Ophthalmic composition for treating non-infectious inflammatory diseases

Abstract

An ophthalmic composition for treating non-infectious inflammatory diseases. The ophthalmic composition comprises an active substance and an ophthalmic excipient, wherein the active substance is a JAK inhibitor; and the ophthalmic excipient comprises a pH buffer, an osmotic pressure regulator, a solubilizer, and water for injection. The ophthalmic composition is used for topical eye drop administration, is compatible and stable with eyes, can improve the bioavailability of the active substance in the ophthalmic composition, can be used for treating non-infectious inflammatory diseases, is less invasive, has small side effects, involves a simple production process, and is amenable to large-scale production.

Description

Ophthalmic composition for treating non-infectious inflammatory diseases

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on April 28, 2023, with application number 202310484101.X and invention name “An ophthalmic composition for treating non-infectious inflammatory diseases”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present application relates to the field of pharmaceutical technology, and in particular to an ophthalmic composition comprising a JAK inhibitor for treating non-infectious inflammatory diseases. Background Art

[0003] The eye is one of the most vital organs in the human body. Any impairment of vision can severely impact daily activities and life. Uveitis, a vision-threatening inflammation of the uveal tract, is very common worldwide, with anterior uveitis being one of the most common intraocular inflammations. Recurrent or untreated anterior uveitis has potentially serious consequences. Anterior uveitis is an inflammation of the middle layer of the eye (including the iris and adjacent tissues), which can be infectious or non-infectious and may be associated with autoimmune or inflammatory diseases.

[0004] Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases consisting of four members: JAK1, JAK2, JAK3, and tyrosine-protein kinase 2 (TYK2). These members mediate cytokine production signals through the JAK-signal transducer and activation of transcription (STAT) pathway, participating in numerous important biological processes, including cell proliferation, differentiation, apoptosis, and immune regulation. This pathway is common in vertebrates, through which many important cytokines, including interleukins (ILs), interferons (IFNs), granulocyte / macrophage colony-stimulating factor (G-CSF), erythropoietin, and thrombopoietin, transmit signals. Therefore, the JAK-STAT pathway is closely linked to the blood and immune systems and plays a crucial role in immune-mediated inflammatory diseases, such as atopic dermatitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, alopecia areata, vitiligo, and non-infectious uveitis. Therefore, by inhibiting the activity of JAK, the JAK-STAT pathway can be blocked and the expression of proinflammatory cytokines can be reduced, thereby achieving the purpose of treating non-infectious inflammatory diseases such as non-infectious uveitis.

[0005] Currently, chronic uveitis is primarily treated with topical corticosteroid eye drops. Corticosteroids, the standard and first-line treatment for uveitis, can be administered intraocularly via eye drops or injection, aiming to reduce, control, or alleviate inflammation. Numerous corticosteroid eye drops are available, such as 0.125% and 1% prednisolone acetate, 1% betamethasone, 0.1% dexamethasone sodium phosphate (also available as a 0.05% ointment), 0.1% and 0.25% fluorometholone (also available as a 0.1% ointment), 0.5% loteprednol (also available as a 0.5% ointment), and 1% rimexolone. However, long-term use of corticosteroid eye drops can significantly increase intraocular pressure, and continued use can also increase the risk of cataract formation. Therefore, there is an urgent need to develop a less invasive alternative to corticosteroids, with fewer side effects or sequelae, and more effective for non-infectious inflammatory diseases such as uveitis.

[0006] Summary of the Invention

[0007] The purpose of this application is to provide an ophthalmic composition that is compatible with and stable in the eye and can be administered topically as eye drops to treat non-infectious inflammatory diseases with good efficacy and minimal side effects. The specific technical solution is as follows:

[0008] The first aspect of the present application provides an ophthalmic composition comprising an active substance and an ophthalmic excipient, wherein the active substance is a JAK inhibitor selected from VVN461, tofacitinib, ruxolitinib, baricitinib, peficitinib, delgocitinib, upadacitinib, filgotinib, abrocitinib, deuterium-containing At least one of deucravacitinib, ritlecitinib, brepocitinib, jaktinib, imacitinib (SHR0302), itacitinib (IBI-377), golidocitinib (AZD4205), KL130008, TLL018, and LYK01001; preferably VVN461; the VVN461 is as shown in Formula I;

[0009] The content of the active substance in the ophthalmic composition is 0.01-5wt%, preferably 0.1-2wt%, more preferably 0.1-1wt%;

[0010] The ophthalmic excipients include a pH buffer, an osmotic pressure regulator, a solubilizer, and water for injection; the content of the pH buffer in the ophthalmic composition is 0.001-2.5 wt%, preferably 0.01-1.5 wt%, and more preferably 0.1-0.25 wt%;

[0011] The content of the osmotic pressure regulator in the ophthalmic composition is 0.01-2.5 wt%, preferably 0.2-2 wt%;

[0012] The content of the solubilizer in the ophthalmic composition is 0.5-15 wt%, preferably 1-12 wt%;

[0013] The pH of the ophthalmic composition is 4-8, preferably 5-7; the osmotic pressure is 200-400 mOsmo / Kg, preferably 240-380 mOsmo / Kg, more preferably 240-320 mOsmol / Kg.

[0014] In some embodiments of the present application, the pH buffer is selected from any one of boric acid-borate, citric acid-citrate, acetic acid-sodium acetate, tris(hydroxymethyl)aminomethane-hydrochloric acid, sodium bicarbonate, and phosphate;

[0015] The borate is selected from at least one of sodium borate, potassium borate, and hydrates thereof;

[0016] The citrate is selected from at least one of potassium citrate, sodium citrate, disodium hydrogen citrate, sodium dihydrogen citrate, dipotassium hydrogen citrate, potassium dihydrogen citrate, and hydrates thereof;

[0017] The phosphate is selected from at least one of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and hydrates thereof.

