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 the priority of a Chinese patent application filed with the State Intellectual Property Office of China on April 27, 2023, with an application number of 202310476403.2 and an invention title of "ophthalmic composition containing VVN001", and all of these are incorporated herein by reference in their entirety.

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

Background Art

[0003] Dry eye (DED), also known as keratoconjunctivitis sicca, is a complex ocular surface disease characterized by symptoms such as visual impairment, eye discomfort, and eye dryness due to incomplete or unstable tear film and non-uniformity of tear film thickness. It has been proven that T cells play a certain role in mediating inflammation. A heterodimer receptor on T cells called integrin contributes to the activation, adhesion to the extracellular matrix, migration, proliferation, and differentiation of T cells after receiving inflammatory signals. On the other hand, the interaction of lymphocyte function-associated antigen-1 (LFA-1) / intercellular adhesion molecule-1 (ICAM-1) promotes the formation of immune synapses by enabling T cells to adhere to endothelial cells, migrate to more inflammatory tissues, and occur antigen presentation and recognition. These immune synapses cause the release of inflammatory mediators, cytokines, chemokines, TNF-α, and IL-1 by promoting the propagation of downstream signals, thereby further progressing and continuing the inflammation in ocular tissues.

[0004] Therefore, there is a need for an eye drop containing a small molecule integrin antagonist that inhibits the inflammatory reaction mediated by T cells by blocking the binding of LFA-1 and ICAM-1 to the mechanism of LFA-1 / ICAM-1 interaction, thereby reducing the inflammatory reaction in the eye and 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 to the tear fluid and comfortable, capable of achieving optimal bioavailability of the active ingredient, reducing inflammatory reactions in the eye, and treating dry eye and / or other ocular surface diseases. The specific technical solutions are as follows.

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

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

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

Chemical formula

[0009] In one embodiment 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.

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

[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 present invention, the osmotic pressure regulator is selected from inorganic osmotic pressure regulators and / or organic osmotic pressure regulators.

[0015] The inorganic osmotic pressure regulator 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 regulator in the ophthalmic aqueous solution composition is 0.01 to 1.5% W / V, preferably 0.2 to 1% W / V.

[0016] The organic osmotic pressure regulator 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 regulator in the ophthalmic composition is 0.001 to 10% W / V, preferably 0.01 to 5% W / V.

[0017] In one embodiment of the present invention, the ophthalmic excipient further contains a surfactant, and the surfactant is a 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, sodium doxsate, quaternary ammonium compound, C6-C20 fatty acid, sucrose fatty acid ester, glycerin fatty acid ester, polysorbate, and tyloxapol. The surfactant is at least one selected from the group consisting of, and the content of the surfactant in the ophthalmic composition is 0.001-1% W / V.

[0018] In one embodiment 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 polyol, cellulose derivative, glucan, polyethylene glycol, polysorbate, 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 hydroxypropyl methylcellulose-E4M, hydroxypropyl methylcellulose-LV, hydroxyethyl cellulose, methylol cellulose, methyl cellulose, hemicellulose, and ethyl cellulose.

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

[0022] In one embodiment of the present invention, the ophthalmic excipient further contains a chelating agent, and the chelating agent is at least one selected from the group consisting of disodium ethylenediaminetetraacetate, alkali metal hexametaphosphate, 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, citrate, tartaric acid, tartrate, and ethylenediaminetetraacetic acid. 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 their hydrates, and the tartrate is at least one selected from the group consisting of sodium tartrate, potassium tartrate, potassium hydrogen tartrate, sodium hydrogen tartrate, and their hydrates.

[0024] In one embodiment of the present invention, 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 0.001 to 1.0% W / V.

[0025] In one embodiment of the present invention, the ophthalmic excipient further contains 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 bisulfate, sodium thiosulfate, ascorbate, urea peroxide, and benzalkonium bromide. 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 the ophthalmic composition according to any one of the above embodiments in the preparation of a medicament for treating dry eye.

