Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame

Definitions

• the present application relates to the field of medical technology, and in particular to an ophthalmic composition containing VVN001.
• Dry eye disease also known as keratoconjunctivitis sicca
• DED Dry eye disease
• T cells play a role in mediating inflammation.
• Heterodimeric receptors on T cells called integrins, help T cells activate, adhere to the extracellular matrix, migrate, proliferate, and differentiate after inflammatory signals.
• the lymphocyte function-associated antigen-1 (LFA-1)/intercellular adhesion molecule-1 (ICAM-1) interaction causes T cells to adhere to endothelial cells and migrate to more inflamed tissues, where antigen presentation and recognition occur, thereby promoting the formation of immune synapses.
• LFA-1 lymphocyte function-associated antigen-1
• IAM-1 intercellular adhesion molecule-1
• These immune synapses promote the propagation of downstream signals, leading to the release of inflammatory mediators, cytokines, chemokines, TNF- ⁇ , and IL-1, which further exacerbate and perpetuate inflammation in ocular tissues.
• an eye drop containing a small molecule integrin antagonist is needed to inhibit T cell-mediated inflammatory response by blocking the binding of LFA-1 and ICAM-1, thereby reducing ocular inflammatory response to treat dry eye disease and/or other ocular surface diseases.
• the purpose of this application is to provide a tear-friendly and comfortable ophthalmic composition, achieve optimal bioavailability of active components, reduce ocular inflammatory response, and treat dry eye and/or other ocular surface diseases.
• the specific technical solution is as follows:
• the present application provides an ophthalmic composition containing VVN001, which comprises 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 further preferably 1.0 to 5.0% W/V;
• the ophthalmic excipient comprises 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;
• the osmotic pressure is 200 to 400 mOsmol/L, preferably 250 to 350 mOsmol/L, and more preferably 280 to 320 mOsmol/L;
• the pH buffer is selected from any one of boric acid, borate, citric acid, citrate, acetic acid-sodium acetate, tris(hydroxymethylaminomethane)-hydrochloric acid, sodium bicarbonate, and phosphate;
• the borate is selected from at least one of sodium borate, potassium borate and hydrates thereof;
• the citrate is selected from at least one of potassium citrate, sodium citrate, disodium hydrogen citrate, sodium dihydrogen citrate, dipotassium hydrogen citrate, potassium dihydrogen citrate and hydrates thereof;
• the phosphate is selected from one or more of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate and hydrates thereof.
• the pH buffer is selected from phosphates; the content of the phosphates in the ophthalmic aqueous solution composition is 0.001-2.0% W/V, preferably 0.01-1.0% W/V, and further preferably 0.005-0.5% W/V.
• the osmotic pressure regulator is selected from inorganic osmotic pressure regulators and/or organic osmotic pressure regulators;
• the inorganic osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, calcium chloride, zinc chloride and magnesium chloride; 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;
• the organic osmotic pressure regulator is selected from any one of erythritol, glucose, glycerol, propylene glycol, glycine, diglycine, alanine, taurine, ectoine, erythritol, mannitol, sorbitol, L-carnitine and trehalose; 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 excipient further comprises a surfactant, the surfactant being selected from at least one of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymers, sodium lauryl sulfate, polyethoxylated sorbitan fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene stearates, poloxamine, sorbitan fatty acid esters, polyethylene glycol, polyethoxylated fatty alcohols, polyoxyethylene 40 hydrogenated castor oil, sodium docusate, quaternary ammonium compounds, C6-C20 fatty acids, fatty acid sugar esters, fatty acid glycerides, polysorbates, and tyrosabor.
• the content of the active agent in the ophthalmic composition is 0.001-1% W/V.
• the ophthalmic excipient further comprises a comfort agent, wherein the comfort agent is selected from at least one of polyols, cellulose derivatives, dextran, polyethylene glycol, polysorbate, povidone, trehalose, hyaluronic acid, carbomer, sodium hyaluronate and sodium alginate;
• the comfort agent is selected from at least one of polyols, cellulose derivatives, dextran, polyethylene glycol, polysorbate, povidone, trehalose, hyaluronic acid, carbomer, sodium hyaluronate and sodium alginate;
• the polyol is selected from at least one of glycerol, propylene glycol, polyvinyl alcohol and mannitol;
• the cellulose derivative is selected from at least one of hydroxypropylmethylcellulose-E4M, hydroxypropylmethylcellulose-LV, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, hemicellulose and ethylcellulose;
• the content of the comfort agent in the ophthalmic composition is 0.001-2% W/V.