[0018] In some embodiments of the present application, the osmotic pressure regulator is selected from inorganic osmotic pressure regulators and / or organic osmotic pressure regulators;

[0019] The inorganic osmotic pressure regulator is selected from at least one of sodium chloride, potassium chloride, calcium chloride, zinc chloride, and magnesium chloride;

[0020] The organic osmotic pressure regulator is selected from at least one of glucose, glycerol, propylene glycol, glycine, diglycine, alanine, taurine, ectoine, erythritol, mannitol, sorbitol, and trehalose.

[0021] In some embodiments of the present application, the solubilizer is a cyclodextrin, selected from at least one of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and hydroxypropyl-γ-cyclodextrin.

[0022] In some embodiments of the present application, the ophthalmic excipient further comprises a mucoadhesive; the mucoadhesive is selected from at least one of polyvinyl pyrrolidone (PVP), polyvinyl alcohol, methylcellulose, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), sodium hyaluronate, sodium alginate, polyethylene glycol (PEG), thiolated polyacrylic acid (PAA-SH), poloxamer, poloxamine, Mrij (oleic acid polyoxyethylene ether ester), Brij (polyoxyethylene fatty alcohol ether), cellulose acetate phthalate (CAP), hydroxyethyl cellulose (HEC), poly(amidoamine) dendrimer (PAMAM), poly(dimethylsiloxane) (PDMS), and hydroxypropyl guar gum (HP-Guar);

[0023] The content of the mucoadhesive in the ophthalmic composition is 0.001-15 wt %, preferably 0.005-10 wt %, more preferably 0.01-5 wt %.

[0024] In some embodiments of the present application, the ophthalmic excipient further comprises a surfactant; the surfactant is selected from at least one of sodium lauryl sulfate, polyethoxylated sorbitan fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene stearate, poloxamine, sorbitan fatty acid esters, polyethylene glycol, polyethoxylated fatty alcohols, polyoxyethylene 40 hydrogenated castor oil, docusate sodium, quaternary ammonium compounds, C6-C20 fatty acids, fatty acid sugar esters, fatty acid glycerides, polysorbates, poloxamers, and tyroxabor;

[0025] The content of the surfactant in the ophthalmic composition is 0.01-5 wt %.

[0026] In some embodiments of the present application, the ophthalmic excipient further comprises a comfort agent; the comfort agent is selected from at least one of polyols, cellulose derivatives, dextran, polyethylene glycol, polysorbate, povidone, trehalose, hyaluronic acid, sodium hyaluronate, and sodium alginate;

[0027] The polyol is selected from at least one of glycerol, propylene glycol, polyvinyl alcohol, and mannitol;

[0028] The cellulose derivative is selected from at least one of hydroxypropyl methylcellulose-E4M, hydroxypropyl methylcellulose-LV, hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, hemicellulose, and ethyl cellulose;

[0029] The content of the comfort agent in the ophthalmic composition is 0.001-15 wt %, preferably 0.01-5 wt %.

[0030] In some embodiments of the present application, the ophthalmic excipient further comprises a preservative; the preservative is selected from at least one of benzalkonium chloride, sorbic acid, disodium edetate, boric acid, sodium borate, sodium bisulfate, sodium thiosulfate, ascorbate, urea peroxide, benzalkonium bromide, sodium chlorite and polyquaternium-1;

[0031] The content of the preservative in the ophthalmic composition is 0.01-0.05 wt %.

[0032] In some embodiments of the present application, the ophthalmic excipient further comprises an antioxidant; the antioxidant is selected from at least one of sodium thiosulfate, sodium metabisulfite, N-acetylcysteine, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT);

[0033] The content of the antioxidant in the ophthalmic composition is 0.01-5 wt %, preferably 0.1-0.5%.

[0034] In some embodiments of the present application, the ophthalmic excipient further comprises a chelating agent; the chelating agent is selected from at least one of nitrotriacetic acid, ethylenediamine disuccinic acid, iminodisuccinic acid, methylglycine diacetic acid, L-glutamic acid N,N-diacetic acid, ethylenediamine-N,N'-diglutamic acid, ethylenediamine-N,N'-bismalonic acid, 3-hydroxy-2,2-iminodisuccinic acid, 2-hydroxyethyliminodiacetic acid, pyridine-2,6-dicarboxylic acid, diethylenetriamine pentaacetic acid, hydroxyethyldiamine triacetic acid, 1,2-diaminocyclohexane tetraacetic acid, hydroxyethylaminodiacetic acid, polyphosphates, citric acid and citrates, tartaric acid and tartrates, ethylenediaminetetraacetic acid and disodium ethylenediaminetetraacetic acid, and alkali metal hexametaphosphates;

[0035] The content of the chelating agent in the ophthalmic composition is 0.001-1 wt %, preferably 0.1-0.25 wt %.

[0036] The second aspect of the present application provides use of the ophthalmic composition provided according to the first aspect of the present application in preparing a medicament for treating non-infectious inflammatory diseases.

[0037] In some embodiments of the present application, the non-infectious inflammatory disease includes uveitis; the uveitis is selected from at least one of anterior uveitis, choroiditis, iridocyclitis, intermediate uveitis, iritis, panuveitis, pars planitis, posterior uveitis, and retinitis.

[0038] The present application provides an ophthalmic composition comprising a JAK inhibitor for the treatment of non-infectious inflammatory diseases. The ophthalmic composition having the composition and content of the present application is used for topical eye drop administration, is compatible and stable with the eyes, is tear-friendly and comfortable, can improve the bioavailability of the active substances in the ophthalmic composition, can be used to treat non-infectious inflammatory diseases, and has good therapeutic effects, is less invasive and has few side effects. At the same time, its production process is simple and convenient for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other embodiments can also be obtained based on these drawings.

