JP5440635B2 - Eye drops - Google Patents

Description

  The present invention relates to an ophthalmic solution having a pH of 5 to 6.5 and pranoprofen, 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. It has been reported that the solubility is very high at a pH at which the carboxyl group easily dissociates is 7.1 or more, but it does not dissolve in the acidic region. (Non-Patent Document 1). Therefore, it is usually used as an eye drop by dissolving at pH 7-8.

  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 is an example of a component that has a mild effect on the living body and exhibits a sufficient antiseptic effect.

  However, this chlorobutanol is known to be unstable at pH 7 to 8 where pranoprofen dissolves, and is rapidly decomposed so that it cannot exhibit the antiseptic effect.

  Conventionally, suspension syrups containing pranoprofen and a water-soluble polymer have been disclosed (Patent Documents 1 and 2), but no ophthalmic solution containing chlorobutanol in a solution state has been reported.

JP-A-5-255086 JP-A-10-287565 Pharmaceutical Research, Vol. 7, No. 2, 200-210, 1976

  An object of the present invention is to provide an eye drop that does not cause precipitation or cloudiness even when chlorobutanol is used as an antiseptic to an eye drop formulated with pranoprofen, and that chlorobutanol is stably maintained over time. There is.

  As a result of investigations to solve the problems, the present inventors have dissolved pranoprofen at pH 6.5 or higher, and then added a certain water-soluble polymer, sugar or sugar alcohol to the solution, and adjusted the pH to 5 When adjusted to 6.5 or less and chlorobutanol is blended, it is surprising that pranoprofen is usually dissolved even at pH 6.5 or less where pranoprofen precipitates and the solution becomes cloudy. The present inventors have found that an eye drop that maintains the stability of chlorobutanol over time can be obtained.

That is, the present invention is 1. An ophthalmic solution having a pH of 5 or more and 6.5 or less, comprising pranoprofen, a water-soluble polymer and chlorobutanol.
2. An ophthalmic solution having a pH of 5 or more and 6.5 or less, wherein pranoprofen, a saccharide and chlorobutanol are blended.
3. An ophthalmic solution having a pH of 5 or more and 6.5 or less, comprising pranoprofen, sugar alcohol and chlorobutanol.
4). The eye drop according to 1, wherein the water-soluble polymer is one or more selected from polyvinyl alcohol, polyoxyethylene polyoxypropylene glycol surfactant, polyvinyl pyrrolidone, hydroxyethyl cellulose, and hydroxypropyl methylcellulose.
5. 3. The eye drop according to 2, wherein the saccharide is one or more selected from glucose, mannitol and trehalose.
6). 4. The eye drop according to 3, wherein the sugar alcohol is sorbitol.
7). The following step (a) a step of adjusting pranoprofen to pH 6.5 or higher with a pH adjuster and dissolving to obtain a pranoprofen aqueous solution;
(B) adding a water-soluble polymer, saccharide, sugar alcohol or an aqueous solution thereof to the pranoprofen aqueous solution and uniformly mixing the solution,
(C) adjusting the pH of the aqueous solution obtained in step (b) to 5 or more and 6.5 or less using a pH adjuster;
(D) An eye drop produced by the step of further adding chlorobutanol to the aqueous solution obtained in step (c).
8). (A) a step of adjusting pranoprofen to pH 6.5 or higher with a pH adjusting agent and dissolving to obtain a pranoprofen aqueous solution;
(B) adding a water-soluble polymer, saccharide, sugar alcohol or an aqueous solution thereof to the pranoprofen aqueous solution and uniformly mixing the solution,
(C) adjusting the pH of the aqueous solution obtained in step (b) to 5 or more and 6.5 or less using a pH adjuster;
(D) A method for producing eye drops comprising the step of further adding chlorobutanol to the aqueous solution obtained in step (c).
9. The ophthalmic solution according to 1, which is a clear solution.
It is.

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

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

  As the water-soluble polymer used in the present invention, those usually used for ophthalmic agents can be used. Specifically, polyvinyl alcohol, polyoxyethylene polyoxypropylene glycol surfactants, polyvinyl pyrrolidone, hydroxyethyl cellulose And one or more selected from hydroxypropylmethylcellulose are preferred, and polyvinyl alcohol, polyoxyethylene polyoxypropylene glycol surfactants and polyvinylpyrrolidone are more preferred.

  As the saccharide used in the present invention, those usually used for ophthalmic agents can be used, and specifically, one or more selected from glucose, mannitol and trehalose are preferable.

  As the sugar alcohol used in the present invention, those usually used for ophthalmic agents can be used, and sorbitol can be mentioned as a particularly preferable one.

  In the present invention, the blending amount of the water-soluble polymer is 0.05 to 20 w / v%, preferably 0.1 to 5 w / v%. Moreover, the compounding quantity of saccharide | sugar or sugar alcohol is 0.1-10 w / v%, Preferably it is 0.5-6 w / v%.

