KR20180077719A - Sustained release eyedrops - Google Patents

Abstract

The present invention relates to a sustained release eye-drop composition which can maintain the medicinal effect while having excellent application, and a manufacturing method thereof. More specifically, the present invention relates to a sustained release eye-drop composition having low viscosity, and a manufacturing method thereof. The sustained release eye-drop composition comprises: trehalose or a hydrate thereof; and at least one biopolymer selected from the group consisting of hyaluronic acid or pharmaceutically acceptable salt thereof, carboxymethylcellulose sodium, polyvinylpyrrolidone, and polyvinyl alcohol as effective components.

Description

{SUSTAINED RELEASE EYEDROPS}

The present invention relates to an eye drop composition containing trehalose and a method for producing the same, and is directed to an eye drops composition having an effect persistence of an extended duration of action of a drug and having an appropriate viscosity in eye drops and excellent pharmaceutical formulation stability, will be.

The tears consist of an oily layer, an aqueous layer and a mucous layer, and the tear film shows a three-layer structure thereof. The concept of ocular dry to dry eye (hereinafter, referred to as 'ocular dry') is wide and its causes are not disclosed in many cases. Therefore, ocular dryness is not a single disease, The tear film is defined as an unsteady abnormal eye condition in which the tear film disappears more rapidly than normal. According to the above definition, the categories of ocular dryness include dry corneal conjunctivitis, angular conjunctival epithelial disorder, leukodystrophy, Stevens-Johnson syndrome, ocular dryness syndrome, Schogren syndrome, tear deficiency, ocular hypertension, tear film instability, The same diseases are included. Also included in the category of ocular dryness are allergic conjunctivitis, viral conjunctivitis, or ocular dryness after cataract surgery. In addition, as the number of contact lens users has recently increased, the time spent in artificial air-conditioned environments has increased, and the wide use of TVs and computers has increased the chance of viewing VDT (visual display terminals) The factors have increased dramatically, and consequently category of ocular dryness includes contact lens wear-related eye dryness or VDT work-related eye dryness. In addition, in the case of ocular dryness, in many cases, it causes conjunctivitis disorders. Particularly, when the mucous layer lacks tears, the corneal damage is serious, which causes each conjunctival epithelium disorder. The categories of dry eye, corneal epithelium defect, corneal epithelium defect, corneal epithelium erosion, Infections of corneal ulcer, keratitis, conjunctivitis, punctate superficial keratopathy, dry keratoconjunctivitis, conjunctival keratoconjunctivitis, conjunctival keratitis, corneal ulcer, and conjunctival epithelium from each conjunctival epithelium disorder include infiltration, corneal perforation or corneal epithelial detachment. And eye diseases. Each conjunctival epithelial defect may also be caused by intraocular trauma, microsurgery, or hard contact lenses. Dry eye can occur in the eye, in addition to the normal eye. In the case of loss of eyeball due to various eye diseases, industrial accidents, or traffic accidents, the eyeball is removed and the eyeball is worn. Patients wearing the eyeball may also have symptoms of eyeball dryness Because.

An eye drop composition is the basis of ocular dry treatment. Currently, a wide variety of compositions and concentrations of agents are commercially available in eye drop compositions, and eye drops compositions containing trehalose are also commercially available (e.g., Haitok®).

Trehalose is a disaccharide in which two glucose molecules are bonded together at their reducing moieties, and has three optical isomers of?,? -Trehalose,?,? -Trehalose and?,? - trehalose. In the natural world, trehalose is widely distributed in bacteria, plants and animals, and trehalose is widely used because it has excellent properties such as relatively low sweetness, prevention of aging of starch and prevention of protein denaturation during freezing / drying.

However, the dosage-dosage of these eye-drop compositions is often several drops per eye, one drop per day for each eye if needed. That is, it means that the duration of the drug effect in the eye is as short as that, and therefore, there is an inconvenience that it is necessary to use it continuously frequently in order to continuously obtain the effective effect. Furthermore, in cases of severe ocular dryness, frequent eye drops should be used to maximize discomfort.

