VVN001 contains an ophthalmic composition

Abstract

The present invention provides an ophthalmic composition containing VVN001. The ophthalmic composition containing VVN001 contains an active substance and an ophthalmic excipient, and the active substance is selected from the sodium salt represented by Formula I and / or the free acid of Formula I. The present invention reduces the inflammatory reaction in the eye by inhibiting the inflammatory reaction mediated by T cells by the active substance. The present invention further selects a low concentration of pH buffer concentration to match the buffer capacity of the pH buffer concentration in tears, is gentle to tears, has a strong sense of comfort, increases the mean residence time of the active substance of the present invention, and improves the bioavailability of the active substance represented by Formula I of the present invention. 【Chemical 1】 JPEG2025516407000025.jpg70136

Description

[Technical Field]

[0001] The present invention claims priority to a Chinese patent application filed with the State Intellectual Property Office of the People's Republic of China on April 27, 2023, bearing application number 202310476403.2 and entitled "Ophthalmic Composition Containing VVN001," the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the field of pharmaceutical technology, and in particular to an ophthalmic composition containing VVN001. [Background technology]

[0003] Dry eye disease (DED), also known as keratoconjunctivitis sicca, is a complex ocular surface disease characterized by symptoms such as visual impairment, ocular discomfort, and dryness due to an incomplete or unstable tear film and uneven tear film thickness. T cells have been shown to play a role in mediating inflammation. Heterodimeric receptors on T cells, called integrins, contribute to T cell activation, adhesion to the extracellular matrix, migration, proliferation, and differentiation after receiving inflammatory signals. Meanwhile, lymphocyte function-associated antigen-1 (LFA-1) / intercellular adhesion molecule-1 (ICAM-1) interaction promotes T cell adhesion to endothelial cells, migration to inflamed tissues, and the formation of immune synapses through antigen presentation and recognition. These immune synapses promote downstream signaling, resulting in the release of inflammatory mediators, such as cytokines, chemokines, TNF-α, and IL-1, which further promote and sustain inflammation in ocular tissues.

[0004] Therefore, there is a need for eye drops containing small molecule integrin antagonists that address the mechanism of LFA-1 / ICAM-1 interaction by blocking the binding of LFA-1 to ICAM-1, thereby inhibiting T cell-mediated inflammatory responses and thereby reducing inflammatory responses in the eye, thereby treating dry eye and / or other ocular surface diseases. Summary of the Invention

[0005] The present invention aims to provide an ophthalmic composition that is gentle on tears and comfortable to the eye, which can achieve optimal bioavailability of the active ingredient, reduce inflammatory reactions in the eye, and treat dry eye and / or other ocular surface diseases. Specific technical solutions are as follows:

[0006] A first aspect of the present invention provides a VVN001-containing ophthalmic composition, the VVN001-containing ophthalmic composition comprising an active substance and an ophthalmic excipient, wherein the active substance is selected from the sodium salt of Formula I and / or the free acid of Formula I, and the content of the active substance in the ophthalmic composition is 0.01 to 10% W / V, preferably 0.1 to 7.5% W / V, and more preferably 1.0 to 5.0% W / V.

[0007] The ophthalmic excipient includes a pH buffer and an osmotic pressure adjuster, and the content of the pH buffer in the ophthalmic composition is 0.001 to 2.0% W / V, preferably 0.005 to 1.0% W / V, and more preferably 0.005 to 0.5% W / V.

[0008] The pH of the ophthalmic composition is 6.5 to 7.8, preferably 7.0 to 7.4, and the osmotic pressure of the ophthalmic composition is 200 to 400 mOsmol / L, preferably 250 to 350 mOsmol / L, and more preferably 280 to 320 mOsmol / L. [ka]

[0009] In one embodiment of the present invention, the pH buffer is any one selected from the group consisting of boric acid, borate salts, citric acid, citrate salts, acetic acid-sodium acetate, trimethylolaminomethane-hydrochloric acid, sodium bicarbonate, and phosphate salts.

[0010] The borate is at least one selected from the group consisting of sodium borate, potassium borate, and hydrates thereof.

[0011] 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 hydrates thereof.

[0012] The phosphate is one or more selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and hydrates thereof.

[0013] In one embodiment of the present invention, the pH buffer is selected from phosphates, and the content of the phosphate in the ophthalmic aqueous solution composition is 0.001 to 2.0% W / V, preferably 0.01 to 1.0% W / V, and more preferably 0.005 to 0.5% W / V.

[0014] In one embodiment of the invention, the osmotic agent is selected from inorganic osmotic agents and / or organic osmotic agents.

[0015] The inorganic osmotic pressure adjuster is one or more selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, zinc chloride, and magnesium chloride, and the content of the inorganic osmotic pressure adjuster in the ophthalmic aqueous solution composition is 0.01 to 1.5% W / V, and preferably 0.2 to 1% W / V.

