Ophthalmic compositions for treating non-infectious inflammatory diseases

Abstract

The present invention provides an ophthalmic composition for treating non-infectious inflammatory diseases. The ophthalmic composition contains an active substance and an ophthalmic excipient. The active substance is a JAK inhibitor, and the ophthalmic excipient contains a pH buffer, an osmotic pressure regulator, a solubilizer, and water for injection. The ophthalmic composition having the composition and content of the present invention is used for topical eye drop administration, is compatible with the eye, stable, gentle and comfortable to the tear fluid, can improve the bioavailability of the active substance in the ophthalmic composition, can be used for the treatment of non-infectious inflammatory diseases, has excellent therapeutic effects, has low invasiveness and few side effects, and has a simple production process and is suitable for large-scale production.

Description

Technical Field

[0001] This invention claims the priority of a Chinese patent application filed with the China National Intellectual Property Administration on April 28, 2023, with an application number of 202310484101.X and an invention title of "Ophthalmic Composition for Treating Non-Infectious Inflammatory Diseases", and all of these are incorporated into this invention by reference in their entirety.

[0002] This invention relates to the field of pharmaceutical technology, and particularly to an ophthalmic composition for treating non-infectious inflammatory diseases, which contains a JAK inhibitor.

Background Art

[0003] The eye is one of the most important organs of the human body. Any functional disorder in vision will have a profound impact on daily activities and life. Uveitis is an inflammation of the uvea that threatens vision and is quite common worldwide. Anterior uveitis is one of the most common intraocular inflammations. Recurrent or untreated anterior uveitis can cause serious problems. Anterior uveitis is an inflammation of the central layer of the eye (including the iris and adjacent tissues), including infectious or non-infectious anterior uveitis, and may be related to 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). Janus kinases mediate signals generated by cytokines and are transmitted via the JAK-signaling and signal transducer and activation of transcription (STAT) signaling pathways, participating in many important biological processes such as cell proliferation, differentiation, apoptosis, and immunomodulation. This pathway is one of the most common signaling pathways in vertebrates, and many important cytokines, including IL, IFN, granulocyte / macrophage colony-stimulating factor, erythropoietin, and thrombopoietin, all transmit signals through this pathway. Therefore, the JAK-STAT pathway is closely related to the hematopoietic 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 JAK activity, the JAK-STAT pathway can be blocked, reducing the expression of pro-inflammatory cytokines, thereby achieving the goal of treating non-infectious inflammatory diseases such as non-infectious uveitis.

[0005] Currently, chronic uveitis is primarily treated with topical corticosteroid eye drops. Corticosteroids are the standard first-line treatment for uveitis and can be administered orally by instillation or injection to reduce, control, or alleviate inflammation. There are currently many options for corticosteroid eye drops, including 0.125% and 1% prednisolone acetate, 1% betamethasone, 0.1% dexamethasone sodium phosphate (also available in 0.05% ointment form), 0.1% and 0.25% fluorometholone (also available in 0.1% ointment form), 0.5% loteprednol (also available in 0.5% ointment form), and 1% rimexolone. However, prolonged use of corticosteroid eye drops can significantly increase intraocular pressure, and continuous use of corticosteroid eye drops also increases the risk of cataract formation. Therefore, there is an urgent need to develop drugs that are less invasive, have fewer side effects or sequelae, and are more effective for non-infectious inflammatory diseases such as uveitis, as an alternative to corticosteroids. [Overview of the project]

[0006] The present invention aims to provide an ophthalmic composition that is compatible with the eye and stable, capable of treating non-infectious inflammatory diseases by topical administration as eye drops, with excellent efficacy and few side effects. The specific technical solutions are as follows.

[0007] A first aspect of the present invention 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 VVN461, tofacitinib, ruxolitinib, baricitinib, peficitinib, delgocitinib, upadacitinib, filgotinib, abrocitinib, Duke Lavasitinib At least one selected from the group consisting of deucravacitinib, ritlecitinib, brepocitinib, jaktinib, ivarmacitinib (SHR0302), itacitinib (IBI-377), golidocitinib (AZD4205), KL130008, TLL018, and LYK01001, preferably VVN461, where VVN461 is shown in formula I.

[0008] The content of the active substance in the ophthalmic composition is 0.01 to 5 wt%, preferably 0.1 to 2 wt%, and more preferably 0.1 to 1 wt%.

[0009] [ka]

[0010] The ophthalmic excipient comprises a pH buffer, an osmotic pressure regulator, a solubilizer, and water for injection, wherein the content of the pH buffer in the ophthalmic composition is 0.001 to 2.5 wt%, preferably 0.01 to 1.5 wt%, and more preferably 0.1 to 0.25 wt%.

[0011] The content of the osmotic pressure adjusting agent in the ophthalmic composition is 0.01 to 2.5 wt%, preferably 0.2 to 2 wt%,

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

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

[0014] In some embodiments of the present invention, the pH buffer is one selected from the group consisting of boric acid-borate, citrate, acetate-sodium acetate, trimethylolaminomethane-hydrochloride, sodium bicarbonate, and phosphate.

