KR102461699B1 - Gargle solution with improved stability comprising benzidamine hydrochloride - Google Patents

Abstract

The present invention relates to a gargle solution with benzydamine hydrochloride, which can maintain stability for a long period of time in a polyethylene pouch material. The gargle solution has a slightly acidic pH, and thus can maintain stability for a long period of time even if the gargle solution is packed in a pouch with a polyethylene pouch material. The gargle solution of the present invention includes benzydamine hydrochloride, an aqueous solvent, a preservative and a buffer agent.

Description

Mouthwash with improved stability containing benzidamine hydrochloride {GARGLE SOLUTION WITH IMPROVED STABILITY COMPRISING BENZIDAMINE HYDROCHLORIDE}

The present invention relates to a gargle solution containing benzidamine hydrochloride that has a weakly acidic pH and maintains long-term stability in a polyethylene spore material.

The oral cavity is prone to diseases such as bad breath, tartar formation, tooth decay, gingivitis, and periodontitis due to food intake. In particular, tartar is the cause of tooth decay and at the same time the biggest cause of inflammatory diseases in the oral cavity such as gingivitis and periodontitis.

Gingivitis refers to inflammation of the gingiva (gum), and is a relatively mild disease because the inflammation is limited to the gums and does not spread to the periodontal ligaments or gum bones. When gingivitis worsens, inflammation spreads to the area around the gums, which is called periodontitis. It is a chronic inflammatory disease caused by bacteria and toxins in the tartar due to inflammation of the supporting tissues surrounding the teeth.

If inflammation is left unattended, teeth will be lost, so there are products in the form of mouthwash, toothpaste, and strip preparations to relieve or treat inflammatory diseases in the oral cavity. Mouthwash is used in the form of rinsing and spitting out the mouth, and it is widely used in the treatment and prevention of oral inflammation in daily life. However, since most of the gargle liquids on the market are sold in large quantities, they are inconvenient to carry and store, and there is the inconvenience of having to gargle after adjusting the amount each time you use them.

The present inventors individually packaged the mouthwash containing benzidamine hydrochloride in a polyethylene pouch to improve the discomfort. However, when the pouch is stored for a long period of time, the content of benzidamine hydrochloride is reduced, and related substances are generated, resulting in reduced stability. The present inventors have completed the present invention by confirming that the pH of the gargle solution is adjusted in various ranges to improve the stability when the gargle solution is packaged in a pouch, and the stability of the gargle solution is improved at a slightly acidic pH. Accordingly, it is an object of the present invention to provide a gargle solution that maintains stability even when packaged in a pouch form.

The present invention provides a gargle solution containing benzidamine hydrochloride, an aqueous solvent, a preservative and a buffer, having a pH of 3.0 to 6.0, and maintaining stability in a spore material made of polyethylene.

The present inventors individually packaged the gargle solution (pH 6 to 7) containing benzidamine hydrochloride in a pouch to improve ease of use and portability, but it was confirmed that the stability of the gargle solution stored in the pouch was reduced under severe storage conditions.

Specifically, in bottle packaging products, the content of benzidamine hydrochloride was constant and related substances did not increase by more than 0.1%, whereas in pouch packaging products, the content of benzidamine hydrochloride decreased by more than 5% and related substances increased to about 2.9% in pouch packaging products. stability was significantly reduced (Tables 3 and 4).

Therefore, in order to improve the stability of the pouch product, benzidamine hydrochloride was dissolved in weak acid, neutral and weak base aqueous solutions, respectively, and stored under severe conditions (60C, 75% RH) for 4 weeks to evaluate stability according to pH. As a result, it was confirmed that the amount of related substances increased by 1% or more in aqueous solutions of neutral and weak bases, but increased to less than 0.1% in weakly acidic aqueous solutions (Table 6). Accordingly, the gargle solution according to an embodiment of the present invention may have a pH of 3.0 to 5.5, preferably 3.0 to 5.0, which is in the weakly acidic range.

The pH may be adjusted by adding a buffer or a pH adjusting agent to the gargle solution. Although not limited thereto, the buffer may be selected from the group consisting of citric acid, phosphoric acid, citric acid hydrate, tartaric acid, acetic acid, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and mixtures thereof, According to one embodiment of the invention, it may be a combination of citric acid and potassium monohydrogen phosphate.

