Lotilaner-containing ophthalmic formulation, preparation method therefor, and use thereof

Abstract

The present invention provides a Lotilaner-containing microemulsion eye drop, a preparation method therefor, and a use thereof in eye diseases such as demodex blepharitis, ocular rosacea, and meibomian gland dysfunction.

Description

A loteranal ophthalmic formulation, its preparation method and application Technical Field

[0001] This invention pertains to an ophthalmic preparation, specifically an ophthalmic pharmaceutical composition containing loteranal, its preparation method, and its uses. Background Technology

[0002] Demodex blepharitis is a chronic inflammatory reaction of the eyelid margin caused by Demodex mites, the most common ectoparasite in humans. It causes significant damage to the eyelid margin, is prone to recurrence, and is difficult to cure completely. Demodex mites in the eye can be divided into Demodex folliculorum and Demodex brevis. Demodex folliculorum inhabits the hair follicles of the eyelashes, while Demodex brevis inhabits the sebaceous glands and meibomian glands of the eyelashes. Clinical manifestations include itchy eyes, foreign body sensation, dry eyes, eyelid congestion, scaling, and cuff-like discharge at the base of the eyelashes. Current treatment strategies for Demodex blepharitis mainly include local physical therapy, local drug therapy, and systemic treatment. Among these treatments, local physical therapy, such as intense pulsed light (IPL), can affect the repair of corneal epithelial damage, and its safety remains to be observed. Topical medications such as tea tree oil or anti-mite wipes can only reach the eyelid margin and cannot penetrate deep into the glands, resulting in limited therapeutic effects. These wipes and cotton pads also pose risks of irritation, abrasion, and corneal abrasion, complicating treatment for patients. Systemic medications, such as oral ivermectin and doxycycline, should be used with caution due to potential allergic reactions and interactions. Therefore, there is an urgent need for a drug that can effectively treat Demodex blepharitis with minimal irritation.

[0003] Loteranal is a highly selective γ-aminobutyric acid-gated chloride channel (GABACls) inhibitor with antiparasitic activity against mites. On July 25, 2023, the FDA approved Tarsus Pharmaceuticals' 0.25% loteranal eye drops, marketed under the name Xdemvy, for the treatment of Demodex blepharitis, making it the first and only FDA-approved treatment directly targeting Demodex mites. Two clinical trials, Saturn-1 and Saturn-2, showed that XDEMVY had a good safety profile, but in terms of efficacy, only 44% and 56% of subjects, respectively, achieved the primary endpoint of an upper eyelid cuff secretion score of 0 on day 43 after administration. Because loteranal is poorly water-soluble, according to patents WO2020257663A1, CN111655241B, and information disclosed by Tarsus Pharmaceuticals, the maximum concentration achievable in an aqueous solution of loteranal is 0.25% (2.5 mg / mL).

[0004] XDEMVY is an aqueous solution eye drop. However, after administration of conventional solution eye drops, the drug will be rapidly lost from the ocular surface due to blinking, tear flushing and nasolacrimal duct drainage. Furthermore, due to the special physiological barrier of the human eye, the drug has difficulty penetrating into the ocular tissue, and its bioavailability is usually less than 5%.

[0005] Therefore, there is an urgent need to develop a new formulation of loteranal to improve its solubility, increase its exposure in the ocular parasitic tissues of Demodex mites, and enhance its therapeutic effect on Demodex blepharitis. Summary of the Invention

[0006] This invention addresses the problem of loteranar's poor water solubility by employing microemulsion theory. It selects a suitable oil phase to dissolve loteranar and then screens surfactants and multiple co-surfactants to increase the maximum concentration of the lipid-soluble drug loteranar in aqueous solutions. Furthermore, microemulsions are spontaneously formed, thermodynamically stable systems. The oil phase in a microemulsion can interact with the lipid layer of the tear film, thus retaining the drug in the conjunctival sac for a longer period, effectively acting as a drug reservoir. Utilizing the hydrophilic-lipophilic properties of microemulsions, poorly soluble drugs can be dissolved and dispersed in aqueous solutions, forming nanoscale particles with stronger tissue penetration. These particles easily penetrate the eyelid margin tissue from the intercellular spaces, reaching areas where Demodex mites aggregate and parasitize, potentially enhancing the drug's maximum therapeutic effect.

[0007] The present invention provides an ophthalmic formulation, characterized in that the ophthalmic formulation comprises a pharmaceutically active ingredient and a co-surfactant; wherein the pharmaceutically active ingredient is loteranal; and the co-surfactant is PEG400 or a combination of PEG400 and propylene glycol.

[0008] In some embodiments of the present invention, the present invention provides an ophthalmic preparation, characterized in that the ophthalmic preparation comprises a pharmaceutically active ingredient, a surfactant, and a co-surfactant; wherein the pharmaceutically active ingredient is loteranal; and the co-surfactant is PEG400 or a combination of PEG400 and propylene glycol.

[0009] In some embodiments of the present invention, the present invention provides an ophthalmic preparation, characterized in that the ophthalmic preparation comprises a pharmaceutically active ingredient, an oil phase, a surfactant, and a co-surfactant, wherein the pharmaceutically active ingredient is loteranal; and the co-surfactant is PEG400 or a combination of PEG400 and propylene glycol.

[0010] In some embodiments of the present invention, the present invention provides an ophthalmic preparation, characterized in that the ophthalmic preparation comprises a pharmaceutically active ingredient, an oil phase, a surfactant, a co-surfactant, and water;

[0011] The active ingredient of the drug is loteranal;

[0012] The co-surfactant is PEG400 or a combination of PEG400 and propylene glycol.

[0013] In some embodiments of the present invention, the content of the active ingredient loteranal, based on the total weight of the ophthalmic preparation, is 0.25% w / w to 0.7% w / w, preferably 0.26% w / w to 0.6% w / w, more preferably 0.3% w / w to 0.55% w / w, and most preferably 0.3% w / w, 0.35% w / w, 0.4% w / w, 0.45% w / w, or 0.5% w / w.

[0014] In some embodiments of the present invention, the content of the co-surfactant PEG400, based on the total weight of the ophthalmic formulation, is 0.25% w / w to 2% w / w, preferably 0.3% w / w to 1.5% w / w, more preferably 0.4% w / w to 1.2% w / w, and most preferably 0.5% w / w or 1% w / w. As an example, it can be 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, 1.0% w / w, 1.1% w / w, 1.2% w / w, 1.3% w / w, 1.4% w / w, or 1.5% w / w.