[0015] The borate is at least one selected from the group consisting of sodium borate, potassium borate, and their hydrates.

[0016] The citrate is at least one selected from the group consisting of potassium citrate, sodium citrate, disodium hydrogen citrate, sodium dihydrogen citrate, dipotassium hydrogen citrate, potassium dihydrogen citrate, and their hydrates.

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

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

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

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

[0021] In some embodiments of the present invention, the solubilizing agent is at least one cyclodextrin selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and hydroxypropyl-γ-cyclodextrin.

[0022] In some embodiments of the present invention, the ophthalmic excipient further comprises a mucosal adhesive, the mucosal adhesive being at least one selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinyl alcohol, methylcellulose, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), sodium hyaluronate, sodium alginate, polyethylene glycol (PEG), thiolated polyacrylic acid (PAA-SH), poloxamer, poloxamine, Mrij (polyoxyethylene ether oleate), Brij (polyoxyethylene aliphatic alcohol ether), cellulose phthalate acetate (CAP), hydroxyethylcellulose (HEC), poly(amideamine) dendrimer (PAMAM), poly(dimethylsiloxane) (PDMS), and hydroxypropyl guar gum (HP-Guar).

[0023] The content of the mucosal adhesive in the ophthalmic composition is 0.001 to 15 wt%, preferably 0.005 to 10 wt%, and more preferably 0.01 to 5 wt%.

[0024] In some embodiments of the present invention, the ophthalmic excipient further contains a surfactant, and the surfactant is selected from at least one of the group consisting of sodium dodecyl sulfate, polyoxyethylated sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene stearate, poloxamine, sorbitan fatty acid ester, polyethylene glycol, polyoxyethylated aliphatic alcohol, polyoxyethylene 40 hydrogenated castor oil, sodium doxsate, quaternary ammonium compound, C6-C20 fatty acid, sucrose fatty acid ester, glycerin fatty acid ester, polysorbate, poloxamer, and tyloxapol,

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

[0026] In some embodiments of the present invention, the ophthalmic excipient further contains a comfort agent, and the comfort agent is selected from at least one of the group consisting of polyol, cellulose derivative, glucan, polyethylene glycol, polysorbate, povidone, trehalose, hyaluronic acid, sodium hyaluronate, and sodium alginate,

[0027] The polyol is selected from at least one of the group consisting of glycerin, propylene glycol, polyvinyl alcohol, and mannitol, The cellulose derivative is selected from at least one of the group consisting of hydroxypropyl methylcellulose-E4M, hydroxypropyl methylcellulose-LV, hydroxyethylcellulose, methylolcellulose, methylcellulose, hemicellulose, and ethylcellulose,

[0028] The content of the comfort agent in the ophthalmic composition is 0.001-15 wt%, preferably 0.01-5 wt%.

[0029] In some embodiments of the present invention, the ophthalmic excipient further comprises a preservative, the preservative being at least one selected from the group consisting of benzalkonium chloride, sorbic acid, disodium ethylenediaminetetraacetate, boric acid, sodium borate, sodium bisulfate, sodium thiosulfate, ascorbate, urea peroxide, benzalkonium bromide, sodium chlorite, and polyquaternium-1.

[0030] The content of the preservative in the ophthalmic composition is 0.01 to 0.05 wt%.

[0031] In some embodiments of the present invention, the ophthalmic excipient further comprises an antioxidant, the antioxidant being at least one selected from the group consisting of sodium thiosulfate, sodium pyrosulfite, N-acetylcysteine, butylhydroxyanisole (BHA), and butylhydroxytoluene (BHT).

[0032] The content of the antioxidant in the ophthalmic composition is 0.01 to 5 wt%, preferably 0.1 to 0.5 wt%.

[0033] In some embodiments of the present invention, the ophthalmic excipient further comprises a chelating agent, the chelating agent being at least one selected from the group consisting 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, polyphosphates, citric acid and citrates, tartaric acid and tartrates, ethylenediaminetetraacetic acid and disodium ethylenediaminetetraacetic acid, and alkali metal salts of hexametaphosphate.

[0034] The content of the chelating agent in the ophthalmic composition is 0.001 to 1 wt%, preferably 0.1 to 0.25 wt%.

[0035] A second aspect of the present invention provides the use of an ophthalmic composition according to the first aspect of the present invention in the preparation of pharmaceuticals for treating non-infectious inflammatory diseases.

[0036] In some embodiments of the present invention, the non-infectious inflammatory disease includes uveitis, which is at least one selected from the group consisting of anterior uveitis, choroiditis, iridocyclitis, intermediate uveitis, iritis, panuveitis, ciliary squamous ulceritis, posterior uveitis, and retinitis.

