Ophthalmic composition 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 the application number 202310484101.X and the invention title "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, including JAK inhibitors.

Background Art

[0003] The eye is one of the most important organs of the human body, and any functional impairment of 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 kinase (JAK) is an intracellular non-receptor tyrosine kinase family consisting of four members: JAK1, JAK2, JAK3, and tyrosine-protein kinase 2 (TYK2). Janus kinase mediates the signals generated by cytokines and transmits them through the JAK-signal transducer and activation of transcription (STAT) signaling pathway, and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. This pathway is one of the commonly seen 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 blood and immune systems and plays an important role in immune-mediated inflammatory diseases such as atopic dermatitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, alopecia areata, vitiligo, and non-infectious uveitis. Thus, by inhibiting the activity of JAK, the JAK-STAT pathway can be blocked, and the expression of inflammation-inducing cytokines can be reduced, thereby achieving the purpose of treating non-infectious inflammatory diseases such as non-infectious uveitis.

[0005] Currently, chronic uveitis is mainly treated with topical corticosteroid eye drops. Corticosteroids can be administered ophthalmically by eye drops or injection in order to reduce, control or relieve inflammation as the standard first-choice drug for treating uveitis. Currently, there are many choices of corticosteroid eye drops. For example, 0.125% and 1% prednisolone acetate, 1% betamethasone, 0.1% dexamethasone sodium phosphate (there is also a 0.05% ointment form), 0.1% and 0.25% fluorometholone (there is also a 0.1% ointment form), 0.5% loteprednol (a 0.5% ointment form is also available), 1% rimexolone can be mentioned. However, using corticosteroid eye drops over a long period of time can cause a significant increase in intraocular pressure, and continuously using corticosteroid eye drops also increases the risk of cataract formation. Therefore, there is an urgent need to develop pharmaceuticals that are less invasive, have fewer side effects or sequelae, and are more effective for non-infectious inflammatory diseases such as uveitis instead of corticosteroids.

Summary of the Invention

[0006] An object of the present invention is to provide an ophthalmic composition that is compatible with the eye and stable, and the ophthalmic composition can treat non-infectious inflammatory diseases by topical eye drop administration, has excellent effects and few side effects. The specific technical solutions are as follows.

[0007] A first aspect of the present invention provides an ophthalmic composition, the ophthalmic composition comprising an active substance and an ophthalmic excipient, the active substance being a JAK inhibitor, the JAK inhibitor being at least one selected from the group consisting of VVN461, tofacitinib, ruxolitinib, baricitinib, peficitinib, delgocitinib, upadacitinib, filgotinib, abrocitinib, deucravacitinib, ritlecitinib, brepocitinib, Jaktinib, ivarmacitinib (SHR0302), itacitinib (IBI-377), Golidocitinib (AZD4205), KL130008, TLL018, and LYK01001, preferably VVN461, the VVN461 being as 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%, more preferably 0.1 to 1 wt%,

[0009]

Chemical formula

[0010] The ophthalmic excipient includes 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 to 2.5 wt%, preferably 0.01 to 1.5 wt%, more preferably 0.1 to 0.25 wt%,

[0011] The content of the osmotic pressure regulator 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, more preferably 240 to 320 mOsmol / Kg.

[0014] In some embodiments of the present invention, the pH buffer is any one selected from the group consisting of boric acid-borate, citric acid-citrate, acetic acid-sodium acetate, trimethylolaminomethane-hydrochloric acid, 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, ectoine, 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 contains a mucoadhesive, and the mucoadhesive is polyvinylpyrrolidone (PVP), polyvinyl alcohol, methylcellulose, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), sodium hyaluronate, sodium alginate, polyethylene glycol (PEG), thiolated polyacrylic acid (PAA-SH), poloxamer, poloxamine, Mrij (polyoxyethylene oleate ether ester), Brij (polyoxyethylene aliphatic alcohol ether), cellulose acetate phthalate (CAP), hydroxyethylcellulose (HEC), poly(amidoamine) dendrimer (PAMAM), poly(dimethylsiloxane) (PDMS), and hydroxypropyl guar gum (HP-Guar). It is at least one selected from the group consisting of,

