JP2002080314A - Preservative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a preservative which comprises the combination of ingredients having generally been used as additives for aqueous liquid formulations and has high safety. SOLUTION: This preservative comprises the combination of boric acid and/or borax, ethylenediaminetetraacetic acid or its salt, and polyvinylpyrrolidone. The preservative is preferably further mixed with a cellulosic polymer to reinforce the effect of the preservation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preservative comprising a combination of boric acid, ethylenediaminetetraacetic acid and polyvinylpyrrolidone, and further to a preservative obtained by using a cellulose polymer in combination therewith. It can be suitably used for aqueous liquids such as solutions.

[0002]

2. Description of the Related Art Conventionally, benzalkonium chloride, benzethonium chloride, sorbic acid and the like have been used as preservatives for eye drops and contact lens solutions.

[0003]

However, benzalkonium chloride and benzethonium chloride have a high preservative effect, but may cause corneal damage depending on their concentration.
There are restrictions on the concentration used. Furthermore, they also have the property of easily adsorbing to contact lenses and plastic containers.

[0004] Sorbic acid, which is widely used as an antiseptic for eye drops for contact lenses, has a problem that the antiseptic effect is weak, though it has few side effects and little adsorption to contact lenses and plastic containers.

[0005] On the other hand, components that can be used as preservatives in pharmaceuticals such as eye drops are limited.

[0006]

The inventors of the present invention have conducted intensive studies to combine the components already used in aqueous preparations such as eye drops and the like to exert an antiseptic effect. Boric acid and / or borax as a buffer in eye drops,
In addition, ethylenediaminetetraacetic acid or a salt thereof has been widely used as a stabilizer, and attention has been paid to the fact that these compounds have a preservative effect although they are weak, and a study for enhancing the preservative effect was conducted. as a result,
It has been found that the addition of (C) polyvinylpyrrolidone, which is widely used as a thickener, to (A) boric acid and / or borax and (B) ethylenediaminetetraacetic acid can significantly enhance the preservative effect. Was completed. It was also found that the addition of a cellulosic polymer, which is also commonly used as a thickener, to this combination further enhances the preservative effect.

[0007]

DETAILED DESCRIPTION OF THE INVENTION The preservative of the present invention is composed of three essential components, the first of which is boric acid and / or borax. The preferred range of the amount of boric acid and / or borax is 0.05 to 3.0% by weight, and the more preferred range is 0.5 to 2.0% by weight. If the amount of the first component is too small, a sufficient preservative effect cannot be obtained,
If it is too large, it is not preferable from the viewpoint of safety for eyes.

The second component of the present invention is ethylenediaminetetraacetic acid or a salt thereof. As the salt, a tetrasodium salt or a disodium salt (sodium edetate) can be suitably used. A preferred range of the amount of ethylenediaminetetraacetic acid or a salt thereof added is 0.01 to 0.3% by weight, and a more preferable range is 0.05 to 0.2% by weight. If the amount of the second component is too small, sufficient stability and preservative effect cannot be obtained, and if it is too large, it is not preferable from the viewpoint of safety for eyes.

The third component of the present invention is polyvinylpyrrolidone (PVP), for example, "PVP K-25"
(Average molecular weight 25,000), "PVP K-30"
(Average molecular weight 40,000), "PVP K-90"
(Average molecular weight 360,000) can be used. P
The preferred range of the amount of VP added is 0.02 to 4.0% by weight, and the more preferred range is 0.1 to 2.0% by weight. If the amount of the third component is too small, a sufficient antiseptic effect cannot be obtained. If the amount is too large, unpleasant stickiness is undesirably caused.

In the present invention, the addition of a cellulosic polymer in addition to the first to third components further enhances the preservative effect. Examples of the cellulosic polymer include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose and the like, with hydroxypropylmethylcellulose being particularly preferred. The addition amount of the cellulosic polymer is not particularly limited, but the preferred range is 0.01 to
0.5% by weight, more preferably 0.05 to 0.3
% By weight.

Since the preservative of the present invention has high safety to the human body and little adsorption to contact lenses and plastic containers, it is suitably used for aqueous pharmaceutical solutions such as eye drops and solution for contact lenses. In preparing these aqueous liquid preparations, in addition to the above-mentioned components, other additives such as a tonicity agent, a pH regulator, a solubilizer, and a preservative can be appropriately compounded.

