KR20060102282A - Ophthalmic solution - Google Patents

Abstract

The present invention is an eye drop comprising a nitrogen monoxide donating compound and alginic acid or a salt thereof. In addition, the present invention is an enhancer of a nitric oxide donor compound having alginic acid or a salt thereof as an active ingredient.

The addition of alginic acid or a salt thereof to an eye drop containing the nitrogen monoxide donor compound as an active ingredient can enhance the effect of the nitrogen monoxide donor compound.

Eye drops, glaucoma, ocular hypertension, nitric oxide donor compounds, alginic acid

Description

Eye drops {Ophthalmic Solution}

1 is a graph showing the difference in intraocular pressure drop between the eye drop of Example 1 and the eye drop of Comparative Example 1. Here, ΔIOP represents the amount of intraocular pressure change.

FIG. 2 is a graph showing the difference in intraocular pressure drop between the eye drop of Example 2 and the eye drop of Comparative Example 2. FIG. Here, ΔIOP represents the amount of intraocular pressure change.

3 is a graph showing the difference in intraocular pressure drop between the eye drop of Comparative Example 3 and the eye drop of Comparative Example 4. FIG. Here, ΔIOP represents the amount of intraocular pressure change.

4 is a graph showing the difference in intraocular pressure drop between the eye drop of Comparative Example 5 and the eye drop of Comparative Example 6. FIG. Here, ΔIOP represents the amount of intraocular pressure change.

The present invention relates to eye drops, and more particularly, to eye drops used for the treatment of glaucoma, ocular hypertension, and the like containing a nitric oxide donating compound and alginic acid or a salt thereof.

Glaucoma is a refractory disease in which visual function is impaired by an increase in intraocular pressure that the eye can tolerate, and the treatment includes mainly drugs and surgery.

In addition, ocular hypertension refers to a condition in which ocular hypertension above normal levels is recognized but does not accompany visual abnormality, and is considered to be likely to develop glaucoma in the long term. Generally recommended.

Drug treatment of the disease may include the use of eye drops such as pilocarpine, epinephrine, β-blockers or certain types of prostaglandins, carbonic anhydrase inhibitors such as acetazolamide, or hyperosmotic agents. The method of systemic administration is performed.

However, in some cases, only one of these therapeutic agents is ineffective, and sufficient intraocular pressure cannot be obtained. Therefore, in the actual treatment, it is common to use a plurality of therapeutic agents in combination with eye drops and systemic or multiple eye drops. to be. Specifically, a case where a β blocker, a prostaglandin-related drug and a carbonic anhydrase inhibitor are combined is often used (see Non-Patent Document 1).

Regarding the combination of many therapeutic agents, more specifically, for example, use of betazolol and isopropyl unoprostone (see Non-Patent Document 2), but a nitric oxide donor compound and prostaglandin Combination of compounds (see Patent Document 1) and the like are known.

However, the combination of many therapeutic agents has enhanced effects, but there are many problems such as decreased compliance, increased medical expenses, increased side effects, and increased medical expenses. As a result, there is a demand for the development of a drug having a superior intraocular pressure lowering effect.

[Non-Patent Document 1] Ophthalmology Clinic Practice, 4, Vol. 5, 2-6, 2001

[Non-Patent Document 2] Glaucoma, 148, Vol. 9, 1999

[Patent Document 1] WO 02/85372

The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an eye drop which can be used for the treatment of glaucoma, ocular hypertension, and the like having an excellent hypotension effect.

MEANS TO SOLVE THE PROBLEM In order to solve the said subject, as a result of earnestly examining, when the alginic acid or its salt is used together with the eyedrop containing a nitrogen monoxide donor compound, the effect of the intraocular pressure reduction of a nitrogen monoxide donor compound is remarkable. Confirmed to be enhanced, the present invention was completed.

That is, the present invention is an eye drop comprising a nitrogen monoxide donating compound and alginic acid or a salt thereof.

In addition, the present invention is a method for enhancing the potency of a nitric oxide donor compound, comprising adding alginic acid or a salt thereof to an eye drop containing the nitric oxide donor compound as an active ingredient.

In addition, the present invention is an enhancer of a nitric oxide donor compound having alginic acid or a salt thereof as an active ingredient.

To practice the invention  for Best  shape

The nitrogen monoxide donor compound used in the eye drop of the present invention refers to a compound which can release nitrogen monoxide in vivo. The nitrogen monoxide donating compound is not particularly limited, but specific examples thereof include nipradilol, sodium nitroprusside, nitroglycerin, isosorbide dinitrate, and N-nitroso acetyl. N-nitrosoacetylpenicillamine, 3-morpholino-sydnonimine hydrochloride, S-nitroso-N-acetyl-DL-penicillamine (SNAP), S-nitrosoglutathione , 4-phenyl-3-furoxanecarbonitryl, nicorandil, arginine, sodium nitrite, and the like.