[0016] The organic osmolality adjuster is any one selected from the group consisting of erythritol, glucose, glycerin, propylene glycol, glycine, diglycine, alanine, taurine, ectoine erythritol, mannitol, sorbitol, L-carnitine, and trehalose, and the content of the organic osmolality adjuster in the ophthalmic composition is 0.001 to 10% W / V, and preferably 0.01 to 5% W / V.

[0017] In one embodiment of the present invention, the ophthalmic excipient further comprises a surfactant, and the surfactant is at least one selected from the group consisting of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, sodium dodecyl sulfate, polyethoxylated sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene stearate, poloxamine, sorbitan fatty acid ester, polyethylene glycol, polyethoxylated fatty alcohol, polyoxyethylene 40 hydrogenated castor oil, docusate sodium, quaternary ammonium compound, C6 to C20 fatty acid, sucrose fatty acid ester, glycerin fatty acid ester, polysorbate, and tyloxapol, and the content of the surfactant in the ophthalmic composition is 0.001 to 1% W / V.

[0018] In one embodiment of the invention, the ophthalmic vehicle further comprises a comfort agent, wherein the comfort agent is at least one selected from the group consisting of polyols, cellulose derivatives, glucans, polyethylene glycols, polysorbates, povidone, trehalose, hyaluronic acid, carbopol, sodium hyaluronate, and sodium alginate.

[0019] The polyol is at least one selected from the group consisting of glycerin, propylene glycol, polyvinyl alcohol, and mannitol.

[0020] The cellulose derivative is at least one selected from the group consisting of hydroxypropylmethylcellulose-E4M, hydroxypropylmethylcellulose-LV, hydroxyethylcellulose, methylolcellulose, methylcellulose, hemicellulose, and ethylcellulose.

[0021] The content of the comfort agent in the ophthalmic composition is 0.001 to 2% W / V.

[0022] In one embodiment of the present invention, the ophthalmic excipient further comprises a chelating agent, which is at least one selected from the group consisting of disodium ethylenediaminetetraacetate, alkali metal hexametaphosphate, nitrotriacetic acid, ethylenediaminedisuccinic acid, iminodisuccinic acid, methylglycine diacetate, L-glutamic acid N,N-diacetic acid, ethylenediamine-N,N'-diglutamic acid, ethylenediamine-N,N'-dimalonic acid, 3-hydroxy-2,2-iminodisuccinic acid, 2-hydroxyethyliminodiacetic acid, pyridine-2,6-dicarboxylic acid, diethylenetriaminepentaacetic acid, hydroxyethyldiaminetriacetic acid, 1,2-diaminocyclohexanetetraacetic acid, hydroxyethylaminodiacetic acid, polyphosphate, citric acid, citrate salts, tartaric acid, tartrate salts, and ethylenediaminetetraacetic acid, and the content of the chelating agent in the ophthalmic composition is 0.001 to 1% W / V.

[0023] The citrate is at least one selected from the group consisting of potassium citrate, sodium citrate, and hydrates thereof, and the tartrate is at least one selected from the group consisting of sodium tartrate, potassium tartrate, potassium hydrogen tartrate, sodium hydrogen tartrate, and hydrates thereof.

[0024] In one embodiment 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 metabisulfite, N-acetylcysteine, butylhydroxyanisole, and butylhydroxytoluene, and the content of the antioxidant in the ophthalmic composition is 0.001 to 1.0% W / V.

[0025] In one embodiment 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, sodium chlorite, polyquaternium-1, sorbic acid, ethylenediaminetetraacetic acid, boric acid, sodium borate, sodium hydrogen sulfate, sodium thiosulfate, ascorbate, urea peroxide, and benzalkonium bromide, and the content of the preservative in the ophthalmic composition is 0.001 to 0.1% W / V.

[0026] A second aspect of the present invention provides the use of an ophthalmic composition according to any one of the above embodiments in the preparation of a medicament for treating dry eye.

[0027] Beneficial technical effects of the present invention: The ophthalmic composition provided by the present invention targets the lymphocyte function-associated antigen-1 (LFA-1) / intercellular adhesion molecule-1 (ICAM-1) interaction mechanism and inhibits T cell-mediated inflammatory responses by blocking the binding of LFA-1 to ICAM-1 with a small molecule integrin antagonist represented by Formula I, thereby alleviating inflammatory responses in the eye and treating dry eye and / or other ocular surface diseases. The present invention further selects a low pH buffer concentration, which matches the buffering capacity of tears, resulting in a composition that is gentle on tears, provides a strong sense of comfort, increases the mean residence time of the active substance of the present invention, and improves the bioavailability of the active substance in the aqueous ophthalmic composition.

[0028] Of course, it is not necessary for all of the above advantages to be achieved simultaneously in practicing any one product or method of the present invention. The drawings described herein are used to provide a further understanding of the present invention and constitute a part of the present invention. The exemplary embodiments of the present invention and their descriptions are used to interpret the present invention and do not constitute undue limitations on the present invention. [Brief explanation of the drawings]

[0029] [Figure 1]FIG. 1 is a schematic diagram illustrating the mechanism by which the active agents in the ophthalmic compositions of the present invention treat dry eye. DETAILED DESCRIPTION OF THE INVENTION

[0030] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be described in more detail below with reference to the drawings by way of examples. Obviously, the described examples are only a part of the embodiments of the present invention, and are not all of the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention fall within the scope of protection of the present invention.