[0015] In some embodiments of the present invention, the content of the co-surfactant propylene glycol, based on the total weight of the ophthalmic formulation, is 0.25% w / w to 2% w / w, preferably 0.3% w / w to 1.8% w / w, more preferably 0.4% w / w to 1.6% w / w, and most preferably 0.5% w / w, 1% w / w, or 1.5% w / w. As an example, it can be 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, 1.1% w / w, 1.2% w / w, 1.3% w / w, 1.4% w / w, or 1.5% w / w.

[0016] In some embodiments of the present invention, the oil phase of the ophthalmic formulation is selected from medium-chain triglycerides and fatty acid esters. Isopropyl myristate, isopropyl palmitate, ethyl oleate, coconut oil, olive oil, soybean oil, castor oil, or medium-chain triglycerides, or combinations of two, three, or more of these, with castor oil or medium-chain triglycerides being most preferred.

[0017] In some embodiments of the present invention, the oil phase content, based on the total weight of the ophthalmic preparation, is 0.1% w / w to 1% w / w, preferably 0.4% w / w to 0.9% w / w, more preferably 0.5% w / w to 0.9% w / w, and most preferably 0.5% w / w, 0.6% w / w, 0.7% w / w, or 0.8% w / w. As an example, it can be 0.2% 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, or 0.9% w / w.

[0018] In some embodiments of the present invention, the surfactant of the ophthalmic preparation is selected from polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, 15-hydroxystearic acid polyethylene glycol ester, Tween 80, or a combination of two, three or more of them, preferably polyoxyethylene 35 castor oil.

[0019] In some embodiments of the present invention, the surfactant content of the ophthalmic preparation is 0.1% w / w to 6% w / w, preferably 0.2% w / w to 5.8% w / w, more preferably 0.25% w / w to 5.5% w / w, 4.5% to 5.5% w / w, and most preferably 5% w / w. As an example, it can be 0.5% w / w, 1.0% w / w, 1.5% w / w, 2.0% w / w, 2.5% w / w, 3.0% w / w, 3.5% w / w, 4.0% w / w, 4.5% w / w, 5% w / w, 5.5% w / w, or 6% w / w.

[0020] In some embodiments of the present invention, the weight ratio of the oil phase of the ophthalmic formulation to the surfactant is 0.4:5 to 1.25:5, preferably 0.1:6 to 1.25:5, more preferably 0.5:5 to 1:5, and most preferably 0.6:5 ​​to 0.8:5.

[0021] In some embodiments of the present invention, the ophthalmic preparation may further include a pH adjuster, a mucosal adhesive, an osmotic pressure regulator, or a preservative, or a combination of two, three, or more of these.

[0022] In some embodiments of the present invention, the pH adjuster is selected from sodium hydroxide, tromethamine, disodium hydrogen phosphate, sodium dihydrogen phosphate, or a combination of two, three, or more of them.

[0023] In some embodiments of the present invention, the pH of the ophthalmic preparation is preferably 5 to 9, more preferably 6 to 8. For example, the pH can be 6.79, 6.87, 7.23, or 7.2.

[0024] In some embodiments of the present invention, the mucosal adhesive is hydroxypropyl methylcellulose, chitosan, polyvinylpyrrolidone, sodium hyaluronate, or a combination of two, three, or more of them.

[0025] In some embodiments of the present invention, the content of the mucosal adhesive in the ophthalmic preparation is 0.05% w / w to 1% w / w, preferably 0.1% w / w to 0.5% w / w.

[0026] In some embodiments of the present invention, the osmotic pressure regulator is selected from mannitol, sorbitol, lactose, sodium chloride, or a combination of two, three, or more of them, preferably mannitol.

[0027] In some embodiments of the present invention, the content of the osmotic pressure regulator in the ophthalmic preparation is 0.1% w / w to 5% w / w, preferably 1.2% w / w to 4.5% w / w, more preferably 1.3% w / w to 4.1% w / w, and most preferably 1.4% w / w.

[0028] In some embodiments of the present invention, the preservative of the ophthalmic preparation is selected from potassium sorbate, benzalkonium chloride, benzalkonium bromide, chlorobutanol, methylparaben, ethylparaben, propylparaben, or a combination of two, three, or more of them, preferably potassium sorbate.

[0029] In some embodiments of the present invention, the preservative content of the ophthalmic preparation is 0-1% w / w, preferably 0.05% w / w to 0.5% w / w, more preferably 0.08% w / w to 0.3% w / w, and most preferably 0.1% w / w.

[0030] In some embodiments of the present invention, the ophthalmic formulation comprises 0.25% w / w to 0.7% w / w loteranal, 0.1% w / w to 1% w / w oil phase, 0.1% w / w to 6% w / w surfactant, 0.25% w / w to 2% w / w PEG400, 0 to 1% w / w preservative, 0.1% w / w to 5% w / w osmotic pressure regulator, and the balance being water.

[0031] In some embodiments of the present invention, the ophthalmic formulation comprises 0.25% w / w to 0.7% w / w loteranal, 0.1% w / w to 1% w / w oil phase, 0.1% w / w to 6% w / w surfactant, 0.25% w / w to 2% w / w PEG400, 0.1% w / w to 2% w / w propylene glycol, 0% w / w preservative, 0.1% w / w to 5% w / w osmotic pressure regulator, and the balance being water.

[0032] In some embodiments of the present invention, the ophthalmic formulation comprises 0.25% w / w to 0.7% w / w loteranal, 0.1% w / w to 1% w / w oil phase, 0.1% w / w to 6% w / w surfactant, 0.25% w / w to 2% w / w PEG400, 0 to 1% w / w preservative, 0.1% w / w to 5% w / w osmotic pressure regulator, pH adjuster to adjust pH to 5 to 9, and the balance being water.

[0033] In some embodiments of the present invention, the ophthalmic formulation comprises 0.25% w / w to 0.7% w / w loteranal, 0.1% w / w to 1% w / w oil phase, 0.1% w / w to 6% w / w surfactant, 0.25% w / w to 2% w / w PEG400, 0.1% w / w to 2% w / w propylene glycol, 0 to 1% w / w preservative, 0.1% w / w to 5% w / w osmotic pressure regulator, pH adjuster to adjust pH to 5 to 9, and the balance being water.

[0034] In some embodiments of the present invention, the ophthalmic formulation comprises 0.25% w / w to 0.7% w / w loteranal, 0.1% w / w to 1% w / w oil phase, 0.1% w / w to 6% w / w surfactant, 0.25% w / w to 2% w / w PEG400, 0.1% w / w to 2% w / w propylene glycol, 0% w / w preservative, pH adjuster adjusted to pH 5 to 9, and the balance being water.