Among these, nipradilol, sodium nitroprusside, and the like are preferable in view of the strength and stability of the action.

In addition, the alginic acid used as the eye drop of the present invention is brown algae, especially kelp ( Laminaria Japonica Areschoug ) and the like are cell wall viscous polysaccharides extracted and purified. The alginic acid has a chain structure in which D-mannuronic acid of β-1,4 bond and L-gluronic acid of α-1,4 bond are connected, and the ratio of both components varies depending on the type of raw material. The salts of the alginic acid, in particular its potassium and sodium salts, are water-soluble and, when dissolved in water, become highly viscous liquids and are commercially available as food additives, emulsifying stabilizers and the like using the viscosity.

The alginic acid used in the present invention may be any of those extracted and purified from the brown algae and those commercially available as salts thereof. Moreover, as a salt of alginic acid, alkali metal salts, such as the potassium salt of alginic acid, a sodium salt, are preferable, and sodium alginate is especially preferable. In any case, it is preferable that the M / G ratio (the ratio of D-mannuronic acid and L-gluronic acid) is 1.0 or more.

The eye drop of the present invention is prepared by, for example, formulating the nitric oxide donor compound and alginic acid or a salt thereof in an appropriate solvent in a conventional manner.

Although content of a nitrogen monoxide donor compound in the eye drop of this invention is not specifically limited, Generally, it is 0.01-5 mass% with respect to the whole eye drop, It is preferable that it is 0.05-2 mass%, Especially 0.1-1 mass It is more preferable that it is%. When the amount is less than 0.01% by mass, the effect of lowering the intraocular pressure is small, and when it is more than 5% by mass, problems may occur in terms of solubility and side effects.

Moreover, content of alginic acid or its salt is not specifically limited, What is necessary is just to be the grade which can raise the intraocular pressure drop of the said nitric acid donor compound, Specifically, 0.01-2 mass% is preferable with respect to the whole eye drop, 0.05- 1 mass% is more preferable. If it is less than 0.01 mass%, the intraocular pressure-lowering effect of a nitrogen monoxide donor compound cannot fully be enhanced, and when more than 2 mass%, an eye drop becomes a slurry form, it may become difficult to use.

In addition to the nitrogen monoxide donating compound, alginic acid or salt thereof, which are the essential components, the eye drop of the present invention may be formulated with any conventionally known optional ingredient in the eye drop, for example, a buffer, a viscous agent, a stabilizer, an isotonic agent, a preservative, and the like. Can be.

Among these, well-known buffers, such as a citrate, a phosphate, an acetate, an amino acid salt, are mentioned.

Examples of the viscous agent include polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose, povidone, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carmellose, polyethylene glycol, chondroitin or salts thereof.

Moreover, as a stabilizer, Antioxidants, such as sodium nitrite, sodium hydrogen sulfite, sodium hydrogen sulfite; Chelating agents such as sodium edetate, cyclodextrin, citric acid, citrate, and the like.

As the tonicity agent, salts such as sodium chloride and potassium chloride; Polyhydric alcohols such as glycerin and propylene glycol; Sugars such as glucose and sucrose; Sugar alcohols such as xylitol and sorbitol; Polyethers such as polyethylene glycol; Amide sulfonic acids, such as taurine, etc. are mentioned.

As the preservative, benzalkonium chloride, benzethonium chloride, chlorobutanol, paraoxybenzoic acid ester, thimerosal, sorbic acid, sorbate, chlorohexidine gluconate Etc. can be mentioned.

In the eye drop of the present invention, the pH at room temperature is preferably 4.5 to 8.5, more preferably 5.5 to 8, and particularly preferably 6 to 8. The pH is measured using a pH meter (eg, Accumet model 25 pH / Ion meter from Fisher Scientific, etc.) at room temperature.

Meanwhile, the present invention provides a method for enhancing the potency of a nitric oxide donor compound and an alginate or salt thereof for use as an active ingredient, comprising adding an alginate or a salt thereof to an eye drop containing the nitrogen monoxide donating compound as an active ingredient. It also includes potentiators of nitric oxide donor compounds.

That is, as in the present invention, even if the eye drop is added to the nitric oxide donor compound and alginic acid or its salt from the beginning, an eye drop containing an already existing nitrogen monoxide donor compound as an active ingredient (hereinafter referred to as a conventional eye drop) ) And a potentiator using a conventional alginic acid or a salt thereof as an active ingredient, the same effect can be obtained.

