JPH11189533A - Eye drops - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an eye drop excellent in removing effects on hyperemic symptoms such as conjunctivitis and useful for inflammatory morbid states of ophthalmic conjunctiva by formulating ketotifen with a vitamin. SOLUTION: This eye drop is obtained by formulating (A) ketotifen 4,9- dihydro-4-(1-methyl-4-piperidylidene)-10H-benzo[4,5]cyclohepta[1,2'-b] thiophen-10- one} or its salt (e.g. a fumarate) and (B) a vitamin (i) vitamin A and a vitamin B group [(ii) vitamin B1, (iii) vitamin B2, (iv) vitamin B6, (v) vitamin B12, a derivative thereof or the like], (vi) vitamin E or the like and its derivative}. In the agent, the amounts of the ingredients contained are preferably 0.001-0.5 wt.% ingredient A, 0.1-10 wt.% ingredient Bi, 0.01-0.5 wt.% ingredient Bii, 0.005-0.3 wt.% ingredient Biii, 0.01-0.5 wt.% ingredient Biv, 0.000005-0.003 wt.% ingredient Bv and 0.005 0.2 wt.% ingredient Bvi.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to eye drops having an enhanced and improved vasoconstrictive action and exhibiting an excellent effect in removing or alleviating hyperemia of the ocular mucosa in various diseases such as conjunctivitis. .

[0002]

2. Description of the Related Art Diseases showing hyperemia of the ocular mucosa, such as conjunctivitis, are inflammatory diseases of the ocular mucosa. The causes of conjunctivitis are diverse, and in the past, symptoms mainly based on bacterial infections have been noted, but in recent years, allergies have become the main etiology. There are also many types of allergen-causing substances (allergens), and pollen, house dust, fine particles in exhaust gas, food components, and the like are allergens.

[0003] In general, it is thought that allergy is treated by removing allergens, but it is difficult to carry out such measures in daily life. In addition, desensitization therapy for reducing sensitivity to allergens is also performed, but the treatment period is very long and requires frequent outpatient visits, so that it is not widely used at present. Therefore, from such a situation, treatment of conjunctivitis is centered on symptomatic treatment.

[0004] As symptomatic treatment for hyperemia of the ocular mucosa, in general, removal and reduction of red eye by a vasoconstrictor, removal and reduction of eye pain, pruritus and discomfort by a local anesthetic are commonly used. In addition, antihistamines are used to suppress allergic reactions typified by hay fever or to eliminate or reduce eye pruritus, and vitamins are used as vitamins for improving microcirculation and improving eyestrain. Used for replenishment purposes.

[0005] In the treatment of conjunctivitis and the like, basically,
It is an important factor in treatment and daily life how to eliminate or reduce various symptoms such as hyperemia of the ocular mucosa. In particular, among them, hyperemia, including swelling of the ocular mucosa, is considered to be a therapeutic point to be improved early from the viewpoint of QOL and from the viewpoint of prevention of transition to serious symptoms, It is an important factor to exert such effects also in the field of over-the-counter drugs. However, such effects cannot be sufficiently obtained with the drugs used for the symptomatic treatment as described above, and thus it has been difficult to provide eye drops that sufficiently exhibit the effects as described above.

[0006]

Accordingly, an object of the present invention is to eliminate various symptoms such as conjunctivitis, in particular, hyperemia of the ocular mucosa,
An object of the present invention is to provide eye drops having a high effect of reducing the amount of eye drops.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object, and as a result, an ophthalmic solution obtained by blending ketotifen or a salt thereof with a vitamin as an active ingredient,
The present inventors have found that the present invention shows a dramatic effect in eliminating or reducing hyperemia of the ocular mucosa due to conjunctivitis and the like, and completed the present invention.

[0008] That is, the present invention provides an eye drop comprising (a) ketotifen or a salt thereof and (b) a vitamin.

In the eye drops of the present invention, the vitamin is preferably selected from the group of vitamins B (vitamin B1, vitamin B2, vitamin B6 and vitamin B12), vitamin E and its derivatives.

The ketotifen or a salt thereof used in the eye drops of the present invention has been conventionally used in eye drops for allergic inflammatory symptoms due to its antihistamine effect, and vitamins are also used as described above. It has been conventionally used in eye drops. However, the present invention
When ketotifen or its salts are used in combination with vitamins,
It is based on the finding that they are much more effective than simply adding or removing the effect of eliminating or reducing hyperemia caused by conjunctivitis or the like obtained when they are used alone.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION Ketotifen (4,9-dihydro-4- (1-methyl-4-) used in the eye drops of the present invention.
Piperidylidene) -10H-benzo [4,5] cyclohepta [1,2-b] thiophen-10-one) is a known antiallergic agent, can be synthesized by a known method, and is also available as a commercial product. .

