JP5304108B2 - Eye drops - Google Patents

Description

  The present invention relates to eye drops containing a sulfa drug such as sulfamethoxazole.

  A sulfa drug is an antibacterial drug having a sulfanilamide group. For the treatment of conjunctivitis (spotting), stylus, blepharitis (eyelid sore) that are bacterial infections that occur in the ocular mucosa, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole or sulfa It is common to apply eye drops containing sulfa drugs such as isomidine sodium to the ocular mucosa. However, since the ophthalmic solution is quickly discharged from the ocular mucosa, it is known that the antibacterial component does not necessarily exhibit a sufficient medicinal effect. That is, in an eye drop applied to the ocular mucosa, it is necessary to improve the drug retention in the ocular mucosa in order to increase the bioavailability of the drug. Then, the formulation design which improved the drug retention is performed by mix | blending cellulose type thickeners, such as methylcellulose and hydroxypropyl methylcellulose, and making a composition have viscosity. However, if a cellulosic thickener is blended in order to impart drug retention and the viscosity of the eye drop is increased too much, there is a problem that it is difficult to sterilize by filtration during the preparation of the eye drop.

  In order to solve the above problems, development of eye drops having high ocular mucosal retention and low viscosity during storage is required. Solutions include gellan gum-containing eye drops shown below.

Gellan gum is known as a substance having a property of gelling when a certain amount of cations such as free Na ⁺ coexist. Gellan gum-containing eye drops that use gellan gum as a gelling agent and gel by cations such as Na ⁺ contained in tears are known (see Patent Documents 1 and 2). . When these eye drops containing gellan gum are instilled, gellan gum gels on the surface of the ocular mucosa, the residence time of the drug contained in the gel on the surface of the ocular mucosa is prolonged, and more of the drug retained on the surface of the ocular mucosa migrates into the eye. Thus, the effect of the drug is sustained. That is, although it is a low-viscosity liquid during storage, it has a function of gelling and increasing the viscosity during administration, so that the medicinal effect is sustained.

Also, a composition that increases the viscosity with cations such as Na ⁺ by blending pectin (see Patent Document 3), and a high viscosity with cations such as Na ⁺ that blends an alginate derivative and blends with alginic acid derivatives. A composition (see Patent Document 4) is known.

By the way, when a sulfa agent is added to gellan gum-containing eye drops, if a sodium salt sulfa agent that is widely used from the viewpoint of good solubility is used, gellan gum reacts with Na ⁺ and precipitates are generated in the eye drops. This is presumably because gellan gum rapidly gels and precipitates when a sodium salt sulfa agent is added to gellan gum formulation eye drops. In eye drops, the formation of precipitates is a fatal problem.

On the other hand, if a sulfa drug that does not form a metal salt is used, the above problem can be easily solved, but it is not widely used because its solubility is not sufficient. In order to dissolve a sulfa drug that does not form a metal salt, it is necessary to add an alkali. However, when sodium hydroxide that is generally used is used, a precipitate is formed in the eye drop as described above. Thus, in order to produce gellan gum-containing eye drops using a sulfa drug that does not form a metal salt, there are no reports yet because of the problem of solubility of sulfa drug and precipitate formation.

Japanese Patent Laid-Open No. Sho 62-181228 Japanese Patent Laid-Open No. 4-230631 JP 2002-265671 A JP 2002-332248 A

  An object of the present invention is to provide an eye drop that has high ocular mucosal retention and excellent antibacterial activity, but has a viscosity that is low enough to allow filtration sterilization during production, and that does not cause precipitation during storage. It is to be.

  As a result of intensive studies for solving the problems, the present inventors surprisingly stabilize the pH value in an eye drop containing (a) a sulfa drug not forming a metal salt and (b) gellan gum. It was found that (c) trometamol used as a buffering agent for mixing a certain amount or more of trometamol as an alkali dissolves a sulfa drug that does not form a metal salt and can solve the above-mentioned problems, thereby completing the present invention. It was. Furthermore, when the blending amount of gellan gum is limited, it is found that the above problem can be solved by blending monoethanolamine as an alkali, as well as trometamol, and blending trometamol and monoethanolamine together. I found it good.