In order to solve this problem, when the viscosity is increased, there arises a problem that the lining of the dots is poor or the liquid of the eye drops is not dripped during the occlusion, and in some cases, the phenomenon of falling from the tip of the eye drop to the outside occurs .

Accordingly, there has been a demand for the development of an eye drop composition having excellent lining and durability as the medicinal effect continues.

An object of the present invention is to provide an eye drop composition having excellent lining and a method of manufacturing the composition, while retaining the advantageous effects.

The problem to be solved by the present invention is to provide an eye drop composition having an efficacy of 1 to 10 cP, more preferably 1 to 5 cP, and most preferably 1 to 1.5 cP, and a method for producing the composition.

In order to solve the above-mentioned problems, the present invention relates to trehalose or a hydrate thereof; And at least one biopolymer selected from the group consisting of hyaluronic acid or a pharmaceutically acceptable salt thereof, carboxymethylcellulose sodium, polyvinylpyrrolidone, and polyvinyl alcohol as an active ingredient, a method for producing the same, Thereby providing a method for preventing or treating ophthalmic diseases.

The present inventors have made intensive efforts to improve the disadvantage that the eye drop composition containing trehalose or a hydrate thereof has a short time for the effective action of the eye drop, and thus it is necessary to repeatedly and repeatedly administer the composition. As a result, hyaluronic acid or its pharmaceutically acceptable salt, sodium carboxymethylcellulose, The addition of one or more biopolymers selected from the group consisting of polyvinylpyrrolidone and polyvinyl alcohol significantly improves the action time and further makes it possible to produce an eye drop composition having a low viscosity and thereby obtain an eye drop composition having excellent lining And completed the present invention.

The eyedropper according to the present invention comprises, as an active ingredient, i. Trehalose or its hydrate, and ii. At least one biopolymer selected from the group consisting of hyaluronic acid or a pharmaceutically acceptable salt thereof, carboxymethyl cellulose sodium, polyvinyl pyrrolidone, and polyvinyl alcohol.

In the present invention, "trehalose", "hyaluronic acid", "carboxymethylcellulose sodium", "polyvinylpyrrolidone", and "polyvinyl alcohol" Regardless of its origin.

"Trehalose" is a disaccharide in which two glucose molecules are bonded together at their reducing moieties, and as their active ingredient, three optical isomers of?,? -Trehalose,?,? -Trehalose and?,? . ≪ / RTI >

"Hydrate of trehalose" means additionally containing a stoichiometric or non-stoichiometric amount of water bound to the trehalose by non-covalent intermolecular forces.

"Hyaluronic acid" is a complex polysaccharide composed of amino acid and uronic acid, and is a high molecular compound composed of N-acetylglucosamine and glucuronic acid. Linear or cross-linked. The degree of crosslinking can be appropriately controlled by a person skilled in the art. But is not limited thereto, it can be generally used that the average molecular weight is 100 to 1,200 kDa.

"Pharmaceutically acceptable salts of hyaluronic acid" include salts of any hyaluronic acid, including, for example, sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate and calcium hyaluronate. Preferably, sodium hyaluronate can be used. The sodium hyaluronate is a highly hydrophilic hydrophilic polymer and is described in the Merck Index, 11th edition (Merck Index No. 12, 4793), and is described in the European Pharmacopoeia, 3rd Edition, (Supplement 2000, pages 1190 -1193, Appendix 3)], and the CAS number is CAS 9067-32-7. But are not limited to, those having an average molecular weight of 200 to 4,000 kDa, 750 to 2,000 kDa, 800 to 1,750 kDa, 900 to 1,500 kDa, or 1,000 kDa.