In addition, although not limited thereto, the aqueous solvent may be water, preferably purified water.

On the other hand, the preservative is a material for preventing denaturation of the drug, but is not limited thereto, and a paraoxybenzoic acid-based preservative may be used, for example, methyl paraoxybenzoate or propyl paraoxybenzoate may be used. Methyl paraoxybenzoate has high solubility in ethanol, but when ethanol is used, the bitter taste is very strong. Therefore, the present inventors dissolved methyl paraoxybenzoate at a high temperature to exclude the use of ethanol, thereby greatly improving the taste of mouthwash.

In one embodiment of the present invention, the benzdamine hydrochloride may be included in an amount of 1.2 to 1.8 mg/ml in the mouthwash, preferably in an amount of 1.4 to 1.6 mg/ml. Benzidamine hydrochloride is a non-steroidal anti-inflammatory drug (NSAID) that reduces pain and soothes inflammation. can be used for treatment.

Meanwhile, in the present invention, the gargle solution may further include an additive selected from the group consisting of an emulsifier, a thickener, and a flavoring agent.

The emulsifier is a material added to prevent layer separation of the liquid agent. In one embodiment of the present invention, the emulsifier may be tocopherol polyethylene glycol succinate.

In addition, the flavoring agent refers to a substance that blocks an unpleasant smell or taste or gives a refreshing feeling when using the gargle, for example, L-menthol, peppermint oil, fruit flavor, honey flavor, vanilla flavor, etc. may be used. In one embodiment of the present invention, the flavoring agent may be L-menthol and peppermint oil.

Thickener is a substance that controls the viscosity of gargle solution to prevent leakage during pouch packaging. These include xanthan gum, guar gum, carboxymethyl cellulose sodium (CMC sodium), and D-sorbitol. In one embodiment of the present invention, the thickening agent may be D-sorbitol.

On the other hand, the mouthwash that maintains stability in the polyethylene spore material according to an embodiment of the present invention is benzidamine hydrochloride 1.2 to 1.8 mg/ml, methyl paraoxybenzoate 0.08 to 0.12 mg/ml, and buffer 0.2 to 100 mg/ml It may contain 0.4 to 200 mg/ml of tocopherol polyethylene glycol succinate, 0.5 to 480 mg/ml of a sweetener, and 0.12 to 200 mg/ml of a flavoring agent.

Specifically, benzidamine hydrochloride 1.2 to 1.8 mg/ml, methyl paraoxybenzoate 0.08 to 0.12 mg/ml, citric acid 0.3 to 0.6 mg/ml, potassium monohydrogen phosphate 0.4 to 0.6 mg/ml, tocopherol polyethylene glycol succinate 0.4 to 0.6 mg/ml, D-sorbitol solution at 320 to 480 mg/ml, L-menthol at 0.12 to 0.18 mg/ml, and peppermint oil at 0.04 to 0.06 mg/ml.

More specifically, the gargle solution according to an embodiment of the present invention contains benzidamine hydrochloride at 1.4 to 1.6 mg/ml, methyl paraoxybenzoate at 0.09 to 0.11 mg/ml, citric acid at 0.4 to 0.5 mg/ml, potassium monohydrogen phosphate at 0.45 to 0.55 mg. /ml, tocopherol polyethylene glycol succinate 0.45 to 0.55 mg/ml, D-sorbitol solution 350 to 450 mg/ml, L-menthol 0.14 to 0.16 mg/ml and peppermint oil 0.045 to 0.055 mg/ml.

If necessary, the gargle solution according to the present invention may contain an appropriate amount of a pharmaceutically acceptable colorant and sweetener.

The gargle solution according to an embodiment of the present invention has a weakly acidic pH, so that long-term stability is maintained even when packaged with a polyethylene spore material.

Hereinafter, one or more specific examples will be described in more detail through examples. However, these examples are for illustrative purposes of one or more embodiments, and the scope of the present invention is not limited to these examples.