[0040] FIG1 shows the anterior chamber inflammatory cell scoring results in an experimental anterior uveitis model after eye drop administration of the ophthalmic composition of the present application;

[0041] FIG2 shows the conjunctival congestion scoring results in an experimental anterior uveitis model after eye drop administration of the ophthalmic composition of the present application;

[0042] Figure 3 is a diagram showing the mechanism of action of VVN461 in treating non-infectious inflammatory diseases. DETAILED DESCRIPTION

[0043] The following will be combined with the accompanying drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the embodiments described are only part of the embodiments of the present application, rather than all the embodiments. All other embodiments obtained by ordinary technicians in this field based on this application are within the scope of protection of this application.

[0044] In a first aspect, the present application provides an ophthalmic composition comprising an active substance and an ophthalmic excipient, wherein the active substance is a JAK inhibitor, and the JAK inhibitor is selected from but not limited to at least one of VVN461, tofacitinib, ruxolitinib, baricitinib, pegfitinib, diagatinib, upadacitinib, filgotinib, abrocitinib, deuterocelexinib, rituxitinib, brepazotinib, jaktinib, aimaxinitinib, itatinib, golixitinib, KL130008, TLL018, LYK01001, and the like; preferably, the JAK1 / TYK2 dual inhibitor VVN461; the VVN461 is as shown in Formula I;

[0045] The content of the active substance in the ophthalmic composition is 0.01-5wt%, preferably 0.1-2wt%, more preferably 0.1-1wt%;

[0046] The ophthalmic excipients include a pH buffer, an osmotic pressure regulator, a solubilizer, and water for injection; the content of the pH buffer in the ophthalmic composition is 0.001-2.5 wt%, preferably 0.01-1.5 wt%, and more preferably 0.1-0.25 wt%;

[0047] The content of the osmotic pressure regulator in the ophthalmic composition is 0.01-2.5 wt%, preferably 0.2-2 wt%;

[0048] The content of the solubilizer in the ophthalmic composition is 0.5-15 wt%, preferably 1-12 wt%;

[0049] The pH of the ophthalmic composition is 4-8, preferably 5-7; the osmotic pressure is 200-400 mOsmo / Kg, preferably 240-380 mOsmo / Kg, more preferably 240-320 mOsmol / Kg.

[0050] In the present application, the compound VVN461 as shown in Formula I has a molecular weight of 324.38, a chemical name of (R)-2-(1-(2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile, properties of white to light yellow solid or powder, melting point of 225.6-228.9°C (differential scanning calorimetry-onset point (DSC onset) value), and solubility of almost insoluble in water. The present application does not particularly limit the crystal form of the compound VVN461, as long as the purpose of the present application can be achieved. For example, the compound VVN46 is crystal form A (X-ray powder diffraction (XRDP) method).

[0051] The inventors have discovered that by regulating the content of the active substance within the above-mentioned range and regulating the pH buffer within the above-mentioned low concentration range, the buffering capacity of the ophthalmic composition described in the present application can be matched with the buffering capacity of tears, making the composition tear-friendly and comfortable, and increasing the average residence time of the active substance of the present application, while also improving the bioavailability of the active substance.

[0052] In the present application, by regulating the content of the osmotic pressure regulator within the above range, the amount used is equivalent to 0.9% sodium chloride solution or 2.7% glycerol solution, so that the osmotic pressure of the ophthalmic composition described in the present application is close to the osmotic pressure of normal tears (270-310mOsmol / Kg), thereby greatly reducing the discomfort of the patient when using the ophthalmic composition. In the present application, if the ophthalmic composition is simply prepared using water for injection without adding an osmotic pressure regulator, hypotonicity will result, and an excessive amount of osmotic pressure regulator may form a hypertonic solution, and both hypotonic and hypertonicity will cause the lens to lose its required optical parameters. And hypertonic solutions can also cause stinging, eye irritation, and dryness of the ocular surface.

[0053] The ophthalmic composition containing a JAK inhibitor provided in the present application is used for topical eye drop administration, is compatible and stable with the eyes, is tear-friendly and comfortable, can improve the bioavailability of the active substances in the ophthalmic composition, has a good therapeutic effect when used to treat non-infectious inflammatory diseases, and is administered by ocular surface drops without damaging or invading eye tissues, is less invasive, and has few side effects.

[0054] In some embodiments of the present application, the pH buffer is selected from any one of boric acid-borate, citric acid-citrate, acetic acid-sodium acetate, tris(hydroxymethyl)aminomethane-hydrochloric acid, sodium bicarbonate, and phosphate;

[0055] The borate is selected from at least one of sodium borate, potassium borate, and any suitable hydrate thereof, wherein, illustratively, the hydrate is such as sodium borate pentahydrate or sodium borate decahydrate;

[0056] The citrate is selected from at least one of potassium citrate, sodium citrate, disodium hydrogen citrate, sodium dihydrogen citrate, dipotassium hydrogen citrate, potassium dihydrogen citrate, and any suitable hydrates thereof, wherein, illustratively, the hydrate is such as sodium citrate dihydrate or sodium citrate trihydrate;

[0057] The phosphate is selected from at least one of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and any suitable hydrates thereof, wherein, illustratively, the hydrate is such as disodium hydrogen phosphate heptahydrate or disodium hydrogen phosphate dodecahydrate.

[0058] The citric acid and citrate can be used as both a pH buffer and a chelating agent, and their specific role in the ophthalmic composition of the present application can be determined according to the specific formulation.