The drug to which the aqueous solution can be applied is not particularly limited. For example, various kinds of vitamins (vitamin B2, vitamin B6, vitamin B12, vitamin B12)
E, panthenol, etc.), decongestants (tetrahydrozoline hydrochloride, naphazoline hydrochloride, etc.), anti-inflammatory agents (dipotassium glycyrrhizinate, epsilon-aminocaproic acid, etc.), antihistamines (chlorpheniramine maleate, diphenhydramine hydrochloride, etc.), anti-allergy Agents (eg, sodium cromoglycate), antibacterial agents (eg, sulfamethoxazole), amino acids (eg, potassium L-aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate), sodium hyaluronate, and neostigmine methyl sulfate. Can be.

Examples of the tonicity agent include glycerin, propylene glycol, sodium chloride, potassium chloride,
Sorbitol, mannitol and the like can be mentioned.

Examples of the pH adjuster include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.

Examples of the solubilizing agent include polysorbate 80, polyexylene ethylene-hardened castor oil 60, Macrogol 4000 and the like.

The preservative of the present invention can be used in combination with commonly used preservatives such as sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl parahydroxybenzoate, propyl paraoxybenzoate and chlorobutanol. it can. In this case, since the preservative of the present invention can complement the preservative effect of the general-purpose preservative, it also has the effect of greatly reducing the amount of the general-purpose preservative used.

When the liquid preparation of the present invention is used as eye drops, it is desirable to adjust the pH to around 7.0 and the osmotic pressure ratio to around 1.0.

Hereinafter, the present invention will be described in detail with reference to examples, but this does not limit the scope of the present invention.

[0019]

EXAMPLES In order to examine the preservative effect of the preservative of the present invention, a preservative efficacy test was performed as follows.

(Preservation Efficacy Test) Table 1
The liquid components were prepared by adding the components shown in Examples 1 to 4 and Comparative Examples 1 to 3. Further, sodium chloride is added to each liquid as an isotonic agent, the osmotic pressure is adjusted to 1.0, and if necessary, sodium hydroxide is added to adjust the pH to 7.0.
Adjusted to zero. The preservative efficacy test was performed in accordance with the preservative efficacy test method of the 13th revised Japanese Pharmacopoeia. In this test, Staphyrococcus aureus (S. aureus) was used as a test bacterium, and the survival rate of the bacterium was calculated according to the following formula. Table 1 shows the obtained values.

Survival rate (%) = number of bacteria after 2 weeks / initial number of bacteria ×
100

[0022]

[Table 1]

[0023]

[0024]

As is clear from Table 1, in Examples 1 and 2 of the present invention, the antiseptic effect is remarkably improved as compared with Comparative Examples 1 to 3. Further, in Examples 3 and 4 to which HPMC was added, the antiseptic effect was improved as compared with Examples 1 and 2. Thus, (A) boric acid and / or borax,
(B) In addition to ethylenediaminetetraacetic acid or a salt thereof,
In the preservative of the present invention containing (C) polyvinylpyrrolidone, each component acts synergistically to increase the preservative power. Further, if a cellulosic polymer is further added thereto, the antiseptic effect of the present invention can be further enhanced.
Therefore, the preservative of the present invention enhances the preservative effect of the liquid preparation by combining a compound widely used as a buffer, a stabilizer, and a thickener, so that it is highly safe for the human body and is suitable for pharmaceutical use. . Further, the preservative of the present invention can be used in combination with preservatives such as benzalkonium chloride and sorbic acid which are widely used, and in this case, the amount of the general-purpose preservative can be reduced.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (reference) A61K 47/32 A61K 47/32 47/38 47/38 F term (reference) 4C076 AA12 BB24 DD22 DD49 EE16 EE32 FF39 4H011 AA02 BA02 BB06 BB09 BB18 BC19 DA13 DC05 DF04 DH10

Claims (7)

[Claims] (A) boric acid and / or borax, (B)
A preservative comprising a combination of ethylenediaminetetraacetic acid or a salt thereof and (C) polyvinylpyrrolidone. 2. The preservative according to claim 1, further comprising (D) a cellulosic polymer. 3. An aqueous solution containing the preservative according to claim 1 or 2. 4. The aqueous liquid preparation according to claim 3, wherein the dosage form is an eye drop. 5. A preservative comprising (A) 0.05 to 3.0% by weight of boric acid and / or borax, (B) 0.01 to 0.3% by weight of ethylenediaminetetraacetic acid or a salt thereof, and (C) Aqueous solution containing 0.02 to 4.0% by weight of polyvinylpyrrolidone. 6. The method according to claim 1, further comprising:
The aqueous liquid preparation according to claim 5, comprising 1 to 0.5% by weight. 7. The preservative according to claim 2, wherein the cellulosic polymer is hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose or hydroxyethylcellulose.