[0023] The content of the mucoadhesive 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 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 doxycycline, quaternary ammonium compounds, C6-C20 fatty acids, sucrose fatty acid esters, glycerin fatty acid esters, polysorbates, poloxamers, and tyloxapol, and is at least one selected from the group consisting of

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

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

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

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

[0029] In some embodiments of the present invention, the ophthalmic excipient further comprises a preservative, and the preservative is 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, and the antioxidant is 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, and the chelating agent is at least one selected from the group consisting of nitrilotriacetic acid, ethylenediaminedisuccinic acid, iminodisuccinic acid, methylglycine diacetic acid, L-glutamic acid N,N-diacetic acid, ethylenediamine-N,N'-diglutamic acid, ethylenediamine-N,N'-dimaleic 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 ethylenediaminetetraacetate, and alkali metal 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] The second aspect of the present invention provides the use of the ophthalmic composition according to the first aspect of the present invention in the preparation of a pharmaceutical for treating non-infectious inflammatory diseases.

[0036] In some embodiments of the present invention, 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, pars planitis, posterior uveitis, and retinitis.

[0037] The present invention provides an ophthalmic composition for treating non-infectious inflammatory diseases, which contains a JAK inhibitor. 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, 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 treatment effects, has little invasiveness and few side effects, and has a simple production process and is suitable for large-scale production.

Brief Description of the Drawings

[0038] To more clearly illustrate the technical solutions of the examples of the present invention and the prior art, the drawings used in the examples or the prior art will be briefly described below. However, the drawings described below are only some examples of the present invention, and it is obvious to those skilled in the art that other examples can be obtained based on these drawings.

Figure 1

Figure 2

Figure 3

Embodiments for Carrying Out the Invention

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

[0040] The first aspect of the present invention provides an ophthalmic composition, the ophthalmic composition contains an active substance and an ophthalmic excipient, 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, dukeravacitinib, litretacitinib, brepocitinib, jakitinib, ibrarmacitinib, itacitinib, golidocitinib, KL130008, TLL018, and LYK01001, but is not limited thereto, preferably the JAK1 / TYK2 dual inhibitor VVN461, and the VVN461 is as shown in Formula I.

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

[0042]

Chemical formula

[0043] The ophthalmic excipient includes 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%, more preferably 0.1 - 0.25 wt%.

[0044] The content of the osmotic pressure regulator 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, more preferably 240 to 320 mOsmol / Kg.

[0047] In the present invention, for the compound VVN461 represented by the formula I, its molecular weight is 324.38, the chemical name is (R)-2-(1-(2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile, the property is a white to pale yellow solid or powder, the melting point is 225.6 to 228.9 °C (differential scanning calorimetry - onset point (DSC onset) value), and the solubility is that it hardly dissolves in water. In the present invention, the crystal form of the compound VVN461 is not particularly limited as long as the object of the present invention can be achieved. For example, the compound VVN46 is crystal form A (X-ray powder diffraction (XRDP) method).

[0048] The present inventors have found that by controlling the content of the active substance within the above range and controlling the pH buffer within the above low concentration range, the buffering ability of the ophthalmic composition of the present invention can be made to match the buffering ability of tears, be gentle to tears and have a strong sense of comfort, and at the same time increase the average residence time of the active substance of the present invention and improve the bioavailability of the active substance.

[0049] In the present invention, by controlling the content of the osmotic pressure regulator within the above range and making the usage amount equivalent to a sodium chloride solution of 0.9% or a glycerin solution of 2.7%, the osmotic pressure of the ophthalmic composition according to the present invention is made close to the osmotic pressure of normal tears (270 - 310 mOsmol / Kg), thereby significantly reducing the discomfort when a patient uses the ophthalmic composition. In the present invention, if the ophthalmic composition is simply prepared using water for injection without adding an osmotic pressure regulator, it will become hypotonic. On the other hand, an excessive amount of the osmotic pressure regulator may form a hypertonic solution. Either hypotonic or hypertonic will cause the loss of the optical parameters required for the lens. Furthermore, a hypertonic solution causes stinging pain, irritation to the eyes, and dryness of the eye surface, etc.