[0037] The present invention provides an ophthalmic composition for treating non-infectious inflammatory diseases, comprising a JAK inhibitor. The ophthalmic composition having the composition and content of the present invention is used for topical eye drop administration, is compatible and stable with the eye, is gentle and comfortable with tears, can improve the bioavailability of the active substance in the ophthalmic composition, can be used to treat non-infectious inflammatory diseases, has excellent therapeutic effects, is minimally invasive, has few side effects, has a simple production process, and is suitable for large-scale production. [Brief explanation of the drawing]

[0038] To more clearly illustrate embodiments of the present invention and prior art solutions, the drawings used in the embodiments or prior art will be briefly described below. However, the drawings described below represent only a few embodiments of the present invention, and it will be obvious to those skilled in the art that other embodiments can be obtained based on these drawings. [Figure 1] Figure 1 shows the scoring results of anterior chamber inflammatory cells in an experimental anterior uveitis model after administration of the ophthalmic composition of the present invention as eye drops. [Figure 2] Figure 2 shows the scoring results for conjunctival hyperemia in an experimental anterior uveitis model after administration of the ophthalmic composition of the present invention as eye drops. [Figure 3]Figure 3 shows the mechanism of action by which VVN461 treats non-infectious inflammatory diseases. [Modes for carrying out the invention]

[0039] The technical solutions in embodiments of the present invention will be clearly and completely described below with reference to the drawings of the embodiments. Clearly, the embodiments described are only a part of, and not all, embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention are all within the scope of protection of the present invention.

[0040] A first aspect of the present invention 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 at least one selected from the group consisting of compounds such as VVN461, tofacitinib, ruxolitinib, baricitinib, peficitinib, delgocitinib, upadacitinib, filgotinib, abrocitinib, duklavacitinib, ritrecitinib, brepocitinib, jactinib, ivarmacitinib, itacitinib, golidocitinib, KL130008, TLL018, and LYK01001, but is not limited thereto, and is preferably a JAK1 / TYK2 dual inhibitor VVN461, wherein VVN461 is represented by formula I.

[0041] The content of the active substance in the ophthalmic composition is 0.01 to 5 wt%, preferably 0.1 to 2 wt%, and more preferably 0.1 to 1 wt%.

[0042] [ka]

[0043] The ophthalmic excipient comprises a pH buffer, an osmotic pressure regulator, a solubilizer, and water for injection, wherein the content of the pH buffer in the ophthalmic composition is 0.001 to 2.5 wt%, preferably 0.01 to 1.5 wt%, and more preferably 0.1 to 0.25 wt%.

[0044] The content of the osmotic pressure adjusting agent in the ophthalmic composition is 0.01 to 2.5 wt%, preferably 0.2 to 2 wt%,

[0045] The content of the solubilizer in the ophthalmic composition is 0.5 to 15 wt%, preferably 1 to 12 wt%,

[0046] The pH of the ophthalmic composition is 4 to 8, preferably 5 to 7, and the osmotic pressure of the ophthalmic composition is 200 to 400 mOsmo / Kg, preferably 240 to 380 mOsmo / Kg, and more preferably 240 to 320 mOsmol / Kg.

[0047] In the present invention, the compound VVN461 represented by 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]pyridine-1(6H)-yl)piperidine-4-yl)acetonitrile, is a white to pale yellow solid or powder, has a melting point of 225.6~228.9°C (differential scanning calorimetry-start point (DSC onset) value), and is practically insoluble in water. In the present invention, the crystalline form of compound VVN461 is not particularly limited as long as the objectives of the present invention can be achieved. For example, compound VVN46 is crystalline form A (X-ray powder diffraction (XRDP) method).

[0048] The inventors have found that by controlling the content of the active substance within the above range and controlling the pH buffering agent within the above low concentration range, the buffering capacity of the ophthalmic composition of the present invention can be made to match the buffering capacity of tears, resulting in a composition that is gentle on tears, provides a strong sense of comfort, increases the average residence time of the active substance of the present invention, and improves the bioavailability of the active substance.

[0049] In the present invention, by controlling the content of the osmotic pressure adjusting agent within the above range, and by using an amount equivalent to a 0.9% sodium chloride solution or a 2.7% glycerin solution, the osmotic pressure of the ophthalmic composition according to the present invention is brought closer to the osmotic pressure of normal tears (270-310 mOsmol / Kg), thereby significantly reducing discomfort experienced by patients when using the ophthalmic composition. In the present invention, if the ophthalmic composition is prepared simply using sterile water for injection without adding the osmotic pressure adjusting agent, it becomes hypotonic. On the other hand, an excess amount of osmotic pressure adjusting agent may form a hypertonic solution. Both hypotonic and hypertonic solutions cause the loss of necessary optical parameters for lenses. Furthermore, hypertonic solutions can cause stinging pain, eye irritation, and dryness of the eye surface.

[0050] The ophthalmic composition containing a JAK inhibitor provided by the present invention is used for topical eye drop administration, is compatible and stable with the eye, is gentle and comfortable with the tear film, can improve the bioavailability of the active substance in the ophthalmic composition, has excellent therapeutic effects when used for the treatment of non-infectious inflammatory diseases, and, because it is administered as eye drops to the ocular surface, is less invasive and has fewer side effects without damaging or invading the tissues of the eye.

[0051] In some embodiments of the present invention, the pH buffer is one selected from the group consisting of boric acid-borate, citrate, acetate-sodium acetate, trimethylolaminomethane-hydrochloride, sodium bicarbonate, and phosphate.