[0059] In some embodiments of the present application, the pH buffer is selected from citric acid-citrate; the citrate can be any known citrate; and the content of the citric acid-citrate in the ophthalmic composition is 0.001-2.5 wt %, preferably 0.01-1.5 wt %, and more preferably 0.1-0.25 wt %. The inventors have discovered that by selecting a citric acid-citrate buffer system and regulating the content of the citric acid-citrate within the above range, the concentration of the citric acid-citrate is matched to the buffering capacity of tears, thereby minimizing the irritation and / or discomfort experienced by buffer systems with higher ionic strength. Furthermore, the high ionic strength of the citric acid-citrate buffer system can improve the solubility of the active substance in the ophthalmic composition, thereby providing the ophthalmic composition with better stability.

[0060] In some embodiments of the present application, the osmotic pressure regulator is selected from inorganic osmotic pressure regulators and / or organic osmotic pressure regulators;

[0061] The inorganic osmotic pressure regulator is selected from at least one of sodium chloride, potassium chloride, calcium chloride, zinc chloride, and magnesium chloride;

[0062] The organic osmotic pressure regulator is selected from at least one of glucose, glycerol, propylene glycol, glycine, diglycine, alanine, taurine, ectoine, erythritol, mannitol, sorbitol, and trehalose.

[0063] Among them, the glycerol, propylene glycol, mannitol, and trehalose can be used as both osmotic pressure regulators and comfort agents, and their roles in the ophthalmic composition of the present application can be determined according to the specific formula.

[0064] In some embodiments of the present application, the solubilizer is a cyclodextrin, selected from at least one of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and hydroxypropyl-γ-cyclodextrin.

[0065] The inventors have discovered that the active substances, such as compound VVN461, are lipophilic molecules with low water solubility. By using the solubilizer of the present application and controlling the content of the solubilizer within the above-mentioned range, the permeability of the ophthalmic composition can be improved, and the average residence time of the ophthalmic composition on the ocular surface can be increased, thereby improving the bioavailability of the active substance, ensuring that sufficient and stable active substance dissolves in tears and passes through the tear film barrier, thereby achieving a better therapeutic effect. When the content of the solubilizer is too low or too high, the permeability of the active substance of the present application will be limited. The inventors have found that when the content of the solubilizer of the present application meets the above-mentioned range, the ophthalmic composition of the present application has good permeability.

[0066] In some embodiments of the present application, the ophthalmic excipient further comprises a mucoadhesive agent; the mucoadhesive agent is a mucoadhesive polymer, which can be selected from at least one of polyvinyl pyrrolidone, polyvinyl alcohol, methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose of different molecular weights, sodium hyaluronate of different molecular weights, sodium alginate, polyethylene glycol, thiolated polyacrylic acid, poloxamer, poloxamine, Mrij, Brij, cellulose acetate phthalate, hydroxyethyl cellulose, poly(amidoamine) dendrimers, poly(dimethylsiloxane), and hydroxypropyl guar gum;

[0067] The content of the mucoadhesive in the ophthalmic composition is 0.001-15 wt %, preferably 0.005-10 wt %, more preferably 0.01-5 wt %.

[0068] Among them, the poloxamer can be used as both a mucosal adhesive and a surfactant; the carboxymethyl cellulose, sodium hyaluronate, sodium alginate, and hydroxyethyl cellulose can be used as both a mucosal adhesive and a comfort agent; the polyethylene glycol can be used as both a mucosal adhesive and a surfactant, and can also be used as a comfort agent; the role of each substance in the ophthalmic composition of the present application can be determined according to the specific formula.

[0069] The inventors have discovered that by adopting the mucoadhesive of the present application and controlling the content of the mucoadhesive in the ophthalmic composition within the above-mentioned range, the interruption of the human tear film and eye irritation can be reduced, the residence time of the drug in the ocular drug delivery system in front of the cornea can be increased, and the bioavailability of the active substance can be improved, while reducing eye irritation and dryness.

[0070] In some embodiments of the present application, the ophthalmic excipient further comprises a surfactant; the surfactant may be selected from at least one of sodium lauryl sulfate, polyethoxylated sorbitan fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene stearate, poloxamine, sorbitan fatty acid esters, polyethylene glycol, polyethoxylated fatty alcohols, polyoxyethylene 40 hydrogenated castor oil, docusate sodium, quaternary ammonium compounds, C6-C20 fatty acids, fatty acid sugar esters, fatty acid glycerides, polysorbates, poloxamers, and tyroxabor;

[0071] The content of the surfactant in the ophthalmic composition is 0.01-5 wt %.

[0072] In the present application, the surfactant may be a surfactant that is beneficial to the eyes, and the surfactant may reduce the surface tension of the ophthalmic composition to less than 50 dyes / cm 2 .

[0073] In some embodiments of the present application, the ophthalmic excipient further comprises a comfort agent; the comfort agent is selected from at least one of polyols, cellulose derivatives, dextran, polyethylene glycol, polysorbate, povidone, trehalose, hyaluronic acid, sodium hyaluronate, and sodium alginate;

[0074] The polyol is selected from at least one of glycerol, propylene glycol, polyvinyl alcohol, and mannitol;

[0075] The cellulose derivative is selected from at least one of hydroxypropyl methylcellulose-E4M, hydroxypropyl methylcellulose-LV, hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, hemicellulose, and ethyl cellulose;

[0076] The content of the comfort agent in the ophthalmic composition is 0.001-15 wt %, preferably 0.01-5 wt %.

[0077] In the present application, by adding the above-mentioned comfort agent and regulating the content of the comfort agent within the above-mentioned range, the comfort of the patient when using the ophthalmic composition described in the present application can be further improved.

[0078] In the present application, the ophthalmic composition may or may not contain a preservative; in some embodiments of the present application, the ophthalmic excipient further comprises a preservative; the preservative is selected from at least one of benzalkonium chloride, sorbic acid, disodium edetate, boric acid, sodium borate, sodium bisulfate, sodium thiosulfate, ascorbate, urea peroxide, benzalkonium bromide, sodium chlorite and polyquaternium-1; the content of the preservative in the ophthalmic composition is 0.01-0.05 wt%.

