RU2659158C2 - Ophthalmic composition for soft contact lenses - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, particularly to ophthalmology, and is intended for the preparation of an ophthalmic composition for soft contact lenses. Ophthalmic composition for soft contact lenses comprises pranoprofen and/or a pharmaceutically acceptable salt thereof and cations other than hydrogen ions, in an equivalent of 140 mEq/l or less. Said composition has a pH in the range of 5.5 to 8. Also disclosed are methods for suppressing the adsorption of pranoprofen and/or a pharmaceutically acceptable salt thereof on soft contact lenses.

EFFECT: use of the group of inventions makes it possible to suppress the adsorption of pranoprofen and/or salt thereof on soft contact lenses in order to avoid a side effect on soft contact lenses, providing an effective therapeutic effect of pranoprofen and/or salt thereof.

12 cl, 8 tbl, 7 ex

Description

FIELD OF THE INVENTION

The present invention relates to an ophthalmic composition for soft contact lenses, which suppresses the adsorption of pranoprofen and / or its salt on soft contact lenses. The present invention also relates to a method for suppressing the adsorption of pranoprofen and / or its salt on soft contact lenses (MKL).

State of the art

Pranoprofen and / or its salt inhibit the biosynthesis of prostaglandin, responsible for inflammation or pain. In the field of ophthalmology, they are widely used to relieve symptoms such as redness and burning in the eyes, and to prevent or treat blepharitis, conjunctivitis, scleritis, including episiscleritis, postoperative inflammation, anterior uveitis, and the like.

Various pharmaceutical formulations of ophthalmic compositions containing pranoprofen and / or its salt are described. For example, Patent Document 1 shows that an aqueous topical liquid containing pranoprofen and / or its salt and antihistamine has a good anti-inflammatory and antipruritic effect. Patent Document 2 shows that eye drops containing 0.01-2.0 wt./about. % pranoprofen and / or its salt and 0.0005-0.1 wt./about. % of a specific vasoconstrictor, such as naphazoline, can effectively remove or alleviate redness of the eyes in the outer region of the eye.

Alternatively, soft disposable disposable or long-term soft contact lenses (hereinafter referred to as MKL) have recently been developed, and thus the number of people wearing contact lenses has increased. To increase the comfort of wearing contact lenses, eye drops are necessary that can be used when wearing MKL (eye drops for MKL). It is necessary that the eye drops for MKL provide the necessary therapeutic effects and be made according to such a formulation that they do not cause side effects on MKL. The adsorption of drugs in eye drops for MKL with soft contact lenses causes deformation of the lenses and reduces comfort during use and the like, and in addition, can eliminate the necessary pharmacological effects on the mucous membrane of the eyes, which suggests that suppression of drug adsorption on soft lenses is an important task for eye drops for MKL. To suppress the adsorption of drugs on soft contact lenses in eye drops for MKL, pharmaceutical formulations are standardly developed containing a selected drug that is difficult to adsorb with MKL; a component that suppresses the adsorption of the drug MKL, and more.

For example, Patent Document 3 describes a composition for MKL comprising a basic drug formed from an amino compound containing a secondary or tertiary amino group; an amino acid, its salt, acid mucopolysaccharide, its salt, or cyclodextrin; and having a pH of from 3.5 to 4.8, as a pharmaceutical formulation capable of suppressing the adsorption of the main drug MKL.

Prior Art Documents

Patent documents

Patent Document 1: Japanese Patent Application Laid-Open No. 2002-193805

Patent Document 2: WO 01/87304

Patent Document 3: WO 2007/77783

SUMMARY OF THE INVENTION

Problems to be Solved by the Present Invention

The inventors of the present invention encountered a tendency to adsorption of pranoprofen and / or its salt on MKL as a result of studies on the practical application of ophthalmic compositions for MKL containing pranoprofen and / or its salt. In addition, it was also found that pranoprofen and / or its salt, although they correspond to the main drug in terms of structure, differ from other main drugs, such as neostigmine and chlorpheniramine, in terms of adsorption on MKL (see Control example 1, described below).

Thus, the authors of the present invention have found that suppressing the adsorption of pranoprofen and / or its salt on MKL requires the development of methods for pharmaceutical preparations that are different from those used for other essential drugs. However, in the technical field to which this invention relates, there is no information on research on methods for producing pharmaceutical preparations intended to suppress the adsorption of pranoprofen and / or its salt on MKL in ophthalmic compositions for MKL, such as eye drops for MKL.

Accordingly, it is an object of the present invention to provide a method for suppressing adsorption of pranoprofen and / or its salt on MKL in an ophthalmic composition for MKL, where the ophthalmic composition contains pranoprofen and / or its salt.

Means of solving the problem

Intensive studies of the authors of the present invention to solve the above problems have established that there is a relationship between the equivalent of cations other than a hydrogen ion and the adsorption of pranoprofen and / or its salt on MKL in an ophthalmic composition for MKL containing pranoprofen and / or its salt, and that the adsorption of pranoprofen and / or its MKL salt can be effectively suppressed by regulating the equivalent of cations other than a hydrogen ion to 140 mEq / L or lower in the ophthalmic composition for MKL. The present invention has been completed through further studies based on these observations.

Thus, the present invention provides the following aspects.

Item 1. An ophthalmic composition for soft contact lenses comprising pranoprofen and / or a pharmaceutically acceptable salt thereof and cations other than a hydrogen ion in an equivalent of 140 mEq / L or less.

