22, and to determine the changes in loteranal content.

[0106] Light exposure test: The samples were placed in a light stability test chamber and sampled at 0, 5d, 10d and 15d under an illuminance of 4500lx±500lx to examine the changes in appearance and loteranal content of the formulations of Examples 3, 10, 15 and 22.

[0107] The stability results of Examples 3, 10, 15, and 22 under various conditions are shown in Table 9. Examples 3, 10, 15, and 22 all exhibited drug precipitation under conditions of 60°C and 5 days of light exposure. It is speculated that the Brownian motion of both drug and solvent molecules significantly increased under these test conditions, leading to greater drug molecule detachment from the co-solvent and subsequent drug precipitation. Since significant drug precipitation was observed in Examples 3, 10, 15, and 22, the loteranar content was not determined.

[0108] surface

[0109]

[0110] Stability tests of Experiment 3, Examples 4, 11, 16, and 23

[0111] The formulations prepared in Examples 4, 11, 16, and 23 were used for stability studies.

[0112] High temperature 60℃: Samples were taken at 0, 5d, 10d, and 15d under 60℃ conditions to observe the appearance of the formulations in Examples 4, 11, 16, and 23, and to determine the changes in loteranal content.

[0113] Light exposure test: The samples were placed in a light stability test chamber and sampled at 0, 5d, 10d and 15d under an illuminance of 4500lx±500lx to examine the changes in appearance and loteranal content of the formulations listed in Examples 4, 11, 16 and 23.

[0114] The stability results under each condition are shown in Table 10.

[0115] surface

[0116]

[0117] The results showed that the formulations under all conditions were clear and transparent, and the loteranal content changes met the requirements, all within the range of 98% to 102%. Formulation Examples 4, 11, 16, and 23 exhibited excellent stability; after being placed under high temperature and light conditions for 15 days, the loteranal content remained stable.

[0118] Experimental Example 3: Ocular Tissue Distribution Test of Loteranal Eye Drops

[0119] 1. Test drug:

[0120] Eye tissue distribution test samples were prepared according to Examples 4 and 16.

[0121] Refer to the prescription composition of the commercially available preparation XDEMVY, and prepare an aqueous solution of lotilaner as a control. The specific prescription is shown in Table 11:

[0122] Table

[0123]

[0124] 2. Test animals:

[0125] 36 New Zealand rabbits, male, 2 - 4 kg, purchased from Hunan Taiping Biotechnology Co., Ltd., with animal production license SCXK(Xiang)2023 - 0011.

[0126] 3. Test methods:

[0127] Animal grouping:

[0128] 1) Lotilaner aqueous solution group: 12 New Zealand rabbits (2 rabbits per time point, 6 time points in total, 12 rabbits in total), the administration dose is 50 mg / eye, the preparation is instilled into both eyes, without fasting or water restriction;

[0129] 2) Lotilaner perfluorohexyl octane group prepared in Example 4: 12 New Zealand rabbits (2 rabbits per time point, 6 time points in total, 12 rabbits in total), the administration dose is 50 mg / eye, the preparation is instilled into both eyes, without fasting or water restriction;

[0130] 3) Lotilaner perfluorobutyl pentane group prepared in Example 16: 12 New Zealand rabbits (2 rabbits per time point, 6 time points in total, 12 rabbits in total), the administration dose is 50 mg / eye, the preparation is instilled into both eyes, without fasting or water restriction;

[0131] Sample collection and processing:

[0132] Collection time points: 0.25 h, 1 h, 2 h, 6 h, 12 h, 24 h after administration.

[0133] After the rabbits are anesthetized with isoflurane gas, the surface is cleaned with normal saline before collecting at each time point. Then, the upper and lower eyelid margins of the left and right eyes are collected respectively, and then washed with normal saline once after collection. Finally, it is quickly stored in an ultra - low temperature refrigerator until sample analysis.

[0134] Sample analysis

[0135] Lotilaner is extracted from the homogenate by the protein precipitation method, and quantitative analysis is carried out by the multiple reaction monitoring mode of a triple quadrupole tandem mass spectrometer. The quantitative range is 2.00 - 8000 ng / mL.