[0031] It should be noted that, as used herein, the terms "comprises," "having," or any variations thereof are intended to cover a non-exclusive inclusion, such that a process, method, or article comprising a set of elements is not necessarily limited to those elements, but may include other elements not expressly stated or inherent to those processes, methods, or articles.

[0032] A first aspect of the present invention provides a VVN001-containing ophthalmic composition, the VVN001-containing ophthalmic composition comprising an active substance and an ophthalmic excipient, wherein the active substance is selected from the sodium salt of Formula I and / or the free acid of Formula I. The chemical name of the sodium salt of Formula I is sodium (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-methylsulfonyl)phenyl)propionate, and the molecular formula is C 26 H 25 Cl2NO7PSNa, the molecular weight of the free acid is 598.4 and the molecular weight of the sodium salt is 620.4. [ka]

[0033] The content of the active substance in the ophthalmic composition is 0.01 to 10% W / V, preferably 0.1 to 7.5% W / V, and more preferably 1.0 to 5.0% W / V. For example, the content of the active substance in the ophthalmic aqueous solution composition may be 0.01% W / V, 0.025% W / V, 0.05% W / V, 0.10% W / V, 0.25% W / V, 0.50% W / V, 1.0% W / V, 2.0% W / V, 3.0% W / V, 4.0% W / V, 5.0% W / V, 6.0% W / V, 7.0% W / V, 8.0% W / V, 9.0% W / V, or 10.0% W / V, or may be within a range consisting of any two of these values. In the present invention, the unit of "W / V" is g / mL.

[0034] The ophthalmic excipient includes a pH buffer and an osmolality adjuster, and the content of the pH buffer in the ophthalmic composition is 0.001 to 2.0% W / V, preferably 0.005 to 1.0% W / V, and more preferably 0.005 to 0.5% W / V. For example, the content of the pH buffer in the ophthalmic composition may be 0.001% W / V, 0.005% W / V, 0.01% W / V, 0.025% W / V, 0.05% W / V, 0.10% W / V, 0.25% W / V, 0.50% W / V, 1.0% W / V, 1.5% W / V, or 2.0% W / V, or may be within a range consisting of any two of these values.

[0035] The ophthalmic composition has a pH of 6.5 to 7.8, preferably 7.0 to 7.4, and an osmolality of 200 to 400 mOsmol / L, preferably 250 to 350 mOsmol / L, and more preferably 280 to 320 mOsmol / L. For example, the pH of the ophthalmic composition may be 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.6, or 7.8, or may be within a range consisting of any two of these values. The osmolality of the aqueous ophthalmic composition may be 200 mOsmol / L, 220 mOsmol / L, 250 mOsmol / L, 260 mOsmol / L, 270 mOsmol / L, 280 mOsmol / L, 290 mOsmol / L, 300 mOsmol / L, 320 mOsmol / L, 350 mOsmol / L, 380 mOsmol / L, or 400 mOsmol / L, or may be in a range consisting of any two of these values.

[0036] The inventors have discovered that, as shown in Figure 1, VVN001, an active substance 10, is a small molecule integrin antagonist that blocks the interaction between lymphocyte function-associated antigen-1 (LFA-1) 20 and intercellular adhesion molecule-1 (ICAM-1) 30. VVN001 inhibits the binding of T cell receptor (TCR) 40 to major histocompatibility complex (MHC) 50 on the membrane of antigen-presenting cell (APC) 60 by blocking the binding between lymphocyte function-associated antigen-1 (LFA-1) 20 and intercellular adhesion molecule-1 (ICAM-1) 30, thereby inhibiting the formation of an immune synapse between T cells (T-cells) 70 and antigen-presenting cell (APC) 60 membranes, thereby reducing inflammatory responses in the eye and achieving the effect of treating dry eye and / or other ocular surface diseases. The inventors have also discovered that by controlling the content of the active substance within the above range and the pH buffer within the above low concentration range, the concentration of the pH buffer can be matched to the buffering capacity of tears (pH 7.0 to 7.4), making the composition gentle on tears and providing a strong sense of comfort, while increasing the mean residence time of the active substance of the present invention and improving the bioavailability of the active substance. In the present invention, VVN001 refers to the sodium salt of Formula I and / or the free acid of Formula I.