[0050] The ophthalmic composition containing a JAK inhibitor provided by the present invention is used for topical eye drop administration, is compatible with the eye, stable, gentle and comfortable to the tears, can improve the bioavailability of the active substance in the ophthalmic composition, and has an excellent therapeutic effect when used for the treatment of non-infectious inflammatory diseases. Moreover, since it is administered by eye drops to the eye surface, it has little invasiveness and few side effects without damaging or invading the eye tissues.

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

[0052] The borate is at least one selected from the group consisting of sodium borate, potassium borate, and any suitable hydrates thereof. Exemplarily, 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 hydrates 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 hydrates thereof. Exemplarily, the hydrate is, for example, disodium hydrogen phosphate heptahydrate or disodium hydrogen phosphate dodecahydrate.

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

[0056] In some embodiments of the present invention, the pH buffer is selected from citric acid - citrate, the citrate is any known citrate, and the content of the citric acid - citrate in the ophthalmic composition is 0.001 to 2.5 wt%, preferably 0.01 to 1.5 wt%, more preferably 0.1 to 0.25 wt%. The inventor selects the citric acid - citrate buffer system and controls the content of the citric acid - citrate within the above range, so as to match the citrate concentration with the buffering capacity in tears, thereby reducing the irritation and / or discomfort caused by the buffer system with high ionic strength as much as possible. Moreover, since the citric acid - citrate buffer system has a high ionic strength, the solubility of the active substance of the present invention in the ophthalmic composition can be improved, thereby making the ophthalmic composition according to the present invention have 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, ectoine, erythritol, mannitol, sorbitol, and trehalose.

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

[0061] In some embodiments of the present invention, the solubilizer 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 inventor has found that the active substance, for example, compound VVN461, is a lipophilic molecule with low water solubility. However, 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, the bioavailability of the active substance can be improved, and a sufficient and stable amount of the active substance can be dissolved in the tear fluid to ensure passage through the tear film barrier, thereby exerting a better therapeutic effect. If the content of the solubilizer is too low or too high, it will limit the permeability of the active substance of the present invention. The inventor has 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 mucoadhesive, and the mucoadhesive is a mucoadhesive polymer and is at least one selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose with different molecular weights, sodium hyaluronate with different molecular weights, sodium alginate, polyethylene glycol, thiolated polyacrylic acid, poloxamer, poloxamine, Mrij, Brij, cellulose acetate phthalate, hydroxyethylcellulose, poly(amidoamine) dendrimer, poly(dimethylsiloxane), and hydroxypropyl guar gum.

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

[0065] The poloxamer may be used as a mucoadhesive or as a surfactant. The carboxymethyl cellulose, sodium hyaluronate, sodium alginate, and hydroxyethyl cellulose may be used as a mucoadhesive or as a comfort agent. The polyethylene glycol may be used as a mucoadhesive, as a surfactant, or as a comfort agent. The role of each substance in the ophthalmic composition of the present invention can be determined according to a specific formulation.

[0066] By using the mucoadhesive of the present invention and controlling the content of the mucoadhesive in the ophthalmic composition within the above range, the present inventors can reduce the disruption of the human tear film and ocular irritation, increase the residence time of the pharmaceutical in front of the cornea in an ocular 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 contains a surfactant, and the surfactant is at least one selected from the group consisting of sodium dodecyl sulfate, polyethoxylated sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene stearate, poloxamine, sorbitan fatty acid ester, polyethylene glycol, polyethoxylated aliphatic alcohol, polyoxyethylene 40 hydrogenated castor oil, sodium doxsate, quaternary ammonium compound, C6-C20 fatty acid, sucrose fatty acid ester, fatty acid glycerin ester, polysorbate, poloxamer, and tyloxapol,

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

[0069] In the present invention, the surfactant may be a surfactant beneficial to the eyes, and the surfactant can reduce the surface tension of the ophthalmic composition to less than 50 dynes / cm 2 ​