"Sodium Carboxymethyl cellulose" (CMC) is an odorless white to pale yellow powder, granular or fibrous material. It is well dispersed in water and forms a colloidal solution. However, it does not dissolve in alcohol, acetone, or ether. The aqueous solution is viscous and has good protective colloid properties. It exhibits the most stable maximum viscosity at pH 7 ~ 9, decreases at pH 5 and below, and precipitates at pH 2 ~ 3. In addition, Na + &lt; K + &lt; NH4 + in the order of decreasing viscosity in the order of increasing negative ions Cl- <Br- <I- in that order. This solution is relatively stable, but it solidifies with metal ions such as aluminum, copper, iron, lead and zinc. Increase in acidity or alkalinity, or decrease in viscosity due to ultraviolet rays and microorganisms. The glucose constituting cellulose has three etherizable OH groups and can be made into various etherification degrees. In general, etherification is also referred to as substitution of one carboxymethyl group per glucose unit, which is theoretically possible up to three. However, most of the products on the market have etherification rates of 0.6-0.9. The water is melted when the degree of etherification is 0.4 or more, but is preferably 0.8 or more if it has acid resistance or salt resistance. Viscosity to water is from 10 cps or less in 2% solution to 10,000 cps or more in water, but commercial product is approximately 30 to 400 CPS, and polymerization degree is 200 to 500. The CAS number is CAS 9004-32-4.

"Polyvinyl pyrrolidone (PVP)" is a polymer (polymer) of N-vinyl-2-pyrrolidone. It is hygroscopic and soluble in water, alcohols, amines and many other organic solvents and does not dissolve in hydrocarbons. The CAS number is CAS 9003-39-8. Although not limited thereto, it can be generally used that the average molecular weight is 7 to 1,500 kDa.

"Polyvinyl alcohol (PVA)" is a water-soluble polymer that can be produced by the hydrolysis of a polyvinyl acetate polymer following polymerization of vinyl acetate. The vinyl alcohol monomer is unstable and is present as tautomeric form, acetaldehyde The degree of polymerization determines the molecular weight and the viscosity of the solution. The water-soluble polymer is not soluble in an organic solvent and has good solvent resistance, but it is not limited thereto, but an average molecular weight of 10 to 200 kDa can be generally used. The CAS number is CAS 9002-89-5.

In the present invention, "trehalose", "hyaluronic acid", "carboxymethylcellulose sodium", "polyvinylpyrrolidone" and "polyvinyl alcohol" are not specifically defined, And pharmaceutically acceptable variants or derivatives thereof will be recognized as having or providing the same biological function and / or activity as these, and as long as the object of the present invention is not impaired, A prodrug thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a co-crystal thereof.

The term "pharmaceutically acceptable" means that it must be chemically, physically, and / or toxicologically compatible with the other ingredients of the eye drop composition and / or the mammal being treated therewith.

The term " prodrug "means that an amount of trehalose, hyaluronic acid, carboxymethylcellulose sodium, polyvinylpyrrolidone, or polyvinyl alcohol is formed in an amount that can be experimentally detected within a predetermined time after administration through metabolism. For example, esters or amide derivatives of hyaluronic acid may be included.

The term &quot; solvate &quot; means a compound further comprising a stoichiometric or non-stoichiometric amount of solvent bound by noncovalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

The term &quot; co-crystal &quot; refers to a crystalline form comprising at least one compound in the crystal lattice. The co-crystals comprise a crystalline molecular complex of two or more non-volatile compounds joined together in a crystal lattice through non-ionic interactions. In the present invention, co-crystals include pharmaceutical co-crystals which are crystalline molecular complexes comprising these compounds and one or more additional non-volatile compounds (hereinafter referred to as counter-molecules). In pharmaceutical co-determination, the counter-molecule may be a non-toxic pharmaceutically acceptable molecule such as, for example, food additives, preservatives, pharmaceutical excipients, or other APIs. In some embodiments, pharmaceutical co-crystals enhance some of the physical properties of the drug (e.g., solubility, dissolution rate, bioavailability / stability, etc.) without compromising the chemical structural integrity of the API.