Experimental Example 1: Stability evaluation according to spore material of mouthwash containing benzidamine hydrochloride

1-1. Mouthwash production

According to Table 1 below, a gargle solution (pH 6 to 7) containing benzidamine hydrochloride was prepared and packaged with two types of spores to confirm stability for 4 weeks under severe conditions.

purpose of mixing additive chief ingredient benzidamine hydrochloride preservative methyl paraoxybenzoate emulsifier concentrated glycerin sweetener steviol glycoside pH regulator sodium bicarbonate emulsifier Polysorbate 20 flavoring agent peppermint oil coloring agent Blue No. 1 coloring agent Yellow No. 4 (Tartrazine) pH regulator citric acid hydrate solvent Purified water solvent ethanol

- Storage conditions: Severe conditions (60C, 75% RH)

- Storage period: 4 weeks

- Type of spore material

Bottle packaging: bottle-HDPE, stopper-PP),

Pouch packaging: PET16/PE15/AL9/PE15/MLLD30 (Manufacturer-Woojin Chem; PET, PE, Al, PE, MLLD are abbreviations for the material of the packaging material, and the number next to it is the thickness of the material in μm)

1-2. Content analysis method

The standard solution and the sample solution were analyzed according to the Korean Pharmacopoeia liquid chromatography method as follows.

1) Preparation of placebo solution

Precisely take 5 mL of this drug except for benzidamine hydrochloride, put it in a 50 mL volumetric flask, align the mark with the mobile phase, and filter it with a 0.45 μm filter. After discarding the initial 3-4 mL, the filtrate was used as a placebo solution.

2) Preparation of standard solution

150.0 mg of benzidamine hydrochloride standard and 10.0 mg of methyl paraoxybenzoate standard were precisely taken and placed in a 100 mL volumetric flask, and after adding about 50 mL of the mobile phase, it was dissolved by sonication. After cooling, align the mark with the mobile phase, take 5 mL of this solution, put it in a 50 mL volumetric flask, and align the mark with the mobile phase. This solution was filtered through a 0.45 μm filter, the initial 3 to 4 mL was discarded, and the filtrate was used as a standard solution.

[0.15 mg/mL as benzidamine hydrochloride] [0.01 mg/mL as methyl paraoxybenzoate]

3) Preparation of sample solution

Precisely take 5 mL of this drug, put it in a 50 mL volumetric flask, align the mark with the mobile phase, and filter this solution with a 0.45 μm filter. After discarding the initial 3-4 mL, the filtrate was used as a sample solution.

[0.15 mg/mL as benzidamine hydrochloride] [0.01 mg/mL as methyl paraoxybenzoate]

4) Analysis method

① Detector: Ultraviolet absorbance spectrometer (measurement wavelength: 254 nm)

② Column: YMC-Pack Pro C18, 4.6 x 150 mm, 5 μm

(Product number: AS12S05-1546WT)

③ Column temperature: 40℃

④ Flow rate: 1.3 mL/min

⑤ Injection volume: 5 μL

⑥ mobile phase

- 10 mM ammonium acetate: acetonitrile: glacial acetic acid = 60: 40: 1 (v/v/v)

10 mM ammonium acetate was prepared by dissolving 0.77 g of ammonium acetate in 1000 mL of purified water.

⑦ Flowing order: Benzidamine hydrochloride, methyl paraoxybenzoate, in that order

5) Calculation of benzidamine hydrochloride content

The content of benzidamine hydrochloride was calculated according to Equation 1 below.

[Equation 1]

A _T : Peak area of benzidamine hydrochloride in the sample solution

A _S : Peak area of benzidamine hydrochloride in standard solution

C _S : Benzidamine hydrochloride concentration of standard solution (mg/mL)

C _T : concentration of benzidamine hydrochloride in the sample solution (mg/mL)

P: standard purity (%)

6) System suitability

When the standard solution was analyzed 6 times, the relative standard deviation of the peak area of benzidamine hydrochloride was 2.0% or less, the USP Tailing Factor was 2.0 or less, and the number of theoretical plates was 2000 or more.

1-3. Related substance test method

It was analyzed according to the Korean Pharmacopoeia liquid chromatography method in the following way.

