Mouthwash with improved stability, containing benzylamine hydrochloride.

Abstract

The invention relates to a mouthwash containing benzydamine hydrochloride and having its stability maintained for a long time in packaging made of polyethylene, and this mouthwash has a slightly acidic pH, and thus has its stability maintained for a long time even when packaged in pouches of packaging made of polyethylene.

Description

Gargle solution with improved stability containing benzydamine hydrochloride

[0001] The present invention relates to a gargle containing benzydamine hydrochloride, which has a slightly acidic pH and is stable for a long period of time in a polyethylene material packaging material.

[0002] The oral cavity is prone to diseases such as bad breath, tartar buildup, cavities, gingivitis, and periodontitis due to food intake. In particular, tartar is not only the cause of cavities but also the biggest cause of oral inflammatory diseases such as gingivitis and periodontitis.

[0003] Gingivitis is an inflammation of the gingiva (gum). It is relatively mild, as the inflammation is confined to the gums and does not spread to the periodontal ligament or gum bone. If gingivitis worsens, it can spread to the gum bone, a condition called periodontitis. This chronic inflammatory disease occurs when the supporting tissues surrounding the teeth become inflamed, triggered by bacteria and toxins in tartar. This gradual destruction of the periodontal tissue supporting the teeth can lead to loosening and eventual loss of the teeth.

[0004] Left untreated, inflammation can lead to tooth loss. Products designed to alleviate or treat oral inflammation include mouthwashes, toothpastes, and strips. Mouthwashes are used by rinsing the mouth and spitting it out, and are widely used in everyday life to treat and prevent oral inflammation. However, most commercially available mouthwashes are sold in large quantities, making them inconvenient to carry and store. Furthermore, they require adjusting the dosage before each use, adding the additional inconvenience of having to gargle.

[0005] To address the above-mentioned inconvenience, the inventors individually packaged a gargle containing benzydamine hydrochloride in a polyethylene pouch. However, upon long-term storage of the pouch, the benzydamine hydrochloride content decreased, and volatile substances were generated, reducing stability. Therefore, the inventors adjusted the pH of the gargle to various ranges to improve stability when packaged in a pouch, and confirmed that the stability of the gargle was improved at a slightly acidic pH, thereby completing the present invention. Therefore, the purpose of the present invention is to provide a gargle that maintains stability even when packaged in a pouch form.

[0006] The present invention provides a gargle comprising benzydamine hydrochloride, an aqueous solvent, a preservative and a buffer, having a pH of 3.0 to 6.0, and maintaining stability in a polyethylene material packaging material.

[0007] The inventors of the present invention individually packaged a gargle solution (pH 6 to 7) containing benzydamine hydrochloride in a pouch to improve the convenience of use and portability, but confirmed that the stability of the gargle solution stored in the pouch decreased under harsh storage conditions.

[0008] Specifically, in bottle-packaged products, the content of benzydamine hydrochloride was constant and the amount of flexible substances did not increase by more than 0.1%, whereas in pouch-packaged products, the content of benzydamine hydrochloride decreased by more than 5% and the amount of flexible substances increased by about 2.9%, resulting in a significant decrease in stability in pouch-packaged products (Tables 3 and 4).

[0009] Accordingly, in order to improve the stability of the pouch product, benzydamine hydrochloride was dissolved in weakly acidic, neutral, and weakly basic aqueous solutions, respectively, and stored under harsh conditions (60°C, 75% RH) for 4 weeks to evaluate the stability according to pH. As a result, it was confirmed that the content of reactive substances increased by more than 1% in neutral and weakly basic aqueous solutions, but the content of reactive substances increased by less than 0.1% in the weakly acidic aqueous solution (Table 6). Therefore, the gargle solution according to one specific example of the present invention may have a pH in the weakly acidic range of 3.0 to 5.5, preferably 3.0 to 5.0.

[0010] The pH can be adjusted by adding a buffer or pH adjuster to the gargle solution. The buffer may be selected from the group consisting of, but not limited to, citric acid, phosphoric acid, citric acid monohydrate, tartaric acid, acetic acid, potassium dihydrogen phosphate, potassium monohydrogen phosphate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and mixtures thereof, and according to one specific example of the present invention, may be a combination of citric acid and potassium monohydrogen phosphate.