The term "pharmaceutically acceptable salt" refers to any organic or inorganic addition salt that has a relatively nontoxic and innocuous effective action on the patient, such that the side effects caused by the salt do not impair the beneficial effects of the compound Examples of the free acid include organic acids, inorganic acids and non-toxic salts. Examples of the inorganic acids include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid and tartaric acid. Examples of the organic acids include methanesulfonic acid, p-toluenesulfonic acid, , Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycol Glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbon , Banil acid, hydroiodic acid and the like (hydroiodic acid), may be, for example, hydrochloride. The acid addition salt can be prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The molar amount of the compound and the acid or alcohol in water may be heated, followed by evaporation of the mixture to dryness, or the precipitated salt may be subjected to suction filtration. Examples of the non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphate chlorides, bromides, iodides, fluorides , Acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, Fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate phthalate , Terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene Sulfonate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-1-sulphonate, naphthalene-1-sulphonate, Naphthalene-2-sulfonate, or mandelate.

Trehalose or a hydrate thereof, hyaluronic acid or a pharmaceutically acceptable salt thereof, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, or polyvinyl alcohol, including a pharmaceutically acceptable derivative or variant thereof, as described above, may be chemically or enzymatically And may be manufactured by various methods known in the art, or a commercially available product may be purchased and used.

In the present invention, the trehalose or its hydrate thereof contains 1 to 5% by weight, more preferably 2 to 4% by weight, most preferably 3 to 4% by weight based on the total weight of the composition. Within this range, the most excellent effect is exhibited by using in combination with at least one biopolymer selected from the group consisting of hyaluronic acid or a pharmaceutically acceptable salt thereof, carboxymethyl cellulose sodium, polyvinyl pyrrolidone, and polyvinyl alcohol.

In the present invention, at least one biopolymer selected from the group consisting of hyaluronic acid or a pharmaceutically acceptable salt thereof, carboxymethyl cellulose sodium, polyvinyl pyrrolidone, and polyvinyl alcohol may be used in an amount of from 0.0005 to less than 0.01 By weight, more preferably from 0.0005 to less than 0.01% by weight, most preferably from 0.001 to less than 0.005% by weight. Within this range, trehalose or its hydrate exhibits the most excellent effect.

In the present invention, the total amount of at least one biopolymer selected from the group consisting of hyaluronic acid or a pharmaceutically acceptable salt thereof, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, and polyvinyl alcohol with respect to the total weight of trehalose or its hydrate The weight ratio is 300-3000: 1, more preferably 600-3000: 1, most preferably 2000-3000: 1 (trehalose or its hydrate: hyaluronic acid or a pharmaceutically acceptable salt thereof, carboxymethylcellulose sodium, polyvinyl At least one biopolymer selected from the group consisting of pyrrolidone, and polyvinyl alcohol). Within this range, they exhibit the best effect durability and point lining.

The composition according to the present invention may further contain various components in addition to the above-mentioned components, so long as the object of the present invention is not impaired.

For example, an inert polymer may be further included. The useable polymer is selected from the group consisting of glycerin, hydroxypropylmethyl cellulose, hydroxyethylcellulose, chondroitin sulfate, glucosamine, dextran, polysorbate 80 Polysorbate 80, Polyethylene glycol 400 and Glucose, and the like.

For example, additives such as pharmaceutically acceptable carrier, excipient or diluent may be included. Properties to be considered in the excipient include compatibility with other components contained in the composition, biocompatibility, processing temperature, etc. However, But is not limited thereto.

The eye drop composition according to the present invention may be prepared in a dosage form such as a liquid preparation, an ointment and the like, and when it is prepared from a liquid preparation, any form of administration used as an ophthalmic solution such as aqueous ophthalmic solution, aqueous emulsion ophthalmic solution, Aqueous ophthalmic solutions such as ophthalmic solutions and dissolved ophthalmic solutions; Or non-aqueous ophthalmic solutions such as non-aqueous ophthalmic solutions and non-aqueous emulsion ophthalmic solutions.