[0136] The concentration of loteranar in the biological samples obtained in this experiment was determined using LC-MS / MS. Corresponding pharmacokinetic parameters were obtained to evaluate the differences in exposure among different formulations.

[0137] 4. Experimental Results:

[0138] The upper eyelid margins of the 0.25% loteranal perfluorohexyloctane group prepared in Example 4 and the 0.25% loteranal perfluorobutylpentane group prepared in Example 16 of the present invention (as shown in Table 12 and...) Figure 1 As shown), the lower eyelid margin (as shown in Table 13 and...) Figure 2 The drug exposure in the sample (as shown) was significantly higher than that of the same strength of loteranal aqueous solution. Figure 3 As shown, compared to the loteranar aqueous solution group, the perfluorohexyloctane group prepared in Example 4 showed higher AUC values ​​at both the upper and lower eyelid margins. 0-24h The perfluorobutylpentane group prepared in Example 16 showed increases of 3.2 times and 2.7 times, respectively, and increases of 6.3 times and 5.6 times, respectively.

[0139] The results of the drug distribution in the eyelid margin tissue indicate that using perfluorohexyloctane and perfluorobutylpentane as non-aqueous eye drop delivery carriers in Examples 4 and 16, respectively, can significantly improve the ocular bioavailability of loteranar, increase the exposure of the drug in the deeper glandular regions of the eyelid sebaceous glands and meibomian glands infested by Demodex mites, as well as deep into the hair follicles, and enhance the therapeutic effect, showing good application prospects.

[0140] surface PK parameters of lotelanar in the upper eyelid margin

[0141]

[0142] Table 13 PK parameters of loteranar in the lower eyelid margin

[0143] .

Claims

1. An ophthalmic composition for treating eye diseases, characterized in that... The ophthalmic composition comprises a pharmaceutically active ingredient, a solvent, and a cosolvent. The active ingredient of the drug is loteranal; The co-solvent includes one or both of co-solvent A and co-solvent B; The cosolvent A is selected from one or more fatty acid glycerides; The cosolvent B is selected from one or more of C2-C6 monohydric alcohols, polyhydric alcohols, and polyethylene glycols with an average molecular weight of 200 to 900.

2. The ophthalmic composition according to claim 1, characterized in that... The content of the active ingredient loteranal, based on the weight of the composition, is 0.2% w / w to 0.7% w / w, preferably 0.21% w / w to 0.6% w / w, more preferably 0.22% w / w to 0.55% w / w, and most preferably 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.

3. The ophthalmic composition according to claim 1, characterized in that, The solvent is a semi-fluorinated alkane, wherein the semi-fluorinated alkane is selected from one or more of the general formula FnHm, wherein n is selected from 4 to 6 and m is selected from an integer in the range of 5 to 10.

4. The ophthalmic composition according to claim 3, characterized in that... The semi-fluorinated alkane is preferably one or more of F4H5, F4H6, F4H8, F6H6, F6H8, and F8H8, and more preferably one or more of F4H5 and F6H8.

5. The ophthalmic composition according to claim 1, characterized in that... The solvent content, by weight of the composition, is 49.5% w / w to 99% w / w, more preferably 60% w / w to 85% w / w, and most preferably 49.5% w / w, 64.5% w / w, 68.05% w / w, 71.6% w / w, 75.15% w / w, 78.7% w / w, 82.25% w / w, or 84.25% w / w.

6. The ophthalmic composition according to claim 1, characterized in that... The cosolvent A is preferably one or more of medium-chain fatty acid glycerides. More preferably, it is a medium-chain diglyceride or a medium-chain triglyceride, and even more preferably, it is a medium-chain triglyceride.

7. The ophthalmic composition according to claim 1, characterized in that... The content of the cosolvent A, based on the weight of the composition, is 0.1% w / w to 50% w / w, preferably 12.5% ​​w / w to 35% w / w, and most preferably 15% w / w, 17.5% w / w, 21.00% w / w, 24.5% w / w, 28% w / w, 31.5% w / w, 35% w / w, or 50% w / w.

8. The ophthalmic composition according to claim 1, characterized in that... The cosolvent B is preferably one or more of ethanol, isopropanol, propylene glycol, glycerol, and polyethylene glycol with an average molecular weight of 400, with ethanol being the most preferred.

