EG017 ointment

Abstract

According to the EG017 semisolid preparation provided by the invention, the EG017 semisolid preparation (such as an ointment) can be used for treating and / or preventing eye symptoms caused by xerophthalmia, corneal injury and new coronavirus in an external smearing administration manner by adjusting the type of a fat-soluble matrix, adding an antibacterial agent and optimizing a preparation process, so that the EG017 semisolid preparation can be used for treating and / or preventing the eye symptoms caused by the xerophthalmia, the corneal injury and the new coronavirus. The problem that local administration of EG017 eyes in the prior art has no obvious effect is solved.

Description

EG017 ointment

[0001] This application requires the following:

[0002] Priority to the prior application entitled “EG017 Ointment” with patent application number 202310138428.1 filed with the State Intellectual Property Office of China on February 20, 2023; the full text of the prior application is incorporated into this application by reference. Technical Field

[0003] The invention belongs to the field of pharmaceutical preparations, and particularly relates to an EG017 ointment. Background Art

[0004] EG017, chemical name is (S)-1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-ylnicotinate, English chemical name is (S)-1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-ylnicotinate, molecular formula is C 25 H 17 F3N4O4, molecular weight is 494.43. The chemical structure is as follows:

[0005] Dry eye disease refers to a broad range of conditions characterized by abnormal tear quality, quantity, or dynamics, resulting in decreased tear film stability and accompanied by ocular discomfort and / or ocular surface pathology. These conditions can cause keratoconjunctivitis and impair vision. In recent years, with the widespread use of computers and smartphones, people are spending more time with their eyes. This, combined with poor eye habits, has led to a significant increase in the incidence of dry eye disease. Dry eye disease has become a global epidemic, with its incidence in my country steadily increasing and trending toward younger patients. Studies have shown that inflammatory responses in ocular surface tissues are the primary cause of decreased tear secretion in dry eye disease. Currently, treatments for dry eye mainly rely on artificial tears, corticosteroids, and immunosuppressants such as cyclosporine A. Artificial tears are merely tear substitutes and have no therapeutic effect on their own. Long-term use of drugs such as corticosteroids and cyclosporine A can have toxic side effects on the ocular surface. Therefore, there is an urgent clinical need for effective treatments that are free of significant local and systemic side effects with long-term use.

[0006] CN112043693A describes the use of ester-containing aromatic propionamide compounds in the preparation of drugs for treating dry eye. It shows that topical ocular administration of EG-17 (i.e., EG017) has no significant effect on experimental dry eye, while oral administration has a significant improvement effect on the dry eye model. Therefore, the dosage form of EG017 that was first approved for clinical trials for dry eye was also a tablet. However, for dry eye, topical ocular administration has the advantages of rapid drug delivery to the relevant site, concentrated drug action, and ease of use. Therefore, it is urgent to solve the problem of the existing technology of EG017 having no significant effect when administered topically to the eye, and ultimately develop an effective topical ocular administration formulation.

[0007] Summary of the Invention

[0008] To address the aforementioned technical issues, the present invention provides a semisolid formulation of EG017, particularly an ointment (e.g., a topical suspension ointment), which can be used to treat dry eye. Administration can be by application to the upper and lower eyelids. Commonly used strengths of the semisolid formulation include 1%, 3%, 5%, and 9% EG017 content; each individual package can contain 1-10g of the semisolid formulation, for example, 2g per tube.

[0009] In a first aspect, the present invention provides an EG017 semisolid formulation comprising EG017 as an active substance, a fat-soluble matrix, and an antibacterial agent;

[0010] The structural formula of EG017 is shown below:

[0011] In some embodiments, the content (weight percentage) of the active substance EG017 is 0.1%-20%, preferably 0.5%-10%, for example 1%, 3%, 5%, 9%;

[0012] The weight percentage of the fat-soluble matrix is ​​75%-99%, preferably 90%-99%, such as 98.94%, 96.94%, 94.94%, 90.94%;

[0013] The weight percentage of the antibacterial agent is 0.01%-0.5%, preferably 0.01%-0.1%, such as 0.06%.