1) Preparation of blank test solution

The diluted solution was filtered through a 0.45 μm filter, the initial 3 to 4 mL was discarded, and the filtrate was used as a blank test solution.

2) Preparation of positioning solution

Precisely take 2.0 mg of analog A standard, 2.5 mg of analog B standard, 2.0 mg of analog C standard, and 1.0 mg of benzidamine hydrochloride standard, put them in a 100 mL volumetric flask, add about 50 mL of diluent, and then dissolve by sonication did it After cooling, align the mark with the diluent, take 3 mL of this solution, put it in a 10 mL volumetric flask, and align the mark with the diluent. Then, this solution was filtered through a 0.45 μm filter, the initial 3 to 4 mL was discarded, and the filtrate was used as a positioning solution.

[Associated substance A: 0.0060 mg/mL] [Associated substance B: 0.0075 mg/mL] [Associated substance C: 0.0060 mg/mL]

[Benzidamine hydrochloride: 0.0030 mg/mL]

3) Preparation of placebo solution

Except for benzidamine hydrochloride, this drug was filtered through a 0.45 μm filter, the initial 3-4 mL was discarded, and the filtrate was used as a placebo solution.

4) Preparation of standard solution

15.0 mg of benzidamine hydrochloride standard was precisely taken, put into a 100 mL volumetric flask, about 50 mL of a diluent was added, and then sonicated to dissolve. After cooling, align the mark with the diluent, take 4 mL of this solution, put it in a 200 mL volumetric flask, and align the mark with the diluent. Then, this solution was filtered through a 0.45 μm filter, the initial 3 to 4 mL was discarded, and the filtrate was used as a standard solution.

[0.0030 mg/mL as benzidamine hydrochloride]

5) Preparation of sample solution

Filter this drug through a 0.45 μm filter, discard the initial 3 to 4 mL, and use the filtrate as a sample solution.

[1.5000 mg/mL as benzidamine hydrochloride]

6) Analysis method

① Detector: UV absorbance spectrometer (measurement wavelength: 320 nm)

② Column: CAPCELL PAK C18, 4.6 x 250 mm, 5 μm or similar column

③ Column temperature: 25℃

④ Flow rate: 1.5 mL / min

⑤ Injection volume: 40 μL

⑥ mobile phase

- mobile phase A: pH 3.0 buffer

- mobile phase B: methanol

The pH 3.0 buffer was dissolved in 1.36 g of potassium dihydrogen phosphate and 1.16 g of sodium octyl sulfate in 1 L of purified water, and then phosphoric acid was added thereto to adjust the pH to 3.0±0.1.

- Diluent: 50% methanol

⑦ Mobile phase composition

time (minutes) Mobile phase A (%) Mobile phase B (%) 0 50 50 0 → 10 30 70 10 → 20 30 70 20 → 30 50 50

1-4. Test result

1) Benzidamine hydrochloride content: 90% to 110% of standard

period
packaging container Early 1 week harsh harsh 2 weeks harsh 4 weeks rate of change
│Severe 4 weeks-early │ bottle packaging 101.6% 100.9% 99.8% 101.3% -0.3% pouch packaging 100.6% 98.8% 97.5% 95.1% -5.5%

2) Related Substances (Unknown Max(Unk. Max)): Standard 0.2%, Total 2.0%

softness
matter Early 1 week harsh harsh 2 weeks harsh 4 weeks party pouch party pouch party pouch Unk. Max 0.06% 0.06% 0.70% 0.08% 1.47% 0.06% 2.41% Total 0.16% 0.17% 1.43% 0.18% 2.88% 0.19% 2.95%

As a result of the test, it was confirmed that the pouch packaging product had lower stability than the bottle packaging product. In bottle packaging, the content of benzidamine hydrochloride was constant and the amount of related substances did not increase by more than 0.1%, whereas in pouch packaging products, the content of benzidamine hydrochloride decreased by more than 5% and the amount of related substances increased by about 2.9%. Through the above results, it was confirmed that stability improvement was necessary for the development of pouch packaging products.