Ketotifen salts are not particularly limited as long as they are pharmaceutically acceptable as those used in eye drops. For example, inorganic acids such as hydrochloride, bromate, sulfate, nitrate, phosphate and the like can be used. Salt, methanesulfonate, benzenesulfonate, paratoluenesulfonate, acetate, propionate, tartrate, fumarate, maleate, malate, oxalate, succinate, citric acid Organic salts such as salts, benzoates, mandelates, cinnamates and lactates can be used. Fumarate is particularly preferred.

The amount of ketotifen or a salt thereof in the eye drops of the present invention may be generally 0.001 to 0.5% by weight, preferably 0.01 to 0.5% by weight as ketotifen, based on the total amount of the ophthalmic preparation. It is about 1% by weight.

The vitamin as the other active ingredient in the eye drops of the present invention is synergistic when various vitamins are used in combination with ketotifen or a salt thereof in removing or reducing hyperemia of the ocular mucosa as described above. It turned out that an effect was obtained. For example, vitamin A, vitamin B group (vitamin B1, vitamin B2, vitamin B
6 and vitamin B12), vitamin C, vitamin E, etc., and can be used alone or in combination of two or more. In addition, various derivatives of these vitamins having physiologically equivalent activities can also be used, for example,
Retinol as vitamin A, bisibutiamine as vitamin B1, flavin adenine dinucleotide as vitamin B2, salts of pyridoxine and pyridoxal as vitamin B6, hydroxocobalamin as vitamin B12, ascorbin as vitamin C Examples of vitamin E such as acid salts include tocopherol succinic acid. Other vitamins such as nicotinate, pantothenate, biotin and the like can also be used.

The amount of vitamins in the eye drops of the present invention is generally 0.1 to 10% by weight, preferably 0.25 to 5% by weight, for vitamin A and its derivatives, based on the total amount of the eye drops composition. About 0.01 to 0.5% by weight for vitamin B1 and its derivatives,
It is preferably about 0.03 to 0.3% by weight, and vitamin B2 and its derivatives are generally 0.005 to 0.3% by weight.
It is about 0.3% by weight, preferably about 0.01 to 0.2% by weight. For vitamin B6 and its derivatives, it is generally 0.01 to 0.5% by weight, preferably 0.03 to 0.3% by weight.
About 3% by weight, generally about 0.000005 to 0.003% by weight, preferably about 0.00001 to 0.0015% by weight for vitamin B12 and its derivatives, and generally about 0.000001 to 0.0015% by weight for vitamin C and its derivatives. 0.005 to 0.2% by weight, preferably 0.01 to
It is about 0.1% by weight, and the amount of vitamin E and its derivatives is generally about 0.005 to 0.2% by weight, preferably about 0.01 to 0.1% by weight. 2 vitamins
When two or more kinds are used in combination, it is preferable that each of them is in the above range.

The eye drops of the present invention contain, in addition to the above-mentioned active ingredients, other drugs, if necessary, such as dipotassium glycyrrhizinate, epsilon aminocaproic acid, allantoin, berberine chloride, berberine sulfate, sodium azulene sulfonate, zinc sulfate, Anti-inflammatory drugs such as zinc lactate; anti-allergic drugs such as diphenhydramine hydrochloride and chlorpheniramine maleate; and antihistamine drugs; vasoconstrictors such as tetrahydrozoline hydrochloride, naphazoline hydrochloride, and phenylephrine hydrochloride; Medicines, local anesthetics such as lidocaine hydrochloride, steroidal anti-inflammatory drugs such as prednisolone, anti-inflammatory enzymes and anti-inflammatory drugs such as lysozyme chloride, serrapeptase and bromelain, benzethonium chloride, bactericides such as chlorhexidine gluconate, It can be blended drugs like.

The eye drops of the present invention can be prepared into solid or liquid eye drops by a conventional method. In the case of solid eye drops, excipients such as crystalline cellulose, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, lubricants such as magnesium stearate, hydrogenated castor oil, talc and the like It is manufactured by blending the active ingredient and optionally the above-mentioned drugs. In the case of a liquid eye drop, it is produced by dissolving the above active ingredient in a solvent usually used as a carrier of the liquid eye drop such as purified water. Liquid eye drops, in addition to the above active ingredient and optional ingredients, for example, methyl cellulose, hydroxyethyl cellulose,
Carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, sodium carboxymethylcellulose, thickeners such as chondroitin sulfate, chlorobutanol, sodium dehydroacetate, benzalkonium chloride, cetylpyridium chloride, phenethyl alcohol, methyl paraoxybenzoate, benzethonium chloride, Preservatives such as methyl paraben and sorbic acid, buffers such as borax, boric acid, potassium dihydrogen phosphate, solubilizers such as polysorbate 80, polyoxyethylene hydrogenated castor oil, surfactants, sodium edetate, and hydrogen sulfite Sodium, stabilizers such as ethylenediaminetetraacetate,
Menthol, camphor, peppermint water, peppermint oil, fragrances such as borneol, sulfa agents, pigments such as sicon extract, preservatives and the like can be appropriately compounded within a range that does not impair the effects of the present invention.