[0035] In some embodiments of the present invention, the ophthalmic preparation contains loteranal in a preferred concentration of 0.26% w / w to 0.6% w / w, more preferably 0.3% w / w to 0.55% w / w, and most preferably 0.3% w / w, 0.35% w / w, 0.4% w / w, 0.45% w / w, or 0.5% w / w.

[0036] In some embodiments of the present invention, the ophthalmic formulation preferably contains 0.3% w / w to 1.5% w / w, more preferably 0.4% w / w to 1.2% w / w, and most preferably 0.5% w / w and 1% w / w. As an example, the content can be 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, 1.0% w / w, 1.1% w / w, 1.2% w / w, 1.3% w / w, 1.4% w / w, or 1.5% w / w.

[0037] In some embodiments of the present invention, the oil phase of the ophthalmic formulation is selected from medium-chain triglycerides and fatty acid esters. Isopropyl myristate, isopropyl palmitate, ethyl oleate, coconut oil, olive oil, soybean oil, castor oil, or medium-chain triglycerides, or combinations of two, three, or more of these, with castor oil or medium-chain triglycerides being most preferred.

[0038] In some embodiments of the present invention, the ophthalmic formulation preferably comprises an oil phase content of 0.4% w / w to 0.9% w / w, more preferably 0.5% w / w to 0.9% w / w, and most preferably 0.5% w / w, 0.6% w / w, 0.7% w / w, or 0.8% w / w. As an example, it can be 0.2% 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, or 0.9% w / w.

[0039] In some embodiments of the present invention, the surfactant of the ophthalmic formulation is selected from polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, 15-hydroxystearic acid polyethylene glycol ester, Tween 80, or a combination of two, three, or more of them, preferably polyoxyethylene 35 castor oil.

[0040] In some embodiments of the present invention, the surfactant content of the ophthalmic formulation is preferably 0.2% w / w to 5.8% w / w, more preferably 0.25% w / w to 5.5% w / w, 4.5% to 5.5% w / w, and most preferably 5% w / w. As an example, the surfactant content can be 0.5% w / w, 1.0% w / w, 1.5% w / w, 2.0% w / w, 2.5% w / w, 3.0% w / w, 3.5% w / w, 4.0% w / w, 4.5% w / w, 5% w / w, 5.5% w / w, or 6% w / w.

[0041] In some embodiments of the present invention, the preservative of the ophthalmic preparation is selected from potassium sorbate, benzalkonium chloride, benzalkonium bromide, chlorobutanol, methylparaben, ethylparaben, or a combination of two, three, or more of them, preferably potassium sorbate.

[0042] In some embodiments of the present invention, the preservative content of the ophthalmic preparation is preferably 0.05% w / w to 0.5% w / w, more preferably 0.08% w / w to 0.3% w / w, and most preferably 0.1% w / w.

[0043] In some embodiments of the present invention, the propylene glycol content of the ophthalmic formulation is preferably 0.3% w / w to 1.8% w / w, more preferably 0.4% w / w to 1.6% w / w, and most preferably 0.5% w / w, 1% w / w, and 1.5% w / w. As an example, it can be 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, 1.1% w / w, 1.2% w / w, 1.3% w / w, 1.4% w / w, or 1.5% w / w.

[0044] In some embodiments of the present invention, the osmotic pressure regulator of the ophthalmic preparation is selected from mannitol, sorbitol, lactose, sodium chloride, or a combination of two, three, or more of them, preferably mannitol.

[0045] In some embodiments of the present invention, the content of the osmotic pressure regulator in the ophthalmic preparation is preferably 1.2% w / w to 4.5% w / w, more preferably 1.3% w / w to 4.1% w / w, and most preferably 1.4% w / w.

[0046] In some embodiments of the present invention, the pH adjuster of the ophthalmic preparation is selected from sodium hydroxide, tromethamine, disodium hydrogen phosphate, sodium dihydrogen phosphate, or a combination of two, three or more of them.

[0047] In some embodiments of the present invention, the pH of the ophthalmic preparation is preferably 5-9, more preferably 6-8.

[0048] In some embodiments of the present invention, the weight ratio of the oil phase of the ophthalmic formulation to the surfactant is 0.4:5 to 1.25:5, preferably 0.1:6 to 1.25:5, more preferably 0.5:5 to 1:5, and most preferably 0.6:5 ​​to 0.8:5.

[0049] In some embodiments of the present invention, the ophthalmic formulation comprises loteranal 0.25% w / w to 0.7% w / w, castor oil 0.1% w / w to 1% w / w, polyoxyethylene 35 castor oil 0.1% w / w to 6% w / w, PEG400 0.25% w / w to 2% w / w, propylene glycol 0.1% w / w to 2% w / w, potassium sorbate 0 to 1% w / w, mannitol 0.1% w / w to 5% w / w, with the balance being water (e.g., diluted to 100%).

[0050] In some embodiments of the present invention, the content of the ophthalmic preparation loteranal is preferably 0.26% w / w to 0.6% w / w, more preferably 0.3% w / w to 0.55% w / w, and most preferably 0.3% w / w, 0.35% w / w, 0.4% w / w, 0.45% w / w and 0.5% w / w.

[0051] In some embodiments of the present invention, the content of castor oil in the ophthalmic preparation is preferably 0.4% w / w to 0.9% w / w, more preferably 0.5% w / w to 0.9% w / w, and most preferably 0.5% w / w, 0.6% w / w, or 0.8% w / w.

[0052] In some embodiments of the present invention, the content of polyoxyethylene 35 castor oil in the ophthalmic preparation is preferably 0.2% w / w to 5.8% w / w, more preferably 0.25% w / w to 5.5% w / w, and most preferably 5% w / w.

[0053] In some embodiments of the present invention, the content of the ophthalmic formulation PEG400 is preferably 0.3% w / w to 1.5% w / w, more preferably 0.4% w / w to 1.2% w / w, and most preferably 0.5% w / w and 1% w / w. As an example, the content can be 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, 1.0% w / w, 1.1% w / w, 1.2% w / w, 1.3% w / w, 1.4% w / w, or 1.5% w / w.

[0054] In some embodiments of the present invention, the content of propylene glycol in the ophthalmic preparation is preferably 0.3% w / w to 1.8% w / w, more preferably 0.4% w / w to 1.6% w / w, and most preferably 0.5% w / w, 1% w / w, or 1.5% w / w. As an example, it can be 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, 1.1% w / w, 1.2% w / w, 1.3% w / w, 1.4% w / w, or 1.5% w / w.