Experimental Example 2: Stability evaluation of benzidamine hydrochloride according to aqueous solution pH

2-1. Preparation of aqueous solution of benzidamine hydrochloride with different pH

Benzidamine hydrochloride was dissolved in an aqueous solution and stored under severe conditions (60C, 75% RH) for 4 weeks to evaluate stability according to pH. First, benzidamine hydrochloride was dissolved in 500 mL of distilled water so that the final concentration was 1.5 mg/mL, and the pH was adjusted according to Table 5 under weak acid, neutral or weak base conditions. For the control group, an aqueous solution in which the pH was not adjusted by dissolving benzidamine hydrochloride at 1.5 mg/mL in distilled water was used.

Manufacturing method final pH control Distilled water + benzidamine hydrochloride (1.5 mg/mL) - weakly acidic Distilled water + benzidamine hydrochloride (1.5 mg/mL) + citric acid (0.5 mg/mL) 3.5 neutrality distilled water+benzidamine hydrochloride (1.5 mg/mL)+K ₂ HPO ₄ and KH ₂ PO ₄ (0.5 mg/mL each) 7.4 weak base Distilled water + benzidamine hydrochloride (1.5 mg/mL) + sodium bicarbonate (0.5 mg/mL) 8.2

- Packaging material information: Bottle packaging (bottle-HDPE, stopper-PP), pouch packaging- PET16/PE15/AL9/PE15/MLLD30

2-2. Stability evaluation result

The content of related substances was analyzed according to the method of Experimental Example 1-3. As a result of the analysis, it was confirmed that the related substances increased by 1% or more in the control, neutral and weakly basic aqueous solutions, but the related substances increased by less than 0.1% in the weakly acidic aqueous solution (Table 6).

related substances Early harsh 2 weeks harsh 4 weeks Increased amount of related substances
│Severe 4 weeks-early │ control Unk. Max 0.00% 0.81% 1.64% 1.64% Total 0.00% 1.18% 1.96% 1.96% weakly acidic
(pH 3.5) Unk. Max 0.07% 0.07% 0.09% 0.02% Total 0.07% 0.09% 0.15% 0.08% neutrality
(pH 6.8) Unk. Max 0.07% 0.72% 1.12% 1.05% Total 0.08% 0.91% 1.19% 1.11% weak base
(pH 8.2) Unk. Max 0.00% 1.16% 1.92% 1.92% Total 0.01% 1.65% 2.28% 2.27%

From the results of Table 6, it was found that benzidamine hydrochloride was stabilized in a weakly acidic condition than in an aqueous solution of a neutral or weak base.

Experimental Example 3: Confirmation of stability of pouch-packed gargle solution containing benzidamine hydrochloride_1

A gargle solution containing benzidamine hydrochloride was prepared with the composition shown in Table 7 below, the pH range was adjusted to 3.0 to 6.0, and packaged in a pouch. Thereafter, the pouch was placed in a stability chamber and stored under severe conditions (60C, 75% RH) for 1 week to check stability according to pH. The packaging material of the pouch was PET16/PE15/AL9/PE15/MLLD30.

purpose of mixing additive chief ingredient benzidamine hydrochloride preservative methyl paraoxybenzoate emulsifier Tocopherol polyethylene glycol succinate sweetener D-sorbitol solution flavoring agent L-menthol flavoring agent peppermint oil buffer citric acid buffer Potassium monohydrogen phosphate

According to the methods of Experimental Examples 1-2 and 1-3, changes in benzidamine hydrochloride (standard: 90% to 110%) and related substances (Unknown Max: 0.2%, Total: 2.0%) were confirmed. As a result, under mildly acidic conditions (pH 3.0-4.5), the total amount of related substances increases to within about 0.3% until one week of harshness, but from pH 5.5, individual related substances increase by more than 0.5% and the content of benzidamine hydrochloride is up to about 5-8%. It was found that the stability was greatly reduced (Tables 8 and 9). As a result, it was confirmed that not only the case of using benzidamine hydrochloride alone, but also the gargle solution containing various additives improved stability at slightly acidic pH (3.0-4.5).