[0011] Additionally, but not limited to, the aqueous solvent may be water, preferably purified water.

[0012] Meanwhile, the preservative is not limited to a substance that prevents the denaturation of the drug, and a parahydroxybenzoic acid-based preservative may be used, for example, methyl parahydroxybenzoate or propyl parahydroxybenzoate. Methyl parahydroxybenzoate has high solubility in ethanol, but when ethanol is used, it has a very bitter taste, so the inventors of the present invention have greatly improved the taste of the gargle by dissolving methyl parahydroxybenzoate at high temperatures and eliminating the use of ethanol.

[0013] In one specific example of the present invention, the benzydamine hydrochloride may be included in the gargle solution in a content of 1.2 to 1.8 mg / ml, and preferably in a content of 1.4 to 1.6 mg / ml. Benzydamine hydrochloride is a non-steroidal anti-inflammatory drug (NSAID) that has the effect of reducing pain and calming inflammation, and can be used to treat gingivitis, stomatitis, thrush, post-tooth extraction, pharyngitis, tonsillitis, etc.

[0014] Meanwhile, in the present invention, the gargle liquid may additionally contain an additive selected from the group consisting of an emulsifier, a thickener, and a flavoring agent.

[0015] An emulsifier is a substance added to prevent separation of layers of a liquid. In one specific example of the present invention, the emulsifier may be tocopherol polyethylene glycol succinate.

[0016] In addition, a flavoring agent refers to a substance that blocks unpleasant odors or tastes or provides a refreshing feeling when using a mouthwash, and examples of which may be used include L-menthol, peppermint oil, fruit flavors, honey flavors, vanilla flavors, etc. In one specific example of the present invention, the flavoring agent may be L-menthol and peppermint oil.

[0017] A thickener is a substance that adjusts the viscosity of a gargle solution to prevent leakage during pouch packaging. Thickeners used in pharmaceutical manufacturing include carbomer, polyethylene oxide having a molecular weight of 5,000 to 5,000,000, hydroxypropylmethylcellulose, hydroxypropylcellulose, xanthan gum, guar gum, carboxymethyl cellulose sodium (CMC sodium), D-sorbitol, and the like. In one specific embodiment of the present invention, the thickener may be D-sorbitol.

[0018] Meanwhile, a gargle liquid that maintains stability in a polyethylene material pouch according to one specific example of the present invention may contain 1.2 to 1.8 mg / ml of benzydamine hydrochloride, 0.08 to 0.12 mg / ml of methyl paraoxybenzoate, 0.2 to 100 mg / ml of a buffer, 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.

[0019] Specifically, it may include 1.2 to 1.8 mg / ml of benzydamine hydrochloride, 0.08 to 0.12 mg / ml of methyl paraoxybenzoate, 0.3 to 0.6 mg / ml of citric acid, 0.4 to 0.6 mg / ml of potassium hydrogen phosphate, 0.4 to 0.6 mg / ml of tocopherol 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.

[0020] More specifically, a gargle according to one specific example of the present invention may contain 1.4 to 1.6 mg / ml of benzydamine hydrochloride, 0.09 to 0.11 mg / ml of methyl paraoxybenzoate, 0.4 to 0.5 mg / ml of citric acid, 0.45 to 0.55 mg / ml of potassium hydrogen phosphate, 0.45 to 0.55 mg / ml of tocopherol polyethylene glycol succinate, 350 to 450 mg / ml of D-sorbitol solution, 0.14 to 0.16 mg / ml of L-menthol, and 0.045 to 0.055 mg / ml of peppermint oil.

[0021] If necessary, the gargle according to the present invention may contain an appropriate amount of a pharmaceutically acceptable colorant or sweetener.

[0022] A gargle solution according to an example of the present invention has a slightly acidic pH and thus maintains long-term stability even when packaged in a polyethylene material.

[0023] Hereinafter, one or more specific examples will be described in more detail through examples. However, these examples are provided for illustrative purposes only and the scope of the present invention is not limited to these examples.