[0055] In some embodiments of the present invention, the content of potassium sorbate in the ophthalmic preparation is preferably 0.05% w / w to 0.5% w / w, more preferably 0.08% w / w to 0.3% w / w, and most preferably 0.1% w / w.

[0056] In some embodiments of the present invention, the content of mannitol in the ophthalmic preparation is preferably 1.2% w / w to 4.5% w / w, more preferably 1.3% w / w to 4.1% w / w, and most preferably 1.4% w / w.

[0057] In some embodiments of the present invention, the weight ratio of castor oil to polyoxyethylene 35 castor oil in the ophthalmic preparation is 0.4:5 to 1.25:5, preferably 0.1:6 to 1.25:5, more preferably 0.5:5 to 1:5, and most preferably 0.6:5 ​​to 0.8:5.

[0058] In some embodiments of the present invention, the ophthalmic formulation comprises loteranal 0.5% w / w, castor oil 0.8% w / w, polyoxyethylene 35 castor oil 5% w / w, PEG400 1% w / w, propylene glycol 1% w / w, potassium sorbate 0.1% w / w, mannitol 1.4% w / w, with the balance being water.

[0059] In some embodiments of the present invention, the ophthalmic formulation is preferably a microemulsion.

[0060] In some embodiments of the present invention, the ophthalmic preparation is preferably an eye drop.

[0061] In some embodiments of the present invention, the ophthalmic preparation is used to treat eye diseases such as Demodex blepharitis, ocular rosacea, and meibomian gland dysfunction. Attached Figure Description

[0062] Figure 1. Changes in drug concentration over time in the upper eyelid margin of New Zealand rabbits after eye drops were administered in Examples 19, 30 and Comparative Example 18.

[0063] Figure 2. Changes in drug concentration over time in the lower eyelid margin of New Zealand rabbits after eye drops were administered in Examples 19, 30 and Comparative Example 18.

[0064] Figure 3. AUC of ophthalmic administration of Examples 19, 30 and Comparative Example 18 in the upper / lower eyelid margins of New Zealand rabbits. 0-24h . Detailed Implementation

[0065] To better understand the above technical solutions, the technical solutions of the present invention will be described in detail below through specific embodiments.

[0066] In a first aspect, the present invention provides an ophthalmic loteranal microemulsion, wherein the microemulsion is an oil-in-water emulsion and its components include: a therapeutically effective amount of loteranal, an oil phase, a surfactant, a co-surfactant, an osmotic pressure regulator, a pH regulator, a mucosal adhesive, a preservative, and water.

[0067] Further, by mass percentage, the content of loteranar is 0.25%-0.7%, the content of the oil phase is 0.1% w / w to 1% w / w, the content of the surfactant is 0.1% w / w to 6% w / w, the content of the co-surfactant PEG400 is 0.25% w / w to 2% w / w, the content of the co-surfactant propylene glycol is 0.25% w / w to 2% w / w, the content of the mucosal adhesive is 0.05% w / w to 1% w / w, the content of the preservative is 0 to 1% w / w, the content of the osmotic pressure regulator is 0.1% w / w to 5% w / w, the osmotic pressure is adjusted to 260 to 350 mOsmol / kg, the pH is adjusted to 5 to 9, and the balance is water.

[0068] Solubility of loteranar in Comparative Examples 1–13

[0069] The solubility of loteranal in different oil phases, aqueous solutions of surfactants, and aqueous solutions of co-surfactants was investigated. The solubility test method is as follows: solutions were prepared according to the mass ratios in Table 1, stirred at room temperature, and loteranal active pharmaceutical ingredient was added. After stirring, the state of the solution was observed. The solubility results of loteranal in aqueous solutions of different surfactants are shown in Table 1.

[0070] Table 1

[0071] As shown in Table 1, loteranar only exhibits a solubility greater than 2.5 mg / g in a 4.5% aqueous solution of polyoxyethylene 35 castor oil. Polyoxyethylene 35 castor oil acts as a surfactant and has a solubilizing effect on the drug.

[0072] The solubility of loteranal in ophthalmic oil phases and solubilizers was investigated as follows: The tested solution was added according to the mass ratio of the formulation in Table 2, and loteranal was added with stirring at room temperature. The dissolution state of loteranal was observed after stirring. The dissolution results of loteranal in different solutions are shown in Table 2.

[0073] Table 2

[0074] As can be seen from the results in Table 2, loteranar has high solubility in castor oil and propylene glycol. Therefore, castor oil is considered as the oil phase, and propylene glycol and PEG400 are considered as co-surfactants for formulation screening.

[0075] Comparative Examples 14–17

[0076] Polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, 15-hydroxystearic acid polyethylene glycol ester, and Tween 80 were selected as surfactants. Comparative Examples 14-17 in Table 3 were investigated to screen the types of surfactants.

[0077] Microemulsion preparation method:

[0078] According to Table 3, different surfactants were heated and stirred with castor oil according to the mass ratio to obtain the first product; the volume was then replenished with water for injection at the same temperature and cooled to room temperature to obtain the final product.

[0079] Characterization of microemulsions: Microemulsions were characterized by visual inspection, Tyndall effect, and particle size determination.

[0080] (1) Visual inspection: Microemulsion is a transparent or slightly bluish opalescent solution.

[0081] (2) Particle size determination: The hydration dynamic particle size was determined by dynamic light scattering.

[0082] Table 3

[0083] The results of the different surfactants are shown in Table 3. It can be seen that when the oil phase is castor oil and the surfactant is polyoxyethylene 35 castor oil, a clear light blue liquid can be formed. Polyoxyethylene 35 castor oil was subsequently used as the surfactant for formulation screening.

[0084] Examples 1-5

[0085] The amount of castor oil in the oil phase of the formulation was set at 0.5%, and the amount of surfactant was screened. According to the mass ratio of the formulation in Table 4, castor oil, polyoxyethylene 35 castor oil, and PEG400 were heated and stirred in a water bath until homogeneous, yielding the first product. Loteranal was added to the first product and dissolved to obtain the second product. Mannitol and potassium sorbate were added to water for injection and heated to dissolve at the same temperature to obtain the third product. The third product was added to the second product under stirring and mixed thoroughly. The mixture was then made up to the final volume with water for injection.

[0086] The particle size of Examples 3-5 was measured using dynamic light scattering (DLS), and the results are shown in Table 4.

[0087] Table 4

[0088] As shown in Table 4, in Examples 1-5, when the amount of polyoxyethylene 35 castor oil was less than 4.5%, the formed microemulsions could not exist stably, and drug precipitation was observed after standing. The PDI was consistently within a small range, indicating a uniform particle size distribution. A castor oil content of 0.5% and a polyoxyethylene 35 castor oil content ranging from 4.5% to 5% yielded microemulsions with an average particle size of approximately 20 nm.