benzidamine hydrochloride
initial content 1 week harsh rate of change
│Severe 1 week - Early │ pH3.0 101.30% 97.30% -4.00% pH3.5 96.60% -4.70% pH4.5 95.70% -5.60% pH5.5 94.20% -7.10% pH6.0 92.80% -8.50%

related substances
initial content 1 week harsh rate of change
│Severe 1 week - Early │ pH3.0 Unk Max 0.02% 0.02% 0.00% Total Imp 0.04% 0.04% 0.00% pH3.5 Unk Max 0.02% 0.03% 0.01% Total Imp 0.04% 0.09% 0.05% pH4.5 Unk Max 0.02% 0.15% 0.13% Total Imp 0.04% 0.32% 0.28% pH5.5 Unk Max 0.02% 0.58% 0.56% Total Imp 0.04% 0.75% 0.71% pH6.0 Unk Max 0.02% 0.71% 0.69% Total Imp 0.04% 1.13% 1.09%

Experimental Example 4: Confirmation of stability of pouch-packed gargle solution containing benzidamine hydrochloride_2

In Experimental Example 3, a gargle solution was prepared and stability according to pH was confirmed. However, the pouch packaging material was repeated in Experimental Example 3 using a different packaging material from that used in Experimental Example 3 because the ratio of the components of the packaging material and part of the material were different for each manufacturer. The spore material used is PET12/AL9/PE40 (manufacturer-Amcor).

According to the methods of Experimental Examples 1-2 and 1-3, changes in benzidamine hydrochloride (standard: 90% to 110%) and related substances (Unknown Max: 0.2%, Total: 2.0%) were confirmed. As a result, under mildly acidic conditions (pH 3.0-4.0), the total amount of related substances increased to less than 0.1% by 1 week of severe severity, and the content of benzidamine hydrochloride also decreased to less than 5%, but the stability was further reduced as the pH increased. Specifically, under the pH 7.0 condition, the amount of related substances increased to 0.23% and the content of benzidamine hydrochloride showed a large decrease of about 23% (Tables 10 and 11).

pH benzidamine hydrochloride
initial content 1 week harsh harsh 2 weeks rate of change
│Severe 2 weeks - early │ pH3.0 101.30% 97.30% 96.50% -4.80% pH4.0 96.60% 96.70% -4.60% pH 5.0 95.70% 95.80% -5.50% pH6.0 94.20% 91.90% -9.40% pH7.0 92.80% 78.20% -23.10%

pH Early 1 week harsh harsh 2 weeks rate of change
│Severe 2 weeks - early │ pH3.0 Unk Max 0.05% 0.05% 0.05% 0.00% Total Imp 0.07% 0.08% 0.08% 0.01% pH4.0 Unk Max 0.05% 0.05% 0.04% -0.01% Total Imp 0.07% 0.07% 0.05% -0.02% pH 5.0 Unk Max 0.05% 0.06% 0.04% -0.01% Total Imp 0.07% 0.09% 0.10% 0.03% pH6.0 Unk Max 0.05% 0.02% 0.09% 0.04% Total Imp 0.07% 0.08% 0.20% 0.13% pH7.0 Unk Max 0.05% 0.71% 0.14% 0.09% Total Imp 0.07% 0.15% 0.30% 0.23%

Through the results so far, it was confirmed that the stabilizing effect of benzidamine hydrochloride was shown in weakly acidic conditions (pH 3.0-4.5) even if there was a difference in some components of the pouch spore material when using the pouch spore material.

PET16/PE15/AL9/PE15/MLLD30 in Experimental Example 3 and PET12/AL9/PE40 in Experimental Example 4 were used as pouch packaging materials. Since both spores are made of polyethylene on the drug-contacting surface, the interaction mechanism with the drug is considered to be similar.