[0052] The borate is at least one selected from the group consisting of sodium borate, potassium borate, and any suitable hydrate thereof, and exemplary the hydrate is, for example, sodium borate pentahydrate or sodium borate decahydrate.

[0053] The citrate is at least one selected from the group consisting of potassium citrate, sodium citrate, disodium hydrogen citrate, sodium dihydrogen citrate, dipotassium hydrogen citrate, potassium dihydrogen citrate, and any suitable hydrate thereof. Exemplarily, the hydrate is, for example, sodium citrate dihydrate or sodium citrate trihydrate.

[0054] The phosphate is at least one selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and any suitable hydrate thereof, and exemplary the hydrate is, for example, disodium hydrogen phosphate heptahydrate or disodium hydrogen phosphate dodecahydrate.

[0055] The citric acid and citrate may be used as pH buffering agents or as chelating agents. The roles of citric acid and citrate in the ophthalmic composition of the present invention can be determined according to the specific formulation.

[0056] In some embodiments of the present invention, the pH buffer is selected from citrate-citrate, the citrate being any known citrate, and the citrate content in the ophthalmic composition is 0.001 to 2.5 wt%, preferably 0.01 to 1.5 wt%, and more preferably 0.1 to 0.25 wt%. The inventors select a citrate-citrate buffer system and control the citrate content within the above range to match the citrate concentration to the buffering capacity in tears, thereby minimizing irritation and / or discomfort caused by a buffer system with high ionic strength. Furthermore, the high ionic strength of the citrate-citrate buffer system improves the solubility of the active substance of the present invention in the ophthalmic composition, thereby providing the ophthalmic composition according to the present invention with better stability.

[0057] In some embodiments of the present invention, the osmotic pressure regulator is selected from inorganic osmotic pressure regulators and / or organic osmotic pressure regulators.

[0058] The inorganic osmotic pressure regulator is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, zinc chloride, and magnesium chloride.

[0059] The organic osmotic pressure regulator is at least one selected from the group consisting of glucose, glycerin, propylene glycol, glycine, diglycine, alanine, taurine, ectoin, erythritol, mannitol, sorbitol, and trehalose.

[0060] The glycerin, propylene glycol, mannitol, and trehalose may be used as osmotic pressure modifiers or as comforting agents. Their roles in the ophthalmic composition of the present invention can be determined according to the specific formulation.

[0061] In some embodiments of the present invention, the solubilizing agent is at least one cyclodextrin selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and hydroxypropyl-γ-cyclodextrin.

[0062] The inventors have found that although the active substance, for example, compound VVN461, is a lipophilic molecule with low water solubility, by using the solubilizer of the present invention and controlling the content of the solubilizer within the above range, the permeability of the ophthalmic composition can be improved, the average residence time of the ophthalmic composition on the ocular surface can be increased, and the bioavailability of the active substance can be improved, ensuring that a sufficient and stable active substance dissolves in the tear film and passes through the tear film barrier, thereby exhibiting a better therapeutic effect. If the content of the solubilizer is too low or too high, both limit the permeability of the active substance of the present invention. The inventors have found that when the content of the solubilizer of the present invention satisfies the above range, the ophthalmic composition of the present invention has good permeability.

[0063] In some embodiments of the present invention, the ophthalmic excipient further comprises a mucosal adhesive, the mucosal adhesive being a mucosal adhesive polymer, at least one selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose of different molecular weights, sodium hyaluronate of different molecular weights, sodium alginate, polyethylene glycol, thiolated polyacrylic acid, poloxamer, poloxamine, Mrij, Brij, cellulose phthalate acetate, hydroxyethylcellulose, poly(amidoamine)dendrimer, poly(dimethylsiloxane), and hydroxypropyl guar gum.

[0064] The content of the mucosal adhesive in the ophthalmic composition is 0.001 to 15 wt%, preferably 0.005 to 10 wt%, and more preferably 0.01 to 5 wt%.

[0065] The poloxamer may be used as a mucosal adhesive or as a surfactant. The carboxymethylcellulose, sodium hyaluronate, sodium alginate, and hydroxyethylcellulose may be used as mucosal adhesives or as comforting agents. The polyethylene glycol may be used as a mucosal adhesive, as a surfactant, or as a comforting agent. The role of each substance in the ophthalmic composition of the present invention can be determined according to the specific formulation.

[0066] The inventors of the present invention have found that by using the mucosal adhesive of the present invention and controlling the content of the mucosal adhesive in the ophthalmic composition within the above range, it is possible to reduce the interruption of the human tear film and irritation to the eye, increase the retention time of the drug in front of the cornea in an ophthalmic administration system, improve the bioavailability of the active substance, and reduce eye irritation and dryness.

[0067] In some embodiments of the present invention, the ophthalmic excipient further comprises a surfactant, the surfactant being at least one selected from the group consisting of sodium dodecyl sulfate, polyethoxylated sorbitan fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene stearate, poloxamine, sorbitan fatty acid esters, polyethylene glycol, polyethoxylated aliphatic alcohols, polyoxyethylene 40 hydrogenated castor oil, sodium doxert, quaternary ammonium compounds, C6-C20 fatty acids, sucrose fatty acid esters, fatty acid glycerol esters, polysorbate, poloxamer, and tyroxapole.