Aqueous emulsion ophthalmic solution may contain various additives known in the art so long as the object of the present invention is not impaired. Examples thereof include isotonic agents, buffering agents, stabilizers, pH adjusting agents, thickening agents, preservatives, chelating agents, solubilizing agents And solvents and the like. The buffer may be selected from the group consisting of phosphate buffers, borate buffers, citrate buffers, tartrate buffers, acetate buffers (e.g., sodium acetate), tromethamine and amino acids, but is not limited thereto. Preferably, a phosphate buffer can be used. Isotonic agents may be selected from the group consisting of sugars such as sorbitol, glucose erythritol and mannitol, polyhydric alcohols such as glycerin, polyethylene glycol and polypropylene glycol, and salts such as sodium chloride, but are not limited thereto. Preservatives include, but are not limited to, alkyl paraoxybenzoates such as benzalkonium chloride, benzethonium chloride, methyl para-oxybenzoate and ethyl para-oxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid and its salts, thimerosal, polyquaternium , Benzododecinium bromide, oxychloro complex and chlorobutanol, but are not limited thereto. Stabilizer is a cyclodextrin and its derivatives, poly (vinyl pyrrolidone) and the group consisting of water-soluble polymer, and polysorbate 80 (Tween 80 ^®), Polysorbate 20, a surfactant, tromethamine as tirok sapol such , And preferably, but not limited to, tromethamine. The pH adjusting agent may be selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, monoethanolamine, ammonia water and ammonium hydroxide, but is not limited thereto. The thickening agent may be selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose, carbomer, povidone, poloxamer, polycarbophil and salts thereof, It does not. The chelating agent may be selected from the group consisting of sodium edetate, sodium citrate and condensed sodium phosphate, but is not limited thereto. The solubilizing agent or solvent may be selected from, but not limited to, glycerin, DMSO, DMA, N-methylpyrrolidone, ethanol, benzyl alcohol, isopropyl alcohol, polyethylene glycols having various molecular weights or propylene glycol. There may be some overlap between the components that can be used as solvent or solubilizer, and any component may be used as one of the solvent or solubilizer, and if any component acts as the solvent in the preparation, If not, it can be seen as a solubilization agent. Alternatively, the solubilizer may be a surfactant in some variations. A combination of surfactants comprising various types of surfactants can be used. For example, nonionic, anionic (i.e., soap, sulfonate), cationic (i.e., CTAB), tritiated, polymeric, amphoteric surfactants may be used. For example, surfactants that may be used include those having an HLB of 10, 11, 12, 13, or 14, including but not limited to. Examples of surfactants include, but are not limited to, polyoxyethylene products of hydrogenated vegetable oils, polyethoxylated castor oil or polyethoxylated hydrogenated castor oil, polyoxylated castor oil or derivatives thereof, polyoxyethylene-sorbitan fatty acid esters , Polyoxyethylene castor oil derivatives, and the like. But is not limited thereto. According to a specific embodiment, the ophthalmic compositions of the present invention comprise trehalose or a hydrate thereof; At least one biopolymer selected from the group consisting of hyaluronic acid or a pharmaceutically acceptable salt thereof, carboxymethylcellulose sodium, polyvinylpyrrolidone, and polyvinyl alcohol; And isotonic agents, pH adjusting agents, stabilizers, solvents or mixtures thereof.