9. The ophthalmic composition according to claim 1, characterized in that... The content of the cosolvent B, based on the weight of the composition, is 0.1% w / w to 1% w / w, preferably 0.15% w / w to 0.8% w / w, more preferably 0.2% w / w to 0.6% w / w, and most preferably 0.5% w / w.

10. The ophthalmic composition according to claim 1, characterized in that... The mass ratio of the solvent to cosolvent A is 9.5:0.5 to 4.9:5.0, preferably 9.5:0.5 to 5:5, and more preferably 8.5:1.5 to 6.5:3.

5.

11. The ophthalmic composition according to claim 1, characterized in that... The ophthalmic composition comprises loteranal 0.2% w / w to 0.7% w / w, solvent 0.1% w / w to 99% w / w, cosolvent A 0.1% w / w to 50% w / w, and cosolvent B 0.1% w / w to 1% w / w.

12. The ophthalmic composition according to claim 11, characterized in that... The content of loteranal is preferably 0.21% w / w to 0.6% w / w, more preferably 0.22% w / w to 0.55% w / w, and most preferably 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.

13. The ophthalmic composition according to claim 11, characterized in that... The solvent is a semi-fluorinated alkane, wherein the semi-fluorinated alkane is selected from one or more of the general formula FnHm, wherein n is selected from 4 to 6 and m is selected from an integer in the range of 5 to 10.

14. The ophthalmic composition according to claim 13, characterized in that... The semi-fluorinated alkane is preferably one or more of F4H5, F4H6, F4H8, F6H6, F6H8, and F8H8, and more preferably one or more of F4H5 and F6H8.

15. The ophthalmic composition according to claim 13 or 14, characterized in that... The content of the semi-fluorinated alkane, based on the weight of the composition, is preferably 45% w / w to 90% w / w, more preferably 60% w / w to 85% w / w, and most preferably 49.5% w / w, 64.5% w / w, 68.05% w / w, 71.6% w / w, 75.15% w / w, 78.7% w / w, 82.25% w / w, or 84.25% w / w.

16. The ophthalmic composition according to claim 11, characterized in that... The cosolvent A is selected from one or more fatty acid glycerides, preferably one or more medium-chain fatty acid glycerides. More preferably, medium-chain diglycerides and medium-chain triglycerides are selected, and even more preferably, medium-chain triglycerides are selected.

17. The ophthalmic composition according to claim 11, characterized in that... The content of the cosolvent A, based on the weight of the composition, is 0.1% w / w to 50% w / w, preferably 12.5% ​​w / w to 35% w / w, and most preferably 15% w / w, 17.5% w / w, 21.00% w / w, 24.5% w / w, 28% w / w, 31.5% w / w, 35% w / w, or 50% w / w.

18. The ophthalmic composition according to claim 11, characterized in that... The cosolvent B is selected from one or more of C2-C6 monohydric alcohols, polyhydric alcohols, and polyethylene glycols with an average molecular weight of 200 to 900, preferably one or more of ethanol, isopropanol, propylene glycol, glycerol, and polyethylene glycols with an average molecular weight of 400, with ethanol being the most preferred.

19. The ophthalmic composition according to claim 11, characterized in that... The content of the cosolvent B, based on the weight of the composition, is preferably 0.15 to 0.8% w / w, more preferably 0.2% w / w to 0.6% w / w, and most preferably 0.5% w / w.

20. The ophthalmic composition according to claim 11, characterized in that... The mass ratio of the solvent to cosolvent A is 9.5:0.5 to 4.9:5.0, preferably 9.5:0.5 to 5:5, and more preferably 8.5:1.5 to 6.5:3.

5.

21. The ophthalmic composition according to any one of claims 1 to 20, characterized in that... The ophthalmic composition comprises loteranal 0.2% w / w to 0.7% w / w, F4H5 0.1% w / w to 99% w / w, medium-chain triglycerides 0.1% w / w to 50% w / w, and ethanol 0.1% w / w to 1% w / w.

22. The ophthalmic composition according to any one of claims 1 to 20, characterized in that... The ophthalmic composition comprises loteranal 0.2% w / w to 0.7% w / w, F6H8 0.1% w / w to 99% w / w, medium-chain triglycerides 0.1% w / w to 50% w / w, and ethanol 0.1% w / w to 1% w / w.