[0037] In one embodiment of the present invention, the pH buffer is any one selected from the group consisting of boric acid, borate salts, citric acid, citrate salts, acetic acid-sodium acetate, trimethylolaminomethane-hydrochloric acid, sodium bicarbonate, and phosphate salts. The borate salt is at least one selected from the group consisting of sodium borate, potassium borate, and hydrates thereof. The citrate salt 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 hydrates thereof. The phosphate salt is one or more selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and hydrates thereof. In the present invention, the method for preparing the pH buffer is not particularly limited as long as the object of the present invention can be achieved, and may be prepared by a method known in the present invention. Citric acid and citrate salts may be used as pH buffers or as chelating agents. The role of citric acid and citrate salts in the ophthalmic composition can be determined depending on the specific formulation. In the present invention, the above phrase "the borate is at least one selected from the group consisting of sodium borate, potassium borate, and hydrates thereof" means that the borate may be at least one selected from the group consisting of sodium borate, potassium borate, sodium borate hydrate, and potassium borate hydrate, and other similar expressions are understood accordingly. In the present invention, the hydrate of each substance is not particularly limited as long as it can achieve the object of the present invention, and may be a common hydrate known in the art.

[0038] In one embodiment of the present invention, the pH buffer is selected from a phosphate, and the content of the phosphate in the ophthalmic composition is 0.001 to 2.0% W / V, preferably 0.005 to 1.0% W / V, and more preferably 0.005 to 0.5% W / V. For example, the content of the phosphate in the ophthalmic composition may be 0.001% W / V, 0.005% W / V, 0.01% W / V, 0.025% W / V, 0.05% W / V, 0.10% W / V, 0.25% W / V, 0.50% W / V, 1.5% W / V, or 2.0% W / V, or may be within a range consisting of any two of these values. The inventors have found that by selecting a phosphate buffer system and controlling the phosphate content within the above range, the phosphate concentration can be matched to the buffer capacity of tears, thereby minimizing irritation and / or discomfort caused by buffer systems with high ionic strength.

[0039] In one embodiment of the present invention, the pH buffer is any one selected from the group consisting of boric acid, borate salts, citric acid, citrate salts, acetic acid-sodium acetate, trimethylolaminomethane-hydrochloric acid, and sodium bicarbonate, and the content of the pH buffer in the ophthalmic composition is 0.001 to 2.0% W / V, preferably 0.005 to 1.0% W / V, and more preferably 0.005 to 0.5% W / V.

[0040] In one embodiment of the invention, the osmotic agent is selected from inorganic osmotic agents and / or organic osmotic agents.

[0041] The inorganic osmotic adjuster is one or more selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, zinc chloride, and magnesium chloride, and the content of the inorganic osmotic adjuster in the ophthalmic composition is 0.01 to 1.5% W / V, preferably 0.2 to 1% W / V. For example, the content of the inorganic osmotic adjuster in the ophthalmic composition may be 0.01% W / V, 0.025% W / V, 0.05% W / V, 0.10% W / V, 0.25% W / V, 0.50% W / V, 1.0% W / V, or 1.5% W / V, or may be within a range consisting of any two of these values.

[0042] The organic osmotic adjuster is any one selected from the group consisting of erythritol, glucose, glycerin, propylene glycol, L-carnitine, and trehalose, and the content of the organic osmotic adjuster in the ophthalmic composition is 0.001 to 10.0% W / V, preferably 0.01 to 5.0% W / V. For example, the content of the organic osmotic adjuster in the ophthalmic aqueous solution composition may be 0.001% W / V, 0.01% W / V, 0.05% W / V, 0.10% W / V, 0.25% W / V, 0.50% W / V, 1.0% W / V, 5.0% W / V, or 10.0% W / V, or may be within a range consisting of any two of these values. Glycerin and propylene glycol may be used as organic osmolality adjusters or comfort agents, and the effects of glycerin and propylene glycol in ophthalmic compositions can be determined depending on the specific formulation. The inventors discovered that by selecting the above organic osmolality adjusters and / or inorganic osmolality adjusters and controlling the content of the organic osmolality adjusters and / or inorganic osmolality adjusters within the above respective ranges, the osmolality of the ophthalmic composition can be adjusted to 280-320 mOsmol / L, which is close to the osmolality of normal tears (270-310 mOsmol / L), significantly reducing discomfort experienced by patients when using the ophthalmic composition. If the content of the organic osmolality adjuster and / or inorganic osmolality adjuster is too low, the osmolality of the ophthalmic composition will be too low. On the other hand, excessive amounts of osmolality adjusters may result in the formation of a hypertonic solution. Both hypotonicity and hypertonicity can result in the loss of necessary optical parameters for lenses. Furthermore, hypertonic solutions can cause stinging, eye irritation, and dryness of the eye surface.In one embodiment of the present invention, the ophthalmic excipient further comprises a surfactant, and the surfactant is at least one selected from the group consisting of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, sodium dodecyl sulfate, polyethoxylated sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene stearate, poloxamine, sorbitan fatty acid ester, polyethylene glycol, polyethoxylated fatty alcohol, polyoxyethylene 40 hydrogenated castor oil, docusate sodium, quaternary ammonium compound, C6 to C20 fatty acid, sucrose fatty acid ester, glycerin fatty acid ester, polysorbate, and tyloxapol, and the content of the surfactant in the ophthalmic composition is 0.001 to 1.0% W / V. For example, the content of the surfactant in the ophthalmic composition may be 0.001% W / V, 0.01% W / V, 0.05% W / V, 0.10% W / V, 0.25% W / V, 0.50% W / V, or 1.0% W / V, or may be within a range consisting of any two of these values.