[0070] In some embodiments of the present invention, the ophthalmic excipient further comprises a comfort agent, and the comfort agent is at least one selected from the group consisting of polyols, cellulose derivatives, glucans, polyethylene glycol, polysorbate, 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 comfort 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 comfort agent and controlling the content of the comfort agent within the above range, the comfort of the patient 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 comprises a preservative, and the preservative is 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, and the antioxidant is at least one selected from the group consisting of sodium thiosulfate, sodium pyrosulfite, N-acetylcysteine, butylhydroxyanisole, and butylhydroxytoluene. 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 is gentle to the eye surface and biodegradable. Exemplarily, the chelating agent is at least one selected from the group consisting of nitrilotriacetic acid, ethylenediaminedisuccinic acid, iminodisuccinic acid, methylglycine diacetic acid, L-glutamic acid N,N-diacetic acid, ethylenediamine-N,N'-diglutamic acid, ethylenediamine-N,N'-dimaleic 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 ethylenediaminetetraacetate, and alkali metal hexametaphosphate. 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 adding water for injection in an amount of 75 to 85% of the total content of the ophthalmic composition into a container; adding a solubilizer while stirring, stirring until completely dissolved, then heating the mixed solution to 65 to 75 °C, adding a JAK inhibitor, stirring for 2 h or more, cooling to 20 to 30 °C, and sequentially and gradually adding other ophthalmic excipients, and then stirring for 10 min or more; adding water for injection to make up the volume and continuing to stir for 15 min or more. After sterilizing the obtained solution, obtaining an ophthalmic composition containing the JAK inhibitor according to the present invention.

[0079] In some embodiments of the present invention, the method for preparing the ophthalmic composition is as follows. Adding water for injection accounting for 75 - 85% of the total content of the ophthalmic composition to a container. Adding a solubilizer and a mucoadhesive while stirring, stirring until completely dissolved, then heating the mixed solution to 65 - 75°C, adding the JAK inhibitor, stirring for 2 hours or more, cooling to 20 - 30°C, and sequentially and gradually adding other ophthalmic excipients, then stirring for 10 minutes or more. Adding water for injection to make up the volume and continuing stirring for 15 minutes or more. After sterilizing the obtained solution, obtaining the ophthalmic composition containing the JAK inhibitor according to the present invention.

[0080] The preparation method of the present invention can achieve the 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 object of the present invention can be achieved. For example, sterilization can be performed by methods such as final heat sterilization, filtration sterilization, electron beam sterilization, ultraviolet ray system, etc. Specifically, for example, filtration sterilization can be performed by cold filtration in one step using a 0.22 μm sterilizing filter.

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

[0083] In the present invention, the degree of polymerization or molecular weight of each polymer is not particularly limited as long as the object of the present invention can be achieved. Exemplarily, the polyvinylpyrrolidone may be PVP K30, the hydroxypropylmethylcellulose 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 the ophthalmic composition according to the first aspect of the present invention in the preparation of a medicament for treating non-infectious inflammatory diseases. The present 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, reduces the expression of inflammation-inducing cytokines, and thereby the ophthalmic composition according to the present invention can be used for treating non-infectious inflammatory diseases. Preferably, the JAK inhibitor contains VVN461. In the ophthalmic composition containing VVN461, VVN461 has a dual JAK1 / TYK2 inhibitory effect as an active substance, targets JAK / TYK-dependent cytokines, inhibits the JAK / STAT pathway, and is thereby used for the treatment of non-infectious inflammatory diseases.

[0085] In some embodiments of the present invention, 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, pars planitis, posterior uveitis, and retinitis.

[0086] In the present invention, the ophthalmic composition is used by instilling one drop once a day into one 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, etc.

[0087] Hereinafter, embodiments of the present invention will be described more specifically with reference to examples.

[0088] Example 1 Preparation of an ophthalmic composition containing VVN461 80% of the total content of the ophthalmic composition of water for injection was added to a container. While stirring, sulfobutyl-β-cyclodextrin was added and stirred until completely dissolved. The mixed solution was heated to 70°C, VVN461 represented by Formula I was added, and stirred for 2 h or more, cooled to 25°C. After sequentially adding other ophthalmic excipients gradually, it was stirred for 10 min or more, made up to volume with water for injection, stirring was continued for 20 min, and filtered and sterilized by cold filtration in one step using a 0.22-μm sterilizing filter to obtain an ophthalmic composition.