[0024]

[0025] Experimental Example 1: Stability Evaluation of Gargle Solution Containing Benzydamine Hydrochloride According to the Material of the Pouch

[0026] 1-1. Preparation of gargle solution

[0027] According to Table 1 below, a gargle solution (pH 6 to 7) containing benzydamine hydrochloride was prepared, packaged with two types of packaging materials, and its stability was confirmed for 4 weeks under harsh conditions.

[0028] Mixing purpose, additives, main ingredient, benzydamine hydrochloride, preservative, methyl paraoxybenzoate, emulsifier, concentrated glycerin, sweetener, steviol glycoside, pH regulator, sodium bicarbonate, emulsifier, polysorbate 20, flavoring, peppermint oil, colorant, blue No. 1, colorant, yellow No. 4 (tartrazine), pH regulator, citric acid hydrate, solvent, purifying agent, ethanol

[0029] - Storage conditions: harsh conditions (60℃, 75% RH)

[0030] - Storage period: 4 weeks

[0031] - Type of packaging material

[0032] Bottle packaging: bottle-HDPE, cap-PP),

[0033] 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 them is the thickness of the material in ㎛)

[0034]

[0035] 1-2. Content analysis method

[0036] The standard solution and test solution were analyzed according to the liquid chromatography method of the Korean Pharmacopoeia using the following method.

[0037]

[0038] 1) Preparation of placebo solution

[0039] About 5 mL of this solution, excluding benzydamine hydrochloride, was precisely taken and placed in a 50 mL volumetric flask, adjusted to the mark with the mobile phase, and filtered through a 0.45 μm filter. The initial 3 to 4 mL was discarded, and the filtrate was used as a placebo solution.

[0040]

[0041] 2) Preparation of standard solution

[0042] Accurately weigh 150.0 mg of benzydamine hydrochloride standard and 10.0 mg of methyl paraoxybenzoate standard and place them in a 100 mL volumetric flask, add about 50 mL of mobile phase, and sonicate to dissolve. After cooling, adjust to the mark with the mobile phase, take 5 mL of this solution, place it in a 50 mL volumetric flask, and adjust to 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 the standard solution.

[0043] [0.15 mg / mL as benzydamine hydrochloride] [0.01 mg / mL as methyl paraoxybenzoate]

[0044]

[0045] 3) Preparation of test solution

[0046] About 5 mL of this solution was precisely taken and placed in a 50 mL volumetric flask, adjusted to the mark with the mobile phase, and the solution was filtered through a 0.45 μm filter. The initial 3 to 4 mL was discarded and the filtrate was used as the test solution.

[0047] [0.15 mg / mL as benzydamine hydrochloride] [0.01 mg / mL as methyl paraoxybenzoate]

[0048]

[0049] 4) Analysis method

[0050] ① Detector: UV spectrophotometer (measurement wavelength: 254 nm)

[0051] ② Column: YMC-Pack Pro C18, 4.6 x 150 mm, 5 μm

[0052] (Product number: AS12S05-1546WT)

[0053] ③ Column temperature: 40℃

[0054] ④ Flow rate: 1.3 mL / min

[0055] ⑤ Injection volume: 5 μL

[0056] ⑥ Moving

[0057] - 10 mM ammonium acetate: acetonitrile: glacial acetic acid = 60:40:1 (v / v / v)

[0058] 10 mM ammonium acetate was prepared by dissolving 0.77 g of ammonium acetate in 1000 mL of purified water.

[0059] ⑦ Order of discharge: Benzydamine hydrochloride, methyl paraoxybenzoate discharged in that order.

[0060]

[0061] 5) Calculation of benzydamine hydrochloride content

[0062] The content of benzydamine hydrochloride was calculated according to the following mathematical formula 1.

[0063] [Mathematical Formula 1]

[0064]

[0065] A T : Peak area of ​​benzydamine hydrochloride in the test solution

[0066] A S : Peak area of ​​benzydamine hydrochloride in standard solution

[0067] C S : Standard solution benzydamine hydrochloride concentration (mg / mL)

[0068] C T : Concentration of benzydamine hydrochloride in the test solution (mg / mL)

[0069] P: Standard purity (%)

[0070]

[0071] 6) System suitability

[0072] When the standard solution was analyzed six times, the relative standard deviation of the peak area of ​​benzydamine 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.