[0043] In the present invention, the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer is a specific block copolymer under the trademark Pluronic, which is also known as poloxamer. If the number of hydrophilic polyoxyethylene units (PEO) hydrophilic groups in the block copolymer is a and the number of hydrophobic polyoxypropylene units (PPO) in the block copolymer is b, the larger the value of a / b, the larger the hydrophilic-lipophilic balance (HLB) (equal to a / b) of the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, and the more hydrophilic it is. In the present invention, the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, i.e., Pluronic, has an HLB of >10.

[0044] In one embodiment of the present invention, the ophthalmic excipient further comprises a comfort agent, which is at least one selected from the group consisting of polyols, cellulose derivatives, glucans, polyethylene glycol, polysorbates, povidone, trehalose, hyaluronic acid, carbopol, sodium hyaluronate, 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 hydroxypropyl methylcellulose-E4M (HPMC-E4M), hydroxypropyl methylcellulose-LV (HPMC-LV), hydroxyethyl cellulose, methylol cellulose, methyl cellulose, hemicellulose, and ethyl cellulose; and the content of the comfort agent in the ophthalmic composition is 0.001 to 2.0% W / V. For example, the content of the comfort agent in the aqueous ophthalmic composition may be 0.001% W / V, 0.01% W / V, 0.05% W / V, 0.10% W / V, 0.25% W / V, 0.50% W / V, 1.0% W / V, or 2.0% W / V, or may be a range consisting of any two of these values.

[0045] In the present invention, by adding the above comfort agent and controlling the content of the comfort agent within the above range, the comfort felt by patients when using the ophthalmic composition can be further improved.

[0046] In one embodiment of the invention, the ophthalmic excipient further comprises a chelating agent, and the chelating agent is at least one selected from the group consisting of ethylenediaminetetraacetic acid disodium (EDTA), alkali metal hexametaphosphate, nitrotriacetic acid, ethylenediaminedisuccinic acid, iminodisuccinic acid, methylglycine diacetate, L-glutamic acid N,N-diacetic acid, ethylenediamine-N,N'-diglutamic acid, ethylenediamine-N,N'-dimalonic acid, 3-hydroxy-2,2-iminodisuccinic acid, 2-hydroxyethyliminodiacetic acid, pyridine-2,6-dicarboxylic acid, diethylenetriaminepentaacetic acid, hydroxyethyldiaminetriacetic acid, 1,2-diaminocyclohexanetetraacetic acid, hydroxyethylaminodiacetic acid, polyphosphate, citric acid, citrate salts, tartaric acid, tartrate salts, and ethylenediaminetetraacetic acid. The citrate is at least one selected from the group consisting of potassium citrate, sodium citrate, and hydrates thereof, and the tartrate is at least one selected from the group consisting of sodium tartrate, potassium tartrate, potassium hydrogen tartrate, sodium hydrogen tartrate, and hydrates thereof. The content of the chelating agent in the ophthalmic composition is 0.001 to 1.0% W / V. For example, the content of the chelating agent in the ophthalmic aqueous solution composition may be 0.001% W / V, 0.005% W / V, 0.01% W / V, 0.025% W / V, 0.05% W / V, 0.10% W / V, 0.25% W / V, 0.50% W / V, or 1.0% W / V, or may be within a range consisting of any two of these values. The above phrase "the tartrate salt is at least one selected from the group consisting of sodium tartrate, potassium tartrate, potassium hydrogen tartrate, sodium hydrogen tartrate, and hydrates thereof" means that the tartrate salt is at least one selected from the group consisting of sodium tartrate, potassium tartrate, potassium hydrogen tartrate, sodium hydrogen tartrate, and hydrates of the above salts, and the hydrates of the above salts are known common hydrates of the corresponding salts.

[0047] In one embodiment of the present invention, the ophthalmic excipient further comprises an antioxidant, which is at least one selected from the group consisting of sodium thiosulfate, sodium metabisulfite, N-acetylcysteine, butylhydroxyanisole (BHA), and butylhydroxytoluene (BHT), and the content of the antioxidant in the ophthalmic composition is 0.001 to 1.0% W / V. For example, the content of the antioxidant in the ophthalmic composition may be 0.001% W / V, 0.005% W / V, 0.01% W / V, 0.025% W / V, 0.05% W / V, 0.10% W / V, 0.25% W / V, 0.50% W / V, or 1.0% W / V, or may be within a range consisting of any two of these values.