[0089] Examples 6-9

[0090] Loteranar was fixed at 0.5%, and the amount of oil phase was screened. Polyoxyethylene 35 castor oil was used at 5%. The drugs and excipients were weighed according to the mass ratio of the prescription in Table 5, and the preparations of Examples 6-9 were prepared using the same preparation method as described above.

[0091] Table 5

[0092] As shown in Table 5, Examples 7-9 all produced clear, transparent, pale blue liquids. In Example 6, drug precipitation occurred after standing overnight. In Example 9, after standing at 60°C for 5 days, emulsion droplets aggregated, and the solution turned milky white. The experimental results indicate that a suitable microemulsion particle size can be obtained with an oil phase content of 0.6-0.8%.

[0093] Examples 10-13

[0094] The effect of different loteranal strengths on the formulation was investigated, and loteranal microemulsions of different strengths were prepared. Drugs and excipients were weighed according to the mass ratios in Table 6, and the same preparation methods as described above were used to prepare Examples 10–13.

[0095] Table 6

[0096] As can be seen from the results in Table 6, Examples 8 and 10-13 show that loteranal content of 0.3% to 0.5% can be used to prepare clear and transparent microemulsion formulations.

[0097] Examples 14-20

[0098] Loteranar, with a specification of 0.5%, was used to investigate the effect of different co-surfactants on particle size. Microemulsions were prepared with a fixed amount of castor oil (0.8%), polyoxyethylene 35 castor oil (5%), and different co-surfactants. The drugs and excipients were weighed according to the mass ratios in Table 7, and the preparation methods described above were used to prepare Examples 14–20.

[0099] The particle size of Examples 14-20 was measured using dynamic light scattering (DLS), and the results are shown in Table 7.

[0100] Table 7

[0101] As can be seen from the results in Table 7, in Examples 14-20, a stable system could be obtained by using 0.5% loteranar, 0.8% castor oil, 5% polyoxyethylene 35 castor oil, 0.5% or 0.5% to 1% PEG400 in combination with different proportions of propylene glycol as co-surfactants. The amount of co-surfactant had little effect on the particle size.

[0102] Examples 21-24

[0103] The effects of different mucosal adhesives on microemulsion particle size were investigated.

[0104] According to the mass ratio of the formulation in Table 8, castor oil, polyoxyethylene 35 castor oil, propylene glycol, and PEG400 were heated and stirred in a water bath until homogeneous to obtain the first product. Loteranal was added to the first product and dissolved to obtain the second product. Mannitol and potassium sorbate were added to water for injection and heated to dissolve at the same temperature to obtain the third product. Hydroxypropyl methylcellulose, chitosan, polyvinylpyrrolidone, or sodium hyaluronate were added to water for injection and dissolved at the same temperature to obtain the fourth product. The third and fourth products were added to the second product under stirring and mixed evenly. The mixture was then made up to the final volume with water for injection to obtain the final product.

[0105] The particle size of Examples 21–24 was measured using dynamic light scattering (DLS), and the results are shown in Table 8.

[0106] Table 8

[0107] As can be seen from the results in Table 8, when different mucosal adhesives were added to the formulation, all of Examples 21 to 24 could be prepared into clear and transparent microemulsion formulations with particle sizes within 100 nm and PDI values ​​within a small range, indicating that the particle size distribution was uniform.

[0108] Examples 25-27

[0109] Weigh the drugs and excipients according to the mass ratio of the prescription in Table 9, and prepare Examples 25-27 using the same preparation method as described above. Adjust the pH value to 7.2 and conduct stability influencing factor investigation tests.

[0110] Table 9

[0111] Examples 28-29

[0112] Different pH adjusters were screened, and four different pH adjuster formulations were prepared for stability factor tests. The drugs and excipients were weighed according to the mass ratio of the formulations in Table 10, and the same preparation method as above was used to prepare Examples 28-29, as shown in Table 10.

[0113] Table 10

[0114] Stability test in Experiment Example 1

[0115] Preparation Examples 25–27 were used for stability studies.

[0116] High temperature test: Samples were taken at 0, 10 and 15 days under 60℃ conditions to examine the various indicators of the prescriptions listed in Examples 25 to 27.

[0117] Light exposure test: The samples were placed in a light stability test chamber and sampled at 0, 10 and 15 days under an illuminance of 4500 lx ± 500 lx. The various indicators of the formulations listed in Examples 25 to 27 were examined.

[0118] The results of stability tests for Examples 25-27 are shown in Table 11.

[0119] Table 11

[0120] As can be seen from the results in Table 11, with the fixed lotilaner specification of 0.5%, stability influencing factor tests were conducted on the formulations. For Examples 25 to 27, there were no significant changes in appearance, content, particle size, and osmotic pressure under the test conditions, while the pH decreased slightly during storage.

[0121] pH Stability Investigation of Experimental Example 2

[0122] Prepare Examples 19, 27 to 29 for stability investigation.

[0123] High Temperature Test: Samples were taken at 0, 10d, and 15d under the condition of 60°C to investigate various indicators of the formulations listed in Examples 19, 27 to 29.

[0124] Light Exposure Test: The samples were placed in a light stability test chamber, and samples were taken at 0, 10d, and 15d under the condition of illuminance of 4500lx ± 500lx to investigate various indicators of the formulations listed in Examples 19, 27 to 29.

[0125] The stability test results of Examples 19, 27 to 29 are shown in Table 12.

[0126] Table 12

[0127] From the stability results in Table 12, it shows that: under the test conditions, the pH values of Examples 27 and 28 decreased slightly during storage, while the pH values of Examples 19 and 29 changed little during storage.

[0128] Ocular Tissue Distribution Test of Lotilaner Eye Drops with Different Formulations in Experimental Example 3

[0129] 1. Tested Drugs:

[0130] Prepare ocular tissue distribution test samples according to the mass ratio of Example 19, Example 30, and Comparative Example 18. Prepare lotilaner microemulsion and solution, and the specific formulations are shown in Table 13:

[0131] Table 13

[0132] 2. Test Animals:

[0133] New Zealand rabbits, male, 2 - 4 kg, purchased from Hunan Taiping Biotechnology Co., Ltd., with animal production license SCXK(Xiang)2023 - 0011.

[0134] 3. Test Methods:

[0135] [[ID=4█]]Animal Grouping:

[0136] 1) Comparative group 18: 12 New Zealand rabbits (2 rabbits / time point, 6 time points, 12 rabbits in total), the dosage was 50 μL / eye, the preparation was administered in both eyes, and food and water were allowed.