Clause 2. An ophthalmic composition for soft contact lenses according to claim 1, used for soft contact lenses from Group IV or contact lenses made of silicone hydrogel from Group III according to the classification of soft contact lenses of the US Food and Drug Administration.

Item 3. Ophthalmic composition for soft contact lenses according to paragraphs. 1 or 2, where the pH is from 5.5 to 8.

Item 4. Ophthalmic composition for soft contact lenses according to any one of paragraphs. 1-3, comprising at least one source of cations selected from the group consisting of metal chlorides, metal salts of organic acids, metal salts of inorganic acids, and ammonium salts.

Item 5. Ophthalmic composition for soft contact lenses according to any one of paragraphs. 1-4, comprising at least one cationic source selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, ammonium hydrogen phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium citrate, sodium nitrate, calcium acetate , and sodium tetraborate.

Item 6. Ophthalmic composition for soft contact lenses according to any one of paragraphs. 1-5, additionally containing trometamol.

Item 7. Ophthalmic composition for soft contact lenses according to any one of paragraphs. 1-6, which is eye drops for soft contact lenses.

Item 8. The use of a liquid containing pranoprofen and / or its pharmaceutically acceptable salt and cations other than a hydrogen ion in an equivalent of 140 mEq / L or less, to obtain an ophthalmic composition for soft contact lenses.

Clause 9. The use of claim 8, wherein the ophthalmic composition for soft contact lenses is used for soft contact lenses from Group IV or contact lenses made of silicone hydrogel from Group III according to the classification of soft contact lenses of the US Food and Drug Administration.

Item 10. A method of suppressing the adsorption of pranoprofen and / or its pharmaceutically acceptable salt on soft contact lenses, comprising adjusting the equivalent of cations other than a hydrogen ion to 140 mEq / l or less in an ophthalmic composition for soft contact lenses comprising pranoprofen and / or its pharmaceutically acceptable salt.

Clause 11. The method of claim 10, wherein the soft contact lenses are Group IV soft contact lenses or Group III silicone hydrogel contact lenses according to the US Food and Drug Administration's soft contact classification.

Paragraph 12. A method of suppressing the adsorption of pranoprofen and / or its pharmaceutically acceptable salt with soft contact lenses, comprising contacting soft contact lenses with a liquid containing pranoprofen and / or its pharmaceutically acceptable salt and cations other than a hydrogen ion, in an equivalent of 140 mEq / l or less.

Clause 13. The method of claim 12, wherein the soft contact lenses are Group IV soft contact lenses or Group III silicone hydrogel contact lenses according to the United States Food and Drug Administration's soft contact classification.

Technical Results of the Present Invention

The present invention allows to suppress the adsorption of pranoprofen and / or its salt on MKL in order to avoid side effects on MKL, providing an effective therapeutic effect of pranoprofen and / or its salt. In addition, the present invention has the advantage of a small number of restrictions on pharmaceutical formulations, since the adsorption of pranoprofen and / or its SCL salt is suppressed by regulating the cation equivalent in the ophthalmic composition for SCL in a predetermined range, and thus, free choice of the type of components other than pranoprofen and / or its salt.

Embodiments of the present invention

1. Ophthalmic composition for MKL.

The ophthalmic composition for MKL according to the present invention contains pranoprofen and / or its pharmaceutically acceptable salt and cations other than a hydrogen ion in an equivalent of 140 mEq / L or less. The ophthalmic composition for MKL according to the present invention is described below in detail. The term "ophthalmic composition for MKL", used in this application, is used in the field of ophthalmology and means a composition used in contact with MKL. Unit "weight./about. % ”, Used in this application for the concentration of each component, means the percentage when the ratio of weight to volume, in accordance with the Japanese Pharmacopoeia, 16th edition, and is used as a synonym for g / 100 ml The unit "mEq / g" used in this application means the milliequivalent of cations in 1 liter of composition, and represents the value obtained by multiplying the millimolar concentration of cations in 1 liter of composition by valency.

The ophthalmic composition for MKL according to the present invention contains pranoprofen and / or a pharmaceutically acceptable salt thereof.

Pranoprofen, which is also referred to as α-methyl-5H- [1] -benzopyrano [2,3-b] pyridin-7-acetic acid, is a known compound with a recognized anti-inflammatory effect in the field of ophthalmology.

Pranoprofen salts may be any pharmaceutically acceptable salts without limitation, but examples thereof include metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts, and aluminum salts; and organic base salts such as triethylamine salt, diethylamine salt, morpholine salt, and piperazine salt. These pranoprofen salts can be used individually or in combination.

In the ophthalmic composition for MKL according to the present invention, either pranoprofen or its salts can be used separately, or two or more variants can be used in combination. Pranoprofen is preferred among pranoprofen and its salts.

In the ophthalmic composition for MKL according to the present invention, the concentration of pranoprofen and / or its salt is preferably set in accordance with the applications for the ophthalmic composition for MKL or the like. The concentration is, for example, from 0.005 to 2.0 wt./about. %, preferably from 0.01 to 1.0 wt./about. % or from 0.01 to 0.1 wt./about. %, even more preferably from 0.05 to 0.2 wt./about. %

In the ophthalmic composition for MKL according to the present invention, the equivalent of cations other than a hydrogen ion is set to 140 mEq / L or less. Although pranoprofen and / or its salt, as was established by the authors of the present invention, have their inherent properties for adsorption on MKL, the adsorption of pranoprofen and / or its salt on MKL can be suppressed by appropriate regulation of the equivalent of cations other than a hydrogen ion in a predetermined range in accordance with the present invention. The expression "cations other than a hydrogen ion" used in this application means cations, with the exception of the hydrogen ion, from all cations present in the ophthalmic composition for MKL, regardless of the types of ions, such as metal ion, polyatomic ion, and complex ion . In the present invention, cations can have any valency, but they are preferably monovalent or divalent cations, more preferably monovalent cations.