• the ophthalmic excipient further comprises a chelating agent
• the chelating agent is selected from at least one of disodium ethylenediaminetetraacetic acid, alkali metal hexametaphosphate, nitrotriacetic acid, ethylenediamine disuccinic acid, iminodisuccinic acid, methylglycine diacetic acid, L-glutamic acid N,N-diacetic acid, ethylenediamine-N,N'-diglutamic acid, ethylenediamine-N,N'-dimalonic acid, 3-hydroxy-2,2-iminodisuccinic acid, 2-hydroxyethyliminodiacetic acid, pyridine-2,6-dicarboxylic acid, diethylenetriaminepentaacetic acid, hydroxyethyldiaminetriacetic acid, 1,2-diaminocyclohexanetetraacetic acid, hydroxyethylaminodiacetic acid, polyphosphate, cit
• the citrate is selected from at least one of potassium citrate or sodium citrate and hydrates thereof;
• the tartrate is selected from at least one of sodium tartrate, potassium tartrate, potassium hydrogen tartrate, sodium hydrogen tartrate and hydrates thereof.
• the ophthalmic excipient further comprises an antioxidant, and the antioxidant is selected from at least one of sodium thiosulfate, sodium metabisulfite, N-acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene; the content of the antioxidant in the ophthalmic composition is 0.001 to 1.0% W/V.
• the ophthalmic excipient further comprises a preservative, and the preservative is selected from at least one 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.
• the preservative is selected from at least one 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.
• the second aspect of the present application provides use of the ophthalmic composition described in any one of the above embodiments in the preparation of a medicament for treating dry eye.
• the present application provides an ophthalmic composition, which targets the interaction mechanism of lymphocyte function-associated antigen-1 (LFA-1)/intercellular adhesion molecule-1 (ICAM-1), and uses a small molecule integrin antagonist shown in formula I to block the binding of LFA-1 and ICAM-1 to inhibit T cell-mediated inflammatory response, thereby reducing ocular inflammatory response, to treat dry eye disease and / or other ocular surface diseases.
• LFA-1 lymphocyte function-associated antigen-1
• ICAM-1 intercellular adhesion molecule-1
• the present application further selects a low concentration of pH buffer to match the pH buffer concentration with the buffering capacity in tears, which is tear-friendly and comfortable, and increases the average residence time of the active substance of the present application, while also improving the bioavailability of the active substance in the ophthalmic aqueous solution composition.
• FIG1 is a schematic diagram showing the mechanism of the active substance in the ophthalmic composition of the present application for treating dry eye.
• the present application provides an ophthalmic composition containing VVN001, which comprises 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: (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propionate, molecular formula: C 26 H 25 Cl 2 NO 7 PSNa, the molecular weight of the free acid is 598.4, and the molecular weight of the sodium salt is 620.4;
• 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, 10.0% W/V or a range consisting of any two values therebetween.
• the unit of "W/V" is g/ml.
• the ophthalmic excipient comprises 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/V0.5% W/V; for example, the content of the pH buffer in the ophthalmic composition can 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, 2.0% W/V or a range consisting of any two values therebetween.
• the pH of the ophthalmic composition is 6.5 to 7.8, preferably 7.0 to 7.4; the osmotic pressure is 200 to 400 mOsmol/L, preferably 250 to 350 mOsmol/L, and more preferably 280 to 320 mOsmol/L.
• 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, 7.8, or a range consisting of any two values therebetween
• 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, 400 mOsmol/L, or a range consisting of any two values therebetween.
• lymphocyte function-associated antigen-1 (LFA-1) 20 interacts with intercellular adhesion molecule-1 (ICAM-1) 30, and VVN001, as an active substance 10 and a small molecule integrin antagonist, can block the binding of lymphocyte function-associated antigen-1 (LFA-1) 20 and intercellular adhesion molecule-1 (ICAM-1) 30, inhibit the binding of T cell receptor (TCR) 40 with the major histocompatibility complex (MHC) 50 in the membrane of antigen presenting cell (APC) 60, thereby inhibiting the formation of immune synapses between T cells (T-Cell) 70 and antigen presenting cell (APC) 60 membranes, thereby reducing ocular inflammatory responses and achieving the effect of treating dry eye disease and/or other ocular surface diseases.
• TCR T cell receptor
• MHC major histocompatibility complex
• VVN001 refers to the sodium salt shown in I and/or the free acid of formula I.