[0027] Advantageous technical effects of the present invention: The ophthalmic composition provided by the present invention, with respect to the mechanism of the interaction of lymphocyte function-associated antigen-1 (LFA-1) / intercellular adhesion molecule-1 (ICAM-1), by means of the small molecule integrin antagonist represented by Formula I, blocks the binding of LFA-1 and ICAM-1 to inhibit the inflammation reaction mediated by T cells, thereby reducing the inflammation reaction in the eye and treating dry eye and / or other ocular surface diseases. The present invention further selects a low concentration of pH buffer concentration to match the buffer capacity of the pH buffer in tears, is gentle to tears, has a strong sense of comfort, and increases the average residence time of the active substance of the present invention, while improving the bioavailability of the active substance in the ophthalmic aqueous solution composition.

[0028] Of course, when implementing any one of the products or methods of the present invention, it is not necessarily required to achieve all of the above advantages simultaneously. 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 and their descriptions of the present invention are used to interpret the present invention and do not constitute an undue limitation to the present invention.

Brief Description of the Drawings

[0029]

Figure 1

Mode for Carrying Out the Invention

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

[0031] In the present text, the terms "comprising", "having" or any variants thereof are intended to cover non-exclusive inclusion. Therefore, a process, method or article containing a series of elements is not necessarily limited to those elements, and may include other elements not explicitly listed, or elements inherent to these processes, methods or articles.

[0032] The first aspect of the present invention provides an ophthalmic composition containing VVN001. The VVN001-containing ophthalmic composition 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 chemical name of the sodium salt represented by Formula I is sodium (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamide)-3-(3-methylsulfonyl)phenyl)propionate, with the molecular formula C 26 H 25 Cl 2 NO 7 PSNa, the molecular weight of its free acid is 598.4, and the molecular weight of the sodium salt is 620.4.

Chemical Formula

[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 in the range composed of any two of these numerical values. In the present invention, the unit of "W / V" is g / ml.

[0034] The ophthalmic excipient contains a pH buffer and an osmotic pressure regulator. 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 in the range composed of any two of these numerical values.

[0035] 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. 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 in the range composed of any two of these numerical values. The osmotic pressure of the ophthalmic aqueous 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 the range composed of any two of these numerical values.

[0036] As shown in Fig. 1, for the interaction between lymphocyte function-associated antigen-1 (LFA-1) 20 and intercellular adhesion molecule-1 (ICAM-1) 30, VVN001, the active substance 10, is a small molecule integrin antagonist. VVN001 blocks the binding between lymphocyte function-associated antigen-1 (LFA-1) 20 and intercellular adhesion molecule-1 (ICAM-1), thereby inhibiting the binding between the T cell receptor (TCR) 40 and the major histocompatibility complex (MHC) 50 on the membrane of the antigen-presenting cell (APC) 60, and thus inhibiting the formation of an immune synapse between the T cell (T-Cell) 70 and the membrane of the antigen-presenting cell (APC) 60. Furthermore, it has been found that the inflammatory reaction in the eye can be reduced, and the effects of treating dry eye and / or other ocular surface diseases can be achieved. In addition, the inventor has 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 concentration of the pH buffer is made to match the buffering ability in tears (pH 7.0 - 7.4), which is gentle on the tears, has a strong sense of comfort, and can increase the average residence time of the active substance of the present invention and improve the bioavailability of the above active substance. In the present invention, VVN001 is the sodium salt represented by 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, citric acid, citrate, acetic acid - sodium acetate, tris - hydrochloric acid, sodium hydrogen carbonate, 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 phosphate is one or more selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and their hydrates. In the present invention, the preparation method of the pH buffer is not particularly limited as long as the object of the present invention can be achieved, and it may be prepared by a method known in the present invention. 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 can be determined according to a specific formulation. In the present invention, the above "the borate is at least one selected from the group consisting of sodium borate, potassium borate, and their hydrates" means that the borate may be at least one selected from the group consisting of sodium borate, potassium borate, hydrates of sodium borate, and hydrates of potassium borate, and other similar expressions are understood in this way. In the present invention, the hydrates of each substance are not particularly limited as long as the object of the present invention can be achieved, and they may be general hydrates known in this field.