[0068] The content of the surfactant in the ophthalmic composition is 0.01 to 5 wt%.

[0069] In the present invention, the surfactant may be a surfactant beneficial to the eyes, and the surfactant reduces the interfacial tension of the ophthalmic composition to 50 dyes / cm². 2 It can be reduced to less than [amount].

[0070] In some embodiments of the present invention, the ophthalmic excipient further comprises a comforting agent, the comforting agent being at least one selected from the group consisting of polyols, cellulose derivatives, glucans, polyethylene glycol, polysorbates, povidone, trehalose, hyaluronic acid, sodium hyaluronate, and sodium alginate.

[0071] The polyol is at least one selected from the group consisting of glycerin, propylene glycol, polyvinyl alcohol, and mannitol.

[0072] The cellulose derivative is at least one selected from the group consisting of hydroxypropylmethylcellulose-E4M, hydroxypropylmethylcellulose-LV, hydroxyethylcellulose, methylolcellulose, methylcellulose, hemicellulose, and ethylcellulose.

[0073] The content of the comforting agent in the ophthalmic composition is 0.001 to 15 wt%, preferably 0.01 to 5 wt%.

[0074] In the present invention, by adding the above-mentioned comforting agent and controlling the content of the comforting agent within the above-mentioned range, the comfort experienced by patients when using the ophthalmic composition according to the present invention can be further improved.

[0075] In the present invention, the ophthalmic composition may or may not contain a preservative. In some embodiments of the present invention, the ophthalmic excipient further contains a preservative, the preservative being at least one selected from the group consisting of benzalkonium chloride, sorbic acid, disodium ethylenediaminetetraacetate, boric acid, sodium borate, sodium bisulfate, sodium thiosulfate, ascorbate, urea peroxide, benzalkonium bromide, sodium chlorite, and polyquaternium-1, and the content of the preservative in the ophthalmic composition is 0.01 to 0.05 wt%.

[0076] In some embodiments of the present invention, the ophthalmic excipient further comprises an antioxidant, the antioxidant being at least one selected from the group consisting of sodium thiosulfate, sodium pyrosulfite, N-acetylcysteine, butylhydroxyanisole, and butylhydroxytoluene, and the content of the antioxidant in the ophthalmic composition is 0.01 to 5 wt%, preferably 0.1 to 0.5 wt%.

[0077] In some embodiments of the present invention, the ophthalmic excipient further comprises a chelating agent, preferably the chelating agent being gentle on the ocular surface and biodegradable, and exemplary the chelating agent is 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- The chelating agent is selected from the group consisting of dicarboxylic acids, diethylenetriaminepentaacetic acid, hydroxyethyldiaminetriacetic acid, 1,2-diaminocyclohexanetetraacetic acid, hydroxyethylaminodiacetic acid, polyphosphates, citric acid and citrates, tartaric acid and tartrates, ethylenediaminetetraacetic acid and disodium ethylenediaminetetraacetic acid, and alkali metal salts of hexametaphosphate, and the content of the chelating agent in the ophthalmic composition is 0.001 to 1 wt%, preferably 0.1 to 0.25 wt%.

[0078] In some embodiments of the present invention, the method for preparing the ophthalmic composition is: The steps include adding 75-85% of the total content of the ophthalmic composition to a container of water for injection, The solubilizer is added while stirring, and after stirring until completely dissolved, the mixed solution is heated to 65-75°C, the JAK inhibitor is added, and the mixture is stirred for 2 hours or more, cooled to 20-30°C, and other ophthalmic excipients are added sequentially and gradually, followed by stirring for 10 minutes or more. Add sterile water for injection to make up the volume, and continue stirring for at least 15 minutes. The method includes the step of disinfecting the obtained solution and then obtaining an ophthalmic composition containing a JAK inhibitor according to the present invention.

[0079] In some embodiments of the present invention, the method for preparing the ophthalmic composition is: The steps include adding 75-85% of the total content of the ophthalmic composition to a container of water for injection, The solubilizer and mucosal adhesive are added while stirring, and after stirring until completely dissolved, the mixed solution is heated to 65-75°C, the JAK inhibitor is added, the mixture is stirred for 2 hours or more, cooled to 20-30°C, and other ophthalmic excipients are added sequentially and gradually, followed by stirring for 10 minutes or more. Add sterile water for injection to make up the volume, and continue stirring for at least 15 minutes. The present invention includes the step of sterilizing the obtained solution to obtain an ophthalmic composition containing the JAK inhibitor according to the present invention.

[0080] The preparation method of the present invention can achieve sterility, ideal stability, and extremely low total impurity content of the ophthalmic composition containing the JAK inhibitor.

[0081] In the present invention, the sterilization method in the above preparation method is not particularly limited as long as the objective of the present invention is achieved. For example, sterilization can be performed by methods such as final heat sterilization, filtration sterilization, electron beam sterilization, and ultraviolet sterilization. Specifically, for example, filtration sterilization may be performed by a single-step cold filter using a 0.22 μm sterilization filter.