To more effectively suppress the adsorption of pranoprofen and / or its salt on MKL, the maximum equivalent of cations other than a hydrogen ion in the ophthalmic composition for MKL according to the present invention is typically 140 mEq / l, preferably 120 mEq / l, more preferably 90 mEq / l, even more preferably 75 mEq / l, 70 mEq / l, 55 mEq / l, or 50 mEq / l, particularly preferably 45 mEq / l, most preferably 35 mEq / l.

Since insufficient equivalents of cations other than a hydrogen ion can cause changes in the size of MKL, it is necessary to adjust the pH of the ophthalmic composition for MKL according to the present invention in a range that avoids changing the size of the lens MKL, or to adjust the equivalent of cations other than a hydrogen ion to a certain value or more. For example, when changing the size of the MKL lens is prevented by adjusting the pH, the minimum equivalent of cations other than a hydrogen ion in the ophthalmic composition for MKL according to the present invention is 0 mEq / L. For example, when changes in the size of the MKL lens are prevented by adjusting the equivalent of cations other than the hydrogen ion to a certain value or more, the minimum equivalent of cations other than the hydrogen ion in the ophthalmic composition for MKL according to the present invention is typically 20 mEq / L preferably 30 mEq / L.

Thus, the equivalent of cations other than a hydrogen ion in the ophthalmic composition for MKL according to the present invention is typically controlled in the range from 0 to 140 mEq / l, preferably from 20 to 120 mEq / l, more preferably from 20 to 90 mEq / l, even more preferably from 20 to 75 mEq / l, from 20 to 70 mEq / l, or from 20 to 55 mEq / l, from 20 to 50 mEq / l, particularly preferably from 20 to 45 mEq / l, most preferably from 30 to 35 mEq / l, to more effectively suppress the adsorption of pranoprofen and / or its salt on MKL and to prevent treason the size of the lens MKL.

Specific examples of cations other than a hydrogen ion include metal ions such as sodium ion, potassium ion, magnesium ion, calcium ion, iron (II) ion, iron (III) ion, copper (I) ion, copper (II) ion , zinc ion, and aluminum ion; polyatomic ions such as ammonium ion; and complex ions such as zinc (II) tetraamine ion and copper (II) tetraamine ion. In the ophthalmic composition for MKL according to the present invention, cations other than a hydrogen ion may be present individually or in combination, if the equivalent meets the requirements.

To regulate the equivalent of cations other than a hydrogen ion in the above range in the ophthalmic composition for MKL according to the present invention, the content of sources of cations that generate cations other than a hydrogen ion among the components of the ophthalmic composition MKL can be controlled. Examples of such cationic sources include metal salts, ammonium salts, and metal complexes. These cationic sources may be in the form of hydrates.

To prevent changes in lens size in MKL, improve the stability of the ophthalmic composition for MKL, apply the necessary osmotic pressure, provide the necessary buffering effect, and the like in the ophthalmic composition for MKL according to the present invention, the ophthalmic composition for MKL according to the present invention preferably contains at least one cation source selected from the group consisting of metal chlorides, metal salts of organic acids, metal FIR salts of inorganic acids, and ammonium salts in the range where the requirements are met to the equivalent of cations other than hydrogen ion.

Of the above, sources of cations, metal chlorides are not limited to specific types, provided that they are pharmacologically suitable. Examples of metals constituting metal chlorides include sodium, potassium, magnesium, calcium, iron (II), iron (III), copper (I), copper (II), zinc and aluminum. Specific examples of metal salts of organic acids include sodium chloride, potassium chloride and magnesium chloride. Of these metal chlorides, sodium chloride, potassium chloride, calcium chloride, and magnesium chloride are preferred; more preferred are sodium chloride and potassium chloride, and even more preferred is sodium chloride. These metal chlorides can be used individually or in combination.

Of the aforementioned sources of cations, metal salts of organic acids are not limited to specific types, provided that they are pharmacologically suitable. Examples of organic acids constituting metal salts of organic acids include acetic acid, citric acid, oxalic acid and tartaric acid. Examples of metals constituting metal salts of organic acids include the same metals that make up metal chlorides. Specific examples of metal salts of organic acids include sodium acetate, potassium acetate, sodium citrate, potassium citrate, sodium oxalate, potassium oxalate, sodium tartrate and potassium tartrate. These metal salts of organic acids may be in the form of a hydrate. Of these metal salts of organic acids, sodium citrate, potassium citrate, potassium acetate and calcium acetate are preferred; sodium citrate and calcium acetate are more preferred. These metal salts of organic acids can be used individually or in combination.

Of the above sources of cations, the metal salts of inorganic acids are not limited to specific types, provided that they are pharmacologically suitable. Examples of inorganic acids constituting the metal salts of inorganic acids include phosphoric acid, nitric acid and boric acid. Examples of metals constituting metal salts of inorganic acids include the same metals that make up metal chlorides. Specific examples of metal salts of inorganic acids include sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium nitrate, potassium nitrate, sodium borate and sodium tetraborate. These metal salts of inorganic acids may be in the form of a hydrate. Of these metal salts of inorganic acids, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium nitrate and sodium tetraborate are preferred. These metal salts of inorganic acids can be used individually or in combination.