According to a specific embodiment, the composition of the present invention comprises trehalose or a hydrate thereof; At least one biopolymer selected from the group consisting of hyaluronic acid or a pharmaceutically acceptable salt thereof, carboxymethylcellulose sodium, polyvinylpyrrolidone, and polyvinyl alcohol; And isotonic agents, pH adjusting agents, stabilizers and solvents. According to a specific embodiment, the composition of the present invention comprises 3 to 4% by weight trehalose or its hydrate, relative to the total weight of the composition; 0.001 to 0.005% by weight of at least one biopolymer selected from the group consisting of hyaluronic acid or a pharmaceutically acceptable salt thereof, carboxymethyl cellulose sodium, polyvinyl pyrrolidone, and polyvinyl alcohol; And from 0.2 to 0.3% by weight of a stabilizer. According to a specific embodiment, in the composition of the present invention, the weight ratio (trehalose or its hydrate: stabilizer) of the stabilizer to the total weight of trehalose or its hydrate is 10-12: 1, more preferably 11.1: 1 have. According to a specific embodiment, the composition of the present invention comprises trehalose or a hydrate thereof; At least one biopolymer selected from the group consisting of hyaluronic acid or a pharmaceutically acceptable salt thereof, carboxymethylcellulose sodium, polyvinylpyrrolidone, and polyvinyl alcohol; And tromethamine. According to a specific embodiment, the composition of the present invention comprises 3 to 4% by weight trehalose or its hydrate, relative to the total weight of the composition; 0.001 to 0.005% by weight of at least one biopolymer selected from the group consisting of hyaluronic acid or a pharmaceutically acceptable salt thereof, carboxymethyl cellulose sodium, polyvinyl pyrrolidone, and polyvinyl alcohol; And 0.2 - 0.3 wt.% Tromethamine. According to a specific embodiment, in the composition of the present invention, the weight ratio of tromethamine (trehalose or its hydrate: tromethamine) to the total weight of trehalose or its hydrate is 10-12: 1, more preferably 11.1: . According to a specific embodiment, the composition of the present invention comprises trehalose or a hydrate thereof; At least one biopolymer selected from the group consisting of hyaluronic acid or a pharmaceutically acceptable salt thereof, carboxymethylcellulose sodium, polyvinylpyrrolidone, and polyvinyl alcohol; And sodium chloride, hydrochloric acid, tromethamine, and purified water.

According to a specific embodiment, the composition of the present invention comprises not less than 3 but not more than 4% by weight trehalose or its hydrate, relative to the total weight of the composition; 0.001 to 0.005% by weight of at least one biopolymer selected from the group consisting of hyaluronic acid or a pharmaceutically acceptable salt thereof, carboxymethyl cellulose sodium, polyvinyl pyrrolidone, and polyvinyl alcohol; And 0.5 to 1.0% by weight of sodium chloride, 0.2 to 0.5% by weight of hydrochloric acid, 0.2 to 0.5% by weight of tromethamine and 90 to 98% by weight of purified water.

The aqueous emulsion aqueous ophthalmic solution can be prepared preferably in the form of a nano emulsion. In this case, various additives known in the art can be included in the present invention so long as the object of the present invention is not impaired. For example, oils and surfactants can be included. The oil may be selected from the group consisting of propylene glycol monocaprylate, propylene glycol laurate, medium chain (C8 to C10) triglycerides having 8 to 10 carbon atoms, glyceryl-1, At least one selected from the group consisting of glyceryl-1,3-dioleate, glyceryl monooleate, and glyceryl linoleate. The surfactant may be selected from the group consisting of oleoyl macrogolglycerides, linoleoyl macrogolglycerides, caprylocaproyl polyoxylglycerides, polyoxyl 35 castor oil ), Polyoxyl 35 hydrogenated castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 hydrogenated castor oil, One or more of the condensation product of ethylene oxide with 12-hydroxystearic acid and polysorbate 80 (Polysorbate 80, Croda, UK) can be selected from the group consisting of ethylene oxide and 12-hydroxystearic acid.

The eye drop composition according to the present invention is a persistent eye drop composition.

The term "persistence" refers to a property that slows the rate of release of a drug when bioavailability is low or when the drug is either too slowly absorbed or lost too quickly. According to this characteristic, it represents an extended sustained action (action) time.

The eye drop composition according to the present invention is persistent and has a drug release rate of 2 times or more as compared to an eye drop composition containing, for example, trehalose or its hydrate as an active ingredient alone, wherein the drug release rate is pH 7.4, 37 ° C Based on the time taken for the persistent eyedrops composition to homogenize in a balanced salt solution.

The eye drop composition according to the present invention has a low point and excellent point lining.

More specifically, the low viscosity means that the viscosity is 1 to 10 cP at 20 ° C, more preferably 1 to 5 cP, and most preferably 1 to 1.5 cP.