[0014] As used herein, when referring to the percentage content (%) of a component, this refers to the weight percentage (weight % or wt %). Those skilled in the art will appreciate that, when formulating a composition or formulation, and / or expressing the composition of a composition or formulation, using weight percentage is a conventional expression for components in different states of aggregation.

[0015] In some embodiments, the fat-soluble matrix is ​​selected from one, two or more of white petrolatum, light liquid paraffin, lanolin, silicone oil, and beeswax; preferably one or two of white petrolatum, light liquid paraffin, and lanolin.

[0016] In some embodiments, when the fat-soluble matrix consists of white petrolatum, light liquid paraffin, and lanolin, the weight percentage of light liquid paraffin is ≤10%, for example, 4%-10%; preferably, the weight percentage of white petrolatum to light liquid paraffin is 75%-95%:4%-10%.

[0017] In some embodiments, the antibacterial agent is selected from one, two or more of butylparaben, methylparaben, propylparaben, ethylparaben, benzyl alcohol, chlorobutanol, phenol, cresol, benzalkonium bromide, benzethonium chloride, benzoic acid, propionic acid, hydrogen peroxide, and peracetic acid, preferably one, two or more of butylparaben, methylparaben, and propylparaben, more preferably butylparaben;

[0018] And / or, the weight percentage of the antibacterial agent is 0.01%-0.5%, preferably 0.01%-0.2%, more preferably 0.06%.

[0019] In some embodiments, the fat-soluble matrix optionally includes lanolin, and the weight percentage of lanolin is 0%-10%; preferably 0.5%-3%, such as 1%.

[0020] In some embodiments, the semisolid preparation is selected from ointments (salve), creams, emulsions, and microemulsions; preferably, it is an ointment (salve), such as an external suspension ointment.

[0021] In some embodiments, the semisolid formulation includes active substance EG017, white petrolatum, light liquid paraffin, lanolin, and butylparaben;

[0022] The content of the active substance EG017 (weight percentage) is 0.1%-20%, preferably 0.5%-10%, more preferably 1%-9%, for example 1%, 3%, 5%, 9%;

[0023] The content of white vaseline (weight percentage) is 75%-95%, preferably 84%-92%;

[0024] The content of light liquid paraffin (weight percentage) is 4%-10%, preferably 5%-6.5%;

[0025] The content of lanolin (weight percentage) is 0%-10%; preferably 0.5%-3%, for example 1%;

[0026] The content of butylparaben (weight percentage) is 0.01%-0.5%, preferably 0.01%-0.2%, for example 0.06%.

[0027] In some embodiments, the semisolid formulation comprises the following components:

[0028] In some embodiments, the semisolid formulation comprises the following components:

[0029] In some embodiments, the semisolid formulation can be selected from any one of formulations 1-4:

[0030] Preparation 1:

[0031] Preparation 2:

[0032] Preparation 3:

[0033] Preparation 4:

[0034] In some embodiments, the semi-solid formulation optionally includes an antioxidant, which can be selected from sodium metabisulfite, sodium bisulfite, and anhydrous sodium sulfite.

[0035] In some embodiments, the semi-solid formulation optionally includes a penetration enhancer, such as a medium chain triglyceride, and / or a weight percentage of 0-20%.

[0036] In some embodiments, a humectant, such as glycerin, is optionally included in the semisolid formulation.

[0037] In some embodiments, the semisolid preparation is used to treat and / or prevent one or more of the following diseases: dry eye (e.g., dry eye caused by cold wind stimulation), corneal damage, and eye symptoms caused by the new coronavirus.

[0038] In some embodiments, the semi-solid formulation is administered by application, preferably to the skin of the upper and lower eyelids (eyelids).

[0039] In some embodiments, the semisolid dosage form is distributed to various ocular tissues, such as the conjunctiva and meibomian glands, after administration.

[0040] In some embodiments, the semisolid formulation increases tear secretion, and / or increases tear film stability, and / or improves corneal damage, such as symptoms associated with acute corneal damage, after administration.