[0079] In some embodiments of the present application, the ophthalmic excipient further comprises an antioxidant; the antioxidant is selected from at least one of sodium thiosulfate, sodium metabisulfite, N-acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene; the content of the antioxidant in the ophthalmic composition is 0.01-5wt%, preferably 0.1-0.5%.

[0080] In some embodiments of the present application, the ophthalmic excipient further comprises a chelating agent; preferably, the chelating agent is friendly to the ocular surface and biodegradable. For example, the chelating agent is selected from at least one of nitrotriacetic acid, ethylenediamine disuccinic acid, iminodisuccinic acid, methylglycine diacetic acid, L-glutamic acid N,N-diacetic acid, ethylenediamine-N,N'-diglutamic acid, ethylenediamine-N,N'-dimalonic acid, 3-hydroxy-2,2-iminodisuccinic acid, 2-hydroxyethyliminodiacetic acid, pyridine-2,6-dicarboxylic acid, diethylenetriamine pentaacetic acid, hydroxyethyldiamine triacetic acid, 1,2-diaminocyclohexane tetraacetic acid, hydroxyethylaminodiacetic acid, polyphosphate, citric acid and citrate, tartaric acid and tartrate, ethylenediaminetetraacetic acid and disodium ethylenediaminetetraacetic acid, and alkali metal hexametaphosphate; the content of the chelating agent in the ophthalmic composition is 0.001-1wt%, preferably 0.1-0.25wt%.

[0081] In some embodiments of the present application, the method for preparing the ophthalmic composition comprises the following steps:

[0082] Add 75-85% of the total content of the ophthalmic composition to the container; continuously stir and add a solubilizer, stir until completely dissolved, heat the mixed solution to 65-75°C, add the JAK inhibitor, stir for at least 2 hours, cool to 20-30°C, and slowly add other ophthalmic excipients in sequence, and then stir for at least 10 minutes; add water for injection to make up to volume, and continue stirring for at least 15 minutes; sterilize the resulting solution to obtain the ophthalmic composition containing the JAK inhibitor described in the present application.

[0083] In some embodiments of the present application, the method for preparing the ophthalmic composition comprises the following steps:

[0084] Add 75-85% of the total content of the ophthalmic composition to the container; continuously stir and add a solubilizer and a mucoadhesive, stir until completely dissolved, heat the mixed solution to 65-75°C, add the JAK inhibitor, stir for at least 2 hours, cool to 20-30°C, and slowly add other ophthalmic excipients in sequence, and then stir for at least 10 minutes; add water for injection to make up to volume, and continue stirring for at least 15 minutes; sterilize the resulting solution to obtain the ophthalmic composition containing the JAK inhibitor described in the present application.

[0085] The preparation method of the present application achieves sterility, ideal stability and extremely low total impurity content of the ophthalmic composition containing the JAK inhibitor.

[0086] In the present application, there is no particular restriction on the sterilization method in the above preparation method, as long as the purpose of the present application can be achieved. For example, sterilization can be carried out by terminal heating sterilization, filtration sterilization, electron beam sterilization, ultraviolet light system, etc. Specifically, for example, a 0.22 μm sterilizing filter can be used for one-step cold filtration for filtration sterilization.

[0087] In the present application, there is no particular limitation on the packaging method of the ophthalmic composition containing a JAK inhibitor, as long as the purpose of the present application can be achieved. For example, it can be a traditional multi-dose bottle and a blow-fill-seal (BFS) disposable bottle or a multi-dose bottle.

[0088] In the present application, there is no particular limitation on the degree of polymerization or molecular weight of each polymer, as long as the purpose of the present application can be achieved; for example, the polyvinyl pyrrolidone may be PVP K30, the hydroxypropyl methylcellulose may be HPMC E4M or HPMC LV, the polyethylene glycol may be PEG300 or PEG400, the poloxamer may be poloxamer 407 or poloxamer 188, the weight-average molecular weight of the carboxymethyl cellulose is 400,000-600,000, and the weight-average molecular weight of the sodium hyaluronate is 800,000-1.2 million.

[0089] The second aspect of the present application provides the use of the ophthalmic composition provided in the first aspect of the present application in the preparation of a medicament for treating non-infectious inflammatory diseases. The inventors have discovered that the JAK inhibitor described herein, as an active substance, can block the JAK-STAT pathway by inhibiting the activity of JAK, thereby reducing the expression of pro-inflammatory cytokines, thereby making the ophthalmic composition described herein useful for treating non-infectious inflammatory diseases; preferably, the JAK inhibitor comprises VVN461, and the ophthalmic composition comprising VVN461, wherein VVN461, as an active substance, has dual JAK1 / TYK2 inhibitory effects, can target JAK / TYK-dependent cytokines, inhibit the JAK / STAT pathway, and thus can be used to treat non-infectious inflammatory diseases.

[0090] In some embodiments of the present application, the non-infectious inflammatory disease includes uveitis; the uveitis is selected from at least one of anterior uveitis, choroiditis, iridocyclitis, intermediate uveitis, iritis, panuveitis, pars planitis, posterior uveitis, and retinitis.

[0091] In the present application, the method and dosage of the ophthalmic composition are as follows: drop into the eyes 4-6 times a day, one drop per eye at a time.

[0092] In the present application, the ophthalmic composition comprising the JAK inhibitor can be used topically in the eyes, ears, nose and the like.

[0093] Hereinafter, embodiments of the present application will be described in more detail with reference to examples.

