JPH11228404A - Stable aqueous eye drop - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation having significantly improved stability of dipivefrin in the vicinity of physiological pH by formulating an aqueous eye drop comprising dipivefrin as an active ingredient with a specific component. SOLUTION: This aqueous eye drop comprises dipivefrin of the formula or its salt as an active ingredient and contains a component selected from an amino acid, benzoic acid and nicotinic acid amide. Glutamic acid, lysine or the like is preferable as the amino acid. In the case of the amino acid, the concentration is preferably 0.1-0.5 (W/V)%. In the case of benzoic acid and nicotinic acid amide, the concentration is preferably 0.5 (W/V)%. The concentration of dipivefrin in the aqueous preparation is preferably 0.04-0.1 (W/V)%. Preferably the aqueous eye drop contains a component selected from a nonionic surfactant, a polyhydric alcohol, a water-soluble polymer and a neutral salt to more improve stability. A polyoxyethylene sorbitan monooleate or the like is preferable as the nonionic surfactant and glycerol or the like is preferable as the polyhydric alcohol.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an aqueous ophthalmic solution containing dipivefrin or a pharmaceutically acceptable salt thereof as a main component, and to an aqueous ophthalmic solution having improved stability of dipivefrin. .

[0002]

BACKGROUND OF THE INVENTION Dipivefrin has the formula:

[0003]

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A compound represented by the formula: (±) -2-methylamino-1- [3,4-bis (pivaloyl-oxy) phenyl] ethanol; epinephrine:

[0005]

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[0006] It is used as a prodrug in anti-glaucoma eye drops. That is, dipivefrin has excellent corneal permeability when administered by eye because dipivefrin has both two phenolic hydroxyl groups of epinephrine which are pivaloyl esterified and has higher fat solubility than epinephrine. After penetrating the cornea, dipivefrin is converted to epinephrine, which is an active metabolite, by hydrolysis, and the resulting epinephrine has a therapeutic effect effective for open-angle glaucoma, high-tension glaucoma, and the like. For this reason, dipivefrin has few side effects,
It exhibits a therapeutic effect at a lower concentration than epinephrine and is known as a useful drug.

However, dipivefrin is susceptible to hydrolysis in an aqueous solution and is very unstable. Therefore, dipivefrin preparations commercially available in Japan are two-drug preparations comprising a lyophilized product and a solution. At present, there is only a formulation. Although this dual preparation has the advantage of being stable under normal storage conditions, it requires preparation of the drug by mixing the lyophilized product and the lysis solution before starting use, and is merely inconvenient. Instead, the patient must be very careful to avoid contamination with dust and bacteria. In addition, it is inconvenient not only inconvenient, but also unavoidable to use the deteriorated formulation by mistake because it is unstable after dissolution and must be used up quickly.

For these reasons, dipivefrin eye drops are preferably in the form of a stable one-part water-soluble agent, and a one-part aqueous preparation is currently used overseas. However, this one-part aqueous formulation has a physiological pH of 3 due to the need to maintain the stability of dipivefrin.
It has a much lower pH than the H range and is therefore strongly irritating to the eyes. This stimulus was unpleasant for the patient because it was a burden on the patient.

[0009]

Under such circumstances, there has been a demand for the development of a stable one-part aqueous dipivefrin preparation with less irritation and being stable. The present invention relates to an aqueous ophthalmic solution containing dipivefrin as a main component, and has a physiological pH.
An object of the present invention is to provide an aqueous eye drop in which the stability of dipivefrin has been significantly improved.

[0010]

Means for Solving the Problems The present inventors have developed an amino acid,
It has been found that the stability of dipivefrin is significantly improved in aqueous solutions containing benzoic acid or nicotinamide. It has also been found that further stabilization can be obtained by adding a nonionic surfactant, a polyhydric alcohol, a water-soluble polymer or a neutral salt to these solutions. Furthermore, they have found that the degree of stabilization is sufficient to enable the commercialization of a one-part ophthalmic solution of dipivefrin, thereby completing the present invention.

That is, the present invention relates to an aqueous ophthalmic solution containing dipivefrin or a pharmaceutically acceptable salt thereof as an active ingredient, wherein at least one component selected from the group consisting of amino acids, benzoic acid and nicotinamide is used. The present invention further provides an aqueous ophthalmic solution characterized by further containing.

[0012]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Pharmaceutically acceptable salts of dipivefrin include, for example, inorganic acid salts such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, and the like. Organic acid salts such as maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid and benzenesulfonic acid can be mentioned.