The viscosity can be measured according to various methods known in the art, such as, for example, Brookfield Digital Viscometer, Model DV-1), Spindle 18, but is not limited thereto.

The composition according to the present invention can be used for improving, preventing or treating ophthalmic diseases, and preferably for improving, preventing or treating disorders due to ocular drying.

The above-mentioned " disorder caused by ocular dryness "includes dry corneal conjunctivitis, angular conjunctival epithelial disorder, leukodystrophy, Stevens-Johnson syndrome, ocular dry syndrome, Schogren's syndrome, tear deficiency, ocular hypertension, tear film instability, or ocular edema; Allergic conjunctivitis, viral conjunctivitis, or ocular dryness after cataract surgery; And contact lens wear-related eye dryness or VDT work-related eye dryness.

In addition, the "corneal epithelium disorder" includes dry eye, corneal epithelium defect, conjunctival epithelium defect, corneal epithelial erosion, corneal thickness reduction, corneal infiltration, corneal perforation, or corneal epithelial detachment; Corneal ulcer, keratitis, conjunctivitis, petechial keratopathy, dry keratoconjunctivitis, conjunctival keratoconjunctivitis, conjunctivitis, infectious ocular disease of corneal ulcer and corneal epithelium; Intraocular trauma, microsurgery, or conjunctival epithelial disorders associated with wearing hard contact lenses.

In the treatment and / or prevention of mammalian patients, particularly humans, the dose of the composition according to the present invention may be routinely determined by the medical practitioner or the related art. For example, when the composition according to the present invention is used as an eye drop for an adult ocularly dry patient, a preferable dosage of the composition is 1 to 4 drops per day (about 0.025 to 0.1 mL) But the present invention is not limited thereto. The medical practitioner or the related art technician can determine the most suitable actual dosage depending on the age, weight, sex and response of the patient to be treated, as well as the condition to be treated.

The composition according to the present invention may be provided by filling in a sterilized container and may be provided with instructions on its use, which may be provided in a container filled with the composition or in a second container Or they may be packed together in a second container.

The composition according to the present invention may be prepared according to various methods known in the art and may be prepared by adding to the solvent trehalose or its hydrate, hyaluronic acid or its pharmaceutically acceptable salt, carboxymethylcellulose sodium, polyvinylpyrrolidone, and poly Vinyl alcohol, and optionally a pharmaceutically acceptable additive, and filtering the mixture.

According to the present invention, it is possible to effectively use an eye drop composition having excellent dentifrice and superior stability in pharmaceutical formulation with improved eye drop convenience in the treatment of ocular dryness and the like, while maintaining the effect thereof.

Hereinafter, embodiments of the present invention will be described in detail to facilitate understanding of the present invention. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

< Example  1 ~ Example  12>

Example  One

Sodium hyaluronate, sodium chloride, and tromethamine were dissolved in 80 mL of sterile purified water and dissolved in hydrochloric acid to adjust the pH to 7.0. Sterilized purified water was further added to make a total volume of 100 mL, followed by filtration through a 0.2 μm membrane filter Filtered.

Example  2 to Example  12

An eye drop composition was prepared in the same manner as in Example 1 except that each component and its content were as shown in Table 1 below.

Comparative Example

An eye drop solution containing 33.16 mg of trehalose hydrate per 1 mL (Guangdong Pharmaceutical, Korea) was purchased.

The eyedrop eye drops do not contain sodium hyaluronate, sodium carboxymethylcellulose, polyvinylpyrrolidone and polyvinyl alcohol at all.

Experimental Example  1. Time Stability Test

The eye drop compositions prepared in Examples 1 to 8 were stored at 40 DEG C and 75% RH for 4 weeks to observe whether or not precipitation occurred, and the results are shown in Table 2 below. In case of precipitation, '0' is indicated. In the case of no precipitation, 'X' is indicated.

As a result, as shown in Table 2, it was confirmed that all of the eye drops except Examples 5 to 8 had excellent stability with time.