[0038] In one embodiment of the present invention, 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, 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 in the range composed of any two of these numerical values. The inventor has found that by selecting a phosphate buffer system and controlling the content of the phosphate within the above range, the concentration of the phosphate is made to match the buffering capacity in tears, thereby reducing the irritation and / or discomfort caused by a buffer system with a high ionic strength as much as possible.

[0039] In one embodiment 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, and sodium hydrogen carbonate, 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% W / V to 0.5% W / V.

[0040] In one embodiment of the present invention, the osmotic pressure regulator is selected from inorganic osmotic pressure regulators and / or organic osmotic pressure regulators.

[0041] The inorganic osmotic pressure regulator is one or more selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, zinc chloride, and magnesium chloride. The content of the inorganic osmotic pressure regulator 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 pressure regulator 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 in the range composed of any two of these numerical values.

[0042] The organic osmotic pressure regulator is any one selected from the group consisting of erythritol, glucose, glycerin, propylene glycol, L-carnitine, and trehalose. The content of the organic osmotic pressure regulator 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 pressure regulator 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 in the range composed of any two of these numerical values. Glycerin and propylene glycol may be used as an organic osmotic pressure regulator or may be used as a comfort agent, and the actions of glycerin and propylene glycol in the ophthalmic composition can be determined according to a specific formulation. The inventor has selected the above organic osmotic pressure regulator and / or inorganic osmotic pressure regulator substance, and by controlling the above organic osmotic pressure regulator and / or inorganic osmotic pressure regulator within the above respective ranges, the osmotic pressure of the ophthalmic composition is made 280 to 320 mOsmol / L, which is close to the osmotic pressure of normal tears (270 to 310 mOsmol / L), so that it has been found that the discomfort when a patient uses the ophthalmic composition is significantly reduced. If the content of the organic osmotic pressure regulator and / or the inorganic osmotic pressure regulator is too low, the osmotic pressure of the ophthalmic composition becomes too low. On the other hand, an excessive amount of the osmotic pressure regulator may form a hypertonic solution. Both hypotonicity and hypertonicity 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.In one embodiment of the present invention, the ophthalmic excipient further contains a surfactant, and the surfactant is 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 aliphatic alcohol, polyoxyethylene 40 hydrogenated castor oil, doxate sodium, quaternary ammonium compound, C6-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 0.001-1.0% 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 in the range composed of any two of these numerical values.

[0043] In the present invention, the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer is a specific block copolymer trademarked as Pluronic, and Pluronic is also called poloxamer. If the number of hydrophilic polyoxyethylene units (PEO) aqueous 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 greater the hydrophilic-lipophilic balance HLB (equal to a / b) of the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, and the higher the hydrophilicity. In the present invention, the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, that is, Pluronic, has an HLB > 10.

[0044] In one embodiment 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 glycols, polysorbates, povidones, trehaloses, 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 hydroxypropylmethylcellulose-E4M (HPMC-E4M), hydroxypropylmethylcellulose-LV (HPMC-LV), hydroxyethylcellulose, methylolcellulose, methylcellulose, hemicellulose, and ethylcellulose. 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 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, or 2.0% W / V, or may be in the range composed of any two of these numerical 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 level of the patient when using the ophthalmic composition is further improved.

[0046] In one embodiment of the present invention, the ophthalmic excipient further contains a chelating agent, and the chelating agent is selected from the group consisting of disodium ethylenediaminetetraacetate (EDTA), alkali metal hexametaphosphate, 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, citrate, tartaric acid, tartrate, 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 in the range constituted by any two of these numerical values. The above "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" means that the tartrate 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, and the antioxidant is at least one selected from the group consisting of sodium thiosulfate, sodium pyrosulfite, N-acetylcysteine, butylhydroxyanisole (BHA), and butylhydroxytoluene (BHT). 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 in the range composed of any two of these numerical values.