[0041] In a second aspect, the present invention provides a process for preparing the semisolid formulation disclosed herein, comprising the following steps:

[0042] 1) Weighing the components of the semi-solid preparation and heating the matrix to melt;

[0043] 2) After the substrate cools down, add the active ingredient EG017 and mix until homogenized;

[0044] 3) After cooling, the paste is formed and then filled and sealed.

[0045] The above matrix refers to other components excluding the active substance EG017.

[0046] In some embodiments, in step 1), the temperature at which the matrix is ​​heated and melted is 80°C±15°C, preferably 80°C±5°C; and / or, in step 2), the matrix is ​​cooled to 55°C±15°C and then the active substance EG017 is added and mixed, preferably the matrix is ​​cooled to 55°C±5°C, and the active substance EG017 is added while stirring.

[0047] In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned semisolid dosage form and other active ingredients.

[0048] In some embodiments, other active ingredients are for example sirolimus, calcipotriol, erythromycin.

[0049] In a fourth aspect, the present invention provides the use of the above-mentioned semisolid preparation or pharmaceutical composition in the preparation of a medicament for treating and / or preventing one or more of the following diseases: dry eye (e.g., dry eye caused by cold wind stimulation), corneal damage, and eye symptoms caused by the new coronavirus.

[0050] In some embodiments, the semi-solid formulation or pharmaceutical composition is administered by application, preferably to the skin surface of the upper and lower eyelids (eyelids).

[0051] In some embodiments, the semisolid formulation or pharmaceutical composition is distributed to various ocular tissues, such as the conjunctiva and meibomian glands, after administration.

[0052] In some embodiments, the semisolid formulation or pharmaceutical composition increases tear secretion and / or increases tear film stability and / or improves corneal damage, such as symptoms associated with acute corneal damage, after administration.

[0053] In a fifth aspect, the present invention provides the use of the above-mentioned semisolid preparation or pharmaceutical composition for treating and / or preventing one or more of the following diseases: dry eye (e.g., dry eye caused by cold wind stimulation), corneal damage, and eye symptoms caused by the new coronavirus;

[0054] Preferably, the semisolid preparation or pharmaceutical composition is administered by application, preferably on the upper and lower eyelid skin surfaces (eyelids);

[0055] and / or, the semisolid formulation or pharmaceutical composition is distributed in various ocular tissues, such as the conjunctiva and meibomian glands, after administration;

[0056] And / or, the semisolid preparation or pharmaceutical composition increases tear secretion, and / or increases tear film stability, and / or improves corneal damage, such as symptoms associated with acute corneal damage, after administration. Beneficial effects

[0057] The present invention provides an EG017 semi-solid preparation. By adjusting the type of fat-soluble matrix, adding antibacterial agents, and optimizing the preparation process, the EG017 semi-solid preparation (such as an ointment) can be applied externally to treat and / or prevent dry eye, corneal damage, and eye symptoms caused by the new coronavirus. The preparation specifications are, for example, 1%, 3%, 5%, and 9%, which solves the problem in the prior art that local administration of EG017 to the eye has no obvious effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 is a bar graph showing the distribution of EG017 in various tissues or plasma of male New Zealand white rabbits after a single eyelid administration of a 3% EG017 ointment. In Figure 1 , the horizontal axis represents 1, 6, 8, and 36 hours after administration, from left to right.

[0059] Figure 2 is a bar graph showing the distribution of EG017 in various tissues or plasma after a single eyelid administration of 3% EG017 ointment to female New Zealand white rabbits; in Figure 2 , the horizontal axis represents 1, 6, 8, and 36 hours after administration, from left to right. DETAILED DESCRIPTION

[0060] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0061] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0062] Example 1 API-excipient compatibility test and results

[0063] The EG017 API was mixed with excipients in the proportions specified in Table 1 and placed under high temperature (60°C) and high humidity (25°C / 92.5% RH) conditions. Samples were taken at 0, 15, and 30 days to examine changes in properties and total impurity content (%) and to evaluate the compatibility between the API and excipients. The results are shown in Table 1.