[0073]

[0074] 1-3. Flexible substance test analysis method

[0075] The analysis was performed according to the liquid chromatography method of the Korean Pharmacopoeia using the following method.

[0076] 1) Preparation of blank test solution

[0077] 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.

[0078]

[0079] 2) Preparation of location confirmation solution

[0080] Accurately weigh 2.0 mg of flexible substance A standard, 2.5 mg of flexible substance B standard, 2.0 mg of flexible substance C standard, and 1.0 mg of benzydamine hydrochloride standard, respectively, and place them in a 100 mL volumetric flask. Approximately 50 mL of diluent is added, and the mixture is dissolved by ultrasonication. After cooling, the volume is adjusted to the mark with the diluent, and 3 mL of this solution is placed in a 10 mL volumetric flask, and the mixture is then adjusted to the mark with the diluent. The solution is then filtered through a 0.45 μm filter, the initial 3 to 4 mL is discarded, and the filtrate is used as a location confirmation solution.

[0081] [Substance A: 0.0060 mg / mL] [Substance B: 0.0075 mg / mL] [Substance C: 0.0060 mg / mL]

[0082] [Benzydamine hydrochloride: 0.0030 mg / mL]

[0083]

[0084] 3) Preparation of placebo solution

[0085] This drug, excluding benzydamine hydrochloride, was filtered through a 0.45 μm filter, the initial 3 to 4 mL was discarded, and the filtrate was used as a placebo solution.

[0086]

[0087] 4) Preparation of standard solution

[0088] Accurately weigh 15.0 mg of benzydamine hydrochloride standard and place it in a 100 mL volumetric flask. Approximately 50 mL of diluent was added and dissolved by sonication. After cooling, the volume was adjusted to the mark with the diluent. 4 mL of this solution was placed in a 200 mL volumetric flask and then the volume was adjusted to the mark with the diluent. The solution was then filtered through a 0.45 μm filter, the initial 3 to 4 mL was discarded, and the filtrate was used as the standard solution.

[0089] [0.0030 mg / mL as benzydamine hydrochloride]

[0090]

[0091] 5) Preparation of test solution

[0092] This drug was filtered through a 0.45 μm filter, the initial 3 to 4 mL was discarded, and the filtrate was used as a test solution.

[0093] [1.5000 mg / mL as benzydamine hydrochloride]

[0094]

[0095] 6) Analysis method

[0096] ① Detector: UV spectrophotometer (measurement wavelength: 320 nm)

[0097] ② Column: CAPCELL PAK C18, 4.6 x 250 mm, 5 μm or similar column

[0098] ③ Column temperature: 25℃

[0099] ④ Flow rate: 1.5 mL / min

[0100] ⑤ Injection volume: 40 μL

[0101] ⑥ Moving

[0102] - Mobile phase A: pH 3.0 buffer

[0103] - Mobile phase B: methanol

[0104] The above pH 3.0 buffer was prepared by dissolving 1.36 g of potassium dihydrogen phosphate and 1.16 g of sodium octyl sulfate in 1 L of purified water, and then adding phosphoric acid to adjust the pH to 3.0±0.1.

[0105] - Dilution: 50% methanol

[0106] ⑦ Composition of mobile phase

[0107] Time (min)Mobile Phase A (%)Mobile Phase B (%)050500 → 10307010 → 20307020 → 305050

[0108]

[0109] 1-4. Test results

[0110] 1) Benzydamine hydrochloride content: 90% to 110% of the standard

[0111] Period Packaging Container Initial Harsh 1 week Harsh 2 weeks Harsh 4 weeks Change rate │ Harsh 4 weeks - Initial │ Bottle packaging 101.6% 100.9% 99.8% 101.3% - 0.3% Pouch packaging 100.6% 98.8% 97.5% 95.1% - 5.5%

[0112]

[0113] 2) Flexible substances (Unknown Max(Unk. Max)): Standard 0.2%, Total 2.0%

[0114] Flexible material Initial Harsh 1 week Harsh 2 weeks Harsh 4 weeks Bottle Pouch Bottle Pouch Bottle 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%

[0115]

[0116] Test results confirmed that pouch-packaged products exhibited lower stability compared to bottle-packaged products. While the bottle-packaged product maintained a constant benzydamine hydrochloride content and did not increase more than 0.1% in benzydamine hydrochloride, the pouch-packaged product exhibited a decrease of more than 5% in benzydamine hydrochloride content and an increase of approximately 2.9% in benzydamine hydrochloride content. These results confirmed the need for improved stability in the development of pouch-packaged products.