[0048] 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 (BAK), sodium chlorite, polyquaternium-1, sorbic acid, ethylenediaminetetraacetic acid, boric acid, sodium borate, sodium bisulfate, sodium thiosulfate, ascorbate, urea peroxide, and benzalkonium bromide. 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 in the range composed of any two of these numerical values.

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

[0050] In one embodiment of the present invention, the active substance is selected from the free acids of Formula I, and the method for preparing the ophthalmic composition containing VVN001 is as follows: Adding water for injection in an amount of 40 - 50% of the total volume of the ophthalmic composition to a container, adding sodium hydroxide while stirring, stirring for 15 minutes or more, 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 - 90% of the total volume of the ophthalmic composition, gradually adding a pH buffer, an osmotic pressure regulator, 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 - 7.8 with 1N NaOH or 1N HCl; Adding water for injection to make up the volume of the solution to 100% of the total volume of the ophthalmic composition, continuing stirring for 15 minutes or more after the makeup is completed, sterilizing the resulting solution, and then obtaining the ophthalmic composition containing VVN001.

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

[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. For example, sterilization can be performed by methods such as final heat sterilization, filtration sterilization, electron beam sterilization, and ultraviolet ray systems. Specifically, for example, filtration sterilization can be performed using a 0.22 μm sterile filter, or heat sterilization can be performed at 121°C for 30 minutes or more.

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

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

[0055] In the present invention, the ophthalmic composition is used by instilling 1 drop once a day into one eye, 1 to 2 times a day.

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

[0057] Examples Example 1 Preparation of Ophthalmic Composition Containing VVN001 Purified water for injection in an amount of 85% of the total volume of the ophthalmic composition was added to a stainless steel mixing container. While stirring, as ophthalmic excipients, sodium dihydrogen phosphate monohydrate, sodium chloride, and sodium thiosulfate pentahydrate were gradually added in this order, and then the resulting solution was stirred for 20 min. The sodium salt represented by formula I was added to the solution obtained as described above, and the mixture was stirred for 30 min. The pH of the solution was adjusted to 7.2 with 1N NaOH or 1N HCl. Purified water for injection was added to make up the volume, stirring was continued for 20 min, and the solution was sterilized by filtration through a 0.22 μm sterile filter to obtain an ophthalmic composition.

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

[0059] Example 2 It was the same as Example 1 except that the parameters of the product were adjusted as shown in Table 2.

[0060] Example 3 It was the same as Example 1 except that the parameters of the product were adjusted as shown in Table 3.

[0061] Example 4 It was the same as Example 1 except that the parameters of the product were adjusted as shown in Table 4.

[0062] Example 5 It was the same as Example 1 except that the parameters of the product were adjusted as shown in Table 5.

[0063] Example 6 It was the same as Example 1 except that the parameters of the product were adjusted as shown in Table 6.

[0064] Example 7 It was the same as Example 1 except that the parameters of the product were adjusted as shown in Table 7.

[0065] Example 8 It was the same as Example 1 except that the parameters of the product were adjusted as shown in Table 8.

[0066] Example 9 It was the same as Example 1 except that the parameters of the product were adjusted as shown in Table 9.

[0067] Example 10 It was the same as Example 1 except that the parameters of the product were adjusted as shown in Table 10.

[0068] Example 11 It was the same as Example 1 except that the parameters of the product were adjusted as shown in Table 11.

[0069] Example 12 It was the same as Example 1 except that the product parameters were adjusted as shown in Table 12.

[0070] Example 13 It was the same as Example 1 except that the product parameters were adjusted as shown in Table 13.

[0071] Example 14 It was the same as Example 1 except that the product parameters were adjusted as shown in Table 14.

[0072] Example 15 It was the same as Example 1 except that the product parameters were adjusted as shown in Table 15.

[0073] Example 16 It was the same as Example 1 except that the product parameters were adjusted as shown in Table 16.