[0064] Compatibility test conclusion of raw materials and auxiliary materials:

[0065] 1) EG017 alone exhibits good stability at high temperatures of 60°C and high humidity of 92.5% RH;

[0066] 2) EG017 exhibits poor compatibility at high temperatures when mixed with excipients containing primary or secondary hydroxyl groups, such as benzyl alcohol, polyethylene glycol, and propylene glycol, possibly due to the hydrolysis of the ester in the API.

[0067] 3) EG017 has good compatibility with common oil-phase matrices, such as white petrolatum, light liquid paraffin, and lanolin;

[0068] 4) EG017 has relatively poor compatibility with most emulsifier compounds, such as polysorbate 80 and glyceryl mono- and distearate, which may be attributed to the easy hydrolysis of the ester in the API;

[0069] 5) EG017 has good compatibility with common antioxidants such as sodium metabisulfite, sodium bisulfite, and anhydrous sodium sulfite;

[0070] Example 2, dosage form screening and results

[0071] According to Tables 2 to 5 below, corresponding dosage forms were prepared and tested for total impurity content (%) at day 0 and at a high temperature of 40°C for 10 days. The neglect limit was 0.05%. If the total impurity content at day 0 was relatively high, the 10-day high temperature of 40°C was not considered. The stability of the different dosage forms was compared, and the results are shown in Tables 2 to 5.

[0072] Table 2 Ointment dosage form prescription ratio

[0073] Table 3 Cream dosage form prescription ratio

[0074] Table 4 Ratio of latex dosage form prescription

[0075] Table 5 Microemulsion formulation ratio

[0076] According to the above stability investigation, the ointment dosage form (ointment) shown in Table 2 has good stability, and the prescription was adjusted on this basis for screening.

[0077] Example 3: Prescription Screening

[0078] 1. Content of API

[0079] The suitable content of the raw material EG017 is 0.5%-10%. The prescription screening is carried out with the 3% raw material specification, and 1%, 5%, and 9% specifications are also prepared, and the proportion of excipients is adaptively adjusted.

[0080] 2. Penetration enhancers

[0081] This product is a semisolid preparation. Generally, drug penetration affects drug efficacy, so we attempted to add a suitable penetration enhancer to the formulation to improve drug absorption. Medium-chain triglycerides, which have a penetration-enhancing effect, were selected for this study.

[0082] However, a comparison of transdermal permeation tests between formulations containing 20%, 5%, and 0% medium-chain triglycerides revealed no significant differences in the results across the formulations. Furthermore, no significant differences were observed in the content and related substance results between the 5% and 0% formulations. Therefore, it can be concluded that comparable transdermal permeation effects can be achieved with or without the addition of medium-chain triglycerides as a permeation enhancer, and omitting the permeation enhancer may be considered.

[0083] 3. Antibacterial agents

[0084] Compatibility testing of raw materials and excipients revealed that the antibacterial agent benzyl alcohol exhibited poor compatibility with EG017. Therefore, methylparaben, propylparaben, and butylparaben were selected as antibacterial agents for testing. Methylparaben and propylparaben are typically used in combination, while butylparaben can be used alone. Samples were prepared according to Table 6. Comparison revealed no significant effect of these different antibacterial agents on the API content or impurity profile. Regarding transdermal absorption, samples containing butylparaben significantly outperformed those containing methylparaben and propylparaben (see Table 7). Based on the transdermal test results, butylparaben was selected as the antibacterial agent.

[0085] The antibacterial efficacy of butylparaben was tested at different concentrations (0.06%, 0.12%, and 0.18%). The results showed that the antibacterial efficacy of the different concentrations was comparable, with 0.06% achieving the desired antibacterial effect. To minimize the side effects of the antibacterial agent, a concentration of 0.06% was established for the formulation. The results of the antibacterial efficacy experiments at different concentrations are shown in Table 8.