As a combination method of a conventional eye drop and a potentiator, the method of adding a potentiator in a conventional eye drop, mixing it uniformly, and then instilling eyedrops, or the method of individually injecting and mixing each other, etc. are mentioned.

In addition, the use ratio of the conventional eye drop and potentiator may be such that the amount of the nitrogen monoxide donating compound and alginic acid or salt thereof as the respective active ingredients are in the ranges as described above.

Next, although an Example is given and this invention is demonstrated again, this invention is not limited to these Examples, It is possible to add various changes to these within the range which does not deviate from this invention.

Example

Example 1 Eye Drops Containing Sodium Nitroprusside and Sodium Alginate

0.399 g of disodium hydrogen phosphate (12hydrate), 0.08 g of potassium dihydrogen phosphate (anhydride) and 0.74 g of sodium chloride are dissolved in purified water, and 5 mL of 0.1 N hydrochloric acid, 0.1 g of sodium nitroprusside (dihydrate) and sodium alginate 0.1 g was added and dissolved, and then purified water was further added to make the whole amount 100 mL. The pH at room temperature of the eye drop was 6.5. Here, "KIMICA ALGIN" (Kimika Co., Ltd. product: M / G ratio of about 1.2) was used as sodium alginate. Its water content was 8 mass%.

Example 2 Eye Drops Containing Nipradil and Alginic Acid

0.25 g of nipradil, 0.1 g of alginic acid, 0.08 g of potassium dihydrogen phosphate (anhydride) and 2.0 g of glycerin were dissolved in purified water, and 0.02 mL of 10% (w / v) benzalkonium chloride solution was added to the solution. Further, purified water was added to make the whole amount 100 mL. The pH at room temperature of the eye drop was 7.0. As the alginic acid, 'KIMICA ACID' (Kimika Co., Ltd. product: M / G ratio of about 1.2) was used. Its water content was 8 mass%.

Comparative Example 1 Eye Drops Containing Sodium Nitroprusside Only

0.399 g disodium hydrogen phosphate (12-hydrate), 0.08 g of potassium dihydrogen phosphate (anhydride) and 0.74 g of sodium chloride are dissolved in purified water, and 0.1 g of sodium nitroprusside and 5 mL of 0.1 N hydrochloric acid are added to this solution, and then dissolved. Purified water was added to make the whole amount 100 mL. PH of this eye drop at room temperature was 6.5.

Comparative Example 2 : Eye Drop Containing Only Nipradilol

0.25 g of nipradil was added to purified water, and 0.28 mL of dilute hydrochloric acid was added thereto. 0.02 mL of benzalkonium chloride / v) solution was added and dissolved, and then purified water was further added to make the total amount 100 mL. The pH at room temperature of this eye drop was 7.0.

Comparative Example 3 : Commercial Eye Drops (RESCULA)

A commercially available eye drop, RESCULA (R) eye drops (isopropyl unoprostone eye drops), were used as they were.

Comparative Example 4 Eye Drops Added Sodium Alginate to Commercial Eye Drops (RESCULA)

RESCULA (R) eye drops were added to 0.01 g of sodium alginate (the same as in Example 1) to dissolve, and further, RESCULA eye drops were added to make the total amount 10 mL.

Comparative Example 5 : Commercial Eye Drops (TIMOPTOL)

A commercial eye drop, TIMOPTOL (trademark of maleic acid maleic acid solution) manufactured by Banyou Pharmaceutical Co., Ltd. was used as it is.

Comparative Example 6 Eye Drops Added Sodium Alginate to Commercial Eye Drops (TIMOPTOL)

After adding TIMOPTOL (registered trademark) to 0.01 g of sodium alginate (the same as that used in Example 1) and dissolving, TIMOPTOL was further added to make the total amount 10 mL.

Test Example 1 :

The male white rabbit was fixed to a rabbit holder, 50 µl of the sample was applied to the left eye, and the right eye was untreated. Subsequently, eyedrops were applied to Santen Pharmaceutical Company's Benoxil (registered trademark) 0.4% solution (Oxybuprocaine hydrochloride), followed by surface anesthesia, and then 60 minutes and 120 minutes before instillation using a pressure tonometer. Left and right intraocular pressure after minutes and 180 minutes was measured.

The intraocular pressure (mmHg) minus the intraocular pressure (mmHg) of the right eye was defined as the intraocular pressure change (mmHg). Similarly, the average value for five rabbits was obtained for each sample. The results are shown in Table 1.