Of the above sources of cations, ammonium salts are not limited to specific types, provided that they are pharmacologically suitable. Specific examples of ammonium salts include ammonium salts of inorganic acids such as ammonium phosphate. Inorganic acid ammonium salts may be used individually or in combination.

Of the above cationic sources, preferred components are sodium chloride, potassium chloride, magnesium chloride, ammonium hydrogen phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium citrate, sodium nitrate, calcium acetate, and sodium tetraborate; more preferred components are sodium chloride and potassium chloride, and sodium chloride is a particularly preferred component in order to avoid changes in the size of the MKL lens, increase the stability of the ophthalmic composition for MKL, provide the necessary osmotic pressure, and the like.

The content of the cation source in the ophthalmic composition for MKL according to the present invention is preferably set in the range where the above requirements for the equivalent of cations other than the hydrogen ion are fulfilled.

The ophthalmic composition for MKL according to the present invention may contain a buffering agent. Specific examples of buffering agents include phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer, Tris buffer, and amino acids. The buffering agents typically consist of a combination of acids and bases, or compounds containing a carboxyl group and an amino group, and the like, and these buffering components are suitably selected. Specific examples of buffering components include trometamol, boric acid, phosphoric acid, citric acid, tartaric acid, acetic acid, hydrochloric acid, maleic acid, an amino acid, in addition to metal salts of organic acids or metal salts of inorganic acids that can serve as sources of cations described above. Of these buffer components, trometamol is preferred to provide a good buffering effect without increasing the equivalent of cations other than a hydrogen ion in the ophthalmic composition for MKL according to the present invention.

The concentration of the buffer component in the ophthalmic composition for MKL according to the present invention is preferably set in accordance with the type of buffer component or the like. When a source of cations is used as the buffer component, the concentration of the buffer component is set to fulfill the requirements for the range of cation equivalent. For example, the total concentration of the buffer component, as a rule, is from 0.01 to 10 wt./about. %, preferably from 0.05 to 5 wt./about. %, more preferably from 0.2 to 2 wt./about. %

The ophthalmic composition for MKL according to the present invention may optionally contain other pharmacological components in addition to the above components. Examples of pharmacological components that can be added include anti-inflammatory agents such as disubstituted potassium glycyrrhizinate, allantoin, epsilon-aminocaproic acid, bromfenac, ketorolac tromethamine, nefafenac, berberine chloride, berberine sulfate, sodium azulene sulfonate, zinc lactosulfate, zinc sulfate, zinc sulfate and zinc sulfate ; antihistamines such as chlorpheniramine maleate and diphenhydramine hydrochloride; antiallergic agents such as sodium cromoglycate, ketotifen fumarate, acitazanolast, amlexanox, pemirolast potassium, tranylast and ibudilast; antibiotics such as norfloxacin, ofloxacin, lomefloxacin, levofloxacin, gentamicin and gatifloxacin; vitamins such as ascorbic acid, flavin adenine sodium dinucleotide, cyanocobalamin, pyridoxine hydrochloride, tocopherol acetate, retinol acetate, retinol palmitate, panthenol, calcium pantothenate and sodium pantothenate; amino acids such as aspartic acid, taurine and sodium chondroitin sulfate; anticholinesterases such as neostigmine methyl sulfate; vasoconstrictors, such as naphazoline, tetrahydrozoline, epinephrine, ephedrine, phenylephrine and dl-methylephedrine; therapeutic agents for conjunctival epithelial diseases, such as sodium hyaluronate; and sulfamide preparations such as sulfadiazine, sulfisoxazole, sulfisomidine, sulfadimethoxine, sulfamethoxypyridazine, sulfamethoxazole, sulfaethiolide, sulfamethomidine, sulfafenazole, sulfaguanidine, phthalyl sulfathiazole and succinyl sulfathiazole. These compounds may be in the form of pharmaceutically acceptable salts, or may be in the form of other salts. These pharmacological components can be used individually or in combination.

The concentration of these pharmacological components is preferably set in accordance with the types of pharmacological components, the use of an ophthalmic composition for MKL, and the like. When the pharmacological components generate cations other than the hydrogen ion in the ophthalmic composition for MKL, the concentration of these pharmacological components is set in the range where the above requirements for the equivalent of cations other than the hydrogen ion are met.

The ophthalmic composition for MKL according to the present invention may optionally contain additives such as tonicity agents, solubilizing agents, viscous bases, chelating agents, cooling agents, pH adjusters, preservatives, stabilizers and surfactants, in addition to the above components.

Examples of tonicity agents include saccharides such as sorbitol, glucose and mannitol; polyhydric alcohols such as glycerol and propylene glycol; and boric acid. These tonicity agents can be used individually or in combination.

Examples of solubilizing agents include nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyloxapol and pluronic; and polyols, such as glycerol and macrogol. These solubilizing agents can be used individually or in combination.

Examples of viscous agents include water-soluble polymers such as polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, carboxyvinyl polymer, xanthan gum, sodium chondroitin sulfate and sodium hyaluronate; and celluloses such as hypromellose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose. These viscous substrates can be used individually or in combination.

Examples of a chelating agent include edetate, citric acid and its salts. These chelating agents can be used individually or in combination.

Examples of cooling agents include 1-menthol, borneol, camphor, and eucalyptus oil. These cooling agents can be used individually or in combination.

Examples of pH adjusters include alkalis such as sodium hydroxide and potassium hydroxide; and acids, such as acetic acid, citric acid, phosphoric acid, and tartaric acid. These pH adjusters can be used individually or in combination.