• the pH buffer is selected from any one of boric acid, borate, citric acid, citrate, acetic acid-sodium acetate, tris(hydroxymethyl)aminomethane-hydrochloric acid, sodium bicarbonate, and phosphate;
• the borate is selected from at least one of sodium borate, potassium borate, and hydrates thereof;
• the citrate is selected from at least one of potassium citrate, sodium citrate, disodium hydrogen citrate, sodium dihydrogen citrate, dipotassium hydrogen citrate, potassium dihydrogen citrate, and hydrates thereof;
• the phosphate is selected from one or more of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and hydrates thereof.
• the present application has no particular restrictions on the preparation method of the pH buffer, and it can be configured using methods known in the present application. As long as the purpose of this application can be achieved. Among them, citric acid and citrate can be used as pH buffers or as chelating agents, and the role of citric acid and citrate in the ophthalmic composition can be determined according to the specific formula.
• the above-mentioned "borate is selected from at least one of sodium borate, potassium borate and hydrates thereof" means that the borate can be selected from at least one of sodium borate, potassium borate, sodium borate hydrate, and potassium borate hydrate, and other similar expressions are understood by analogy.
• the present application has no special restrictions on the hydrates of each substance, which can be conventional hydrates known in the art, as long as the purpose of this application can be achieved.
• the pH buffer is selected from phosphate; the content of the phosphate in the ophthalmic composition is 0.001-2.0% W/V, preferably 0.005-1.0% W/V, and further preferably 0.005-0.5% W/V.
• the content of phosphate in the ophthalmic composition can 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, 2.0% W/V or a range consisting of any two values therebetween.
• the inventors have found that by selecting a phosphate buffer system and regulating the content of phosphate within the above range, the phosphate concentration is matched with the buffering capacity in tears, thereby minimizing the irritation and/or discomfort caused by the higher ionic strength buffer system.
• the pH buffer is selected from any one of boric acid, borate, citric acid, citrate, acetic acid-sodium acetate, tris(hydroxymethylaminomethane)-hydrochloric acid, and sodium bicarbonate, and 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 further preferably 0.005% W/V-0.5% W/V.
• the osmotic pressure regulator is selected from inorganic osmotic pressure regulators and/or organic osmotic pressure regulators;
• the inorganic osmotic pressure regulator is selected from one or more 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 0.01-1.5% W/V, preferably 0.2-1% W/V; for example, the content of the inorganic osmotic pressure regulator in the ophthalmic composition can be 0.01% W/V, 0.025% W/V L, 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 a range consisting of any two values therebetween.
• the organic osmotic pressure regulator is selected from any one of erythritol, glucose, glycerol, propylene glycol, L-carnitine and trehalose; the content of the organic osmotic pressure regulator in the ophthalmic composition is 0.001-10.0% W/V, preferably 0.01-5.0% W/V.
• the content of the organic osmotic pressure regulator in the ophthalmic aqueous solution composition can be 0.001% W/V, 0.01% W/V, 0.05% W/V, 0.10% W/V, 0.25g/% W/V, 0.50% W/V, 1.0% W/V, 5.0% W/V, 10.0% W/V or a range consisting of any two values therebetween.
• glycerol and propylene glycol can be used as organic osmotic pressure regulators or as comfort agents, and the role of glycerol and propylene glycol in the ophthalmic composition can be determined according to the specific formula.
• the inventors have found that by selecting the above-mentioned organic osmotic pressure regulators and/or inorganic osmotic pressure regulators The organic osmotic pressure regulator and/or the inorganic osmotic pressure regulator are adjusted within the above respective ranges so that the osmotic pressure of the ophthalmic composition is 280-320 mOsmol/L, which is close to the osmotic pressure of normal tears (270-310 mOsmol/L), thereby greatly reducing the discomfort of patients when using the ophthalmic composition.
• the osmotic pressure of the ophthalmic composition When 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 will be too low, and an excessive amount of the osmotic pressure regulator may form a hypertonic solution, and both hypotonic and hypertonic solutions will cause the lens to lose its required optical parameters. In addition, a hypertonic solution may also cause stinging, eye irritation, and dryness of the ocular surface.
• the ophthalmic excipient further comprises a surfactant, which is selected from at least one of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, sodium lauryl 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 docusate, quaternary ammonium compound, C6-C20 fatty acid, fatty acid sugar ester, fatty acid glyceride, polysorbate, and tyroxabor, and the content of the surfactant in the ophthalmic composition is 0.001 to 1.0% W/V.