Table 1 :

Eye drops Rabbit number Intraocular pressure change (mmHg) 0 min 60 minutes 120 minutes 180 minutes Example 1 5 0.0 -5.6 ± 1.1 -6.9 ± 0.8 -4.0 ± 0.9 Example 2 5 0.0 -8.6 ± 1.3 -9.0 ± 1.9 -5.8 ± 1.1 Comparative Example 1 5 0.0 -1.3 ± 1.3 -3.2 ± 0.6 -0.7 ± 0.8 Comparative Example 2 5 0.0 -5.0 ± 0.8 -4.2 ± 0.9 -2.6 ± 0.9 Comparative Example 3 5 0.0 -0.8 ± 0.4 -4.4 ± 0.7 -5.4 ± 0.2 Comparative Example 4 5 0.0 -1.9 ± 2.0 -5.3 ± 2.0 -5.9 ± 2.4 Comparative Example 5 5 0.0 -7.0 ± 0.4 -5.2 ± 0.8 -2.7 ± 1.5 Comparative Example 6 5 0.0 -6.4 ± 1.2 -5.8 ± 2.0 -3.9 ± 1.9

When the eye drops of Example 1 containing sodium nitroprusside and sodium alginate were compared with the eye drops of Comparative Example 1 containing sodium nitroprusside but not containing sodium alginate, at a time point of 60 minutes to 180 minutes, Significant differences were observed in the degree of intraocular pressure depression, and it was found that sodium alginate enhances the intraocular pressure-lowering effect of sodium nitroprusside (see FIG. 1).

In addition, as a result of comparing the eye drops of Example 2 containing nipradilol and alginic acid with the eye drops of Comparative Example 2 containing nipradilol but not containing sodium alginate, the intraocular pressure drop was observed at a time point of 60 minutes to 180 minutes. Significant differences were observed in the degree of. Accordingly, it was found that alginic acid enhances the intraocular pressure-lowering effect of nipradil. (See FIG. 2).

However, as a result of comparing Comparative Example 3 using RESCULA and Comparative Example 4 in which sodium alginate was added to RESCULA, no significant difference was recognized in the degree of intraocular pressure drop between the two (see FIG. 3). In addition, no significant difference was observed in the degree of intraocular pressure drop between the Comparative Example 5 using TIMOPTOL and Comparative Example 6 in which sodium alginate was added to TIMOPTOL (see Fig. 4). According to these test results, it was found that alginic acid (salt) acts specifically on the nitric oxide donor compound to enhance the intraocular pressure-lowering effect.

The eye drops of the present invention have enhanced intraocular pressure-lowering effects compared with the case where the nitric oxide donor compound is used alone, and it is not necessary to use a large number of drugs in the treatment of glaucoma and ocular hypertension. Therefore, in the treatment of the disease, it is possible to solve the problems of side effects and patient costs caused by the use of a large number of drugs in combination.

The ophthalmic agent of the present invention has an enhanced intraocular pressure lowering effect than an eye drop using a nitric oxide donor compound alone, and can treat glaucoma, ocular hypertension, and the like without using other therapeutic agents.

In addition, by using the potentiator of the nitrogen monoxide donor compound of the present invention in eye drops containing the nitrogen monoxide donor compound as an active ingredient, it is possible to enhance the effect.

Claims (11)

An eye drop comprising a nitrogen monoxide donating compound and alginic acid or a salt thereof. The method of claim 1, An eye drop containing alginic acid or a salt thereof as an intraocular hypotensive effect enhancer. The method according to claim 1 or 2, The nitric oxide donor compound is eye drops of nipradilol or sodium nitroprusside. The method according to any one of claims 1 to 3, The alginate salt is sodium alginate eye drops. The method according to any one of claims 1 to 4, The eye drop of which the content of a nitrogen monoxide donating compound is 0.01-5 mass% with respect to the said whole eye drop, and content of alginic acid or its salt is 0.01-2 mass%. The method according to any one of claims 1 to 5, eye drops with a pH of 4.5 to 8.5. The method according to any one of claims 1 to 6, Eye drops for the treatment of glaucoma or ocular hypertension. A method for enhancing the potency of a nitric oxide donor compound, comprising adding alginic acid or a salt thereof to an eye drop containing the nitric oxide donor compound as an active ingredient. The method of claim 8, The method for enhancing the potency of the nitrogen monoxide donor compound is nipradilol or sodium nitroprusside. The method according to claim 8 or 9, A method for enhancing the potency of a nitric oxide donor compound, wherein the addition amount of alginic acid or a salt thereof is 0.01 to 2% by mass based on the whole eye drop. A potentiator of a nitric oxide donor compound comprising alginic acid or a salt thereof as an active ingredient.

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