When using an amino acid in the present invention,
Various known amino acids may be used. Particularly preferred amino acids include ε-aminocaproic acid, glutamic acid,
Lysine and histidine are mentioned. When the amino acids are contained in the aqueous eye drops of the present invention, they may be added per se or may be added in the form of a salt. Examples of such salts include sodium glutamate, lysine hydrochloride, histidine hydrochloride, and the like,
It is not limited to these. When an amino acid is used, its concentration is preferably 0.01 to 1 W / V%,
Although it is particularly preferable to set it as 5 to 0.5 W / V%, it is not necessarily limited to these. When using benzoic acid,
The concentration is preferably 0.01 to 1 / V%,
Although it is particularly preferable to set it to 0.1 to 0.5 W / V%, it is not necessarily limited to these. When nicotinamide is used, its concentration is preferably 0.01 to 1 / V%, particularly preferably 0.1 to 0.5 W / V%, but is not necessarily limited thereto. .

In the present invention, satisfactory stabilization can be achieved by the inclusion of an amino acid, benzoic acid or nicotinamide. In addition, a nonionic surfactant, a polyhydric alcohol, a water-soluble polymer, It is more preferable to include at least one component selected from the group consisting of a salt in order to improve stability.

The nonionic surfactant used may be any of the various known nonionic surfactants. Particularly preferred nonionic surfactants include polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene hydrogenated castor oil, and tyloxapol (Tylo).
xapol; United States Pharmacopoeia, 23rd Edition) and polyoxyl 40 stearate. The content of the nonionic surfactant is preferably 0.01 to 10 W / V%,
More preferably, it is set to 0.05 to 5 W / V%,
Although it is particularly preferable to set it to 2 W / V%, it is not necessarily limited to these.

The polyhydric alcohol used may be of various known types. Particularly preferred polyhydric alcohols include propylene glycol, glycerin, sorbitol and xylitol. The concentration of the polyhydric alcohol used is preferably 0.1 to 5 W / V%, particularly preferably 0.3 to 3 W / V%, but is not necessarily limited thereto.

The water-soluble polymer to be used may be various known ones, but particularly preferred examples are polyvinylpyrrolidone, hydroxypropylmethylcellulose,
Examples include polyvinyl alcohol and carboxymethyl cellulose. The concentration of the water-soluble polymer used is 0.
It is preferably set to 1 to 5 W / V%, and 0.3 to 3 W / V.
% Is particularly preferred, but is not necessarily limited thereto.

The neutral salt used is a neutral salt formed from a strong acid and a strong base. Preferred neutral salts include sodium chloride, calcium chloride, magnesium chloride, sodium sulfate, calcium sulfate, magnesium sulfate, sodium nitrate, calcium nitrate and magnesium nitrate. Of these, particularly preferred are sodium chloride, calcium chloride, magnesium chloride and magnesium sulfate. The concentration of the neutral salt used is 0.1-3 W
/ V% is particularly preferred, but is not necessarily limited to this.

The pH of the aqueous eye drop of the present invention is 3.
It is preferably in the range of 5 to 8.5, particularly preferably in the range of 4 to 6. ADVANTAGE OF THE INVENTION According to this invention, since the stabilization of dipivefrin can be attained, pH can be made into a neutral range compared with the conventional one-part dipivefrin ophthalmic solution. As a result, a formulation with low irritation can be provided.

[0020] The concentration of dipivefrin in the aqueous preparation of the present invention is preferably in the range of 0.01 to 1.0 W / V%, particularly preferably in the range of 0.04 to 0.1 W / V%. .

The aqueous eye drop of the present invention may further contain, if necessary, a buffer, a preservative, an isotonic agent and a pH adjuster, provided that these are those used in ordinary eye drops. There is no particular limitation.

Examples of the buffer include acetic acid, phosphoric acid,
Examples thereof include boric acid and salts thereof.

Examples of the preservative include phenolic substances such as phenol, cresol and paraoxybenzoate, chlorobutanol and propylene glycol (which also function as a stabilizer in the present invention as described above). Alcohols, benzoic acid (which also functions as a stabilizer in the present invention as described above),
Examples thereof include acidic substances such as dehydroacetic acid and salts thereof, quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride, and thimerosal.

As the tonicity agent, sodium chloride (which also functions as a stabilizer), boric acid, borax, glycerin, glucose, mannitol and the like can be used.