[0137] 2) Example 19 group: 12 New Zealand rabbits (2 rabbits / time point, 6 time points, 12 rabbits in total), the dosage was 50 μL / eye, the preparation was instilled into both eyes, and food and water were allowed.

[0138] 3) Example 30 group: 12 New Zealand rabbits (2 rabbits / time point, 6 time points, 12 rabbits in total), the dosage was 50 μL / eye, the preparation was instilled into both eyes, and food and water were allowed.

[0139] Sample collection and processing:

[0140] Data collection time points: 0.25h, 1h, 2h, 6h, 12h, and 24h after drug administration.

[0141] After anesthetizing the rabbits with isoflurane gas, the eyelid margins were cleaned with saline solution before collection at various time points. Then, the upper and lower eyelid margins of both eyes were collected separately, and each collection was cleaned again with saline solution. Finally, the samples were rapidly stored in an ultra-low temperature freezer until sample analysis.

[0142] Sample Analysis

[0143] Loteranar was extracted from the homogenate by protein precipitation and quantitatively analyzed using a triple quadrupole tandem mass spectrometer in multiple reaction monitoring mode. The quantitative range was 2.00–8000 ng / mL.

[0144] 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.

[0145] 4. Experimental Results:

[0146] At the same specifications, the tissue exposure of the upper and lower eyelid margins of the 0.25% microemulsion formulation (Example 30) was 1.1 to 1.2 times higher than that of the 0.25% solution group (Comparative Example 18); when the loteranal specification was increased to the 0.5% microemulsion formulation (Example 19), the tissue exposure of the upper and lower eyelid margins was 3.4 to 3.6 times higher than that of the solution (see Table 14, Figure 1, Figure 2, and Figure 3). The 0.5% loteranal microemulsion formulation of the present invention has good pharmacokinetic properties, can significantly improve the ocular bioavailability of loteranal, increase the exposure of the drug in the deeper glandular regions of the eyelid sebaceous glands and meibomian glands infested by Demodex folliculorum, as well as deep into the hair follicles, and enhance the therapeutic effect, showing good application prospects.

[0147] Table 14

[0148] Experimental Example 4: Ocular Irritation Test of Loteranal Eye Drops

[0149] Test samples were prepared according to the mass ratio in Examples 19 and 31, and the specific formulations are shown in Table 15.

[0150] Table 15

[0151] The irritation of loteranal microemulsion formulations (Examples 19 and 31) to the eyes of New Zealand rabbits was evaluated. Three healthy New Zealand rabbits (two females and one male) were selected for each group. A left-right eye control administration method was used. The left eye was given the test substance (1 drop / eye / time, approximately 50 μL per drop, twice daily, with an interval of approximately 12 hours), while the right eye received an equal volume of 0.9% sodium chloride injection. Administration continued for 14 days. The ocular physiological condition of each New Zealand rabbit was observed and recorded before administration, confirming the physiological condition of the cornea, iris, etc. Before grouping, before the first dose each day, and at 1, 2, 4, 24, 48, and 72 hours after the last dose, the local reactions of the animals' eyes were observed and scored (the scoring criteria are shown in Table 16, the standard table for eye irritation response scores). The irritation response scores of the cornea, iris, and conjunctiva of each animal at each observation time point were added together to obtain the total score. The total score was divided by the number of animals in each group to obtain the final score. The degree of irritation was determined according to Table 17.

[0152] Table 16

[0153] Table 17

[0154] The irritation results showed that after 14 consecutive days of ocular administration in New Zealand rabbits, Examples 19 and 31 did not show any obvious abnormalities in the eyes, either by gross observation or by ocular fluorescein examination. The tested Examples 19 and 31 did not cause any irritation to the rabbit eyes. The irritation response scores of the left and right corneas and irises of each animal were 0 at each observation time point, which is within the non-irritating range (0-3).

[0155] Therefore, the loteranal microemulsion eye drops prepared in this invention are non-irritating to rabbit eyes and have good safety for ophthalmic administration.

Claims

1. An ophthalmic formulation characterized in that, The ophthalmic formulation comprises a pharmaceutically active ingredient and a co-surfactant; the pharmaceutically active ingredient is loteranal; and the co-surfactant is PEG400 or a combination of PEG400 and propylene glycol.

2. The ophthalmic formulation of claim 1, wherein, The ophthalmic preparation comprises a pharmaceutically active ingredient, an oil phase, a surfactant, a co-surfactant, and water; The active ingredient of the drug is loteranal; The co-surfactant is PEG400 or a combination of PEG400 and propylene glycol.

3. The ophthalmic formulation of claim 1, wherein Based on the total weight of the ophthalmic preparation, the content of the active ingredient loteranal is 0.25% w / w to 0.7% w / w, preferably 0.26% w / w to 0.6% w / w, more preferably 0.3% w / w to 0.55% w / w, and most preferably 0.3% w / w, 0.35% w / w, 0.4% w / w, 0.45% w / w or 0.5% w / w.

4. The ophthalmic formulation of claim 1, wherein Based on the total weight of the ophthalmic preparation, the content of the co-surfactant PEG400 is 0.25% w / w to 2% w / w, preferably 0.3% w / w to 1.5% w / w, more preferably 0.4% w / w to 1.2% w / w, and most preferably 0.5% w / w or 1% w / w.

5. The ophthalmic formulation of claim 1, wherein Based on the total weight of the ophthalmic preparation, the content of the co-surfactant propylene glycol is 0.25% w / w to 2% w / w, preferably 0.3% w / w to 1.8% w / w, more preferably 0.4% w / w to 1.6% w / w, and most preferably 0.5% w / w, 1% w / w or 1.5% w / w.

6. The ophthalmic formulation of claim 2, wherein The oil phase of the ophthalmic formulation is selected from medium-chain triglycerides and fatty acid esters. Isopropyl myristate, isopropyl palmitate, ethyl oleate, coconut oil, olive oil, soybean oil, castor oil, or medium-chain triglycerides, or combinations of two, three, or more of these, with castor oil or medium-chain triglycerides being the most preferred.

7. The ophthalmic formulation of claim 2, wherein The oil phase content is 0.1% w / w to 1% w / w, preferably 0.4% w / w to 0.9% w / w, more preferably 0.5% w / w to 0.9% w / w, and most preferably 0.5% w / w, 0.6% w / w, 0.7% w / w, or 0.8% w / w, based on the total weight of the ophthalmic preparation.

8. The ophthalmic formulation of claim 2, wherein The surfactant in the ophthalmic formulation is selected from polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, 15-hydroxystearic acid polyethylene glycol ester, Tween 80, or a combination of two, three or more of them, preferably polyoxyethylene 35 castor oil.