That is, the present invention is eye drops listed in the following (1) to (8).
An eye drop comprising (1) (a) a sulfa drug that does not form a metal salt, (b) gellan gum, and (c) trometamol.
(2) (a) A sulfa agent that does not form a metal salt, (b) 0.001 W / V% or more and 0.07 W / V% or less gellan gum, and (c) trometamol and / or monoethanolamine. An eye drop characterized by that.
(3) The eye drop according to (1), wherein the amount of gellan gum is greater than 0.07 W / V% and 1.0 W / V% or less.
(4) The eye drop according to (3), further comprising 0.0001 W / V% or more and 0.9 W / V% or less of monoethanolamine.
(5) The eye drop according to any one of (1) to (4), wherein the pH is 7.6 or more.
(6) The compounding quantity of trometamol is 0.3 W / V% or more and 10 W / V% or less (1)-(5)
Ophthalmic solution according to any of the above.
(7) The compounding quantity of trometamol is 2 W / V% or more and 10 W / V% or less (1)-(5)
Ophthalmic solution according to any of the above.
(8) The eye drop according to any one of (1) to (7), wherein the sulfa drug not forming a metal salt is sulfamethoxazole or sulfisoxazole.

  The ophthalmic solution of the present invention is a gellan gum-containing ophthalmic solution in which a sulfa agent not forming a metal salt is dissolved, does not produce a precipitate, improves the retention of the sulfa agent in the ocular mucosa, and exhibits excellent antibacterial activity be able to. Further, since the viscosity is low at the time of production, filtration sterilization can be easily performed.

  The sulfa drug used in the present invention does not form a metal salt. In the present invention, the metal salt is a metal salt that reacts with gellan gum to form a precipitate, and examples thereof include alkali metal salts (specifically, Na salts) and alkaline earth metal salts. Among the sulfa drugs not forming a metal salt, sulfamethoxazole or sulfisoxazole is preferable. These are known compounds and may be used in combination of two.

  The blending amount of these sulfa drugs in the eye drop of the present invention is not particularly limited as long as it has antibacterial activity when blended into the eye drop, but is usually about 0.01 to 10 W / V%, preferably 0.1. -8 W / V%, more preferably 0.5-4 W / V%.

  In order to dissolve the sulfa drug used in the present invention, an alkali is required. In the present invention, trometamol and / or monoethanolamine can be used. The required amount varies depending on the amount of the sulfa drug. If there is a large amount of gellan gum, precipitation may occur when monoethanolamine is blended, so do not blend monoethanolamine or limit the blending amount of monoethanolamine and blend with trometamol. There is a need to. Trometamol can be blended regardless of the blending amount of gellan gum.

  When the compounding amount of trometamol is shown by specific numerical values, it is usually 0.0001 W / V% or more, preferably 0.3 to 10 W / V%, more preferably 2 to 10 W / V% with respect to the eye drop. More preferably, it is 2.7-5 W / V%. When monoethanolamine is blended, the blending amount is preferably 0.9 W / V% or less in order to avoid the formation of precipitates, but the gellan gum blending amount is 0.07 W / V% or less. If it exists, since a precipitate will not produce | generate, a compounding quantity in particular is not restrict | limited.

  The gellan gum used in the present invention is not particularly limited, and even if it is a natural type, an acetylated type in which a part on the β-D-glucopyranose (β-D-Glcp) residue is o-acetylated. It may be. As the acetylated gellan gum, for example, gellite (Gelrite (registered trademark), manufactured by Merck), which is a low acetylated type, is preferably used. The concentration of gellan gum in the eye drop of the present invention is not particularly limited as long as it is appropriately selected according to the purpose, but is generally within a range of 0.001 to 1.0 W / V%, preferably 0.005. It is -0.2W / V%, More preferably, it is 0.01-0.2W / V%.