[0074] Example 17 In a stainless steel mixing vessel, water for injection equal to 40% of the total volume of the ophthalmic composition was added. Sodium hydroxide was added while stirring, and the mixture was stirred for 20 min. Then, an active substance selected from the free acids represented by Formula I was added to the above solution, and the mixture was stirred until dissolved.

[0075] Water for injection was added again so that the volume of the solution became 85% of the total volume of the ophthalmic composition. As samples, 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 min, and the pH value of the solution was adjusted to 7.2 with 1N NaOH or 1N HCl. Water for injection was added to make up the volume. After the volume makeup was completed, stirring was continued for 20 min. After filtration and sterilization with a 0.22 μm sterile filter, an ophthalmic composition containing VVN001 was obtained. The product parameters (including components, contents, pH, and osmotic pressure) of the ophthalmic composition obtained in Example 17 are shown in Table 17.

[0076]

Table 1

[0077] Note: The "IID content standard" in Table 1 refers to the content standard in the database of inactive ingredients of the US FDA.

[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] Remarks: The "IID content standard" in Table 17 refers to the content standard in the database of inactive ingredients of the US FDA.

[0095] Stability test: The ophthalmic compositions containing VVN001 prepared in Example 1 were filled into vials for multiple administrations (0.5 mL), vials for multiple administrations (1 mL), and vials for multiple administrations (2 mL), respectively, and stored under the conditions of an environmental temperature of 40 °C and a humidity of 75% RH. After 1 month of storage and 3 months of storage, stability tests were conducted on the ophthalmic compositions containing VVN001 in the above-mentioned vials for multiple administrations (0.5 mL), vials for multiple administrations (1 mL), and vials for multiple administrations (2 mL), and the results are shown in Table 17.

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

[0097]

Table 18

[0098] Remarks: The "-" in Table 18 indicates that the corresponding parameter does not exist.

[0099]

Table 19

[0100] Remarks: The "-" in Table 19 indicates that the corresponding parameter does not exist.

[0101]

Table 20

Claims

1. A VVN001-containing ophthalmic composition comprising an active substance and an ophthalmic excipient, wherein the active substance is selected from the sodium salt represented by 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, the ophthalmic excipient includes a pH buffer and an osmotic pressure regulator, 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, 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, a VVN001-containing ophthalmic composition. 【Chemical 1】

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 phosphate is one or more selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and their hydrates, the ophthalmic composition according to Claim 1.

3. 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, preferably 0.01 to 1.0% W / V, and more preferably 0.005 to 0.5% W / V, the ophthalmic composition according to Claim 2.

4. The osmotic pressure regulator is selected from inorganic osmotic pressure regulators and / or organic osmotic pressure regulators, The inorganic osmotic pressure regulator 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 regulator in the ophthalmic composition is 0.01 to 1.5% W / V, preferably 0.2 to 1% W / V. The organic osmotic pressure regulator 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 regulator in the ophthalmic composition is 0.001 to 10% W / V, preferably 0.01 to 5% W / V. The ophthalmic composition according to claim 1.

5. The ophthalmic excipient further contains 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 aliphatic alcohol, polyoxyethylene 40 hydrogenated castor oil, doxate sodium, quaternary ammonium compound, C6-C20 fatty acid, sucrose fatty acid ester, glycerin fatty acid ester, polysorbate, and tyloxapol. The content of the surfactant in the ophthalmic composition is 0.001 to 1% W / V. The ophthalmic composition according to claim 1.

6. 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, 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 according to claim 1, wherein the content of the comfort agent in the ophthalmic composition is 0.001 to 2% W / V.

7. The ophthalmic excipient further contains a chelating agent, The chelating agent is at least one selected from the group consisting of disodium ethylenediaminetetraacetate, alkali metal hexametaphosphate, 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, citrate, tartaric acid, tartrate, 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 their hydrates, 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 their hydrates.

8. The ophthalmic excipient further contains an antioxidant, the antioxidant is 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. The ophthalmic composition according to claim 1.

9. The ophthalmic excipient further contains 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 bisulfate, 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 according to any one of claims 1 to 9 in the preparation of a medicament for treating dry eye.

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