Preparation Example: Benzidamine Hydrochloride Mouthwash for Pouch Packaging

Based on the results of Experimental Examples 1 to 4, the composition of benzidamine hydrochloride gargle solution for pouch packaging was determined as shown in Table 12 below.

combination
purpose Raw material name standard input
chief ingredient benzidamine hydrochloride KP 0.15% preservative methyl paraoxybenzoate KP 0.01% emulsifier Tocopherol polyethylene glycol succinate NF 0.05% thickener D-sorbitol solution KP flavoring agent L-menthol KP 0.015% flavoring agent peppermint oil KP 0.005% buffer citric acid KP 0.046% buffer Potassium monohydrogen phosphate EP 0.05% solvent Purified water KP appropriate amount

L-menthol and peppermint oil were used simultaneously in the benzidamine hydrochloride gargle solution for pouch packaging to enhance the refreshing feeling of the solution. In addition, since the liquid agent may cause layer separation, the phase of the liquid was stabilized by using an emulsifier. Tween 20, which is often used as an emulsifier, is a nonionic surfactant and has a bitter taste of the additive itself, so in the present invention, tocopherol polyethylene glycol succinate was used as an emulsifier.

In addition, the present inventors tested carboxymethyl cellulose sodium (CMC sodium), xanthan gum, and D-sorbitol as thickeners because leakage of gargle liquid may occur when packaged in a pouch. CMC Sodium and xanthan gum had precipitation, so D-sorbitol was finally selected as a thickener.

Comparative Example 1: Taste evaluation results according to the composition of gargle liquid

Since mouthwash is a liquid that is used after rinsing the mouth, the better the taste of the liquid, the higher the compliance. Therefore, as shown in Table 12 below, gargle liquid was prepared and taste was evaluated.

comparative example Example One 2 3 chief ingredient benzidamine hydrochloride preservative methyl paraoxybenzoate sweetener D-sorbitol solution flavoring agent Peppermint Oil, L-Menthol ethanol + - - emulsifier Tween 20 Tween 20 Tocopherol Polyethylene
glycol succinate taste One 3 4 refreshing 2 3 5 overall impression of the product One 3 4 total score 4 9 13

As a result of the evaluation, there was a significant difference in taste evaluation depending on whether ethanol was used or not and the type of emulsifier. When ethanol was added, the bitter taste of ethanol made the taste of mouthwash very bitter. In addition, the evaluation score for taste was higher when tocopherol polyethylene glycol succinate was used than when Tween 20 was used as an emulsifier, which is thought to be because the bitter taste of Tween 20 itself was improved.

Claims (10)

Containing benzidamine hydrochloride, an aqueous solvent, a preservative and a buffer, the pH is 3.0 to 5.0, and stability is maintained in a spore material made of polyethylene, a mouthwash. The gargle solution according to claim 1, wherein the gargle solution further comprises an additive selected from the group consisting of an emulsifier, a thickener, and a flavoring agent. According to claim 1, wherein the pH is 3.0 to 4.5, Mouthwash. The gargle solution according to claim 1, wherein the preservative is a paraoxybenzoic acid-based preservative. The method according to claim 1, wherein the buffer is selected from the group consisting of citric acid, phosphoric acid, citric acid hydrate, tartaric acid, acetic acid, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide and mixtures thereof. , gargle. The gargle according to claim 1, wherein the aqueous solvent is water. The gargle solution according to claim 2, wherein the emulsifier is tocopherol polyethylene glycol succinate. The gargle according to claim 2, wherein the thickening agent is D-sorbitol. The method of claim 2, wherein the gargle solution is benzidamine hydrochloride 1.2 to 1.8 mg/ml, methyl paraoxybenzoate 0.08 to 0.12 mg/ml, buffer 0.2 to 100 mg/ml tocopherol polyethylene glycol succinate 0.4 to 200 mg/ml, sweetener A gargle solution comprising 0.5 to 480 mg/ml of a flavoring agent and 0.12 to 200 mg/ml of a flavoring agent. 10. The method of claim 9, wherein the gargle solution is benzidamine hydrochloride 1.2 to 1.8 mg/ml, methyl paraoxybenzoate 0.08 to 0.12 mg/ml, citric acid 0.3 to 0.6 mg/ml, potassium monohydrogen phosphate 0.4 to 0.6 mg/ml, tocopherol A mouthwash comprising 0.4 to 0.6 mg/ml of polyethylene glycol succinate, 320 to 480 mg/ml of D-sorbitol solution, 0.12 to 0.18 mg/ml of L-menthol, and 0.04 to 0.06 mg/ml of peppermint oil.