• a surfactant which is selected from at least one of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, sodium lauryl sulfate, poly
• the content of the surfactant in the ophthalmic composition can 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 a range consisting of any two values therebetween.
• the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer is a specific type of block copolymer with Pluronic as the trademark, and Pluronic is also called poloxamer.
• a represents the number of hydrophilic polyoxyethylene units (PEO) water groups in the block copolymer
• b represents the number of hydrophobic polyoxypropylene units (PPO) in the block copolymer.
• the larger a/b is, the larger the hydrophilic-lipophilic balance HLB (equal to a/b) of the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer is, and the more hydrophilic it is.
• the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer i.e., Pluronic, has an HLB>10.
• the ophthalmic excipient further comprises a comfort agent
• the comfort agent is selected from at least one of polyols, cellulose derivatives, dextran, polyethylene glycol, polysorbate, povidone, trehalose, hyaluronic acid, carbomer, sodium hyaluronate and sodium alginate
• the polyol is selected from at least one of glycerol, propylene glycol, polyvinyl alcohol and mannitol
• the cellulose derivative is selected from at least one of hydroxypropyl methylcellulose-E4M (HPMC-E4M), hydroxypropyl methylcellulose-LV (HPMC-LV), hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, hemicellulose and ethyl cellulose
• the content of the comfort agent in the ophthalmic composition is 0.001-2.0% W/V.
• the content of the comfort agent in the ophthalmic aqueous solution composition can 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, 2.0% W/V or a range consisting of any two values therebetween.
• the patient's comfort when using the ophthalmic composition is further enhanced.
• the ophthalmic excipient further comprises a chelating agent, wherein the chelating agent is selected from at least one of disodium ethylenediaminetetraacetic acid (EDTA), alkali metal hexametaphosphate, nitrotriacetic acid, ethylenediamine disuccinic acid, iminodisuccinic acid, methylglycine diacetic acid, L-glutamic acid N,N-diacetic acid, ethylenediamine-N,N'-diglutamic acid, ethylenediamine-N,N'-dimalonic acid, 3-hydroxy-2,2-iminodisuccinic acid, 2-hydroxyethyliminodiacetic acid, pyridine-2,6-dicarboxylic acid, diethylenetriaminepentaacetic acid, hydroxyethyldiaminetriacetic acid, 1,2-diaminocyclohexanetetraacetic acid, hydroxyethylaminodiacetic acid, poly(ethylenediaminete
• the content of the chelating agent in the ophthalmic composition is 0.001-1.0% W/V.
• the content of the chelating agent in the ophthalmic aqueous solution composition can 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 or a range consisting of any two values therebetween.
• tartrate is selected from at least one of sodium tartrate, potassium tartrate, potassium hydrogen tartrate, sodium hydrogen tartrate and hydrates thereof.
• tartrate is selected from at least one 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 conventional hydrates known for the corresponding salts.
• the ophthalmic excipient further comprises an antioxidant, and the antioxidant is selected from at least one of sodium thiosulfate, sodium metabisulfite, N-acetylcysteine, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT); the content of the antioxidant in the ophthalmic composition is 0.001-1.0% W/V.
• the antioxidant is selected from at least one of sodium thiosulfate, sodium metabisulfite, N-acetylcysteine, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT); the content of the antioxidant in the ophthalmic composition is 0.001-1.0% W/V.
• the content of the antioxidant in the ophthalmic composition can 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 or a range consisting of any two values therebetween.
• the ophthalmic excipient further comprises a preservative, and the preservative is selected from at least one 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.
• BAK benzalkonium chloride
• the content of the preservative in the ophthalmic composition can 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, or a range consisting of any two values therebetween.
• the active substance is selected from the sodium salt shown in Formula I, and the preparation method of the ophthalmic composition comprises the following steps:
• the active substance is selected from the free acid of formula I, and the preparation method of the ophthalmic composition containing VVN001 comprises the following steps:
• the preparation method of the present application achieves the sterility, ideal stability and extremely low total impurity content of the ophthalmic composition containing VVN001.
• sterilization can be carried out by terminal heating sterilization, filtration sterilization, electron beam sterilization, ultraviolet light system, etc.
• a 0.22 ⁇ m sterile filter can be used for filtration sterilization, or heating sterilization can be performed at 121°C for not less than 30 minutes.
• the packaging method of the ophthalmic composition containing VVN001 there is no particular limitation on the packaging method of the ophthalmic composition containing VVN001, as long as the purpose of the present application can be achieved.
• it can be a traditional multi-dose bottle and a BFS (blow-fill-seal) disposable bottle or a multi-dose bottle.