Examples of preservatives include sorbic acid and its salts, benzoic acid and its salts, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, chlorhexidine gluconate, boric acid, dehydroacetic acid and its benzene chloride, benzene chloride, benzene chloride, benzal chloride, benzene, benzene chloride zinc chloride, parachloromethaxylene, chlorocresol, phenethyl alcohol, polydronium chloride, thiomersal and dibutylhydroxytoluene. These preservatives may be used individually or in combination.

Examples of stabilizers include polyvinylpyrrolidone, sulfite, monoethanolamine, glycerin, propylene glycol, cyclodextrin, dextran, ascorbic acid, edetate, taurine, tocopherol, and dibutylhydroxytoluene. These stabilizers can be used individually or in combination.

Examples of surfactants include nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester and octoxynol; amphoteric surfactants such as alkyl diaminoethyl glycine and lauryl dimethyl betaine amino acetate; anionic surfactants such as alkyl sulfate, a salt of N-acyl-taurine, polyoxyethylene alkyl ether phosphate and polyoxyethylene alkyl ether sulfate; and cationic surfactants such as alkyl pyridinium salts and alkylamine salts. These surfactants can be used individually or in combination.

The concentration of these additives is set in accordance with the type of additives, the use of an ophthalmic composition for MKL, and the like. When additives are added to generate cations other than a hydrogen ion in an ophthalmic composition for MKL, the concentration of these additives is set in the range where the requirements for the above equivalent cations other than a hydrogen ion are met.

The pH of the ophthalmic composition for MKL according to the present invention is not limited to specific values, and is, for example, from 5.5 to 8, preferably from 5.5 to 7.5, even more preferably from 6 to 7.5. In particular, a pH in the range of 5.5 to 7.5 avoids changing the size of the MKL lens even with a low equivalent of cations other than a hydrogen ion.

The ophthalmic composition for MKL according to the present invention is a formulation for liquids containing water as a base, for example, in any form of an aqueous solution, suspension, emulsion, and the like, preferably in the form of an aqueous solution.

The ophthalmic composition for MKL according to the present invention can be produced in accordance with known methods of preparation in accordance with the application, for example, using the method described in the General rules of preparation in the Japanese Pharmacopoeia, 16th edition.

The ophthalmic composition for MKL according to the present invention is used as a contact lens care product or the like, such as eye drops that can be applied to the eyes with MKL (eye drops for MKL); lotions for the eyes with which you can wash your eyes with MKL (eye lotions for MKL); solutions for wetting MKL, multi-purpose solutions for MKL, solutions for cleaning MKL, and liquids for storing MKL. Of these, eye drops for MKL and eye lotions for MKL are preferred, and eye drops for MKL are more preferred.

The ophthalmic composition according to the present invention can be used for any type of MKL, regardless of tonicity, water content, or the like, and can also be used for any MKL from Group I (ionic monomer: less than 1 mol%, water content: less than 50%), Group II (ionic monomer: less than 1 mol%, water content: 50% or more), Group III (ionic monomer: 1 mol% or more, water content: less than 50%), and Group IV Group III (ionic monomer: 1 mol% or more, water content: 50% or more) according to the classification of the Food Control Authority Food and Drug Administration (FDA). The ophthalmic composition for MKL according to the present invention can also be used for contact lenses made of silicone hydrogel. Of these MKL, lenses from Group I, Group IV, and silicone hydrogel contact lenses (Group III) tend to absorb pranoprofen and / or its salt. For these MCLs, there is an urgent need to suppress the adsorption of pranoprofen and / or its salt. With this in mind, the ophthalmic composition for MKL according to the present invention can effectively suppress the adsorption of pranoprofen and / or its salt for MKL from Group I, MKL from Group IV, and contact lenses from a silicone hydrogel from Group III. In light of such advantages of the present invention, as MKL for a targeted application, MKL from Group I, MKL from Group IV, and silicone hydrogel contact lenses from Group III are preferred; more preferred are MKL from Group IV and contact lenses from a silicone hydrogel from Group III; and particularly preferred are MKL from Group IV.

In the ophthalmic composition for MKL according to the present invention, examples of materials for MKL for intended use may include, but are not limited to, materials registered in the US National Proprietary Names Directory (USAN). Specific examples of MKL materials for the intended use of the ophthalmic composition for MKL according to the present invention include polymacon, nelfilcon A, ocufilcon D, vifilcon A, etafilcon A, otrafilcon A, balafilcon A, alfafilcon A, buffilcon A, lotrafilcon A, asmofilcon A, tetrafilcon A, Senofilcon A, Vasurfilcon A, Metafilcon A, Atlafilcon A, Crofilcon A, Deltafilcon A, Droxyphilcon A, Phocofilcon A, Genfilcon A, Govafilcon A, Gefilcon A, Gefilcon B, Gefilcon C, Hilafilcon A, Aioxifoncon, Hyoxifoncon A, Hioxifilcon A, Hyoxyphonon , lidofilcon B, mafilcon A, metafilcon B, mipafilcon A, nelfilcon A, netrafilcon A, okufilcon A, oufilcon B, oufilcon C, oufilcon D, oufilcon E, oufilcon F, ofilcon A, omafilcon A, perfilcon A, pemphilcon A, polycon A, Surf tefilcon A, vifilcon A, and xylophilcon A. Of these, polymacon and nelfilcon A, okufilcon D, vifilcon A, etafilcon A, otrafilcon A, balafilcon A, alfafilcon A, bufilcon A, lotrafilcon A, asmofilcon A, tetrafilcon A, are preferred. A, Vasurfilcon A, Metaphylcon A; more preferred are polymacon, nelfilcon A, ocufilcon D, vifilcon A, etafilcon A, otrafilcon A, balafilcon A; and particularly preferred are etafilcon A, bifilcon A, ocufilcon D, and balafilcon A.