  The eye drop of the present invention can be formulated by combining various components (including pharmacologically active components and physiologically active components) in addition to the sulfa drugs such as sulfamethoxazole within a range not impairing the effects of the present invention. . Decongestant component, ocular muscle modulator component, anti-inflammatory component or astringent component, antihistamine component or antiallergic component, vitamins, amino acids, local anesthetic component, steroid component, etc. It can be illustrated. Specifically, the following components can be exemplified.

  Decongestants: for example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, naphazoline nitrate Can be mentioned. These may be d-form, l-form or dl-form.

  Ocular muscle regulator component: For example, cholinesterase inhibitors having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, atropine sulfate helenien and the like.

  Anti-inflammatory component or astringent component: For example, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, pranoprofen, dipotassium glycyrrhizinate, berberine chloride, berberine sulfate and the like.

  Antihistamine component or antiallergic agent component: for example, acitazanolast, amlexanox, ibudilast, tranilast, diphenhydramine hydrochloride, levocabastine hydrochloride, ketotifen fumarate, potassium pemirolast, chlorpheniramine maleate and the like.

  Vitamins: for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxal phosphate, cyanocobalamin, panthenol, ascorbic acid, tocopherol acetate and the like.

Amino acids: for example, aminoethylsulfonic acid (taurine), glutamic acid, creatinine and the like. These may be d-form, l-form or dl-form.

  Local anesthetic components: for example, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, lidocaine hydrochloride Can be mentioned.

  Steroid component: For example, dexamethasone, hydrocortisone, fluorometholone, prednisolone, methylprednisolone, hydroxymesterone, hydrocortisone caproate, prednisolone caproate, cortisone acetate, hydrocortisone acetate, prednisolone acetate, triamcinolone acetonide, methylprednisolone, etc. It is done.

  In addition, the eye drop of the present invention is appropriately selected from various components and additives according to the conventional method according to its use and form within a range not impairing the effects of the invention, and combined with one or more in combination. May be. As those components or additives, for example, carriers (water, aqueous solvents, aqueous or oily bases, etc.) commonly used in the preparation of liquids, thickeners, sugars, surfactants, preservatives, bactericides Various additives such as an agent or an antibacterial agent, a pH regulator, an isotonic agent, a fragrance or a refreshing agent, a buffer, a stabilizer, a solubilizer, and a base can be mentioned.

  Although the typical component used for the eye drop of this invention is illustrated below, it is not limited to these.

  Thickener: for example, carboxyvinyl polymer, alginic acid, polyvinyl alcohol (completely or partially saponified product), macrogol and the like.

Sugars: Examples include glucose and cyclodextrin.
Sugar alcohols: Examples include xylitol, sorbitol, mannitol and the like.

  Surfactants: For example, glycine-type amphoteric surfactants such as alkyldiaminoethylglycine, alkyl quaternary ammonium salts (specifically, cationic surfactants such as benzalkonium chloride and benzethonium chloride), polyoxyethylene curing Nonionic surfactants such as castor oil and polyoxyethylene sorbitan monooleate are listed.

  Preservatives, bactericides or antibacterial agents: for example, alkyldiaminoethylglycine hydrochloride, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoic acid Examples thereof include propyl, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide), glowkill (trade name, manufactured by Rhodia), and the like.

  pH adjuster: For example, hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, acetic acid, borax and the like can be mentioned.

  Isotonizing agents: for example, glycerin, propylene glycol and the like.

  Perfume or refreshing agent: for example, menthol, camphor, borneol, geraniol, ryuunou, fennel oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil and the like. These may be d-form, l-form or dl-form.