[0082] In the present invention, the method of filling the ophthalmic composition containing the JAK inhibitor is not particularly limited as long as it can achieve the objectives of the present invention, and may be, for example, traditional multiple-dose vials and blow-fill seal (BFS) single-use vials or multiple-dose vials.

[0083] In the present invention, the degree of polymerization or molecular weight of each polymer is not particularly limited as long as the objectives of the present invention are achieved. For example, the polyvinylpyrrolidone 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 carboxymethylcellulose is 400,000 to 600,000, and the weight-average molecular weight of the sodium hyaluronate is 800,000 to 1,200,000.

[0084] A second aspect of the present invention provides the use of an ophthalmic composition according to the first aspect of the present invention in the preparation of pharmaceuticals for the treatment of non-infectious inflammatory diseases. The inventors have found that the JAK inhibitor according to the present invention blocks the JAK-STAT pathway by inhibiting the activity of JAK as an active substance, thereby reducing the expression of pro-inflammatory cytokines, and thus the ophthalmic composition according to the present invention can be used to treat non-infectious inflammatory diseases. Preferably, the JAK inhibitor comprises VVN461, in which the ophthalmic composition comprising VVN461 has dual JAK1 / TYK2 inhibitory activity as an active substance, targets JAK / TYK-dependent cytokines, inhibits the JAK / STAT pathway, and is used for the treatment of non-infectious inflammatory diseases.

[0085] In some embodiments of the present invention, the non-infectious inflammatory disease includes uveitis, which is at least one selected from the group consisting of anterior uveitis, choroiditis, iridocyclitis, intermediate uveitis, iritis, panuveitis, ciliary squamous ulceritis, posterior uveitis, and retinitis.

[0086] In the present invention, the method and dosage of use of the ophthalmic composition is to instill one drop into each eye 4 to 6 times a day. In the present invention, the ophthalmic composition containing the JAK inhibitor can be used topically in the eyes, ears, nose, and other areas.

[0087] The embodiments of the present invention will be described in more detail below with reference to examples.

[0088] Example 1 Preparation of ophthalmic compositions containing VVN461 Water for injection equivalent to 80% of the total content of the ophthalmic composition was added to the container. Sulfobutyl-β-cyclodextrin was added while stirring and stirred until completely dissolved. The mixed solution was heated to 70°C, VVN461 represented by formula I was added, stirred for 2 hours or more, cooled to 25°C, and the other ophthalmic excipients were added sequentially and gradually. After stirring for 10 minutes or more, water for injection was added to make up the volume, stirring continued for 20 minutes, and the mixture was filtered and sterilized in one step using a 0.22 μm sterile filter to obtain the ophthalmic composition.

[0089] Table 1 shows the product parameters (including components, content, pH, and osmotic pressure) of the ophthalmic composition obtained in Example 1.

[0090] Example 2 The procedure was the same as in Example 1, except that the product parameters were adjusted as shown in Table 1.

[0091] Examples 3-4 The procedure was the same as in Example 1, except that the product parameters were adjusted as shown in Table 2.

[0092] Examples 5-11 Preparation of ophthalmic compositions containing VVN461 Water for injection equivalent to 80% of the total content of the ophthalmic composition was added to the container. Hydroxypropyl-β-cyclodextrin and PEG400 were added while stirring, and stirred until completely dissolved. The mixed solution was heated to 70°C, VVN461 represented by formula I was added, stirred for 2 hours or more, cooled to 25°C, and other ophthalmic excipients were added sequentially and gradually. After stirring for 10 minutes or more, water for injection was added to make up the volume, stirring continued for 20 minutes, and the mixture was filtered and sterilized in one step using a 0.22 μm sterile filter to obtain the ophthalmic composition.

[0093] Table 3 shows the product parameters (including components, content, pH, and osmotic pressure) of the ophthalmic compositions obtained in Examples 5 to 11.

[0094] Examples 12-17 The procedure was the same as in Example 5, except that the product parameters were adjusted as shown in Table 4.

[0095] Examples 18-23 The procedure was the same as in Example 5, except that the product parameters were adjusted as shown in Table 5.

[0096] Examples 24-29 The procedure was the same as in Example 5, except that the product parameters were adjusted as shown in Table 6.

[0097] Examples 30-35 The procedure was the same as in Example 5, except that the product parameters were adjusted as shown in Table 7.

[0098] Examples 36-39 Preparation of ophthalmic compositions containing VVN461 Water for injection equivalent to 80% of the total content of the ophthalmic composition was added to the container. Sulfobutyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, poloxamer 407, and PVP K90 were added while stirring, and the mixture was stirred until completely dissolved. The mixed solution was heated to 70°C, VVN461 represented by formula I was added, and the mixture was stirred for more than 2 hours. After cooling to 25°C, the other ophthalmic excipients were added sequentially and gradually, and the mixture was stirred for more than 10 minutes. Water for injection was added to make up the volume, and the mixture was stirred for 20 minutes. The mixture was then filtered and sterilized in one step using a 0.22 μm sterile filter to obtain the ophthalmic composition.