[0025]

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

<Experimental Example 1> As shown in Table 1 below, ε-
Sterilize aminocaproic acid (0.5 g), sodium glutamate (0.5 g), lysine hydrochloride (0.5 g), histidine hydrochloride (0.5 g), benzoic acid (0.3 g) or nicotinamide (0.5 g) After dissolving in purified water, dipivefrin hydrochloride was added, and sterilized purified water and a small amount of hydrochloric acid or sodium hydroxide were added to make the total amount 100 ml, thereby preparing the formulations of Examples 1 to 6. pH was 5.0. Since these additives have a buffering capacity near pH 5, no other buffering agent was added. On the other hand, when dipivefrin hydrochloride generates an acid by decomposition, the pH of the solution decreases,
To the preparation of Comparative Example 1, sodium acetate, which is usually used as a buffer, was added to prepare the same aqueous solution of dipivefrin hydrochloride (pH 5.0) as described above.

[0027]

[Table 1]

These are filled in a glass ampoule, and 25
After storage at 40 ° C., 40 ° C. and 60 ° C., the pH and dipivefrin hydrochloride content of each preparation were measured. The measurement of dipivefrin hydrochloride was performed by HPLC. Percentage of dipivefrin hydrochloride remaining after storage under each condition (initial value 100%) and formulation pH
Are shown in Table 2.

[0029]

[Table 2]

As is evident from Table 2, the residual ratio of each of the examples containing various amino acids, benzoic acid or nicotinamide was maintained higher than the residual ratio of dipivefrin of Comparative Example 1. Significant stabilization was observed with these additions over the entire temperature range tested.

Experimental Example 2 As shown in Table 3 below, a solution containing ε-aminocaproic acid (0.5 g) and sodium glutamate (0.3 g) was added with sodium chloride (3 or 0.4 g) and propylene. Glycol (1
g), tyloxapol (1 or 0.3 g) or polyvinylpyrrolidone (1 g) was dissolved, dipivefrin hydrochloride was added, and sterilized purified water and a small amount of hydrochloric acid or sodium hydroxide were added to make the total volume 100 ml. 7
~ 13 formulations were prepared. The pH was 4.5. For comparison, the same aqueous dipivefrin hydrochloride solution (pH 4.5) as described above except that it contained only ε-aminocaproic acid and sodium glutamate as additives, Comparative Examples 2 and 3, respectively, was prepared.

[0032]

[Table 3]

These are filled in a glass ampoule and
After storage at 60 ° C. and at 60 ° C., the content of dipivefrin hydrochloride and the pH of the preparation were measured. The results are shown in Table 4 below.

[0034]

[Table 4]

As is apparent from Table 4, stabilization of dipivefrin hydrochloride was confirmed by adding sodium chloride, propylene glycol, tyloxapol or polyvinylpyrrolidone to a solution of dipivefrin hydrochloride containing ε-aminocaproic acid or sodium glutamate. Was done. In particular, when sodium glutamate was used and various additives were added, a prediction of chemical stability based on generally performed kinetics was performed.
It was predicted that it could be stored for years. This stability makes it possible to commercialize a one-part ophthalmic solution.

(Formulation Example 1) After dissolving the following base components in sterilized purified water, dipivefrin hydrochloride is dissolved therein, and sterilized purified water and a small amount of hydrochloric acid or sodium hydroxide are added to adjust the pH to 4.5. , Add sterile purified water and add 100m
L.

Dipivefrin hydrochloride 0.1 g Sodium glutamate 0.3 g Propylene glycol 1.0 g Sodium chloride 0.4 g Benzalco chloride Nium: 0.005 g Hydrochloric acid or sodium hydroxide: Appropriate amount of sterilized purified water: Appropriate amount: 100 mL

(Formulation Example 2) After dissolving the following base components in sterilized purified water, dipivefrin hydrochloride is dissolved in the solution, and sterilized purified water and a small amount of hydrochloric acid or sodium hydroxide are added to adjust the pH to 4.5. , Add sterile purified water and add 100m
L.

Dipivefrin hydrochloride 0.1 g sodium glutamate 0.3 g tyloxapol 0.3 g sodium chloride 0.9 g chloride Benzalkonium: 0.005 g Hydrochloric acid or sodium hydroxide: Appropriate amount of sterilized purified water: Appropriate amount: 100 mL

(Formulation Example 3) After dissolving the following base components in sterilized purified water, dipivefrin hydrochloride is dissolved therein, and sterilized purified water and a small amount of hydrochloric acid or sodium hydroxide are added to adjust the pH to 4.5. , Add sterile purified water and add 100m
L.

