JPH0825874B2 - Method for producing stable eye drops containing sodium guaiazulene sulfonate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a stable eye drop containing sodium guaizulene sulfonate.

BACKGROUND OF THE INVENTION Sodium guaiazulene sulfonate (hereinafter GAS)
Is a drug having a wide range of actions such as anti-inflammatory action, anti-allergic action and epithelial regeneration granulation promoting action. In addition, it is a safe drug that has been used as an anti-inflammatory agent for a long time in medicine such as gastrointestinal drug, gargle, nasal drop and eye drop.

However, when GAS is to be prepared as an eye drop, it is necessary to add a preservative to maintain sterility for a long period of time. For conventional eye drops, as a preservative, for example, para-aminobenzoic acid ester (hereinafter parabens),
Thimerosal and chlorobutanol have been used.
Sufficient antiseptic properties can be obtained by combining these preservatives depending on the combination of the type and concentration of the preservative, but the following inconveniences occur when compounded in the GAS aqueous solution.

Generally, GAS is unstable in an aqueous solution, and to maintain its stability over a long period of time, an appropriate pH (pH 7 or more) is required.
It is necessary to set to. However, at such a high pH, the above-mentioned parabens, chlorobutanol and the like easily cause ester decomposition, resulting in a decrease in antiseptic power over time, which is not preferable as an antiseptic agent for GAS aqueous solution.

In addition, thimerosal is a mercury compound, and is legally regulated in terms of accumulation of mercury in the living body and environmental pollution, and therefore it cannot be newly added in the future.

Further, addition of sorbic acid or phenethyl alcohol as an antiseptic to the eye drop may be considered, but these compounds have weak antiseptic power and cannot maintain sterility as an eye drop for a long time.

As described above, the current situation is that no compound suitable as a preservative for GAS aqueous solution has hitherto been available.

Problems to be Solved Although the present inventors have had difficulty in selecting a preservative for GAS water-soluble liquid, it is water-soluble, has sufficient experience in use in the medical field, and has an excellent preservative power. An amphoteric surfactant such as polyaminoethylglycine (APEG) was selected.

APEG is usually an amphoteric surfactant used as the hydrochloride salt and has the following molecular formula.

[RNHCH ₂ CH ₂ NHCH ₂ CH ₂ NHCH ₂ COOH] ・ HCl R = C ₈ H _{17 to} C ₁₆ H ₃₃ (mainly C ₁₂ H _{25 to} C ₁₄ H ₂₉ ) APEG is against Pseudomonas aeruginosa, fungi and general bacteria. It has a strong bactericidal action, and due to its strong bactericidal power, it is used in various fields such as disinfection of medical instruments and operating rooms. On the other hand, it is a preservative that has been used as a medical ophthalmic agent for cleaning and disinfecting conjunctival sac. In addition, it is a compound that has been confirmed to be safe and effective based on its achievements in various fields of medicine, and its compounding is also approved in the standard for approval of general eye drops.

However, GAS originally has a sulfonic acid group in the molecule to make it water-soluble, and normally exists as a crystal of sodium salt, but dissociates in an aqueous solution and has an anionic property. Therefore, if an attempt is made to mix a cationic drug with an aqueous GAS solution at the same time, an insoluble complex is formed and becomes turbid. The preservative APEG taken by the present inventors is also
Since it has both cation and anion properties in aqueous solution, it becomes turbid when mixed with GAS aqueous solution.

When APEG is dissolved in water, concentration range used (0.001-0.1%)
A clear aqueous solution without turbidity can be obtained, but it becomes cloudy in appearance when the highest concentration of GAS (0.02%) used as an eye drop is added. The results are shown in Table 1 below.

Therefore, although sufficient effect can be obtained as antiseptic,
There was a formulation problem (turbidity), and it was necessary to solve that problem.

Means for Solving the Problems The present inventors have studied various additives to prevent turbidity when an amphoteric surfactant such as APEG is mixed with an aqueous GAS solution, and as a result, it is said to be a nonionic surfactant. It was found that turbidity can be prevented by using an additive, and the preservative power inherent to APEG is not reduced.

Here, the non-on surfactant may be added before adding APEG to the GAS aqueous solution, or may be added after adding APEG first and making it cloudy.

Examples of the nonionic surfactant include polyoxyethylene sorbitan fatty acid ester (eg, polysorbate 8
0), polyoxyethylene hydrogenated castor oil (eg polyoxyethylene hydrogenated castor oil 60), polyoxyethylene alkyl ether (eg polyoxyethylene (9) lauryl ether), polyethylene glycol fatty acid ester (eg polyoxyl stearate 40) ) And polyoxyethylene alkyl phenyl ether (eg, polyoxyethylene (10) octyl phenyl ether) and the like. These surfactants are listed in the Japanese Pharmacopoeia and compendial documents such as the standards for cosmetic raw materials, and are widely used as additives for injections and cosmeceuticals.

The concentration of the nonionic surfactant, which depends on the concentration of APEG, has an turbidity-preventing effect even at 0.002% or more, and 0.02% or more, preferably 0.1% to 0.1% to maintain clarity as a pharmaceutical for a long time. 0.5%.

Example 1 Polysorbate 80 was selected as the nonionic surfactant,
To obtain its optimum concentration, various concentrations of polysorbate
An azulene aqueous solution containing 80 was prepared, and the appearance immediately after the preparation was observed. The results are shown in Table 2 below.

Polysorbate 80 for GAS 0.02% and APEG 0.02%
It was found that a clear solution can be obtained when the concentration of is 0.02% or more.

Regarding the APEG concentration, an aqueous solution with a concentration of 0.01% to 0.05% is frequently used for disinfecting mucous membranes and skin at the surgical site, and up to 0.1% is allowed for general ophthalmic drugs.
Therefore, as an additive for eye drops, its 1/5 amount is 0.02%
The following concentrations were examined.

Example 2 Azulene aqueous solutions containing various concentrations of APEG and polysorbate 80 as a nonionic surfactant were prepared and the appearance was observed. The results are shown in Table 3 below.

From the results of Example 2, it was found that when the concentration of APEG decreased, the required concentration of polysorbate 80 also decreased, and when 0.001% of APEG was used, 0.002% or more of polysorbate 80 was sufficient.

However, from the viewpoint of maintaining the quality as an eye drop, a polysorbate 80 concentration of 0.02% or more, preferably 0.1% or more is optimal for maintaining clarity for a long period of time.

Example 3 A solution was prepared by changing the type of nonionic surfactant, and the properties after preparation were observed. The results are shown in Table 4 below.

With any nonionic surfactant, a clear solution is obtained.

Claims (2)

[Claims] 1. A method for producing a stable eye drop, comprising adding an alkyl polyaminoethyl glycine and a nonionic surfactant to an aqueous solution of sodium guaizulene sulfonate. 2. The method for producing an eye drop according to item (1), wherein the nonionic surfactant is added in a concentration range of 0.002% or more, preferably 0.1% or more and 0.5% or less.