[0094] Example 1

[0095] Preparation of ophthalmic compositions containing VVN461

[0096] Add 80% of the total content of the ophthalmic composition in water for injection to a container; add sulfobutyl-β-cyclodextrin while stirring continuously and stirring until completely dissolved; heat the mixed solution to 70° C.; add VVN461 represented by Formula I; stir for at least 2 hours; cool to 25° C.; and slowly add other ophthalmic excipients in sequence; then stir for at least 10 minutes; add water for injection to adjust the volume; continue stirring for 20 minutes; and filter sterilize by cold filtration through a 0.22 μm sterilizing filter in one step to obtain an ophthalmic composition.

[0097] The product parameters (including ingredients, content, pH and osmotic pressure) of the ophthalmic composition obtained in Example 1 are shown in Table 1.

[0098] Example 2

[0099] Except for adjusting the product parameters as shown in Table 1, the rest is the same as Example 1.

[0100] Examples 3-4

[0101] Except for adjusting the product parameters as shown in Table 2, the rest is the same as Example 1.

[0102] Examples 5-11

[0103] Preparation of ophthalmic compositions containing VVN461

[0104] Add 80% of the total content of the ophthalmic composition in water for injection into a container; add hydroxypropyl-β-cyclodextrin and PEG400 while stirring continuously, and stir until completely dissolved. Heat the mixed solution to 70° C., add VVN461 represented by Formula I, and stir for at least 2 hours. Cool the mixture to 25° C., and slowly add other ophthalmic excipients in sequence. Stir for at least 10 minutes, add water for injection to adjust the volume, continue stirring for 20 minutes, and filter sterilize by cold filtration through a 0.22 μm sterilizing filter to obtain an ophthalmic composition.

[0105] The product parameters (including ingredients, content, pH and osmotic pressure) of the ophthalmic compositions obtained in Examples 5-11 are shown in Table 3.

[0106] Examples 12-17

[0107] Except for adjusting the product parameters as shown in Table 4, the rest are the same as Example 5.

[0108] Examples 18-23

[0109] Except for adjusting the product parameters as shown in Table 5, the rest is the same as Example 5.

[0110] Examples 24-29

[0111] Except for adjusting the product parameters as shown in Table 6, the rest is the same as Example 5.

[0112] Examples 30-35

[0113] Except for adjusting the product parameters as shown in Table 7, the rest is the same as Example 5.

[0114] Examples 36-39

[0115] Preparation of ophthalmic compositions containing VVN461

[0116] Add 80% of the total content of the ophthalmic composition in water for injection into a container; add sulfobutyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, poloxamer 407, and PVP K90 while stirring continuously, and stir until completely dissolved; heat the mixed solution to 70° C., add VVN461 represented by Formula I, and stir for at least 2 hours; cool to 25° C., and slowly add other ophthalmic excipients in sequence; then stir for at least 10 minutes; add water for injection to adjust the volume; continue stirring for 20 minutes, and filter sterilize by cold filtration through a 0.22 μm sterilizing filter to obtain an ophthalmic composition.

[0117] The product parameters (including ingredients, content, pH and osmotic pressure) of the ophthalmic compositions obtained in Examples 36-39 are shown in Table 8.

[0118] Example 40

[0119] Preparation of ophthalmic compositions containing VVN461

[0120] Add 80% of the total content of the ophthalmic composition in water for injection into a container; add hydroxypropyl-β-cyclodextrin, poloxamer 407, and PEG400 while stirring continuously, and stir until completely dissolved. Heat the mixed solution to 70° C., add VVN461 represented by Formula I, and stir for at least 2 hours. Cool the mixture to 25° C., and slowly add other ophthalmic excipients in sequence. Stir for at least 10 minutes, add water for injection to adjust the volume, continue stirring for 20 minutes, and filter sterilize the mixture by cold filtration through a 0.22 μm sterilizing filter to obtain an ophthalmic composition.

[0121] The product parameters (including ingredients, content, pH and osmotic pressure) of the ophthalmic composition obtained in Example 40 are shown in Table 9.

[0122] Example 41

[0123] Except for adjusting the product parameters as shown in Table 10, the rest is the same as Example 1.

[0124] Examples 42-64

[0125] Preparation of ophthalmic compositions containing VVN461

[0126] Add 80% of the total content of the ophthalmic composition in water for injection into a container; add hydroxypropyl-β-cyclodextrin while stirring continuously; after visual dissolution, add poloxamer 188, polyvinyl alcohol, PVP K30, PEG400, and CMC, respectively, and stir until completely dissolved; heat the mixed solution to 70° C., add VVN461 represented by Formula I, stir for at least 2 hours, cool to 25° C., and slowly add other ophthalmic excipients in sequence; then stir for at least 10 minutes; add water for injection to make up to volume; continue stirring for 20 minutes, and filter sterilize by cold filtration through a 0.22 μm sterilizing filter to obtain an ophthalmic composition.

[0127] The CMC is a 1wt% CMC aqueous solution, and the preparation method is as follows: add 400mL of water for injection, start stirring, and heat to 85°C, slowly add 5g of CMC (weight average molecular weight is about 250000), stir until there are no white particles and it becomes transparent, cool to room temperature until it is completely dissolved, add water for injection to 500mL, and stir evenly.

[0128] The product parameters (including ingredients, content, pH and osmotic pressure) of the ophthalmic compositions obtained in Examples 42-64 are shown in Table 11.

[0129] Table 1

[0130] Table 2

[0131] Table 3

[0132] Table 4

[0133] Table 5

[0134] Table 6

[0135] Table 7

[0136] Table 8

[0137] Table 9

[0138] Table 10

[0139] Stability test:

[0140] The prepared ophthalmic composition containing VVN461 was canned in multi-dose bottles (5 mL) and stored at 25°C ± 2°C / 40% ± 5% RH and 40°C ± 2°C / 25% ± 5% RH, respectively. After 1 month and 11 months of storage, the ophthalmic composition was subjected to stability tests. The results are shown in Table 12, where the total impurity content of the ophthalmic composition is the sum of the impurity contents obtained by testing the ophthalmic composition using high performance liquid chromatography (HPLC).

