JPS63297322A - Production of stable ophthalmic solution containing sodium guaiazulenesulfonate - Google Patents

Abstract

PURPOSE:To obtain a stable ophthalmic solution containing sodium guaia zulenesulfonate maintaining clarity for a long period, by blending an aqueous solution of sodium guaiazulenesulfonate with an ampholytic surface active agent and a nonionic surface active agent. CONSTITUTION:An aqueous solution of sodium guaiazulenesulfonate well-known as an anti-inflammatory drug from old times is blended with an ampholytic surface active agent (e.g. alkylpolyaminoethylglycine) as an antiseptic and a nonionic surface active agent (e.g. polyoxyethylene sorbitan fatty acid ester or polyoxyethylene alkyl ether) for preventing turbidity in blending of the ampholytic surface active agent. The amount of the nonionic surface active agent is >=0.002%, preferably 0.1-0.5%.

Description

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

Background of the Invention Sodium guaiazulene sulfate (GAS)
) is a drug that has a wide range of effects such as anti-inflammatory, anti-allergic, and promoting epithelial regeneration and granulation formation. It is also a safe drug that has been frequently used as an anti-inflammatory agent in pharmaceuticals such as gastrointestinal drugs, throat preparations, nasal drops, and eye drops.

However, when preparing GAS into eye drops, it is necessary to add a preservative to maintain sterility over a long period of time. Conventional eye drops have used, for example, para-aminobenzoic acid ester (hereinafter referred to as parabens), thimerosal, and chlorobutanol as preservatives. Although these preservatives can have sufficient preservative power depending on the combination of blend type and concentration, when they are blended into a GAS aqueous solution, the following disadvantages occur.

Generally, GAS is unstable in an aqueous solution, and in order to maintain its stability over a long period of time, it is necessary to set the pH to an appropriate level (pH 7 or higher). However, with such a high I)H, the above-mentioned parabens, chlorobutanol, etc. easily cause ester decomposition, resulting in a decrease in preservative power over time, and are not preferred as preservatives for GAS aqueous solutions.

Additionally, thimerosal is a mercury compound and is legally regulated due to mercury accumulation in the body and environmental pollution.
No new combinations will be possible in the future.

Furthermore, it is possible to add sorbic acid or phenethyl alcohol as a preservative to eye drops, but these compounds have weak preservative power and cannot maintain sterility as an eye drop for a long period of time.

As mentioned above, the current situation is that there has been no compound suitable as a preservative for GAS aqueous solutions.

Problems to be Solved The present inventors had a difficult time selecting a preservative for GAS water-soluble liquids, but they chose alkyl, which is water-soluble, has sufficient experience in use in the medical field, and has excellent preservative power. An amphoteric surfactant such as polyaminoethylglycine (hereinafter referred to as APEG) was selected.

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

[RNIICH*CHJHCHtCIIJHCIltC
OOII] ・1lc4R=CsHt7~C+eH33
(Mainly C+Jts to C+-Hzg) APEG has a strong bactericidal effect against Pseudomonas aeruginosa, fungi, and general bacteria, and because of its strong bactericidal power, it is used in many fields such as disinfecting medical instruments and operating rooms. On the other hand, it is a preservative that has been used as a medical ophthalmological agent to clean and disinfect conjunctival sacs. In addition, its stability and effectiveness have been confirmed through experience in various pharmaceutical fields, and its formulation is approved by the approval standards for over-the-counter eye drops.

However, GAS originally has a sulfonic acid group in its molecule to make it water-soluble, and although it normally exists as a sodium salt crystal, it dissociates in an aqueous solution and has anionic properties. Therefore, if a cationic drug is simultaneously added to a GAS aqueous solution, an insoluble complex will be formed and the solution will become cloudy.

The preservative APEG, which was taken up by the present inventors, also has both cationic and anionic properties in an aqueous solution, so GA
When mixed with S aqueous solution, it becomes cloudy.