[0048] In one embodiment of the present invention, the ophthalmic excipient further comprises a preservative, which is at least one selected from the group consisting of benzalkonium chloride (BAK), sodium chlorite, polyquaternium-1, sorbic acid, ethylenediaminetetraacetic acid, boric acid, sodium borate, sodium hydrogen sulfate, sodium thiosulfate, ascorbate, urea peroxide, and benzalkonium bromide, and the content of the preservative in the ophthalmic composition is 0.001 to 0.1% W / V. For example, the content of the preservative in the ophthalmic composition may be 0.001% W / V, 0.005% W / V, 0.01% W / V, 0.025% W / V, 0.05% W / V, or 0.10% W / V, or may be within a range consisting of any two of these values.

[0049] In one embodiment of the invention, the active agent is selected from the sodium salt of Formula I, and the method for preparing the ophthalmic composition comprises: adding water for injection in an amount of 85 to 90% of the total volume of the ophthalmic composition to a container, gradually adding a pH buffer, an osmotic pressure adjuster, and an ophthalmic excipient in this order while stirring, and then stirring for 10 minutes or more; Adding the sodium salt of formula I as an active substance to the solution obtained above, stirring for 20 minutes or more, and then adjusting the pH of the solution to 6.5-7.8 with 1N NaOH or 1N HCl; The method includes the steps of adding water for injection to make the volume of the solution 100% of the total volume of the ophthalmic composition, continuing to stir for 15 minutes or more, sterilizing the resulting solution, and then obtaining the VVN001-containing ophthalmic composition.

[0050] In one embodiment of the present invention, the active agent is selected from the free acid of Formula I, and the method for preparing the VVN001-containing ophthalmic composition comprises: Adding water for injection into a container in an amount of 40-50% of the total volume of the ophthalmic composition, adding sodium hydroxide while stirring, stirring for 15 minutes or more, and then adding the free acid of Formula I to the above solution and stirring until dissolved; adding water for injection again so that the volume of the solution becomes 85 to 90% of the total volume of the ophthalmic composition, gradually adding a pH buffer, an osmotic pressure adjuster, and an ophthalmic excipient in this order, and then stirring for 10 minutes or more; In the solution obtained as described above, adjusting the pH of the solution to 6.5 to 7.8 with 1N NaOH or 1N HCl; and adding water for injection to make the volume of the solution 100% of the total volume of the ophthalmic composition, continuing to stir for 15 minutes or more after the volume is filled up, sterilizing the resulting solution, and then obtaining the VVN001-containing ophthalmic composition.

[0051] According to the preparation method of the present invention, the VVN001-containing ophthalmic composition can achieve sterility, ideal stability, and an extremely low content of total impurities.

[0052] 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, and sterilization can be carried out by, for example, terminal heat sterilization, filtration sterilization, electron beam sterilization, ultraviolet sterilization, etc. Specifically, for example, filtration sterilization using a 0.22 μm sterile filter may be carried out, or heat sterilization at 121° C. for 30 minutes or more may be carried out.

[0053] In the present invention, the packaging method of the VVN001-containing ophthalmic composition 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, BFS (blow-fill-seal) single-use vials, or multiple-dose vials.

[0054] A second aspect of the present invention provides use of the VVN001-containing ophthalmic composition according to any one of the above embodiments in the preparation of a medicament for treating dry eye. The inventors have discovered that the active substance in the VVN001-containing ophthalmic composition, i.e., the sodium salt of Formula I and / or the free acid of Formula I, is a small molecule integrin antagonist that inhibits T cell-mediated inflammatory responses by blocking the binding of LFA-1 to ICAM-1, thereby reducing inflammatory responses in the eye and treating dry eye and / or other ocular surface diseases.

[0055] In the present invention, the ophthalmic composition is administered in a dosage of one drop per eye, once to twice a day.

[0056] In the present invention, the VVN001-containing ophthalmic composition can be used topically on the eyes, ears, nose, etc.

[0057] Example Example 1 Preparation of VVN001-containing ophthalmic composition Water for injection was added to a stainless steel mixing vessel in an amount of 85% of the total volume of the ophthalmic composition. While stirring, ophthalmic excipients, sodium dihydrogen phosphate monohydrate, sodium chloride, and sodium thiosulfate pentahydrate, were gradually added in this order, and the resulting solution was stirred for 20 minutes. The sodium salt of Formula I was added to the solution obtained above, and the solution was stirred for 30 minutes. The pH of the solution was adjusted to 7.2 with 1N NaOH or 1N HCl. Water for injection was added to the solution, and the mixture was stirred for 20 minutes. The mixture was then sterilized by filtration through a 0.22 μm sterile filter to obtain the ophthalmic composition.

[0058] The product parameters (including ingredients, contents, pH and osmotic pressure) of the ophthalmic composition obtained in Example 1 are shown in Table 1.

[0059] Example 2 The same as Example 1, except that the product parameters were adjusted as shown in Table 2.

[0060] Example 3 The same as Example 1, except that the product parameters were adjusted as shown in Table 3.

[0061] Example 4 The same as Example 1, except that the product parameters were adjusted as shown in Table 4.

[0062] Example 5 The same as Example 1, except that the product parameters were adjusted as shown in Table 5.

[0063] Example 6 The same as Example 1, except that the product parameters were adjusted as shown in Table 6.

