JP5434981B2 - Eye drops - Google Patents

Description

The present invention relates to an eye drop containing pranoprofen and a cationic drug and a method for producing the same.

Planoprofen (chemical name: α-methyl-5H- [1] benzopyrano [2,3-b] pyridine-7-acetic acid) suppresses the production of prostaglandins that cause inflammation, itching, hyperemia, etc. To relieve symptoms and treat inflammatory diseases of the external and anterior eye areas (blinditis, conjunctivitis, keratitis, scleritis, episclerosis, anterior uveitis, postoperative inflammation) Widely used clinically as eye drops. Planoprofen is an aryl carboxylic acid having a carboxyl group in the molecule, and its solubility in water varies greatly depending on the degree of dissociation of the carboxyl group. Therefore, it has been reported that pranoprofen has a very high solubility in water when the pH at which carboxyl groups are easily dissociated is 7.1 or higher, but does not dissolve in water in the acidic region. (Non-Patent Document 1). Therefore, when pranoprofen is provided as an eye drop, it is usually used as an eye drop within a pH range of 7-8.

In general, the pH of eye drops is preferably weakly acidic in terms of the feeling of use. However, no weakly acidic eye drops containing pranoprofen have been reported.

Here, the eye drop is a sterile preparation, and antiseptic properties have conventionally been secured by using a preservative for preventing secondary contamination. However, benzalkonium chloride, which is widely used as a preservative, may cause conjunctival hyperemia, lacrimation, foreign body sensation, and the like. Therefore, chlorobutanol has attracted attention as a component that has a mild effect on the living body and exhibits a sufficient antiseptic effect. However, it is known that chlorobutanol is unstable at pH 7 to 8 where pranoprofen dissolves, and cannot be preserved because it decomposes rapidly.

Conventionally, there have been some reports on solutions containing pranoprofen and a cationic drug (Patent Documents 1 and 2), but weakly acidic eye drops containing pranoprofen have not been reported.

International Patent Publication WO 01/087304 JP2002-193805

Pharmaceutical Research, Vol. 7, No. 2, 200-210, 1976

An object of the present invention is to provide an eye drop which is stable over time without causing precipitation or cloudiness even when pranoprofen is blended under weak acidity.

Another object of the present invention is to provide an ophthalmic solution that can provide a sufficient antiseptic effect even when chlorobutanol is incorporated into the ophthalmic formulation containing pranoprofen.

As a result of investigations to solve the problems, the present inventors have dissolved pranoprofen at pH 6.8 or higher, dissolved a cationic drug in the solution, and then adjusted the pH to 5 or higher and 6.5 or lower. Then, surprisingly, pranoprofen is dissolved even at pH 6.5 or less, where pranoprofen usually precipitates and the solution becomes cloudy, and the stability of chlorobutanol was maintained over time. The inventors found that an eye drop can be obtained and completed the present invention.

That is, the present invention
1. An ophthalmic solution containing a) pranoprofen and b) a cationic drug (excluding trometamol) and having a pH of 5 to 6.5 (excluding sorbic acid or a salt thereof) .
2. Instillation according to 1, wherein the cationic drug is one or more selected from chlorpheniramine maleate, diphenhydramine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, methylephedrine hydrochloride, ephedrine hydrochloride, and epinephrine hydrochloride. Agent.
3. The eye drop according to 1, wherein the cationic drug is one or two selected from chlorpheniramine maleate and tetrahydrozoline hydrochloride.
4). The eye drop according to any one of 1 to 3, wherein the cationic drug is 0.01 to 10 parts by mass with respect to 1 part by mass of pranoprofen.
It is.

According to the present invention, an eye drop in which pranoprofen is clearly dissolved even under weak acidity can be provided.

In the present invention, the blending amount of pranoprofen is preferably 0.005 w / v% to 2.0 w / v% of the whole preparation, more preferably 0.05 w / v% to 0.1 w / v%. This is because if the amount is small, the medicinal effect becomes insufficient, and if the amount is too large, precipitation may occur.

In the present invention, the cationic drug refers to a drug that exhibits a cationic (positive charge) property in a normal aqueous solution. Examples of such drugs to be added to eye drops include some antihistamines and vasoconstrictors.

Eye drops containing pranoprofen and cationic drugs such as antihistamines and vasoconstrictors can effectively suppress itch symptoms during allergic reactions, and can effectively remove inflammation and hyperemia associated therewith. Can be considered.

Specifically, the preferred cationic drug of the present invention is one selected from chlorpheniramine maleate, diphenhydramine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, methylephedrine hydrochloride, ephedrine hydrochloride, and epinephrine hydrochloride. Two or more can be listed.

Of these, one or two selected from chlorpheniramine maleate and tetrahydrozoline hydrochloride are particularly preferred.

In the present invention, the compounding amount of the cationic drug is preferably 0.01 to 10 parts by mass, more preferably 0.1 to 5 parts by mass with respect to 1 part by mass of pranoprofen. This is because if the amount is too small, the effect of suppressing precipitation is insufficient, but it is not necessary to add too much.

In the present invention, when chlorobutanol is blended, the blending amount is 0.05 to 0.4 w / v%, preferably 0.06 w / v% to 0.3 w / v%. This is because when the amount is small, the antiseptic effect is insufficient, but it is not necessary to add excessively.