[0086] Table 6 Samples of different types of antibacterial preparations

[0087] Table 7 Transdermal test results

[0088] Table 8 Experimental results of antibacterial efficacy of butylparaben at different concentrations

[0089] 4. Paste base ratio

[0090] Based on compatibility testing of raw materials and excipients, white petrolatum and light liquid paraffin were selected as the ointment matrix. The greater the proportion of liquid paraffin, the lower the sample viscosity, the softer the paste after cooling, and the more transparent the paste appearance. In other words, the greater the proportion of liquid paraffin, the thinner the paste. Light liquid paraffin accounts for ≤10%, which has a certain viscosity but is not too thin. The viscosity when the packaged sample is opened and squeezed out is not too high, and the viscosity is relatively suitable for application, making it a suitable choice. The final paste matrix ratio determined is white petrolatum: light liquid paraffin = 75-95%: 4-10%.

[0091] 5. Selection of auxiliary materials - lanolin

[0092] Lanolin is often used with petrolatum to improve its water absorption and permeability. Lanolin allows the active ingredient to be rapidly absorbed by the mucous membranes and skin, providing strong adhesion, stability, and resistance to rancidity. However, its high viscosity can cause discomfort when applied topically, and it also has a pungent odor. This study compared the effects of adding lanolin with or without it, and the amount of lanolin added, based on their properties. Lanolin screening formulas are shown in Table 9.

[0093] Table 9 Lanolin screening prescription

[0094] Results: From a physical perspective, adding lanolin resulted in a finer, more uniform appearance. The appearance of the skin remained relatively smooth and uniform despite the different lanolin ratios. Because lanolin itself has a pungent odor, reducing the lanolin ratio significantly reduced the odor. Furthermore, a smaller application amount was required, which is expected to improve compliance. Therefore, a lanolin dosage of 1% was selected.

[0095] 6. Specific preparation prescription

[0096] Based on the above prescription screening results, four strengths (1%, 3%, 5%, and 9%) were prepared. The ratios of white petrolatum and light liquid paraffin were slightly adjusted, while the ratios of lanolin and butylparaben remained unchanged. The prescriptions for each strength are shown in Table 10.

[0097] Table 10 Prescriptions for each specification

[0098] 7. Preparation-related characteristics

[0099] Testing of the four formulations above revealed total impurities within 0.11%, API particle sizes below 50 μm, and viscosities of approximately 18,651 mPas, meeting quality standards. Typical batch test results for each formulation are shown in Table 11.

[0100] Table 11 Test results of typical batches of various specifications

[0101] 8. Transdermal test:

[0102] A prepared pig ear was placed in a Franz diffusion cell, with the stratum corneum facing the donor chamber. The ear was then tightened and clamped with a clamp, and excess skin was trimmed. Approximately 300 mg of each of the four EG017 ointments (1%, 3%, 5%, and 9%) listed in Table 10 was evenly applied to the skin. The receiving chamber was filled with receiving solution, and air bubbles were removed. The volume of the receiving solution was adjusted so that the liquid level at the filling tube was approximately level with the skin. The speed was set to 400 rpm and the temperature to 32°C ± 0.5°C. Air bubbles were promptly removed from the receiving chamber during the experiment. The receiving solution was 6.5 ml of physiological saline containing 1% polysorbate 80. At 40, 70, 130, 5, and 24 hours, 2 ml of the solution was withdrawn (replenished with the same receiving solution immediately after withdrawal). The solution was centrifuged at 10,000 rpm for 10 minutes, and the supernatant was sampled. The results are shown in Table 12.

[0103] Table 12 Transdermal test results of EG017 ointment of various specifications

[0104] Conclusion: The 24-hour skin permeation was positively correlated with the dosage.

[0105] Example 4, preparation process

[0106] EG017 begins to melt at around 93°C. The melting points of white petrolatum are 45°C to 60°C, lanolin 36°C to 42°C, and butylparaben 68°C to 71°C. A heating temperature of 80°C ± 5°C allows complete melting of white petrolatum, light liquid paraffin, lanolin, and butylparaben, resulting in a clear, transparent solution. Adding EG017 to the dispersion at this point revealed that the drug substance agglomerated and could not be evenly dispersed in the matrix. This suggests that a temperature of 80°C ± 5°C is sufficient to partially melt the API into agglomerates, making it unsuitable for simultaneous heating with the matrix and excipients or for hot dispersion. Therefore, the matrix was gradually cooled and the API was added. Even when the matrix was cooled to 65°C, a slight tendency for API crystallization and agglomeration was still observed, but the amount was small and had little impact on the overall content. A more reliable method is to cool the matrix to 55°C ± 5°C and then add the API while stirring. This allows the API to be evenly dispersed in the matrix as a suspension. Dispersion at this temperature is very stable. Therefore, the main process steps for the preparation of EG017 ointment are determined to be: weighing, heating and melting the matrix, cooling the matrix, adding the raw material and mixing, homogenizing, cooling to form a paste, and filling and sealing.