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

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

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

[0092] Examples 5 - 11 Preparation of an ophthalmic composition containing VVN461 80% of the total content of the ophthalmic composition of water for injection was added to a container. While stirring, hydroxypropyl-β-cyclodextrin and PEG400 were added and stirred until completely dissolved. The mixed solution was heated to 70°C, VVN461 represented by Formula I was added, and stirred for 2 h or more, cooled to 25°C. After sequentially adding other ophthalmic excipients gradually, it was stirred for 10 min or more, made up to volume with water for injection, stirring was continued for 20 min, and filtered and sterilized by cold filtration in one step using a 0.22-μm sterilizing filter to obtain an ophthalmic composition.

[0093] The parameters of the ophthalmic compositions obtained in Examples 5 to 11 (including components, contents, pH, and osmotic pressure) are shown in Table 3.

[0094] Examples 12 to 17 It was the same as Example 5 except that the product parameters were adjusted as shown in Table 4.

[0095] Examples 18 to 23 It was the same as Example 5 except that the product parameters were adjusted as shown in Table 5.

[0096] Examples 24 to 29 It was the same as Example 5 except that the product parameters were adjusted as shown in Table 6.

[0097] Examples 30 to 35 It was the same as Example 5 except that the product parameters were adjusted as shown in Table 7.

[0098] Examples 36 to 39 Preparation of an ophthalmic composition containing VVN461 80% of the total content of the ophthalmic composition of water for injection was added to a container. While stirring, sulfobutyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, poloxamer 407, and PVP K90 were added, and stirring was continued until completely dissolved. The mixed solution was heated to 70°C, VVN461 represented by Formula I was added, and stirring was carried out for 2 h or more. Then it was cooled to 25°C. After other ophthalmic excipients were sequentially and gradually added, stirring was carried out for 10 min or more, water for injection was added to make up the volume, stirring was continued for 20 min, and filtration sterilization was carried out by cold filtration in one step using a 0.22-μm sterilizing filter to obtain an ophthalmic composition.

[0099] The parameters of the ophthalmic compositions obtained in Examples 36 to 39 (including components, contents, pH, and osmotic pressure) are shown in Table 8.

[0100] Example 40 Preparation of an ophthalmic composition containing VVN461 80% of the total content of the ophthalmic composition of water for injection was added to the container. While stirring, hydroxypropyl-β-cyclodextrin, poloxamer 407 and PEG400 were added, and stirring was continued until completely dissolved. The mixed solution was heated to 70 °C, VVN461 represented by formula I was added, and stirring was carried out for 2 h or more. After cooling to 25 °C and sequentially adding other ophthalmic excipients gradually, stirring was carried out for 10 min or more, water for injection was added to make up the volume, stirring was continued for 20 min, and filtration sterilization was carried out by cold filtration in one step using a 0.22 μm sterilizing filter to obtain the ophthalmic composition.

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

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

[0103] Examples 42 to 64 Preparation of an ophthalmic composition containing VVN461 80% of the total content of the ophthalmic composition of water for injection was added to the container. While stirring, hydroxypropyl-β-cyclodextrin was added, and after visual dissolution, poloxamer 188, polyvinyl alcohol, PVP K30, PEG400 and CMC were added respectively, and stirring was continued until completely dissolved. The mixed solution was heated to 70 °C, VVN461 represented by formula I was added, and stirring was carried out for 2 h or more. After cooling to 25 °C and sequentially adding other ophthalmic excipients gradually, stirring was carried out for 10 min or more, water for injection was added to make up the volume, stirring was continued for 20 min, and filtration sterilization was carried out by cold filtration in one step using a 0.22 μm sterilizing filter to obtain the ophthalmic composition.

[0104] The CMC was a 1 wt% aqueous CMC solution, and the preparation method was to add 400 mL of water for injection, start stirring, heat to 85 °C, gradually add 5 g of CMC (weight average molecular weight is about 250000), stir until no white particles remained and it became transparent, cool to room temperature, completely dissolve, replenish water for injection to 500 mL, and stir uniformly.

[0105] The parameters (including components, contents, pH, and osmotic pressure) of the ophthalmic compositions obtained in Examples 42 to 64 are shown in Table 11.

[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] Remarks: In Table 11, “-” indicates that the corresponding substance is not added.

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

[0120]

Table 12

[0121] Remarks: In Table 12, “-” indicates that the corresponding parameter does not exist.

[0122] *: Since the eye drop vial is a low-density polyethylene vial and a semi-permeable material, when left at 40°C for 11 months, water is lost and the osmotic pressure becomes high.