9. The ophthalmic formulation of claim 2, wherein The surfactant content of the ophthalmic preparation is 0.1% w / w to 6% w / w, preferably 0.2% w / w to 5.8% w / w, more preferably 0.25% w / w to 5.5% w / w, and most preferably 5% w / w.

10. The ophthalmic formulation of claim 2, wherein The weight ratio of the oil phase to the surfactant in the ophthalmic formulation is 0.4:5 to 1.25:5, preferably 0.1:6 to 1.25:5, more preferably 0.5:5 to 1:5, and most preferably 0.6:5 ​​to 0.8:

5.

11. The ophthalmic formulation of claim 1 or 2, wherein The ophthalmic preparation may also include pH adjusters, mucosal adhesives, osmotic pressure regulators or preservatives, or combinations of two, three or more of them.

12. The ophthalmic preparation according to claim 11, characterized in that... The pH adjuster is selected from sodium hydroxide, tromethamine, disodium hydrogen phosphate, sodium dihydrogen phosphate, or a combination of two, three or more of them.

13. The ophthalmic preparation according to claim 11, characterized in that... The pH of the ophthalmic preparation is preferably 5-9, more preferably 6-8.

14. The ophthalmic preparation according to claim 11, characterized in that... The mucosal adhesive is hydroxypropyl methylcellulose, chitosan, polyvinylpyrrolidone, sodium hyaluronate, or a combination of two, three, or more of them.

15. The ophthalmic preparation according to claim 11, characterized in that... The content of the mucosal adhesive in the ophthalmic preparation is 0.05% w / w to 1% w / w, preferably 0.1% w / w to 0.5% w / w.

16. The ophthalmic preparation according to claim 11, characterized in that... The osmotic pressure regulator is selected from mannitol, sorbitol, lactose, sodium chloride, or a combination of two, three or more of them, preferably mannitol.

17. The ophthalmic preparation according to claim 11, characterized in that... The content of the osmotic pressure regulator in the ophthalmic preparation is 0.1% w / w to 5% w / w, preferably 1.2% w / w to 4.5% w / w, more preferably 1.3% w / w to 4.1% w / w, and most preferably 1.4% w / w.

18. The ophthalmic preparation according to claim 11, characterized in that... The preservative in the ophthalmic preparation is selected from potassium sorbate, benzalkonium chloride, benzalkonium bromide, chlorobutanol, methylparaben, ethylparaben, propylparaben, or a combination of two, three or more of them, preferably potassium sorbate.

19. The ophthalmic preparation according to claim 11, characterized in that... The preservative content of the ophthalmic preparation is 0-1% w / w, preferably 0.05% w / w to 0.5% w / w, more preferably 0.08% w / w to 0.3% w / w, and most preferably 0.1% w / w.

20. The ophthalmic formulation according to any one of claims 1 to 19, characterized in that... The ophthalmic formulation comprises loteranal 0.25% w / w to 0.7% w / w, oil phase 0.1% w / w to 1% w / w, surfactant 0.1% w / w to 6% w / w, PEG400 0.25% w / w to 2% w / w, preservative 0 to 1% w / w, osmotic pressure regulator 0.1% w / w to 5% w / w, with the balance being water.

21. The ophthalmic formulation according to any one of claims 1 to 19, characterized in that... The ophthalmic formulation comprises loteranal 0.25% w / w to 0.7% w / w, oil phase 0.1% w / w to 1% w / w, surfactant 0.1% w / w to 6% w / w, PEG400 0.25% w / w to 2% w / w, propylene glycol 0.1% w / w to 2% w / w, preservative 0 to 1% w / w, osmotic pressure regulator 0.1% w / w to 5% w / w, with the balance being water.

22. The ophthalmic formulation according to any one of claims 1 to 19, characterized in that... The ophthalmic formulation comprises loteranal 0.25% w / w to 0.7% w / w, oil phase 0.1% w / w to 1% w / w, surfactant 0.1% w / w to 6% w / w, PEG400 0.25% w / w to 2% w / w, preservative 0 to 1% w / w, osmotic pressure regulator 0.1% w / w to 5% w / w, pH adjuster adjusted to pH 5 to 9, and the balance being water.

23. The ophthalmic formulation according to any one of claims 1 to 19, characterized in that... The ophthalmic formulation comprises loteranal 0.25% w / w to 0.7% w / w, oil phase 0.1% w / w to 1% w / w, surfactant 0.1% w / w to 6% w / w, PEG400 0.25% w / w to 2% w / w, propylene glycol 0.1% w / w to 2% w / w, preservative 0 to 1% w / w, osmotic pressure regulator 0.1% w / w to 5% w / w, pH adjuster adjusted to pH 5 to 9, and the balance being water.

24. The ophthalmic formulation according to any one of claims 1 to 19, characterized in that... The ophthalmic formulation comprises loteranal 0.25% w / w to 0.7% w / w, oil phase 0.1% w / w to 1% w / w, surfactant 0.1% w / w to 6% w / w, PEG400 0.25% w / w to 2% w / w, propylene glycol 0.1% w / w to 2% w / w, preservative 0 to 1% w / w, pH adjuster adjusted to pH 5 to 9, and the balance being water.

25. The ophthalmic preparation according to any one of claims 20 to 24, characterized in that... The ophthalmic preparation contains loteranal in a preferred concentration of 0.26% w / w to 0.6% w / w, more preferably 0.3% w / w to 0.55% w / w, and most preferably 0.3% w / w, 0.35% w / w, 0.4% w / w, 0.45% w / w, or 0.5% w / w.

26. The ophthalmic formulation according to any one of claims 20 to 24, characterized in that... The ophthalmic formulation preferably contains 0.3% w / w to 1.5% w / w, more preferably 0.4% w / w to 1.2% w / w, and most preferably 0.5% w / w or 1% w / w.

27. The ophthalmic formulation according to any one of claims 20 to 24, characterized in that... The oil phase of the ophthalmic formulation is selected from medium-chain triglycerides and fatty acid esters. Isopropyl myristate, isopropyl palmitate, ethyl oleate, coconut oil, olive oil, soybean oil, castor oil, medium-chain triglycerides, or combinations of two, three, or more of these, with castor oil or medium-chain triglycerides being the most preferred.

28. The ophthalmic formulation according to any one of claims 20 to 24, characterized in that... The ophthalmic preparation preferably contains an oil phase of 0.4% w / w to 0.9% w / w, more preferably 0.5% w / w to 0.9% w / w, and most preferably 0.5% w / w, 0.6% w / w, 0.7% w / w, or 0.8% w / w.