[0107] Example 5: Tissue distribution of drug delivery to the eyelids of New Zealand white rabbits

[0108] Twenty-four New Zealand white rabbits were randomly divided into four groups, half male and half female. Ocular tissue and plasma samples were collected 1, 6, 8, and 36 hours after trans-ocular administration of a 3% ointment. Tissues included the cornea, conjunctiva, iris, aqueous humor, meibomian glands, lacrimal glands, lens, and vitreous. EG017 concentrations in plasma and ocular tissues were determined using a validated LC-MS / MS method. The results are shown in Figures 1 and 2.

[0109] As shown in Figures 1 and 2, EG017 is distributed to various ocular tissues and plasma in New Zealand white rabbits, primarily in ocular tissues, with concentrations in the conjunctiva and meibomian glands significantly higher than in other ocular tissues. After 36 hours, EG017 is partially cleared from ocular tissues but remains at relatively high concentrations. Meanwhile, plasma exposure to EG017 is relatively low relative to ocular tissue exposure, indicating a concentrated effect in the eye.

[0110] Example 6: Pharmacodynamic study of EG017 ointment in female cynomolgus monkeys with dry eye

[0111] Six elderly female cynomolgus monkeys were subjected to acute cold wind stimulation to establish a model of acute cold wind. For seven consecutive days before dosing and daily before dosing, the animals' upper and lower eyelids were fixed, the eyeballs exposed, and a high-power hair dryer (cold wind mode) was used to continuously apply cold wind to both eyes for 5 minutes from a distance of 20 cm. After successful model establishment, the animals were sequentially administered with five ointments: vehicle (G1), 1% EG017 (G2), 3% EG017 (G3), 9% EG017 (G4), and 3% EG017 + 0.5% sirolimus (G5). Tear secretion, tear film breakup time, and corneal fluorescein staining scores were measured before dosing, 24 hours after dosing, and on day 4 after dosing.

[0112] Results: (1) Regarding tear secretion (Table 13), 24 hours after administration and on the 4th day after administration, the medium and high doses of EG017 and the combination of EG017 and sirolimus significantly increased the tear secretion of animals in G1 and G2 compared with G3, G4 and G5, respectively. (2) Regarding tear film breakup time (Table 14), compared with the vehicle group, the drug group significantly increased the stability of the tear film, and the improvement in tear film stability showed a dose-dependent effect; compared with the combination of EG017 and sirolimus, at Day 2 and Day 5, the 9% dose of EG017 showed a better improvement in the breakup time of the left eye and the left eye, respectively, and there was a statistical difference. (3) Regarding corneal staining scores (Table 15), compared with the vehicle group, the drug group significantly reduced the corneal staining scores of both eyes, showing an improvement effect on corneal damage, and there was a certain dose-related effect.

[0113] Table 13 Effect of EG017 ointment on tear secretion (mm, mean ± SEM, n = 6)

[0114] Note: ****P<0.0001 compared with vehicle administration.

[0115] Table 14 Effect of EG017 ointment on tear film breakup time (s, mean ± SEM, n = 6)

[0116] Note: Compared with vehicle administration, *P < 0.05, ***P < 0.001, ****P < 0.0001.

[0117] Table 15 Effect of EG017 ointment on corneal fluorescence staining score (score, mean ± SEM, n = 6)

[0118] Note: Compared with vehicle administration, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

[0119] In summary, under the experimental conditions of this study, the medium- and high-dose EG017 and EG017 combined with sirolimus treatment groups showed significant improvements in tear secretion, tear film stability, and corneal damage, and the improvement in tear film stability and corneal damage showed a dose-related effect; compared with the combined treatment group, the high-dose EG017 group performed better in improving tear film breakup time.