2. A method of suppressing the adsorption of pranoprofen and / or its salt on MKL (1)

The present invention also provides a method for inhibiting the adsorption of pranoprofen and / or its pharmaceutically acceptable salt on MKL, comprising adjusting the equivalent of cations other than a hydrogen ion to 140 mEq / L or less in an ophthalmic composition for MKL containing pranoprofen and / or a pharmaceutically acceptable salt thereof . A method of suppressing adsorption is preferable for providing an ophthalmic composition for MKL with effectiveness for suppressing the adsorption of pranoprofen and / or its salt on MKL during the preparation of an ophthalmic composition for MKL.

In the method of suppressing adsorption in accordance with the present invention, pranoprofen and / or its pharmaceutically acceptable salt, the equivalent of cations other than a hydrogen ion, types of pharmacological components and additives introduced into the ophthalmic composition for MKL, the formulation and use of an ophthalmic composition for MKL, type MKL for intended use and more are described above in section “1. Ophthalmic composition for MKL ".

3. A method of suppressing the adsorption of pranoprofen and / or its salt on MKL (2).

The present invention further provides a method for suppressing the adsorption of pranoprofen and / or its pharmaceutically acceptable salt on MKL, comprising contacting soft contact lenses with a liquid containing pranoprofen and / or its pharmaceutically acceptable salt and cations other than a hydrogen ion in an equivalent of 140 mEq / L or less.

In the method of suppressing adsorption, the composition, formulation and use of the liquid used and the like are the same as for the ophthalmic composition for MKL. In the adsorption suppression method, the contact path of the liquid with the MCL is suitably set in accordance with the use of the liquid. For example, when the liquid is eye drops, the liquid is injected into the eyes with MKL. In the adsorption suppression method, the type of MKL for the intended use and the like are the same as for the ophthalmic composition for MKL.

Examples

The present invention is described below in detail using Examples, but the present invention is not limited to them.

Control example 1. The effect of the equivalent of cations on the adsorption of pranoprofen on various types of MCL (1).

Test fluids were prepared by mixing the components described in Table 1 in the usual manner. Each test liquid (2 ml) was placed in a vial, and two MCLs were immersed in the liquid. The vial was shaken at 25 ° C for 2 hours or more. Each test liquid (2 ml) was placed in a vial, and the vial was shaken at 25 ° C for 2 hours or more without immersing MKL in the liquid. After shaking, the pranoprofen content in each test liquid was measured by liquid chromatography, and the amount of pranoprofen adsorbed to MCL was calculated in accordance with the following equation. Since shaking under conditions in which MCL was immersed in the test liquid ensured the equilibrium of pranoprofen adsorption on MCL in two hours, it was confirmed that such shaking did not affect the measured value of the amount of pranoprofen adsorbed on MCL during shaking for two hours or more.

[Equation 1]

The amount of pranoprofen adsorbed on two MKL (μg) = (SS-CT) × V

SS - the content of pranoprofen in the test fluid, in which MKL was not immersed (μg / ml); CT is the content of pranoprofen in the test fluid into which MKL was immersed (μg / ml); V is the volume of the test fluid used in the experiment (ml)

In this assay, the amount of pranoprofen adsorbed on each MKL was calculated using the following seven types of MKL.

Lenses 1: Group I, trademark "Medalist (registered trademark) plus" (supplied by Bausch & Lomb Japan), USAN name: polymacon.

Lenses 2: Group II, trademark "Dailies (registered trademark) Aqua" (supplied by US Vision), USAN name: Nelfilcon A.

Lenses 3: Group IV, Ope-Day Aquair trademark (available from CooperVision, Inc.), USAN name: Okufilcon D.

Lenses 4: Group IV, trademark “Focus (registered trademark) 2 Week” (supplied by US Vision), USAN name: vifilcon A.

Lenses 5: Group IV, brand “Opera-Day Acuvue (registered trademark)” (supplied by Johnson & Johnson Medical, Inc.), USAN name: etafilcon A.

Lens 6: Contact lenses made of silicone hydrogel, Group I, trademark “Air Optix (registered trademark)” (supplied by USA Vision), USAN name: otrafilcon B.

Lens 7: Contact lenses made of silicone hydrogel, Group III, trademark "Medalist (registered trademark), Fresh Fit (registered trademark)" (supplied by Bausch & Lomb Japan), USAN name: balafilcon A.

The results obtained are shown in Table 1. In Comparative Example 2, the cation equivalent was at the same level as the total amount (about 169 mEq / l) of sodium ion 9145 mEq / l) and potassium ion (24.1 mEq / l) in lacrimal fluid. In Comparative Example 2, thus, a test fluid was used that can be a reference (Biochemistry Data Book I, 1st Edition, edited by Japanese Biochemical Society, Tokyo Kagaku Dojin, Tokyo, 1979 (Biochemistry Handbook 1, 1- e edition, edited by the Japanese Biochemical Society.) The results show that the test fluids with the equivalent of cations (Comparative Examples 1 and 2) containing the same or higher level of cations (sodium ion) other than the hydrogen ion, as in the tear fluid exhibit high amounts of pranoprofen adsorbed in contrast to Comparative Example 2, in which the cation equivalent corresponded to tear fluid In particular, the test fluids from Comparative Examples 1-3 showed significant adsorption of pranoprofen on MKL from Group I (lens 1), MKL from group IV (lenses 3 and 4), and contact lenses from silicone hydrogel from Group III (lens 7) . The test fluids of Examples 1-9 provided an effective suppression of pranoprofen adsorption.