[0064] Example 7 The same as Example 1, except that the product parameters were adjusted as shown in Table 7.

[0065] Example 8 The same as Example 1, except that the product parameters were adjusted as shown in Table 8.

[0066] Example 9 Same as Example 1, except that the product parameters were adjusted as shown in Table 9.

[0067] Example 10 Same as Example 1, except that the product parameters were adjusted as shown in Table 10.

[0068] Example 11 Same as Example 1, except that the product parameters were adjusted as shown in Table 11.

[0069] Example 12 Same as Example 1, except that the product parameters were adjusted as shown in Table 12.

[0070] Example 13 Same as Example 1, except that the product parameters were adjusted as shown in Table 13.

[0071] Example 14 Same as Example 1, except that the product parameters were adjusted as shown in Table 14.

[0072] Example 15 Same as Example 1, except that the product parameters were adjusted as shown in Table 15.

[0073] Example 16 Same as Example 1, except that the product parameters were adjusted as shown in Table 16.

[0074] Example 17 A stainless steel mixing vessel was charged with water for injection in an amount of 40% of the total volume of the ophthalmic composition. Sodium hydroxide was added while stirring, and the mixture was stirred for 20 minutes. Then, an active ingredient selected from the free acid of Formula I was added to the above solution and stirred until dissolved.

[0075] Water for injection was added again to make the solution volume 85% of the total volume of the ophthalmic composition. For the sample, sodium dihydrogen phosphate monohydrate, sodium chloride, sodium thiosulfate pentahydrate, and benzalkonium chloride were gradually added in this order. The resulting solution was stirred for 20 minutes, and the pH of the solution was adjusted to 7.2 with 1N NaOH or 1N HCl. Water for injection was added to make up to the final volume. After the final volume was filled up to the final volume, stirring was continued for 20 minutes. After sterilization by filtration through a 0.22 μm sterile filter, an ophthalmic composition containing VVN001 was obtained. The product parameters (including ingredients, contents, pH, and osmolality) of the ophthalmic composition obtained in Example 17 are shown in Table 17.

[0076] [Table 1]

[0077] Note: "IID content standards" in Table 1 refer to the content standards in the US FDA inactive ingredient database.

[0078] [Table 2]

[0079] [Table 3]

[0080] [Table 4]

[0081] [Table 5]

[0082] [Table 6]

[0083] [Table 7]

[0084] [Table 8]

[0085] [Table 9]

[0086] [Table 10]

[0087] [Table 11]

[0088] [Table 12]

[0089] [Table 13]

[0090] [Table 14]

[0091] [Table 15]

[0092] [Table 16]

[0093] [Table 17]

[0094] Note: "IID content standard" in Table 17 refers to the content standard in the US FDA inactive ingredient database.

[0095] Stability testing: The VVN001-containing ophthalmic compositions prepared in Example 1 were filled into multiple-dose vials (0.5 mL), multiple-dose vials (1 mL), and multiple-dose vials (2 mL), and stored at an ambient temperature of 40°C and a humidity of 75% RH. After 1 month and 3 months of storage, stability tests were performed on the VVN001-containing ophthalmic compositions in the multiple-dose vials (0.5 mL), multiple-dose vials (1 mL), and multiple-dose vials (2 mL). The results are shown in Table 17.

[0096] The contents of single impurities in VVN001-containing ophthalmic compositions after different storage times were measured using high-performance liquid chromatography (HPLC). Tables 18 to 20 show the contents of single impurities in VVN001-containing ophthalmic compositions after 1 month and 3 months of storage, respectively.

[0097] [Table 18]

[0098] Note: In Table 18, "-" indicates that the corresponding parameter does not exist.

[0099] [Table 19]

[0100] Note: In Table 19, "-" indicates that the corresponding parameter does not exist.

[0101] [Table 20]

[0102] Note: In Table 20, "-" indicates that the corresponding parameter does not exist.

[0103] As can be seen from the stability data in Tables 18 to 20, the ophthalmic compositions prepared by the method of the present invention were stored for as long as 3 months at an ambient temperature of 40°C and a humidity of 75%RH. All of the ophthalmic compositions stored in single-dose vials (0.5 mL), multi-dose vials (1 mL), and multi-dose vials (2 mL) had good sterility, good stability, and extremely low impurity contents. In Tables 19 and 20, the relative retention time of a single impurity is the ratio of the retention time of the single impurity to the retention time of the sodium salt of Formula I.

[0104] Clinical trials: An ophthalmic composition containing 5% W / V VVN001 provided by the present invention was used in a clinical trial. The subjects were patients with moderate to severe dry eye, and the composition was administered by eye drop administration twice daily. The overall improvement in the subjects' dry eye symptoms was very clear, with staining of multiple corneal regions, including the entire cornea, reaching statistical significance (p<0.05) on Day 84. The tendency for increased tear production in the subjects was also significantly greater than in the blank vehicle control. The blank vehicle control means that the ophthalmic composition used by the subjects did not contain VVN001.