  Buffer: aminoethyl sulfonic acid, epsilon-aminocaproic acid, citrate buffer, carbonate buffer, borate buffer, phosphate buffer and the like. Specific examples include citric acid, sodium citrate, boric acid, borax, disodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate. Preferred buffering agents are borate buffer, phosphate buffer and citrate buffer. Particularly preferred buffering agents are borate buffer or citrate buffer. Examples of the boric acid buffer include borates such as boric acid, alkali metal borates, and alkaline earth metal borates, and combinations of boric acid and borates. Examples of the citrate buffer include citrates such as citric acid, alkali metal citrate salts, and alkaline earth metal citrate salts, and combinations of citric acid and citrate salts. Further, borate or citrate hydrate may be used as borate buffer or citrate buffer. More specifically, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, etc.), citric acid or a salt thereof (sodium citrate, potassium citrate, etc.) can be mentioned.

  Stabilizers: dibutylhydroxytoluene, sodium formaldehyde sulfoxylate (Longalite), tocopherol and the like.

  Solubilizers, bases: octyldodecanol, paraffin, castor oil, plastibase, lanolin, petrolatum and the like.

  The various components and additives described above may contain metal salts. When blending these with the eye drop of the present invention, it is necessary to pay attention to the blending amount so that gellan gum does not gel.

  The eye drop of the present invention is used by adjusting to an osmotic pressure within a range acceptable for a living body, if necessary. The osmotic pressure is about 100 to 1200 mOsm, preferably about 100 to 600 mOsm, particularly preferably about 150 to 400 mOsm, and the osmotic pressure ratio with respect to physiological saline is usually 0.4 to 4.1, preferably 0.3 to 2. 1, particularly preferably about 0.5 to 1.4. The viscosity of the eye drop of the present invention is not limited as long as it can be sterilized by filtration, but is preferably 20 mPa · s or less.

  The eye drop of the present invention is used after adjusting to a pH within a range applicable to a living body, if necessary. The pH is usually pH 6.5 to 10.0, preferably 7.0 to 9.5, particularly preferably 7.6 to 9.0. The pH can be adjusted using a buffer, the pH adjuster, or the like.

  The eye drop of the present invention can be produced by a known method. The liquid preparation can be prepared by mixing the base and each component. Furthermore, if necessary, a filtration sterilization treatment step, a filling step into a container, and the like can be added.

  Hereinafter, the present invention will be described in detail based on test examples and examples, but the present invention is not limited to these examples.

Preparation of Examples and Comparative Examples Preparation of each of the examples and comparative examples used in the test followed the formulations shown in Tables 1-1 to 1-3. Specifically, the preparation method of Example 1 is shown. 0.1 g of disodium edetate and 0.5 g of sodium citrate were stirred and dissolved in 350 mL of purified water, and further 2.0 g of gellan gum was added while heating and dissolved (preparation solution A). 100 g of trometamol was stirred and dissolved in 500 mL of purified water, and 40 g of sulfamethoxazole was further dissolved by stirring (Preparation Solution B). Preparation liquid B was added to preparation liquid A, and purified water was further added to make 1000 mL as a whole. Further, according to Example 1, other examples and comparative examples were also prepared.

Test Example 1 State immediately after preparation The state immediately after preparation of each Example and Comparative Example was performed by visual observation. The determination was made according to the following criteria. The results are shown in Tables 1-1 to 1-3.
×: A large precipitate recognized as a gel exists Δ: A fine particulate precipitate exists ○: No precipitate exists at all

Test Example 2 Gelling power test “All about dry eye” (Bunkodo, 1998), “Ocular Surface diagnosis and treatment” (Medical Kabushi Publishing, 1993), “Eye drops” (Nanyamado, 1984), etc. Then, artificial tears having the composition shown in Table 2 were prepared. A sample was inserted into the artificial tear using a pipette, and after observing the shape for 1 minute, the shape was judged and the gelling power was evaluated. In order to facilitate the determination, a dye having no interaction with the components (Blue No. 1: Brilliant Blue FCF: manufactured by Wako Pure Chemical Industries, Ltd.) was added to the eye drop of each test example. The results are shown in Tables 1-2 and 1-3. The evaluation criteria are as follows.
○: A gel was formed instantaneously, and no change was observed in the shape of the gel even after 1 minute. Δ: Although a gel was formed instantaneously, the shape of the gel was not retained after 1 minute. ×: A gel was formed. Did not