[0141] Table 12

[0142] Note: “-” in Table 12 indicates that the corresponding parameter does not exist.

[0143] *: Because the eye drop bottle is made of low-density polyethylene, a semi-permeable material, it loses water when stored at 40°C for 11 months, and the osmotic pressure will increase.

[0144] The stability data in Table 11 demonstrate that the ophthalmic composition prepared by the preparation method of the present application maintained excellent stability and extremely low impurity content after storage for up to 11 months at 25°C ± 2°C / 40% ± 5% RH and 40°C ± 2°C / 25% ± 5% RH. The relative retention time (RRT) of the individual impurities in Table 12 is the ratio of the retention time of the individual impurities to the retention time of VVN461 represented by Formula I.

[0145] Effects of ophthalmic compositions on experimental autoimmune uveitis

[0146] Anterior uveitis Dutch rabbit model was established to evaluate the effectiveness and safety of the ophthalmic composition. The ophthalmic composition of Example 1, the ophthalmic composition of Example 2, pranoprofen eye drops, and tobramycin dexamethasone eye drops were then topically administered (eye drops) to one eye of each animal, administered 6 times a day for 21 consecutive days; the other eye was not treated as a control. Anterior chamber inflammatory cell scores and conjunctival congestion scores were performed on days 1, 3, 7, 14, and 21 of administration. The anterior chamber inflammatory cell scoring criteria are shown in Table 13, and the conjunctival congestion scoring criteria are shown in Table 14. The anterior chamber inflammatory cell score results are shown in Figure 1, and the conjunctival congestion score results are shown in Figure 2. According to the results of Figures 1 and 2, the ophthalmic composition comprising VVN461 in the present application is better for treating experimental autoimmune uveitis (anterior chamber inflammatory cells are significantly reduced), and has little side effect (conjunctival congestion score is significantly reduced). Its effect is comparable to tobramycin dexamethasone, and is better than pranoprofen. The above results indicate that the ophthalmic composition comprising a JAK inhibitor with the composition and content of the present application has the potential to replace corticosteroids, can be used to treat non-infectious inflammatory diseases such as anterior uveitis, and has good therapeutic effects with few side effects.

[0147] Table 13 Scoring criteria for anterior chamber inflammatory cells

[0148] Table 14 Conjunctival hyperemia scoring criteria

[0149] Mechanism of action of VVN461 in the treatment of non-infectious inflammatory diseases

[0150] The inventors studied the mechanism of action of VVN461 and found that VVN461 is a small molecule drug with a dual mode of action and a dual JAK1 / TYK2 inhibitor; JAK or TYK-dependent cytokines are associated with non-infectious inflammatory diseases (such as uveitis or other eye diseases) and are potential therapeutic targets for immune-mediated uveitis. VVN461 can target both Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), targeting JAK / TYK-dependent cytokines, inhibiting the Janus kinase (JAK) / signal transducer and activator of transcription (STAT) pathway, and thus can be used to treat non-infectious inflammatory diseases such as uveitis. Specifically as shown in Figure 3, proinflammatory cytokines send signals through the JAK / STAT pathway. When cytokines (Cytokine) bind to their receptors (Cytokine Receptor), the receptors are in close proximity, and the JAKs become phosphorylated. Then, the tyrosine residues on the intracellular domain of the cytokine receptor are phosphorylated. These phosphorylated receptor residues serve as binding sites for STAT proteins and are activated by JAK phosphorylation, causing STAT to dimerize and translocate to the nucleus, thereby binding to specific DNA sites, regulating gene expression, and leading to inflammation. The present application's VVN461 can target JAK / TYK-dependent cytokines and inhibit the JAK / STAT pathway, and can thus be used to treat non-infectious inflammatory diseases such as uveitis.

[0151] It should be noted that, in this article, the terms "comprises", "includes" or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method or article that includes a series of elements includes not only those elements, but also includes other elements that are not explicitly listed, or also includes elements that are inherent to such process, method or article.

[0152] The above description is only a preferred embodiment of the present application and is not intended to limit the scope of protection of the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application are included in the scope of protection of the present application.

Claims

1. An ophthalmic composition comprising an active substance and an ophthalmic excipient, wherein: The active substance is a JAK inhibitor, and the JAK inhibitor is selected from at least one of VVN461, tofacitinib, ruxolitinib, baricitinib, peftinib, diatinib, upadatinib, filgotinib, abrocitinib, deuterocelexinib, litrexinib, brepoxitinib, jaktinib, amasitinib, itatinib, golixinib, KL130008, TLL018, and LNK01001; preferably VVN461; the VVN461 is as shown in Formula I; The content of the active substance in the ophthalmic composition is 0.01-5wt%, preferably 0.1-2wt%, more preferably 0.1-1wt%; The ophthalmic excipient comprises a pH buffer, an osmotic pressure regulator, a solubilizer and water for injection; the content of the pH buffer in the ophthalmic composition is 0.001-2.5wt%, preferably 0.01-1.5wt%, more preferably 0.1-0.25wt%; The content of the osmotic pressure regulator in the ophthalmic composition is 0.01-2.5wt%, preferably 0.2-2wt%; The content of the solubilizer in the ophthalmic composition is 0.5-15wt%, preferably 1-12wt%; The pH of the ophthalmic composition is 4-8, preferably 5-7; the osmotic pressure is 200-400 mOsmo / Kg, preferably 240-380 mOsmo / Kg, more preferably 240-320 mOsmol / Kg.