Dipibefrin hydrochloride 0.1 g Propylene glycol 1.0 g Sodium chloride 4.0 g Benzalkonium chloride 0.005 g ε-Aminocaproic acid 0.5 g Hydrochloric acid or sodium hydroxide Appropriate amount of sterilized purified water Appropriate amount 100 mL

(Formulation Example 4) The following base components were dissolved in sterilized purified water, and dipivefrin hydrochloride was dissolved in the solution. A small amount of hydrochloric acid or sodium hydroxide was added to adjust the pH to 4.5. Was added to bring the total volume to 100 mL.

Dipivefrin hydrochloride 0.1 g monosodium glutamate 0.1 g propylene glycol 0.5 g polyvinylpyrrolidone 1.0 g concentrated glycerin 1.5 g Benzalkonium chloride 0.005 g Hydrochloric acid or sodium hydroxide Proper amount of sterilized purified water Proper amount 100mL in total

[0044]

As described above, the eye drops of the present invention have a more neutral pH, and therefore are less irritating to the eyes than conventional low-pH one-part dipivefrin eye drops. Further, in the present invention, dipivefrin is stabilized even at such a neutral pH, so that it is not necessary to adopt a two-drug form such as a conventional two-dipivefrine ophthalmic solution, resulting in inconvenience and contamination of patients. Can be eliminated.

Claims (13)

[Claims] 1. An aqueous ophthalmic solution containing dipivefrin or a pharmaceutically acceptable salt thereof as an active ingredient, which further contains at least one component selected from the group consisting of amino acids, benzoic acid and nicotinamide. An aqueous ophthalmic solution, characterized in that: 2. An aqueous ophthalmic solution containing dipivefrin or a pharmaceutically acceptable salt thereof as an active ingredient, comprising at least one component selected from the group consisting of amino acids, benzoic acid and nicotinamide. Further, an aqueous eye drop comprising at least one component selected from the group consisting of a nonionic surfactant, a polyhydric alcohol, a water-soluble polymer and a neutral salt. 3. An aqueous drug containing dipivefrin or a pharmaceutically acceptable salt thereof as an active ingredient, which contains ε-aminocaproic acid, and further contains a nonionic surfactant, a polyhydric alcohol, and a water-soluble agent. A stabilized aqueous ophthalmic solution comprising at least one component selected from the group consisting of a polymer and a neutral salt. 4. The method according to claim 2, wherein the amino acid is selected from the group consisting of glutamic acid, lysine and histidine.
Aqueous eye drops. 5. The method according to claim 2, wherein the nonionic surfactant is selected from the group consisting of polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyloxapol and polyoxyl stearate 40. Aqueous eye drops. 6. The aqueous ophthalmic solution according to claim 3, wherein the nonionic surfactant is selected from the group consisting of polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyloxapol and polyoxyl stearate 40. Agent. 7. The aqueous ophthalmic solution according to claim 2, wherein the polyhydric alcohol is selected from the group consisting of propylene glycol, glycerin, sorbitol and xylitol. 8. The aqueous ophthalmic solution according to claim 3, wherein the polyhydric alcohol is selected from the group consisting of propylene glycol, glycerin, sorbitol and xylitol. 9. The water-soluble polymer is polyvinylpyrrolidone,
The aqueous eye drop according to any one of claims 2, 4, 5, and 7, which is selected from the group consisting of hydroxypropylmethylcellulose, polyvinyl alcohol, and carboxymethylcellulose. 10. The aqueous ophthalmic solution according to claim 3, wherein the water-soluble polymer is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, polyvinyl alcohol and carboxymethylcellulose. 11. The method according to claim 2, wherein the neutral salts are selected from the group consisting of sodium chloride, calcium chloride, magnesium chloride, sodium sulfate, calcium sulfate, magnesium sulfate, sodium nitrate, calcium nitrate, and magnesium nitrate. 10. The aqueous ophthalmic solution according to any one of 10 above. 12. The method according to claim 1, wherein the pH is 3.5 to 8.5.
The aqueous ophthalmic solution according to any one of items 1 to 11. 13. A dipivefrin concentration of 0.01 to 1.0.
The aqueous eye drop according to any one of claims 1 to 12, which is W / V%.