The eye drop of the present invention is produced as follows.

First, pranoprofen is adjusted to pH 6.8 or higher with a pH adjuster and dissolved to obtain an aqueous pranoprofen solution. Next, the cationic drug or an aqueous solution thereof is added to the pranoprofen aqueous solution and mixed uniformly, and the obtained aqueous solution is adjusted to a pH of 5 or more and 6.5 or less with a pH adjuster. If necessary, an eye drop can be produced by further blending chlorobutanol.

Here, when pranoprofen is dissolved at pH 6.8 or higher and the pH is adjusted to 6.5 or lower as it is, pranoprofen is precipitated. However, when a cationic drug is added to the pranoprofen aqueous solution, No precipitation occurs even when the value is lowered. Therefore, by further blending chlorobutanol, an eye drop with sufficiently preserved antiseptic properties can be obtained.

As the pH adjuster, those commonly used for eye drops can be used, and examples thereof include boric acid, phosphoric acid, citric acid and salts thereof, hydrochloric acid, sodium hydroxide and the like.

In the eye drop of the present invention, other pharmaceutically acceptable components can be blended as necessary within a range that does not affect the effects of the present invention. Examples of such components include anti-inflammatory drugs such as epsilon aminocaproic acid and dipotassium glycyrrhizinate, vitamins such as pyridoxine hydrochloride, riboflavin phosphate, cyanocobalamin, panthenol, tocophenol acetate, and flavin adenine dinucleotide sodium, chondroitin Amino acids such as sodium sulfate and aminoethylsulfonic acid, inorganic salts such as sodium chloride and potassium chloride, surfactants such as polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan monooleate, essential oils such as menthol, camphor and eucalyptus oil Other base ingredients include borax, boric acid, paraoxybenzoic acid esters (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), etc. Rukoto can.

The eye drop of the present invention is used once to several times a day, once to several drops at a time.

Hereinafter, the present invention will be described in detail with reference to Examples, Reference Examples and Test Examples.

Formula 100mL Planoprofen 50mg
Chlorpheniramine maleate 40mg
Chlorobutanol 100mg
Citric acid 24mg
Sodium citrate 230mg
Boric acid 500mg
Dilute hydrochloric acid appropriate amount purified water 100mL
Manufacturing method Sodium citrate was dissolved in sterilized purified water (80 mL) to confirm that the pH was 6.8 or more, and pranoprofen was added and dissolved. Next, chlorpheniramine maleate was added and dissolved, and citric acid and boric acid were added. It was confirmed that the pH at this time was about 6, and further, chlorobutanol was added and dissolved, and then adjusted to pH 5.5 using dilute hydrochloric acid, and the total amount was adjusted to 100 mL using sterilized purified water. Thereafter, filtration sterilization was performed to obtain an eye drop.

Reference example 1
Formula 100mL Planoprofen 50mg
Chlorpheniramine maleate 40mg
Chlorobutanol 100mg
Citric acid 24mg
Sodium citrate 230mg
Boric acid 500mg
Dilute hydrochloric acid appropriate amount purified water 100mL

Manufacturing method Each component was added to sterilized purified water (80 mL) and stirred. Although it was confirmed that the pH at this time was about 6, pranoprofen was not completely dissolved, and was not dissolved even when the pH was adjusted to 5.5 with dilute hydrochloric acid.

Test example 1
The eye drops of Example 2 and Comparative Example 1 having the formulations shown in Table 1 were prepared using the same production method as in Example 1, and the presence or absence of precipitates such as crystals at 25 ° C. for one month was examined by visual observation. The presence or absence is shown in Table 1. When there was a precipitate such as a crystal, x was marked as ◯.

As shown in the table, the eye drop of the present invention did not cause the precipitation of pranoprofen even after 1 month at 25 ° C.

Test example 2
Example ophthalmic solutions of the formulations shown in Table 2 and comparative examples were prepared using the same production method as in Example 1, and the presence or absence of precipitate formation such as crystals at 5 ° C. for 1 week was examined by visual observation. The presence or absence was shown in Table 2. When there was a precipitate such as a crystal, x was marked as ◯.

As shown in the table, the eye drop of the present invention did not cause pranoprofen precipitation even after 1 week at 5 ° C.

The eye drop of the present invention can be used as an eye drop for preventing or ameliorating allergic symptoms or removing hyperemia.

Claims (3)

a) pranoprofen and b) one or more cationic drugs (not including trometamol) selected from chlorpheniramine maleate, diphenhydramine hydrochloride, tetrahydrozoline hydrochloride, and naphazoline hydrochloride , pH 5 to 6.5 eye drops (however, sorbic acid or a salt thereof is not included). a) 1 to 10 parts by mass of pranoprofen b) 0.01 to 10 parts by mass of one or more cationic drugs selected from b) chlorpheniramine maleate, diphenhydramine hydrochloride, tetrahydrozoline hydrochloride, and naphazoline hydrochloride The ophthalmic solution according to claim 1. 1) One or more cationic drugs selected from a) pranoprofen and b) chlorpheniramine maleate, diphenhydramine hydrochloride, tetrahydrozoline hydrochloride, and naphazoline hydrochloride (but not including trometamol) and having a pH of An ophthalmic solution which is a clear solution of 5 or more and 6 or less (excluding sorbic acid or a salt thereof).