  As a result of Test Example 1, from Comparative Example 1, when a sodium salt sulfa agent was used, a large amount of gel was produced and could not be prepared. From Comparative Example 2, when sodium hydroxide was used as the alkali, a large amount of gel was generated and could not be prepared. In Comparative Examples 3 to 6 and 9, a large precipitate was not generated, but a fine precipitate was formed and could not be prepared as an eye drop. From Examples 1 to 6, a non-sodium salt sulfa drug was selected as the sulfa drug, and an ophthalmic solution having no problem was prepared when a certain amount of trometamol was added as an alkali. That is, when trometamol was added, an eye drop could be prepared regardless of the amount of gellan gum. Moreover, if the blending amount of gellan gum is 0.07 W / V% or less from Examples 7 to 10 and Comparative Examples 3 to 5, an ophthalmic solution having no problem even when a certain amount of monoethanolamine is added as an alkali can be prepared. It was. Furthermore, from Examples 11 and 12 and Comparative Examples 4 and 5, when the blending amount of gellan gum is 0.07 W / V% or more, there is no problem by adding trometamol by reducing the blending amount of monoethanolamine. The preparation was ready. That is, it was possible to obtain an eye drop having a viscosity that can suppress the formation of precipitates and can be easily sterilized by filtration.

  Moreover, from the results of Comparative Examples 7 and 8, it was also found that not all organic amines exhibited the effects of the present invention as alkalis to be blended. Furthermore, from the results of Example 9 and Comparative Example 9, it was found that when sulfa was added at 4 W / V%, the pH had to be 7.6 or higher. In other words, it was found that alkali blending to a pH of 7.6 or higher is necessary. The pH of all examples is within the above range. From the results of other comparative examples, it can also be seen that the effect of the present invention cannot be obtained only by setting the pH to 7.6 or higher.

  Moreover, since the Example of this invention gels when it touches artificial tears from the result of Test Example 2, it can be said that ocular mucosa staying property is high and it is excellent in antibacterial activity.

In addition, although sodium citrate and EDTA * 2Na were added to Examples 1-12, the problem was not seen from a viewpoint of a viscosity and precipitate production | generation. That is, the addition of a substance capable of generating a cation such as Na ⁺ itself is not a problem for the preparation of eye drops, but is considered to depend on the substance to be blended and the blending amount. Therefore, as long as the effects of the present invention are exerted, it does not preclude appropriately adding a substance capable of generating a cation such as Na ⁺ .

  In Tables 1-1 to 1-3, when the symbol “-” is used in the pH and viscosity columns, it means that the pH and viscosity are not measured, and is used in the gelation force test column. If it is, it means that the gelling power test is not performed. Moreover, the unit of the numerical value described in the column of the blending component in the table is the blending amount (mg / 100 mL) contained in 100 mL when 1000 mL of each Comparative Example and Example was produced.

  According to the present invention, it is possible to provide an ophthalmic solution that has high ocular mucosal retention and excellent antibacterial activity, has low viscosity during storage, and does not cause precipitation.

Claims (5)

(A) sulfamethoxazole or sulfisoxazole , (b) gellan gum greater than 0.07 W / V% and less than or equal to 1.0 W / V% , and (c) 0.3 W / V% or more and 10 W / V % or less of trometamol, blended, eye drops pH is characterized der Rukoto 7.6 or more. (A) sulfamethoxazole or sulfisoxazole, (b) 0.001 W / V% to 0.07 W / V% gellan gum, and (c) 0.3 W / V% to 10 W / V% the following trometamol and / or 0.975W / V% or more of monoethanolamine, blended, eye drops pH is characterized der Rukoto 7.6 or more. The eye drop according to claim 1, further comprising 0.0001 W / V% or more and 0.9 W / V% or less of monoethanolamine. The eye drop according to claim 1 or 3 , wherein the compounding amount of trometamol is 2 W / V% or more and 10 W / V% or less. The eye drop according to claim 2 , wherein the compounding amount of trometamol is 2 W / V% or more and 10 W / V% or less.