• the second aspect of the present application provides the use of an ophthalmic composition containing VVN001 described in any of the above embodiments in the preparation of a medicament for treating dry eye.
• the active substance in the ophthalmic composition containing VVN001 i.e., the sodium salt of Formula I and/or the free acid of Formula I, is a small molecule integrin antagonist that can block the binding of LFA-1 and ICAM-1, inhibit T cell-mediated inflammatory response, thereby reducing ocular inflammatory response, to treat dry eye and/or other ocular surface diseases.
• the method and dosage of the ophthalmic composition are to drop the ophthalmic composition into the eye once or twice a day, one drop per eye at a time.
• the ophthalmic composition containing VVN001 can be used locally in eyes, ears, nose and the like.
• the product parameters (including ingredients, content, pH and osmotic pressure) of the ophthalmic composition obtained in Example 1 are shown in Table 1.
• Example 1 Except for adjusting the product parameters as shown in Table 2, the rest is the same as Example 1.
• Example 1 Except for adjusting the product parameters as shown in Table 3, the rest is the same as Example 1.
• Example 1 Except for adjusting the product parameters as shown in Table 4, the rest is the same as Example 1.
• Example 1 Except for adjusting the product parameters as shown in Table 5, the rest is the same as Example 1.
• Example 1 Except for adjusting the product parameters as shown in Table 6, the rest is the same as Example 1.
• Example 1 Except for adjusting the product parameters as shown in Table 7, the rest is the same as Example 1.
• Example 1 Except for adjusting the product parameters as shown in Table 8, the rest is the same as Example 1.
• Example 1 Except for adjusting the product parameters as shown in Table 9, the rest is the same as Example 1.
• Example 1 Except for adjusting the product parameters as shown in Table 10, the rest is the same as Example 1.
• Example 1 Except for adjusting the product parameters as shown in Table 11, the rest is the same as Example 1.
• Example 1 Except for adjusting the product parameters as shown in Table 12, the rest is the same as Example 1.
• Example 1 Except for adjusting the product parameters as shown in Table 13, the rest is the same as Example 1.
• Example 14 Except for adjusting the product parameters as shown in Table 14, the rest is the same as Example 1.
• Example 1 Except for adjusting the product parameters as shown in Table 15, the rest is the same as Example 1.
• Example 1 Except for adjusting the product parameters as shown in Table 16, the rest is the same as Example 1.
• IID content standards in Table 1 refer to the content standards in the U.S. FDA inactive ingredient database.
• IID content standards in Table 17 refer to the content standards in the U.S. FDA inactive ingredient database.
• the ophthalmic composition containing VVN001 prepared in Example 1 was respectively bottled in multi-dose bottles (0.5 mL), multi-dose
• the ophthalmic compositions containing VVN001 in the multi-dose bottles (0.5 mL), multi-dose bottles (1 mL), and multi-dose bottles (2 mL) were stored at an ambient temperature of 40° C. and a humidity of 75% RH. After 1 month and 3 months of storage, the stability tests were performed on the ophthalmic compositions containing VVN001 in the multi-dose bottles (0.5 mL), multi-dose bottles (1 mL), and multi-dose bottles (2 mL). The results are shown in Table 17.
• the single impurity content of the ophthalmic composition containing VVN001 at different storage times was tested by high performance liquid chromatography (HPLC).
• Tables 18 to 20 show the single impurity content of the ophthalmic composition containing VVN001 after storage for 1 month and 3 months, respectively.
• the ophthalmic composition prepared by the preparation method of the present application has good sterility, good stability and extremely low impurity content after being stored in single-dose bottles (0.5 mL), multi-dose bottles (1 mL) and multi-dose bottles (2 mL) for up to 3 months at an ambient temperature of 40° C. and a humidity of 75% RH.
• the relative retention time of the single impurity in Tables 19 and 20 is the ratio of the retention time of the single impurity to the retention time of the sodium salt shown in I.
• the ophthalmic composition provided by the present application with a 5% W/V content of VVN001 was used for clinical testing.
• the subjects had moderate to severe dry eye disease and were administered by eye drops twice a day.
• the overall trend of improvement in dry eye disease in the subjects was very obvious, and multiple corneal regions, including total corneal staining, reached significant statistical significance at 84 days (p ⁇ 0.05); the trend of increased tear secretion in the subjects was also significantly better than that of the blank solvent control.
• the blank solvent control refers to the ophthalmic composition used by the subjects that does not contain VVN001.

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