[0099] Table 8 shows the product parameters (including components, content, pH, and osmotic pressure) of the ophthalmic compositions obtained in Examples 36-39.

[0100] Example 40 Preparation of ophthalmic compositions containing VVN461 Water for injection equivalent to 80% of the total content of the ophthalmic composition was added to the container. Hydroxypropyl-β-cyclodextrin, poloxamer 407, and PEG400 were added while stirring, and stirred until completely dissolved. The mixed solution was heated to 70°C, VVN461 represented by formula I was added, stirred for 2 hours or more, cooled to 25°C, and the other ophthalmic excipients were added sequentially and gradually, stirred for 10 minutes or more, water for injection was added to make up the volume, stirring continued for 20 minutes, and the mixture was filtered and sterilized in one step using a 0.22 μm sterile filter to obtain the ophthalmic composition.

[0101] Table 9 shows the product parameters (including components, content, pH, and osmotic pressure) of the ophthalmic composition obtained in Example 40.

[0102] Example 41 The procedure was the same as in Example 1, except that the product parameters were adjusted as shown in Table 10.

[0103] Examples 42-64 Preparation of ophthalmic compositions containing VVN461 Water for injection equivalent to 80% of the total content of the ophthalmic composition was added to the container. Hydroxypropyl-β-cyclodextrin was added while stirring and dissolved by visual inspection. Poloxamer 188, polyvinyl alcohol, PVP K30, PEG400, and CMC were then added and stirred until completely dissolved. The mixed solution was heated to 70°C, VVN461 represented by formula I was added, and the mixture was stirred for more than 2 hours. After cooling to 25°C, the other ophthalmic excipients were added sequentially and gradually, and the mixture was stirred for more than 10 minutes. Water for injection was added to make up the volume, and the mixture was stirred for 20 minutes. The mixture was then filtered and sterilized in one step using a 0.22 μm sterile filter to obtain the ophthalmic composition.

[0104] The aforementioned CMC was a 1 wt% aqueous CMC solution. The preparation method involved adding 400 mL of sterile water for injection, starting to stir, heating to 85°C, gradually adding 5 g of CMC (with a weight-average molecular weight of approximately 250,000), stirring until the white particles disappeared and the solution became transparent, cooling to room temperature to completely dissolve, replenishing with sterile water for injection to 500 mL, and stirring uniformly.

[0105] Table 11 shows the product parameters (including components, content, pH, and osmotic pressure) of the ophthalmic compositions obtained in Examples 42 to 64.

[0106] [Table 1]

[0107] [Table 2]

[0108] [Table 3]

[0109] [Table 4]

[0110] [Table 5]

[0111] [Table 6]

[0112] [Table 7]

[0113] [Table 8]

[0114] [Table 9]

[0115] [Table 10]

[0116] [Table 11-1]

[0117] [Table 11-2]

[0118] Note: In Table 11, "-" indicates that the corresponding substance has not been added.

[0119] Stability test: The ophthalmic composition containing the prepared VVN461 was filled into multi-dose vials (5 mL) and stored under conditions of 25°C±2°C / 40%±5%RH and 40°C±2°C / 25%±5%RH, respectively. After storage for 1 month and 11 months, the ophthalmic composition was subjected to stability tests, and the results are shown in Table 12. The total impurity content of the ophthalmic composition was the sum of the impurity content obtained by measuring the ophthalmic composition using high-performance liquid chromatography (HPLC).

[0120] [Table 12]

[0121] Note: In Table 12, "-" indicates that the corresponding parameter does not exist.

[0122] *: The eye drop vial is made of low-density polyethylene and is a semipermeable material. If left at 40°C for 11 months, water will be lost and the osmotic pressure will increase.

[0123] As can be seen from the stability data in Table 11, the ophthalmic compositions prepared by the preparation method of the present invention still exhibit good stability and extremely low impurity content even after being stored for a long period of 11 months under conditions of 25℃±2℃ / 40%±5%RH and 40℃±2℃ / 25%±5%RH. Here, the relative retention time (RRT) of a single impurity in Table 12 is the ratio of the retention time of the single impurity to the retention time of VVN461 represented by formula I.

[0124] Effects of ophthalmic compositions on experimental autoimmune uveitis To evaluate the efficacy and safety of the ophthalmic compositions, anterior uveitis Dutch rabbit models were created. Subsequently, the ophthalmic compositions of Example 1 and Example 2, pranoprofen eye drops, and tobramycin dexamethasone eye drops were administered topically (by instillation) to one eye of each animal, six times a day for 21 consecutive days, while the other eye remained untreated as a control. Next, anterior chamber inflammatory cells and conjunctival hyperemia were scored on days 1, 3, 7, 14, and 21 of administration. The scoring criteria for anterior chamber inflammatory cells are shown in Table 13, the scoring criteria for conjunctival hyperemia are shown in Table 14, the results of the anterior chamber inflammatory cell scoring are shown in Figure 1, and the results of the conjunctival hyperemia scoring are shown in Figure 2. As can be seen from the results in Figures 1 and 2, the ophthalmic composition containing VVN461 of the present invention is highly effective in treating experimental autoimmune uveitis (anterior chamber inflammatory cells were clearly reduced) and has few side effects (conjunctival hyperemia scores were clearly reduced). Its effectiveness is equivalent to that of tobramycin dexamethasone and superior to that of pranoprofen. From the above results, it was found that the ophthalmic composition containing the JAK inhibitor of the present invention, in terms of composition and content, has the potential to replace corticosteroids, can be used to treat non-infectious inflammatory diseases such as anterior uveitis, has excellent therapeutic effects, and has few side effects. [Table 13] [Table 14]