[0123] As can be seen from the stability data in Table 11, the ophthalmic composition prepared by the preparation method of the present invention has good stability and extremely low impurity content even after being stored for as long as 11 months under the conditions of 25°C ± 2°C / 40% ± 5% RH and 40°C ± 2°C / 25% ± 5% RH. Here, the relative retention time (RRT) of the 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] Effect of the ophthalmic composition on experimental autoimmune uveitis To evaluate the efficacy and safety of the ophthalmic composition, an anterior uveitis Dutch rabbit model was established. Subsequently, the ophthalmic composition of Example 1, the ophthalmic composition of Example 2, pranoprofen eye drops, and tobramycin dexamethasone eye drops were topically administered (eyedropped) to one eye of each animal, 6 times a day for 21 consecutive days, and the other eye was not treated as a control. Next, scoring of anterior chamber inflammatory cells and scoring of conjunctival congestion were performed on the 1st, 3rd, 7th, 14th, and 21st days of administration. The scoring criteria for anterior chamber inflammatory cells are shown in Table 13, the scoring criteria for conjunctival congestion are shown in Table 14, the scoring results of the obtained anterior chamber inflammatory cells are shown in Figure 1, and the scoring results of conjunctival congestion are shown in Figure 2. As can be seen from the results of Figure 1 and Figure 2, the ophthalmic composition containing VVN461 of the present invention has excellent effects for treating experimental autoimmune uveitis (the anterior chamber inflammatory cells were significantly reduced), and has small side effects (the scoring of conjunctival congestion was significantly reduced). Its effect is equivalent to that of tobramycin dexamethasone and is superior to pranoprofen. From the above results, it was found that the ophthalmic composition containing the JAK inhibitor with the composition and content of the present invention has the potential to replace corticosteroids and can be used for the treatment of non-infectious inflammatory diseases such as anterior uveitis, has excellent therapeutic effects, and has small side effects.

Table 13

Table 14

[0125] The mechanism of action of VVN461 in treating non-infectious inflammatory diseases When the present inventors studied the mechanism of action of VVN461, they 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 (such as uveitis or other ocular diseases) and are potential therapeutic targets for immune-mediated uveitis. VVN461 may target Janus kinase 1 (JAK1), may target tyrosine kinase 2 (TYK2), and by targeting JAK / TYK-dependent cytokines, inhibits the Janus kinase (JAK) / signal transducer and activator of transcription (STAT) pathway, and thereby can be used for the treatment of non-infectious inflammatory diseases such as uveitis. Specifically, as shown in Figure 3, inflammatory cytokines transmit signals through the JAK / STAT pathway. When a cytokine binds to its receptor, the receptors come into close proximity, the JAKs become phosphorylated, and furthermore, tyrosine residues in the intracellular domain of the cytokine receptor are phosphorylated. These phosphorylated receptor residues serve as binding sites for STAT proteins, are activated by JAK phosphorylation, dimerize the STATs and translocate them to the nucleus, thereby binding to specific DNA sites to regulate gene expression and cause inflammation. On the other hand, the VVN461 of the present invention can be used for the treatment of non-infectious inflammatory diseases such as uveitis by targeting JAK / TYK-dependent cytokines and inhibiting the JAK / STAT pathway.

[0126] In this text, the terms "comprising", "having", or any variations thereof are intended to cover non-exclusive inclusion, so that a process, method, or article containing a series of elements is not necessarily limited to those elements, and may include other elements not expressly listed or elements inherent to these processes, methods, or articles.

[0127] The above are only preferred embodiments of the present invention and are not intended to limit the protection scope of the present invention. Any corrections, equivalent substitutions, improvements, etc. made within the scope of the gist and principle of the present invention shall be included in the protection scope of the present invention.