Experimental Example  2. Osmotic pressure and viscosity measurement test

The osmotic pressure and viscosity of the eye drops prepared according to Examples 1 to 4 and Examples 9 to 12 were measured and the results are shown in Table 3. Osmomat 030-D (Gonotec) was used as an osmotic pressure measuring device. Viscosity was measured using a Brookfield Digital Viscometer (Model DV-1), Spindle 18, and the viscosity was measured at 20 ° C.

As a result, there was no significant difference in the osmotic pressures of Examples 1 to 4, Examples 9 to 12 and Comparative Examples. The viscosities of the comparative examples were similar to those of Examples 1 to 4, and the viscosities of Examples 9 to 12 were somewhat higher than those of Comparative Examples, but all exhibited a viscosity of 10 cP or less.

Experimental Example  3. Drug Release Test

In order to confirm the drug release time of the eye drop compositions prepared according to Examples 1 to 4 and Examples 9 to 12, the test was carried out in the following manner. The solution for drug release test of eyedrops was tested in 37 ° C using balanced salt solution (pH 7.4). A sample of eye drops dyed at a concentration of 5 mg / mL of Red No. 3 dye was carefully placed in a round bottom beaker containing 250 mL of a balanced salt solution, and the red color was homogenized And the time taken for the drug release time to be taken as the drug release time, respectively. The results are shown in Table 4.

As shown in Table 4, it was confirmed that the release time of the eye drop compositions prepared according to Examples 1 to 4 and 9 to 12 of the present invention was extended about twice as much as that of Comparative Example.

Experimental Example  4. Drip test

The eye drop compositions prepared according to Examples 1 to 4 and Examples 9 to 12 were filled in a BFS dropping container and the same operation as that performed by 5 healthy persons at the time of spot observation was performed five times. Whether or not drips (a phenomenon in which the eye drops drop from the tip of the eye drop along the outside) occurred for each operation, and the results are shown in Table 5. The number of times the drip is generated is indicated. When no drip occurs, the number is written as zero.

As shown in Table 5, in the comparative example, there was drip, whereas in the eye drop compositions prepared according to Examples 1 to 4 and Examples 9 to 12, drip was not observed at all. Therefore, it was confirmed that the dripping property was improved.

Claims (9)

Trehalose or a hydrate thereof; And at least one biopolymer selected from the group consisting of hyaluronic acid or a pharmaceutically acceptable salt thereof, carboxymethyl cellulose sodium, polyvinyl pyrrolidone, and polyvinyl alcohol as an active ingredient. [3] The composition of claim 1, wherein the at least one biopolymer selected from the group consisting of sodium hyaluronate, carboxymethyl cellulose sodium, polyvinyl pyrrolidone, and polyvinyl alcohol is present in an amount of 0.0005 to less than 0.01% &Lt; / RTI &gt; The persistent eye drop composition of claim 1, wherein the trehalose or hydrate thereof comprises from 1 to 5% by weight based on the total weight of the sustained release eye drop composition. [3] The method according to claim 1, wherein the total weight ratio of at least one biopolymer selected from the group consisting of sodium hyaluronate, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, and polyvinyl alcohol to the total weight of the trehalose or its hydrate is 300 - &Lt; / RTI &gt; 3000: 1. The persistent eye drop composition of claim 1, wherein the persistent eye drop composition further comprises a pharmaceutically acceptable additive comprising an isotonicity agent, a pH adjusting agent and a stabilizer. 6. The composition of claim 5, wherein the stabilizing agent is tromethamine. 6. The composition of claim 5, wherein the total weight ratio of the stabilizer to the total weight of the trehalose or hydrate thereof is 10-12: 1 (trehalose or a hydrate thereof: stabilizer). The persistent eyedrops composition of claim 1, wherein the persistent eyedrop composition has a viscosity of from 1 to 10 cP. [3] The composition according to claim 1, wherein the drug release rate of the sustained release eye drop composition is at least twice that of an eye drop composition comprising Trehalose or a hydrate thereof as an active ingredient
However, the drug release rate is based on the time required for homogenizing the persistent eye drop composition in a balanced salt solution of pH 7.4, 37.