In the case of a liquid eye drop, it is preferable to make the liquid isotonic with tears. To this end, an isotonic agent such as sodium chloride, potassium chloride or glycerin can be added as needed. In addition, the pH of the liquid eye drop may be within an ophthalmologically acceptable range, and for example, is preferably in a range of about pH 5.0 to 8.0. The desired pH can be obtained using a pH adjuster such as borax, citric acid, sodium citrate, hydrochloric acid, sodium hydroxide and the like.

The dosage and administration of the ophthalmic solution of the present invention may vary depending on the type and degree of the symptoms of the patient, the age, etc., but it is usually 1 to several times a day, and the dosage per day is 0.1 to 0.1 for ketotifen. 005 to 1.2 mg, preferably 0.01 to
0.6mg, 0.001-0.5m for vitamins
g, preferably 0.005 to 0.25 mg, is administered by dropping, spraying, or applying to the eyes.

[0020]

EXAMPLES The present invention will be described more specifically with reference to examples and test examples, but the present invention is not limited to the following examples.

Example 1 The following components were weighed at the indicated weights, mixed uniformly, and dissolved in 100 ml of purified water to produce eye drops. Ketotifen fumarate 25 mg Vitamin B6 100 mg Dipotassium glycyrrhizinate 300 mg Lidocaine hydrochloride 250 mg

Example 2 The following components were weighed at the indicated weights, mixed uniformly, and dissolved in 100 ml of purified water to produce eye drops. Ketotifen fumarate 50 mg Vitamin B1 100 mg Tetrahydrozoline hydrochloride 100 mg Prednisolone 10 mg Lidocaine hydrochloride 300 mg

Example 3 The following components were weighed at the indicated weights, mixed uniformly, and dissolved in 100 ml of purified water to produce eye drops. Ketotifen fumarate 30 mg Vitamin B6 100 mg Vitamin B12 50 μg Tetrahydrozoline hydrochloride 100 mg dl-Chlorpheniramine maleate 250 mg

Example 4 The following components were weighed at the indicated weights, mixed uniformly, and dissolved in 100 ml of purified water to produce eye drops. Ketotifen fumarate 25mg Vitamin B2 50mg Vitamin B6 100mg Vitamin B12 50μg Naphazoline hydrochloride 50mg Flutropium bromide 20mg

Example 5 The following components were weighed at the indicated weights, mixed uniformly, and dissolved in 100 ml of purified water to produce eye drops. Ketotifen fumarate 40mg Vitamin B2 50mg Vitamin B6 100mg Vitamin E 30mg Oxymetazoline hydrochloride 25mg Fluticasone propionate 50mg Lysozyme chloride 250mg Lidocaine hydrochloride 300mg l-menthol 10mg

Test Example: Remission Effect of Combined Preparation on Rabbit Eye Mucosal Hyperemia Response Test Method Three Japanese native white rabbits were used in each group, and 0.2 ml of a 3.5% capsaicin solution was applied to the eyes beforehand. A mucosal hyperemia was induced, and then 0.2 ml of each eye drop prepared according to the formulation in Table 1 (100 ml purified water)
Was instilled in rabbits. One hour after the instillation, the degree of redness and swelling of the mucous membrane of the eyeball and the eyelid was visually observed.
Observation results were expressed in scores according to the following criteria, and the decongestant effect of each eye drop was evaluated.

5 points: very hyperemic (mucosa of eyeball and eyelid are extremely reddened and swollen) 4 point: considerably hyperemic (mucosa of eyeball and eyelid are clearly reddened and swollen 3 points: clearly reddened (mucosa of eyeball and eyelids are clearly reddened) 2 points: slightly reddened (mucosa of eyeballs and eyelids are slightly reddened) 1 point: redness Severe but very weak (slight redness of eyeball and eyelid mucosa) 0 point: Little hyperemia (completely normal or very slight reddening of either eyeball or eyelid mucosa) ing)

[0028]

[Table 1]

Test Results The results are shown in Table 2 below. The score of the degree of congestion was represented by the average of the scores of the three animals.

Regarding the degree of effect on the hyperemia, the groups A to E, which are eye drops of the present invention, were obtained when ketotifen and vitamins shown as control groups were used alone (groups F to L). It shows a decongestant effect that clearly exceeds the additive effect, and it is clear that the eye drops of the present invention show an excellent decongestant effect.

[0031]

[Table 2]

[0032]

Industrial Applicability The eye drops of the present invention exhibit an extremely excellent effect of removing congestive symptoms such as conjunctivitis and provide a very useful drug for inflammatory conditions of the ocular mucosa.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/525 A61K 31/525 31/68 31/68

Claims (2)

[Claims] 1. An eye drop containing (a) ketotifen or a salt thereof and (b) a vitamin. 2. The ophthalmic solution according to claim 1, wherein the vitamin is at least one vitamin selected from the group consisting of vitamin B, vitamin E and derivatives thereof.