Claims

**Claim 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 at least one selected from the group consisting of VVN461, tofacitinib, ruxolitinib, baricitinib, peficitinib, delgocitinib, upadacitinib, filgotinib, abrocitinib, dukeravacitinib, litretacitinib, brepocitinib, jakitinib, ivalmestinib, itacitinib, golidocitinib, KL130008, TLL018, and LNK01001, preferably VVN461, and the VVN461 is as shown in Formula I, the content of the active substance in the ophthalmic composition is 0.01 to 5 wt%, preferably 0.1 to 2 wt%, more preferably 0.1 to 1 wt%, 【Chemical 1】 the ophthalmic excipient includes 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 to 2.5 wt%, preferably 0.01 to 1.5 wt%, more preferably 0.1 to 0.25 wt%, the content of the osmotic pressure regulator in the ophthalmic composition is 0.01 to 2.5 wt%, preferably 0.2 to 2 wt%, the content of the solubilizer in the ophthalmic composition is 0.5 to 15 wt%, preferably 1 to 12 wt%, 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, more preferably 240 to 320 mOsmol / Kg. An ophthalmic composition. **Claim 2** The pH buffer is any one selected from the group consisting of boric acid-borate, citric acid-citrate, acetic acid-sodium acetate, trimethylolaminomethane-hydrochloric acid, 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 osmotic pressure regulator is selected from inorganic osmotic pressure regulators and / or organic osmotic pressure regulators, 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, the organic osmotic pressure regulator is at least one selected from the group consisting of glucose, glycerin, propylene glycol, glycine, diglycine, alanine, taurine, ectoine, erythritol, mannitol, sorbitol, and trehalose. The ophthalmic composition according to claim 1.

4. The solubilizer 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. The ophthalmic composition according to claim 1.

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

6. The ophthalmic excipient further contains a surfactant, and the surfactant is at least one selected from the group consisting of sodium dodecyl sulfate, polyethoxylated sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene stearate, poloxamine, sorbitan fatty acid ester, polyethylene glycol, polyethoxylated aliphatic alcohol, polyoxyethylene hydrogenated castor oil 40, sodium doxybate, quaternary ammonium compound, C6-C20 fatty acid, sucrose fatty acid ester, fatty acid glycerin ester, polysorbate, poloxamer, and tyloxapol. The content of the surfactant in the ophthalmic composition is 0.01 to 5 wt%, and the ophthalmic composition according to any one of claims 1 to 4.

7. The ophthalmic excipient further contains a comfort agent, and the comfort agent is at least one selected from the group consisting of polyol, cellulose derivative, glucan, polyethylene glycol, polysorbate, povidone, trehalose, hyaluronic acid, sodium hyaluronic acid, and sodium alginate. The polyol is at least one selected from the group consisting of glycerin, propylene glycol, polyvinyl alcohol, and mannitol. The cellulose derivative is at least one selected from the group consisting of hydroxypropylmethylcellulose-E4M, hydroxypropylmethylcellulose-LV, hydroxyethylcellulose, methylolcellulose, methylcellulose, hemicellulose, and ethylcellulose. The content of the comfort agent in the ophthalmic composition is 0.001 to 15 wt%, preferably 0.01 to 5 wt%, and the ophthalmic composition according to any one of claims 1 to 4.

8. The ophthalmic excipient further contains a preservative, and the preservative is 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. The content of the preservative in the ophthalmic composition is 0.01 to 0.05 wt%, and the ophthalmic composition according to any one of claims 1 to 4.

9. The ophthalmic excipient further contains an antioxidant, and the antioxidant is at least one selected from the group consisting of sodium thiosulfate, sodium pyrosulfite, N-acetylcysteine, butylhydroxyanisole, and butylhydroxytoluene. The content of the antioxidant in the ophthalmic composition is 0.01 to 5 wt%, preferably 0.1 to 0.5 wt%. The ophthalmic composition according to any one of claims 1 to 4.

10. The ophthalmic excipient further contains a chelating agent, and the chelating agent is nitrilotriacetic acid, ethylenediaminedisuccinic acid, iminodisuccinic acid, methylglycine diacetic acid, L-glutamic acid N,N-diacetic acid, ethylenediamine-N,N'-diglutamic acid, ethylenediamine-N,N'-dimaleic 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 ethylenediaminetetraacetate, and at least one selected from the group consisting of alkali metal hexametaphosphates. The content of the chelating agent in the ophthalmic composition is 0.001 to 1 wt%, preferably 0.1 to 0.25 wt%. The ophthalmic composition according to any one of claims 1 to 4.

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

12. 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, pars planitis, posterior uveitis, and retinitis. The use according to claim 11.

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