[0120] Example 7: Toxicology studies

[0121] In a toxicity study in New Zealand white rabbits with a 4-week topical administration and a 4-week recovery period, no local or systemic toxicity was observed when 2, 6, or 18 mg / kg of EG017 ointment was applied to the bilateral eyelids.

[0122] Rabbit skin irritation and eye irritation tests showed no significant abnormalities in the animals' general condition, behavior, physical signs, or weight during the test period. No animals exhibited erythema, edema, or other abnormal reactions. No significant abnormalities were observed in the conjunctiva, iris, or cornea of ​​either eye, nor were any other eye injuries observed. Based on the skin irritation intensity and eye irritation evaluation standards, EG017 Ointment was non-irritating.

[0123] In addition, active allergy studies and phototoxicity studies were conducted in guinea pigs to investigate the safety of topical administration. The results were all negative, indicating that topical administration of EG017 did not cause irritation at the administration site or allergic skin reactions.

[0124] EG017 was negative in the Ames test, staining aberration test, and micronucleus test.

[0125] In summary, EG017 ointment is highly safe for topical administration.

[0126] In addition, CN112641781B has verified that EG017 has a strong anti-COVID-19 effect and can be used to prepare anti-COVID-19 drugs. Since the new coronavirus can cause eye discomfort, damage and other related symptoms, the composition of the present invention has a good distribution in ocular tissues and can treat and prevent dry eye and corneal damage. Therefore, it can be used to treat and / or prevent eye symptoms caused by the new coronavirus.

[0127] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. An EG017 semisolid preparation comprising an active substance EG017, a fat-soluble matrix and an antibacterial agent; in, The structural formula of EG017 is shown below:

2. The EG017 semisolid preparation according to claim 1, characterized in that The content (weight percentage) of active substance EG017 is 0.1%-20%, preferably 0.5%-10%, for example 1%, 3%, 5%, 9%; and / or, the weight percentage of the fat-soluble matrix is ​​75%-99%, preferably 90%-99%, such as 98.94%, 96.94%, 94.94%, 90.94%; And / or, the weight percentage of the antibacterial agent is 0.01%-0.5%, preferably 0.01%-0.1%, such as 0.06%.

3. The EG017 semisolid preparation according to claim 1 or 2, characterized in that: The fat-soluble matrix is ​​selected from one, two or more of white vaseline, light liquid paraffin, lanolin, silicone oil and beeswax; preferably one or two of white vaseline, light liquid paraffin and lanolin; preferably, when the fat-soluble matrix is ​​composed of white vaseline, light liquid paraffin and lanolin, the weight percentage of light liquid paraffin is ≤10%, for example, 4%-10%; preferably, the weight percentage of white vaseline and light liquid paraffin is 75%-95%:4%-10%; And / or, the antibacterial agent is selected from one, two or more of butyl hydroxybenzoate, methyl paraben, propyl paraben, ethyl hydroxybenzoate, benzyl alcohol, chlorobutanol, phenol, cresol, benzalkonium bromide, benzethonium chloride, benzoic acid, propionic acid, hydrogen peroxide, and peracetic acid, preferably one, two or more of butyl hydroxybenzoate, methyl paraben, and propyl paraben, more preferably butyl hydroxybenzoate; preferably, the weight percentage of the antibacterial agent is 0.01%-0.5%, preferably 0.01%-0.2%, more preferably 0.06%; And / or, the fat-soluble matrix optionally includes lanolin, and the weight percentage of lanolin is 0%-10%; preferably 0.5%-3%, such as 1%; And / or, the semisolid preparation is selected from ointments (salve), creams, emulsions, and microemulsions; preferably ointments (salve), such as external suspension ointments.