[0105] The above is merely a preferred embodiment of the present invention, and is not intended to limit the scope of protection of the present invention. Any amendments, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the scope of protection of the present invention.

[0106] The above is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any amendments, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. An ophthalmic composition containing VVN001, The ophthalmic composition comprises an active agent and an ophthalmic excipient; the active substance is selected from the sodium salt of Formula I and / or the free acid of Formula I, and the content of the active substance in the ophthalmic composition is 0.01 to 10% W / V; the ophthalmic excipient includes a pH buffer and an osmotic pressure adjuster, and the content of the pH buffer in the ophthalmic composition is 0.001 to 2.0% W / V; The ophthalmic composition has a pH of 6.5 to 7.8 and an osmotic pressure of 200 to 400 mOsmol / L. 【Chemical 1】

2. the pH buffer is any one selected from the group consisting of boric acid, borate salts, citric acid, citrate salts, acetic acid-sodium acetate, trimethylolaminomethane-hydrochloric acid, sodium bicarbonate, and phosphate salts; the borate is at least one selected from the group consisting of sodium borate, potassium borate, and hydrates thereof; 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 hydrates thereof; 2. The ophthalmic composition according to claim 1, wherein the phosphate is one or more selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and hydrates thereof.

3. 3. The ophthalmic composition according to claim 2, wherein the pH buffer is selected from phosphates, and the content of the phosphate in the ophthalmic composition is 0.001 to 2.0% W / V.

4. the osmolality modifier is selected from inorganic osmolality modifiers and / or organic osmolality modifiers; the inorganic osmotic pressure adjuster is one or more selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, zinc chloride, and magnesium chloride, and the content of the inorganic osmotic pressure adjuster in the ophthalmic composition is 0.01 to 1.5% W / V; 2. The ophthalmic composition according to claim 1, wherein the organic osmotic pressure adjuster is any one selected from the group consisting of erythritol, glucose, glycerin, propylene glycol, glycine, diglycine, alanine, taurine, ectoine erythritol, mannitol, sorbitol, L-carnitine, and trehalose, and the content of the organic osmotic pressure adjuster in the ophthalmic composition is 0.001 to 10% W / V.

5. the ophthalmic vehicle further comprises a surfactant; the surfactant is at least one selected from the group consisting of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, sodium dodecyl sulfate, polyethoxylated sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene stearate, poloxamine, sorbitan fatty acid ester, polyethylene glycol, polyethoxylated fatty alcohol, polyoxyethylene 40 hydrogenated castor oil, docusate sodium, quaternary ammonium compound, C6 to C20 fatty acid, sucrose fatty acid ester, glycerin fatty acid ester, polysorbate, and tyloxapol; The ophthalmic composition according to claim 1, wherein the content of the surfactant in the ophthalmic composition is 0.001 to 1% W / V.

6. the ophthalmic vehicle further comprises a comfort agent, the comfort agent being at least one selected from the group consisting of polyols, cellulose derivatives, glucans, polyethylene glycols, polysorbates, povidone, trehalose, hyaluronic acid, carbopol, sodium hyaluronate, 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 hydroxypropyl methylcellulose-E4M, hydroxypropyl methylcellulose-LV, hydroxyethyl cellulose, methylol cellulose, methyl cellulose, hemicellulose, and ethyl cellulose; The ophthalmic composition of claim 1, wherein the content of the comfort agent in the ophthalmic composition is 0.001 to 2% W / V.

7. the ophthalmic vehicle further comprises a chelating agent; the chelating agent is at least one selected from the group consisting of disodium ethylenediaminetetraacetate, alkali metal hexametaphosphate, nitrotriacetic acid, ethylenediaminedisuccinic acid, iminodisuccinic acid, methylglycine diacetate, 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, citrates, tartaric acid, tartrates, and ethylenediaminetetraacetic acid; the content of the chelating agent in the ophthalmic composition is 0.001 to 1% W / V, the citrate is at least one selected from the group consisting of potassium citrate, sodium citrate, and hydrates thereof; The ophthalmic composition according to claim 1 , wherein the tartrate is at least one selected from the group consisting of sodium tartrate, potassium tartrate, potassium hydrogen tartrate, sodium hydrogen tartrate, and hydrates thereof.

8. 2. The ophthalmic composition according to claim 1, wherein 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 0.001 to 1% W / V.

9. the ophthalmic vehicle further comprises a preservative; the preservative is at least one selected from the group consisting of benzalkonium chloride, sodium chlorite, polyquaternium-1, sorbic acid, ethylenediaminetetraacetic acid, boric acid, sodium borate, sodium hydrogen sulfate, sodium thiosulfate, ascorbate, urea peroxide, and benzalkonium bromide; The ophthalmic composition according to claim 1, wherein the content of the preservative in the ophthalmic composition is 0.001 to 0.1% W / V.

10. Use of the ophthalmic composition of any one of claims 1 to 9 in the preparation of a medicament for treating dry eye.

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