23. The ophthalmic composition according to any one of claims 1 to 20, characterized in that... The ophthalmic composition comprises loteranal 0.2% w / w to 0.7% w / w, F4H5 0.1% w / w to 99% w / w, and medium-chain triglycerides 0.1% w / w to 50% w / w.

24. The ophthalmic composition according to any one of claims 1 to 20, characterized in that... The ophthalmic composition comprises loteranal 0.2% w / w to 0.7% w / w, F6H8 0.1% w / w to 99% w / w, and medium-chain triglycerides 0.1% w / w to 50% w / w.

25. The ophthalmic composition according to any one of claims 21 to 24, characterized in that... The loteranar, by weight of the composition, is preferably 0.21% w / w to 0.6% w / w, more preferably 0.22% w / w to 0.55% w / w, and most preferably 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.

26. The ophthalmic composition according to any one of claims 21 or 23, characterized in that... The F4H5, based on the weight of the composition, is preferably 45% w / w to 90% w / w, more preferably 60% w / w to 85% w / w, and most preferably 49.5% w / w, 64.5% w / w, 68.05% w / w, 71.6% w / w, 75.15% w / w, 78.7% w / w, 82.25% w / w, or 84.25% w / w.

27. The ophthalmic composition according to any one of claims 22 or 24, characterized in that... The F6H8, based on the weight of the composition, is preferably 45% w / w to 90% w / w, more preferably 60% w / w to 85% w / w, and most preferably 49.5% w / w, 64.5% w / w, 68.05% w / w, 71.6% w / w, 75.15% w / w, 78.7% w / w, 82.25% w / w, or 84.25% w / w.

28. The ophthalmic composition according to any one of claims 21 to 24, characterized in that... The medium-chain triglyceride, based on the weight of the composition, is preferably 10% w / w to 50% w / w, more preferably 12.5% ​​w / w to 50% w / w, and most preferably 15% w / w, 17.5% w / w, 21.00% w / w, 24.5% w / w, 28% w / w, 31.5% w / w, 35% w / w, or 50% w / w.

29. The ophthalmic composition according to claim 21 or 22, characterized in that... The ethanol content, based on the weight of the composition, is preferably 0.15 to 0.8% w / w. More preferably, it is 0.2% to 0.6% w / w, and most preferably, it is 0.5% w / w.

30. The ophthalmic composition according to claim 21 or 23, characterized in that... The optimal mass ratio of F4H5 to medium-chain triglycerides is 8.5:1.5 to 6.5:3.

5.

31. The ophthalmic composition according to claim 22 or 24, characterized in that... The optimal mass ratio of F6H8 to medium-chain triglycerides is 8.5:1.5 to 6.5:3.

5.

32. The ophthalmic composition according to any one of claims 1 to 31, characterized in that... The ophthalmic composition comprises loteranal 0.25% w / w, F6H8 82.25% w / w, and medium-chain triglyceride 17.5% w / w.

33. The ophthalmic composition according to any one of claims 1 to 31, characterized in that... The ophthalmic composition comprises 0.25% w / w loteranal, 84.25% w / w F6H8, 15% w / w medium-chain triglyceride, and 0.5% w / w ethanol.

34. The ophthalmic composition according to any one of claims 1 to 31, characterized in that... The ophthalmic composition comprises loteranal 0.25% w / w, F4H5 82.25% w / w, and medium-chain triglyceride 17.5% w / w.

35. The ophthalmic composition according to any one of claims 1 to 31, characterized in that... The ophthalmic composition comprises 0.25% w / w loteranal, 84.25% w / w F4H5, 15% w / w medium-chain triglyceride, and 0.5% w / w ethanol.

36. The ophthalmic composition according to any one of claims 1 to 35, characterized in that... The ophthalmic composition is a drop, spray, or injection, preferably a drop.

37. The ophthalmic composition according to claim 36, characterized in that... The ophthalmic composition is preferably an eye drop.

38. The ophthalmic composition according to any one of claims 1 to 37, characterized in that... The ophthalmic composition is used to treat eye diseases such as Demodex blepharitis, ocular rosacea, and meibomian gland dysfunction.

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