In this table, the content of each component is given in "wt./about. % ".

In this table, “-” indicates that the amount of pranoprofen adsorbed by MKL was below the detection level.

Comparative control example 1. The effect of the equivalent of cations on the adsorption of basic drugs, other than pranoprofen, on MKL.

To determine the effect of the cation equivalent on the adsorption of basic drugs other than pranoprofen on MKL, the adsorption of neostigmine methyl sulfate and chlorpheniramine maleate on MKL was evaluated. In particular, the amount of neostigmine methyl sulfate and chlorpheniramine maleate adsorbed on MKL was measured in the same manner as in Control Example 1, except that the test liquids were prepared by mixing the components described in Table 2 in the usual way and placed in a vial one MKL. In this test, Lens 5 (Group IV) used as Control Example 1 was used as MCL. The content of neostigmine methyl sulfate or chlorpheniramine maleate in each test liquid was measured by liquid chromatography after shaking, and the adsorption on MCL was calculated according to the following equation.

[Equation 2]

The amount of neostigmine methyl sulfate or chlorpheniramine maleate adsorbed on one MKL: (μg) = (CC-CT) × V, where

SS - the content of neostigmine methyl sulfate or chlorpheniramine maleate in the test liquid, in which MKL was not immersed (μg / ml); CT is the content of neostigmine methyl sulfate or chlorpheniramine maleate in the test liquid, into which MKL was immersed (μg / ml); V is the volume of the test fluid used in the analysis (ml).

The results obtained are shown in Table 2. Table 2 shows that the amount of adsorbed neostigmine methyl sulfate and chlorpheniramine maleate increased with a decrease in the equivalent of cations other than the hydrogen ion. This suggests that the suppression of adsorption on MCL by reducing the equivalent of cations other than a hydrogen ion is an advantage specific to pranoprofen and / or its salt.

In this table, the content of each component is given in "wt./about. % ".

Control example 2. The effect of the type of cations on the adsorption of pranoprofen on MKL.

The studied liquids were prepared by mixing the components described in Table 3 in the usual way, and the amount of pranoprofen adsorbed on MKL was measured in the same manner as in Control Example 1. In this analysis, Lens 5 (Group IV) used in MKL Reference Example 1

The results obtained are shown in Table 3. The results demonstrate that the test fluid containing 168 mEq / L of sodium or potassium ion (Comparative Examples 4 and 6) and the test fluid containing 168 mEq / L of ions of sodium and potassium (Comparative Example 5 ) show large amounts of pranoprofen adsorbed on MKL. In contrast, test fluids containing 121 mEq / L or less of both sodium and potassium ions (Examples 10-16) effectively inhibit pranoprofen adsorption on MCL, regardless of the cation type and the ratio of sodium and potassium ions. The above results allow us to establish that the adsorption of pranoprofen on MKL can be suppressed by regulating the equivalent of cations other than a hydrogen ion to a predetermined value or less, regardless of the type of cations.

In this table, the content of each component is given in "wt./about. % ".

Control example 3. The effect of metal salts of inorganic and organic acids on the adsorption of pranoprofen on MKL.

The test liquids were prepared by mixing the components described in Table 4 in the usual way, and the amount of pranoprofen adsorbed on MKL was measured in the same manner as in Control Example 1. In this analysis, Lens 5 (Group IV) used in MKL was used. Reference Example 1

The results obtained are shown in table 4. As can be seen from table 4, the studied liquids containing approximately 168 mEq / l of cations other than a hydrogen ion (Comparative Examples 7-12) showed significant amounts of pranoprofen adsorbed to MCL, whether there was a metal salt in as a source of cations is formed from an inorganic acid or organic acid. In contrast, test fluids containing 140 mEq / L of cations other than a hydrogen ion (Examples 17-22) effectively suppressed the adsorption of pranoprofen on MKL. The results of this analysis also showed that the adsorption of pranoprofen on MKL is associated with cations other than a hydrogen ion, regardless of the type of cation, and can be suppressed by adjusting the equivalent of cations other than a hydrogen ion to a predetermined value or less.

In this table, the content of each component is given in "wt./about. % ".

Control example 4. The effect of divalent cations on the absorption of pranoprofen on MKL.

The studied liquids were prepared by mixing the components described in Table 5 in the usual way, and the amount of pranoprofen adsorbed on MKL was measured in the same manner as in Control Example 1. In this analysis, Lens (5) was used as MKL (Group IV), used in Control Example 1.

The results obtained are shown in Table 5. As indicated in table 5, test liquids with a cation equivalent content of 168 mEq / L or more (Comparative Examples 13-16) showed large amounts of pranoprofen absorbed on MKL for calcium or magnesium ions. In contrast, test fluids containing a cation equivalent of 140 mEq / L or less (Examples 23-32) effectively suppressed the adsorption of pranoprofen on MKL. Thus, the results of this analysis also showed that the adsorption of pranoprofen on MKL associated with cations other than a hydrogen ion can be suppressed by adjusting the equivalent of cations other than a hydrogen ion to a predetermined value or less.

In this table, the content of each component is given in "wt./about. % ".

Control example 5. The effect of cations on the adsorption of pranoprofen on MCL at a low concentration (0.01 and 0.02 weight / vol.%) Of pranoprofen.