29. The ophthalmic formulation according to any one of claims 20 to 24, characterized in that... The surfactant in the ophthalmic formulation is selected from polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, 15-hydroxystearic acid polyethylene glycol ester, Tween 80, or a combination of two, three or more of them, preferably polyoxyethylene 35 castor oil.

30. The ophthalmic preparation according to any one of claims 20 to 24, characterized in that... The surfactant content of the ophthalmic preparation is preferably 0.2% w / w to 5.8% w / w, more preferably 0.25% w / w to 5.5% w / w, and most preferably 5% w / w.

31. The ophthalmic formulation according to any one of claims 20 to 24, characterized in that... The preservative in the ophthalmic preparation is selected from potassium sorbate, benzalkonium chloride, benzalkonium bromide, chlorobutanol, methylparaben, ethylparaben, or a combination of two, three or more of them, preferably potassium sorbate.

32. The ophthalmic formulation according to any one of claims 20 to 24, characterized in that... The preservative content of the ophthalmic preparation is preferably 0.05% w / w to 0.5% w / w, more preferably 0.08% w / w to 0.3% w / w, and most preferably 0.1% w / w.

33. The ophthalmic formulation according to any one of claims 21, 23, or 24, characterized in that... The propylene glycol content of the ophthalmic preparation is preferably 0.3% w / w to 1.8% w / w, more preferably 0.4% w / w to 1.6% w / w, and most preferably 0.5% w / w, 1% w / w or 1.5% w / w.

34. The ophthalmic formulation according to any one of claims 20 to 23, characterized in that... The osmotic pressure regulator of the ophthalmic preparation is selected from mannitol, sorbitol, lactose, sodium chloride, or a combination of two, three or more of them, preferably mannitol.

35. The ophthalmic preparation according to any one of claims 20 to 23, characterized in that... The content of the osmotic pressure regulator in the ophthalmic preparation is preferably 1.2% w / w to 4.5% w / w, more preferably 1.3% w / w to 4.1% w / w, and most preferably 1.4% w / w.

36. The ophthalmic formulation according to any one of claims 22 to 24, characterized in that... The pH adjuster of the ophthalmic preparation is selected from sodium hydroxide, tromethamine, disodium hydrogen phosphate, sodium dihydrogen phosphate, or a combination of two, three, or more of them.

37. The ophthalmic formulation according to any one of claims 22 to 24, characterized in that... The pH of the ophthalmic preparation is preferably 5-9, more preferably 6-8.

38. The ophthalmic preparation according to any one of claims 20 to 24, characterized in that... The weight ratio of the oil phase to the surfactant in the ophthalmic formulation is 0.4:5 to 1.25:5, preferably 0.1:6 to 1.25:5, more preferably 0.5:5 to 1:5, and most preferably 0.6:5 ​​to 0.8:

5.

39. The ophthalmic preparation according to claim 20, characterized in that... The ophthalmic formulation comprises loteranal 0.25% w / w to 0.7% w / w, castor oil 0.1% w / w to 1% w / w, polyoxyethylene 35 castor oil 0.1% w / w to 6% w / w, PEG400 0.25% w / w to 2% w / w, propylene glycol 0.1% w / w to 2% w / w, potassium sorbate 0 to 1% w / w, mannitol 0.1% w / w to 5% w / w, with the balance being water.

40. The ophthalmic preparation according to claim 39, characterized in that... The content of loteranal in the ophthalmic preparation is preferably 0.26% w / w to 0.6% w / w, more preferably 0.3% w / w to 0.55% w / w, and most preferably 0.3% w / w, 0.35% w / w, 0.4% w / w, 0.45% w / w or 0.5% w / w.

41. The ophthalmic preparation according to claim 39, characterized in that... The castor oil content of the ophthalmic preparation is preferably 0.4% w / w to 0.9% w / w, more preferably 0.5% w / w to 0.9% w / w, and most preferably 0.5% w / w, 0.6% w / w, 0.7% w / w, and 0.8% w / w.

42. The ophthalmic preparation according to claim 39, characterized in that... The content of polyoxyethylene 35 castor oil in the ophthalmic preparation is preferably 0.2% w / w to 5.8% w / w, more preferably 0.25% w / w to 5.5% w / w, and most preferably 5% w / w.

43. The ophthalmic preparation according to claim 39, characterized in that... The content of PEG400 in the ophthalmic preparation is preferably 0.3% w / w to 1.5% w / w, more preferably 0.4% w / w to 1.2% w / w, and most preferably 0.5% w / w or 1% w / w.

44. The ophthalmic preparation according to claim 39, characterized in that... The content of propylene glycol in the ophthalmic preparation is preferably 0.3% w / w to 1.8% w / w, more preferably 0.4% w / w to 1.6% w / w, and most preferably 0.5% w / w, 1% w / w or 1.5% w / w.

45. The ophthalmic preparation according to claim 39, characterized in that... The content of potassium sorbate in the ophthalmic preparation is preferably 0.05% w / w to 0.5% w / w, more preferably 0.08% w / w to 0.3% w / w, and most preferably 0.1% w / w.

46. ​​The ophthalmic formulation according to claim 39, characterized in that... The mannitol content of the ophthalmic preparation is preferably 1.2% w / w to 4.5% w / w, more preferably 1.3% w / w to 4.1% w / w, and most preferably 1.4% w / w.

47. The ophthalmic preparation according to any one of claims 39 to 46, characterized in that... The weight ratio of castor oil to polyoxyethylene 35 castor oil in the ophthalmic preparation is 0.4:5 to 1.25:5, preferably 0.1:6 to 1.25:5, more preferably 0.5:5 to 1:5, and most preferably 0.6:5 ​​to 0.8:

5.

48. The ophthalmic preparation according to any one of claims 39 to 46, characterized in that... The ophthalmic formulation comprises loteranal 0.5% w / w, castor oil 0.8% w / w, polyoxyethylene 35 castor oil 5% w / w, PEG400 1% w / w, propylene glycol 1% w / w, potassium sorbate 0.1% w / w, mannitol 1.4% w / w, with the balance being water.

49. The ophthalmic preparation according to any one of claims 1 to 48, characterized in that... The preferred ophthalmic preparation is an eye drop.

50. The ophthalmic preparation according to any one of claims 1 to 49, characterized in that... The ophthalmic formulation is preferably a microemulsion formulation.

51. The ophthalmic preparation according to any one of claims 1 to 50, characterized in that... The ophthalmic preparation is used to treat eye diseases such as Demodex blepharitis, ocular rosacea, and meibomian gland dysfunction.

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