[0125] Mechanism of action of VVN461 in treating non-infectious inflammatory diseases The inventors of the present invention studied the mechanism of action of VVN461 and found the following: VVN461 is a small molecule drug with a dual mechanism of action and is a dual JAK1 / TYK2 inhibitor. JAK or TYK-dependent cytokines are associated with non-infectious inflammatory diseases (e.g., uveitis or other ocular diseases) and are a potential therapeutic target for immune-mediated uveitis. VVN461 may target Janus kinase 1 (JAK1) or tyrosine kinase 2 (TYK2), and by targeting JAK / TYK-dependent cytokines, it inhibits the Janus kinase (JAK) / signaling and activator of transcription (STAT) pathway, thereby making it usable for the treatment of non-infectious inflammatory diseases such as uveitis. Specifically, as shown in Figure 3, pro-inflammatory cytokines transmit signals through the JAK / STAT pathway. When a cytokine binds to its receptor, the receptors move into close proximity, causing JAK to become phosphorylated, and further phosphorylation of tyrosine residues in the intracellular domain of the cytokine receptor. These phosphorylated receptor residues act as binding sites for the STAT protein. Activated by JAK phosphorylation, they dimerize STAT, causing it to translocate to the cell nucleus, where it binds to specific DNA sites, regulating gene expression and triggering inflammation. On the other hand, VVN461 of the present invention targets JAK / TYK-dependent cytokines and inhibits the JAK / STAT pathway, making it suitable for treating non-infectious inflammatory diseases such as uveitis.

[0126] In this text, the terms “includes,” “possesses,” or any variation thereof are intended to refer to non-exclusive inclusion. Therefore, a process, method, or article that includes a set of elements is not necessarily limited to those elements and may include other elements not explicitly stated, or elements specific to those processes, methods, or articles.

[0127] The foregoing are merely preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. An ophthalmic composition comprising an active substance and an ophthalmic excipient, The active substance is a JAK inhibitor represented by formula I, The content of the active substance in the ophthalmic composition is 0.01 to 5 wt%, 【Chemistry 1】 The ophthalmic excipient consists of a pH buffer, an inorganic osmotic pressure regulator, cyclodextrin, a mucosal adhesive, polyethylene glycol, and water for injection, and the content of the pH buffer in the ophthalmic composition is 0.001 to 2.5 wt%. The content of the inorganic osmotic pressure regulator in the ophthalmic composition is 0.01 to 2.5 wt%, The cyclodextrin content in the ophthalmic composition is 0.5 to 15 wt%, The content of the mucosal adhesive in the ophthalmic composition is 0.001 to 15 wt%, The polyethylene glycol content in the ophthalmic composition is 0.01 to 5 wt%, An ophthalmic composition having a pH of 4 to 8 and an osmotic pressure of 200 to 400 mOsmo / kg.

2. The pH buffer is one selected from the group consisting of boric acid-borate, citrate, acetate-sodium acetate, trimethylolaminomethane-hydrochloride, sodium bicarbonate, and phosphate. The borate is at least one selected from the group consisting of sodium borate, potassium borate, and their hydrates. The citrate is at least one selected from the group consisting of potassium citrate, sodium citrate, disodium hydrogen citrate, sodium dihydrogen citrate, dipotassium hydrogen citrate, potassium dihydrogen citrate, and their hydrates. The ophthalmic composition according to claim 1, wherein the phosphate is at least one selected from the group consisting 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 inorganic osmotic pressure regulator is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, zinc chloride, and magnesium chloride.

4. The ophthalmic composition according to claim 1, wherein the cyclodextrin is at least one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and hydroxypropyl-γ-cyclodextrin.

5. The ophthalmic composition according to claim 1, wherein the mucosal adhesive is at least one selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium hyaluronate, sodium alginate, polyethylene glycol, thiolated polyacrylic acid, poloxamer, poloxamine, mirj, brij, cellulose phthalate acetate, hydroxyethylcellulose, poly(amideamine) dendrimer, poly(dimethylsiloxane), and hydroxypropyl guar gum.

6. The ophthalmic composition according to claim 1, wherein the polyethylene glycol is PEG400.

7. Use of the ophthalmic composition according to claim 1 in the preparation of a pharmaceutical product for treating a non-infectious inflammatory disease.

8. The use according to claim 7, wherein the non-infectious inflammatory disease includes uveitis, and the uveitis is at least one selected from the group consisting of anterior uveitis, choroiditis, iridocyclitis, intermediate uveitis, iritis, panuveitis, ciliary squamous ulceritis, posterior uveitis, and retinitis.

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