2. The ophthalmic composition according to claim 1, wherein The pH buffer is selected from any one of boric acid-borate, citric acid-citrate, acetic acid-sodium acetate, tris(hydroxymethylaminomethane)-hydrochloric acid, sodium bicarbonate, and phosphate; The borate is selected from at least one of sodium borate, potassium borate, and hydrates thereof; The citrate is selected from at least one of potassium citrate, sodium citrate, disodium hydrogen citrate, sodium dihydrogen citrate, dipotassium hydrogen citrate, potassium dihydrogen citrate, and hydrates thereof; The phosphate is selected from at least one of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and hydrates thereof.

3. The ophthalmic composition according to claim 1, wherein The osmotic pressure regulator is selected from inorganic osmotic pressure regulators and / or organic osmotic pressure regulators; The inorganic osmotic pressure regulator is selected from at least one of sodium chloride, potassium chloride, calcium chloride, zinc chloride and magnesium chloride; The organic osmotic pressure regulator is selected from at least one of glucose, glycerol, propylene glycol, glycine, diglycine, alanine, taurine, tetrahydromethylpyrimidine carboxylic acid, erythritol, mannitol, sorbitol and trehalose.

4. The ophthalmic composition according to claim 1, wherein The solubilizing agent is cyclodextrin, which is at least one selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and hydroxypropyl-γ-cyclodextrin.

5. The ophthalmic composition according to any one of claims 1 to 4, wherein The ophthalmic excipient further comprises a mucoadhesive; the mucoadhesive is selected from at least one of polyvinyl pyrrolidone, polyvinyl alcohol, methylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium hyaluronate, sodium alginate, polyethylene glycol, thiolated polyacrylic acid, poloxamer, poloxamine, Mrij, Brij, cellulose acetate phthalate, hydroxyethyl cellulose, poly(amidoamine) dendrimer, poly(dimethylsiloxane), and hydroxypropyl guar gum; The content of the mucoadhesive agent in the ophthalmic composition is 0.001-15 wt %, preferably 0.005-10 wt %, and more preferably 0.01-5 wt %.

6. The ophthalmic composition according to any one of claims 1 to 4, wherein The ophthalmic excipient further comprises a surfactant; the surfactant is selected from at least one of sodium lauryl sulfate, polyethoxylated sorbitan fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene stearate, poloxamine, sorbitan fatty acid esters, polyethylene glycol, polyethoxylated fatty alcohols, polyoxyethylene 40 hydrogenated castor oil, docusate sodium, quaternary ammonium compounds, C6-C20 fatty acids, fatty acid sugar esters, fatty acid glycerides, polysorbates, poloxamers, and tyroxabor; The content of the surfactant in the ophthalmic composition is 0.01-5 wt %.

7. The ophthalmic composition according to any one of claims 1 to 4, wherein The ophthalmic excipient further comprises a comfort agent; the comfort agent is selected from at least one of polyols, cellulose derivatives, dextran, polyethylene glycol, polysorbate, povidone, trehalose, hyaluronic acid, sodium hyaluronate, and sodium alginate; The polyol is selected from at least one of glycerol, propylene glycol, polyvinyl alcohol and mannitol; The cellulose derivative is selected from at least one of hydroxypropyl methylcellulose-E4M, hydroxypropyl methylcellulose-LV, hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, hemicellulose, and ethyl cellulose; The content of the comfort agent in the ophthalmic composition is 0.001-15 wt %, preferably 0.01-5 wt %.

8. The ophthalmic composition according to any one of claims 1 to 4, wherein The ophthalmic excipient further comprises a preservative; the preservative is selected from at least one of benzalkonium chloride, sorbic acid, disodium edetate, boric acid, sodium borate, sodium bisulfate, sodium thiosulfate, ascorbate, urea peroxide, benzalkonium bromide, sodium chlorite and polyquaternium-1; The content of the preservative in the ophthalmic composition is 0.01-0.05 wt %.

9. The ophthalmic composition according to any one of claims 1 to 4, wherein The ophthalmic excipient further comprises an antioxidant; the antioxidant is selected from at least one of sodium thiosulfate, sodium metabisulfite, N-acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene; The antioxidant is contained in the ophthalmic composition in an amount of 0.01-5 wt %, preferably 0.1-0.5 wt %.

10. The ophthalmic composition according to any one of claims 1 to 4, wherein The ophthalmic excipient further comprises a chelating agent; the chelating agent is selected from at least one of nitrotriacetic acid, ethylenediamine disuccinic acid, iminodisuccinic acid, methylglycine diacetic acid, L-glutamic acid N,N-diacetic acid, ethylenediamine-N,N'-diglutamic acid, ethylenediamine-N,N'-dimalonic acid, 3-hydroxy-2,2-iminodisuccinic acid, 2-hydroxyethyliminodiacetic acid, pyridine-2,6-dicarboxylic acid, diethylenetriaminepentaacetic acid, hydroxyethyldiaminetriacetic acid, 1,2-diaminocyclohexanetetraacetic acid, hydroxyethylaminodiacetic acid, polyphosphate, citric acid and citrate, tartaric acid and tartrate, ethylenediaminetetraacetic acid and disodium ethylenediaminetetraacetic acid, and alkali metal hexametaphosphate; The content of the chelating agent in the ophthalmic composition is 0.001-1 wt %, preferably 0.1-0.25 wt %.

11. Use of the ophthalmic composition according to any one of claims 1 to 10 in the preparation of a medicament for treating non-infectious inflammatory diseases.

12. The use according to claim 11, wherein The non-infectious inflammatory disease includes uveitis; the uveitis is selected from at least one of anterior uveitis, choroiditis, iridocyclitis, intermediate uveitis, iritis, panuveitis, pars planitis, posterior uveitis, and retinitis.