When APEG is dissolved in water, the concentration range for use (0,001~
0.1%), a clear aqueous solution with no turbidity can be obtained, but the highest concentration of GAS used as eye drops (0.02%)
%), the appearance becomes cloudy.

The results are shown in Table 1 below.

Table 1 (pH 7, 6 with borate buffer, osmotic pressure 280m05
m/kg) ○Clear, ×Cloudy Therefore, although a sufficient preservative effect can be obtained, it has a formulation problem (turbidity), and it was necessary to solve this problem.

Means to Solve the Problem The present inventors investigated various additives to prevent turbidity when amphoteric surfactants such as APEG are blended into GAS aqueous solutions, and found that they are called nonionic surfactants. It has been found that by using additives, turbidity can be prevented and the inherent preservative power of APEG is not reduced.

Here, the nonionic surfactant may be added before adding APEG to the GAS aqueous solution, or may be added after APEG is added first to make the solution turbid.

Examples of nonionic surfactants include polyoxyethylene sorbitan fatty acid esters (e.g. polysorbate 80
), polyoxyethylene hydrogenated castor oil (e.g. polyoxyethylene hydrogenated castor oil 60), polyoxyethylene alkyl ether (e.g. polyoxyethylene (9) lauryl ether), polyethylene glycol fatty acid ester (
Examples include polyoxyl nistearate 40) and polyoxyethylene alkylphenyl ether (eg polyoxyethylene (!0) octylphenyl ether).

These surfactants are listed in official documents such as the Japanese Pharmacopoeia and the Standards for Cosmetic Ingredients, and are widely used as additives for injections and medicinal cosmetics.

The concentration of the nonionic surfactant depends on the concentration of APEG, but even 0.002% or more has an anti-turbidity effect, and 0.002% or more is necessary to maintain clarity for a long period of time as a pharmaceutical product.
0.02% or more, preferably 0.1% to 0.5%.

Example! Polysorbate 80 was selected as a nonionic surfactant,
In order to obtain the optimum concentration, azulene aqueous solutions containing various concentrations of polysorbate 80 were prepared, and the appearance immediately after preparation was observed. The results are shown in Table 2 below.

Table 2 (pH 7, 6 with borate buffer, osmotic pressure 280m05
m / 9) × turbidity, Δ turbidity after standing at room temperature, ○ clear In the case of GAS 0.02% and APEG 0.02%, if the concentration of polysorbate 80 is 0.02% or more, a clear solution can be obtained. I found out that it can be done.

Next is the APEG concentration, which is 0.0 for disinfecting mucous membranes and skin at the surgical site. Aqueous solutions with concentrations of O1% to 0.05% are frequently used, and concentrations up to 0.1% are permitted for general ophthalmological drugs. Therefore, as additives for eye drops, additives with a concentration of 0.02% or less, which is the amount of 115, were investigated.

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

Table 3 (pH 7, 6 with borate buffer, osmotic pressure 280 m05
ml kg) × Cloudy, △ Cloudy after standing at room temperature, ○ Clear From the results of Example 2, if the concentration of APEG decreases, the concentration of necessary polysorbate 80 also decreases, and APRG 0
．． 0.001%, it was found that polysorbate 80 of 0.002% or more can be used.

However, in order to maintain quality as an eye drop and maintain clarity over a long period of time, polysorbate 80a of 0.02% or more, preferably 0.115% or more is optimal.

Example 3 Solutions were prepared using different types of nonionic surfactants, and the properties after preparation were observed. The results are shown in Table 4 below.

Table 4 (pH 7, 6 with borate buffer, osmotic pressure 280 mOs)
(Prepared to 1 kg of tn) ○Clear A clear solution can be obtained with any nonionic surfactant.

Claims (2)

[Claims] (1) In an aqueous solution of sodium guaiazulene sulfonate,
A method for producing a stable eye drop, which comprises blending an amphoteric surfactant and a nonionic surfactant. (2) The method for producing eye drops 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.