The studied liquids were prepared by mixing the components described in Table 6 in the usual way, and the amount of pranoprofen adsorbed on MKL was measured in the same manner as in Control Example 1. In this analysis, Lens 5 (Group IV) used in MKL Reference Example 1

The results are shown in Table 6. As can be seen from Table 6, adsorption of pranoprofen on MKL was effectively suppressed by regulating the equivalent of cations other than a hydrogen ion to 140 mEq / L or less, even for experimental liquids containing pranoprofen at a low concentration of 0.01 and 0.02 wt./about. %

In this table, the content of each component is given in "wt./about. % ".

Control example 6. The effect of the equivalent of cations on the adsorption of pranoprofen on various types of MCL (2).

The studied liquids were prepared by mixing the components described in Table 7 in the usual way, and the amount of pranoprofen adsorbed on MKL was measured in the same manner as in Control Example 1. In this analysis, Lens 5 (Group IV) used in MKL Reference Example 1

The results obtained are shown in Table 7. The results also showed that pranoprofen adsorption on MKL was suppressed at a lower equivalent of cations other than a hydrogen ion. A comparison of Example 40 and Examples 41-43 showed that the adsorption of pranoprofen on MKL can be significantly suppressed using only sodium chloride as a source of cations other than a hydrogen ion and trometamol as a pH regulator, and regulation of the equivalent of cations other than a hydrogen ion, up to 55 mEq / l or less, 50 mEq / l or less, or 45 mEq / l or less.

In this table, the content of each component is given in "wt./about. % ".

Control example 7. The effect of the equivalent of cations on the size of MKL.

Test fluids were prepared by mixing the components described in Table 8 in the usual manner. After immersing Lens 5 (Group IV) used in Control Example 1 in 2 ml of each test liquid at room temperature for 3 hours, the diameter of each lens was determined using a high-precision two-dimensional measurement system VM-8040 (Keyence Corporation). The test liquid for analysis described in Example 7 is a standard physiological saline solution used to measure the diameter of contact lenses defined in the document “Optics and Optical Instruments - Contact Lenses - Saline Solution for Analysis of Contact Lenses (ISO 10344, 1996)." A large difference in the diameter of the lenses, compared with the test fluid for analysis, indicates a large change in the size of the MCL.

The results obtained are shown in Table 8. The results suggest that the reduced equivalent of cations compared with the test liquid for analysis tends to provide larger MKL. It can also be assumed that a decrease in pH tends to decrease the diameter of the MCL. The results showed that the equivalent of cations other than a hydrogen ion in the range from 29 to 140 mEq / L suppresses adsorption on the MCL while maintaining the size of the MCL in an acceptable range.

In this table, the content of each component is given in "wt./about. % ".

Claims (12)

1. An ophthalmic composition for soft contact lenses containing pranoprofen and / or a pharmaceutically acceptable salt thereof and cations other than a hydrogen ion in an equivalent of 140 mEq / L or less, wherein the pH of the composition is in the range of 5.5 to 8 . 2. An ophthalmic composition for soft contact lenses according to claim 1, which is used for soft contact lenses from Group IV or contact lenses made of silicone hydrogel from Group III, according to the classification of soft contact lenses of the US Food and Drug Administration. 3. An ophthalmic composition for soft contact lenses according to claim 1 or 2, containing at least one cation source selected from the group consisting of metal chlorides, metal salts of organic acids, metal salts of inorganic acids and ammonium salts. 4. The ophthalmic composition for soft contact lenses according to claim 1 or 2, containing at least one source of cations selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, ammonium hydrogen phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate potassium dihydrogen phosphate, sodium citrate, sodium nitrate, calcium acetate and sodium tetraborate. 5. An ophthalmic composition for soft contact lenses according to claim 1 or 2, further comprising trometamol. 6. The ophthalmic composition for soft contact lenses according to claim 1 or 2, which is eye drops for soft contact lenses. 7. The use of a liquid containing pranoprofen and / or its pharmaceutically acceptable salt, and cations other than a hydrogen ion, in an equivalent of 140 mEq / L or less, the pH of which is in the range from 5.5 to 8, to obtain an ophthalmic composition for soft contact lenses. 8. The use according to claim 7, where the ophthalmic composition for soft contact lenses is used for soft contact lenses from Group IV or contact lenses made of silicone hydrogel from Group III, according to the classification of soft contact lenses of the US Food and Drug Administration. 9. A method of suppressing the adsorption of pranoprofen and / or its pharmaceutically acceptable salt on soft contact lenses, comprising adjusting the equivalent of cations other than a hydrogen ion to 140 mEq / L or less in an ophthalmic composition for soft contact lenses containing pranoprofen and / or its pharmaceutically a suitable salt, and adjusting the pH of said composition to a value in the range of 5.5 to 8. 10. The method according to claim 9, where the soft contact lenses are soft contact lenses from Group IV or contact lenses made of silicone hydrogel from Group III, according to the classification of soft contact lenses of the US Food and Drug Administration. 11. A method of suppressing the adsorption of pranoprofen and / or its pharmaceutically acceptable salt on soft contact lenses, comprising contacting soft contact lenses with a liquid containing pranoprofen and / or its pharmaceutically acceptable salt and cations other than a hydrogen ion, in an equivalent of 140 mEq / l or less, the pH of which is in the range from 5.5 to 8. 12. The method according to claim 11, where the soft contact lenses are soft contact lenses from Group IV or contact lenses made of silicone hydrogel from Group III, according to the classification of soft contact lenses of the US Food and Drug Administration.