4. The EG017 semisolid preparation according to any one of claims 1 to 3, characterized in that The semisolid formulation includes the active substance EG017, white petrolatum, light liquid paraffin, lanolin, and butylparaben; The content (weight percentage) of the active substance EG017 is 0.1%-20%, preferably 0.5%-10%, more preferably 1%-9%, for example 1%, 3%, 5%, 9%; and / or, the content of white vaseline (by weight) is 75%-95%, preferably 84%-92%; and / or, the content (by weight) of light liquid paraffin is 4%-10%, preferably 5%-6.5%; And / or, the content of lanolin (by weight) is 0%-10%; preferably 0.5%-3%, for example 1%; and / or, the content of butylparaben (by weight) is 0.01%-0.5%, preferably 0.01%-0.2%, for example 0.06%; Preferably, the semisolid formulation comprises the following components: Preferably, the semisolid formulation comprises the following components: Preferably, the semisolid preparation is selected from any one of preparations 1-4: Preparation 1: Preparation 2: Preparation 3: Preparation 4:

5. The EG017 semisolid preparation according to any one of claims 1 to 4, characterized in that The semisolid preparation optionally includes an antioxidant, the antioxidant being selected from sodium metabisulfite, sodium bisulfite, and anhydrous sodium sulfite; and / or, the semi-solid preparation optionally includes a penetration enhancer, such as medium chain triglycerides, preferably the weight percentage of the penetration enhancer is 0-20%; And / or, the semi-solid formulation optionally includes a humectant, such as glycerin.

6. The EG017 semisolid preparation according to any one of claims 1 to 5, characterized in that Semisolid preparations are used to treat and / or prevent one or more of the following diseases: dry eye (e.g., dry eye caused by cold wind stimulation), corneal damage, and eye symptoms caused by the new coronavirus; And / or, the semi-solid preparation is administered by applying, preferably on the upper and lower eyelid skin surfaces (eyelids) of both eyes; and / or, the semisolid dosage form is distributed in various ocular tissues, such as the conjunctiva and meibomian glands, after administration; And / or, the semisolid preparation increases tear secretion after administration, and / or increases tear film stability, and / or improves corneal damage, such as symptoms associated with acute corneal damage.

7. A process for preparing the semisolid preparation according to any one of claims 1 to 6, comprising the following steps: 1) Weighing the components of the semi-solid preparation and heating the matrix to melt; 2) After the substrate cools down, add the active substance EG017 and mix and homogenize; 3) After cooling, the paste is formed and then filled and sealed. Preferably, in step 1), the temperature at which the matrix is ​​heated and melted is 80°C ± 15°C; And / or, in step 2), the active substance EG017 is added and mixed after the substrate is cooled to 55°C±15°C, preferably while being stirred.

8. A pharmaceutical composition comprising the semisolid dosage form according to any one of claims 1 to 6 and other active ingredients; Preferably, other active ingredients such as sirolimus, calcipotriol, erythromycin.

9. Use of the semisolid preparation according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing one or more of the following diseases: dry eye (e.g., dry eye caused by cold wind stimulation), corneal damage, and eye symptoms caused by the new coronavirus; Preferably, the semisolid preparation or pharmaceutical composition is administered by smearing, preferably on the upper and lower eyelid skin surfaces (eyelids) of both eyes; and / or, the semisolid formulation or pharmaceutical composition is distributed in various ocular tissues, such as the conjunctiva and meibomian glands, after administration; And / or, the semisolid preparation or pharmaceutical composition increases tear secretion and / or increases tear film stability and / or improves corneal damage, such as symptoms associated with acute corneal damage, after administration.

10. Use of the semisolid preparation according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 8 for treating and / or preventing one or more of the following diseases: dry eye (e.g., dry eye caused by cold wind stimulation), corneal damage, and eye symptoms caused by the new coronavirus; Preferably, the semisolid preparation or pharmaceutical composition is administered by smearing, preferably on the upper and lower eyelid skin surfaces (eyelids) of both eyes; and / or, the semisolid formulation or pharmaceutical composition is distributed in various ocular tissues, such as the conjunctiva and meibomian glands, after administration; And / or, the semisolid preparation or pharmaceutical composition increases tear secretion and / or increases tear film stability and / or improves corneal damage, such as symptoms associated with acute corneal damage, after administration.

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