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

  First, pranoprofen is adjusted to a pH of 6.5 or more with a pH adjuster and dissolved to obtain an aqueous pranoprofen solution. Next, one or more of water-soluble polymers, saccharides, sugar alcohols or their aqueous solutions are added to the pranoprofen aqueous solution and mixed uniformly. To do. Furthermore, it can manufacture by mix | blending chlorobutanol with the obtained aqueous solution further.

  Here, when pranoprofen is dissolved at pH 6.5 or higher and the pH is decreased to 6.5 or lower as it is, pranoprofen is precipitated. When one or more alcohols or their aqueous solutions are blended, pranoprofen does not precipitate even when the pH is lowered. Therefore, by adding chlorobutanol thereto, an eye drop with sufficiently secured 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, methyl Focus regulators such as neostigmine sulfate, amino acids such as sodium chondroitin sulfate and aminoethylsulfonic acid, inorganic salts such as sodium chloride and potassium chloride, polyoxyethylene hydrogenated castor oil, surfactants such as polyoxyethylene sorbitan monooleate, Essential oils such as menthol, camphor, eucalyptus oil, and other base ingredients include borax, boric acid, benzalkonium chloride, paraoxybenzoate (methyl paraoxybenzoate, ethyl paraoxybenzoate, Raokishi propyl benzoate, butyl parahydroxybenzoate and the like) and the like.

  The eye drop of the present invention can be administered several times a day, 1 to several drops at a time.

  According to the present invention, in the ophthalmic solution containing pranoprofen and a water-soluble polymer, saccharide or sugar alcohol, pranoprofen was dissolved without causing precipitation or cloudiness, and chlorobutanol could be stably added. .

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

Formula 100mL Planoprofen 50mg
Polyvinyl alcohol 1000mg
(Product name: Gohsenol EG-05, manufactured by Nippon Synthetic Chemical Industry)
Chlorobutanol 100mg
Citric acid 24mg
Sodium citrate 230mg
Boric acid 500mg
Dilute hydrochloric acid appropriate amount purified water 100mL

Production Method Sodium citrate was dissolved in purified water (80 mL) to confirm that the pH was 6.5 or higher, and pranoprofen was added and dissolved. Next, polyvinyl alcohol 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, adjusted to pH 5.5 using dilute hydrochloric acid, and then the total volume was adjusted to 100 mL using sterilized purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.

Reference example 1
Formula 100mL Planoprofen 50mg
Polyvinyl alcohol 1000mg
(Product name: Gohsenol EG-05, manufactured by Nippon Synthetic Chemical Industry)
Chlorobutanol 100mg
Citric acid 24mg
Sodium citrate 230mg
Boric acid 500mg
Dilute hydrochloric acid appropriate amount purified water 100mL

Production Method Each component was added to 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 The eye drops of Examples 2 to 3 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 5 ° C. for 1 month was determined. The presence or absence was examined by visual observation and shown in Table 1. When there was a precipitate such as a crystal, x was marked as ◯.

  The eye drop of the present invention did not precipitate pranoprofen even at 5 ° C.

  The eye drop of the present invention can be used as an eye drop for improving eye inflammation caused by allergic symptoms or ultraviolet rays.

Claims (8)

An ophthalmic solution which is a clear solution having a pH of 5 or more and 6.5 or less , comprising pranoprofen, a water-soluble polymer and chlorobutanol. An ophthalmic solution which is a clear solution having a pH of 5 or more and 6.5 or less , comprising pranoprofen, a saccharide and chlorobutanol. An ophthalmic solution which is a clear solution having a pH of 5 or more and 6.5 or less , characterized in that it contains pranoprofen, sugar alcohol and chlorobutanol. The eye drop according to claim 1, wherein the water-soluble polymer is one or more selected from polyvinyl alcohol, polyoxyethylene polyoxypropylene glycol surfactant, polyvinyl pyrrolidone, hydroxyethyl cellulose and hydroxypropyl methyl cellulose. The eye drop according to claim 2, wherein the saccharide is one or more selected from glucose, mannitol and trehalose. The eye drop according to claim 3, wherein the sugar alcohol is sorbitol. The following step (a) a step of adjusting pranoprofen to pH 6.5 or higher with a pH adjuster and dissolving to obtain a pranoprofen aqueous solution;
(B) adding a water-soluble polymer, saccharide, sugar alcohol or an aqueous solution thereof to the pranoprofen aqueous solution and uniformly mixing the solution,
(C) adjusting the pH of the aqueous solution obtained in step (b) to 5 or more and 6.5 or less using a pH adjuster;
(D) An ophthalmic solution which is a clear solution produced by a step of further adding chlorobutanol to the aqueous solution obtained in step (c). (A) a step of adjusting pranoprofen to pH 6.5 or higher with a pH adjusting agent and dissolving to obtain a pranoprofen aqueous solution;
(B) adding a water-soluble polymer, saccharide, sugar alcohol or an aqueous solution thereof to the pranoprofen aqueous solution and uniformly mixing the solution,
(C) adjusting the pH of the aqueous solution obtained in step (b) to 5 or more and 6.5 or less using a pH adjuster;
(D) A method for producing eye drops, which is a clear solution comprising a step of further adding chlorobutanol to the aqueous solution obtained in step (c).