[0117]

[0118] Experimental Example 2: Evaluation of the stability of benzydamine hydrochloride according to the pH of the aqueous solution.

[0119] 2-1. Preparation of aqueous solutions of benzydamine hydrochloride with different pH values

[0120] Benzydamine hydrochloride was dissolved in an aqueous solution and stored under harsh conditions (60°C, 75% RH) for 4 weeks to evaluate its stability according to pH. First, benzydamine hydrochloride was dissolved in 500 mL of distilled water to a final concentration of 1.5 mg / mL, and the pH was adjusted to weakly acidic, neutral, or weakly basic conditions according to Table 5. The control group used an aqueous solution in which benzydamine hydrochloride was dissolved in distilled water at a concentration of 1.5 mg / mL and the pH was not adjusted.

[0121] Manufacturing methodFinal pH control groupDistilled water + benzydamine hydrochloride (1.5 mg / mL) - slightly acidicDistilled water + benzydamine hydrochloride (1.5 mg / mL) + citric acid (0.5 mg / mL)3.5NeutralDistilled water + benzydamine hydrochloride (1.5 mg / mL) + K2HPO4 and KH2PO4 (0.5 mg / mL each)7.4Slightly basicDistilled water + benzydamine hydrochloride (1.5 mg / mL) + sodium bicarbonate (0.5 mg / mL)8.2

[0122] - Packaging material information: Bottle packaging (bottle-HDPE, cap-PP), pouch packaging (PET16 / PE15 / AL9 / PE15 / MLLD30)

[0123]

[0124] 2-2. Stability Evaluation Results

[0125] The content of flexible substances was analyzed according to the method of Experimental Example 1-3. The analysis results showed that the content of flexible substances increased by more than 1% in the control, neutral, and weakly basic aqueous solutions, but less than 0.1% in the weakly acidic aqueous solution (Table 6).

[0126] Flexible material Initial Harsh 2 weeks Harsh 4 weeks Increase in flexible material│Harsh 4 weeks - Initial│Control Unk. Max 0.00% 0.81% 1.64% 1.64% Total 0.00% 1.18% 1.96% 1.96% Slightly acidic (pH 3.5) Unk. Max 0.07% 0.07% 0.09% 0.02% Total 0.07% 0.09% 0.15% 0.08% Neutral (pH 6.8) Unk. Max 0.07% 0.72% 1.12% 1.05% Total 0.08% 0.91% 1.19% 1.11% Slightly basic (pH 8.2) Unk. Max0.00%1.16%1.92%1.92%Total0.01%1.65%2.28%2.27%

[0127]

[0128] Through the results in Table 6 above, it was found that benzydamine hydrochloride was more stable in weakly acidic conditions than in neutral, weakly basic aqueous solutions.

[0129]

[0130] Experimental Example 3: Stability Verification of Pouch-Packaged Mouthwash Containing Benzydamine Hydrochloride_1

[0131] A gargle containing benzydamine hydrochloride was prepared according to the composition shown in Table 7 below, adjusted to a pH range of 3.0 to 6.0, and packaged in a pouch. The pouch was then placed in a stability chamber and stored under harsh conditions (60°C, 75% RH) for one week to confirm stability according to pH. The packaging material of the pouch was PET16 / PE15 / AL9 / PE15 / MLLD30.

[0132] Mixing purpose, additives, main ingredient, benzydamine hydrochloride, preservative, methyl paraoxybenzoate, emulsifier, tocopherol, polyethylene glycol succinate, sweetener, D-sorbitol, liquid flavoring agent, L-menthol, flavoring agent, peppermint oil, buffering agent, citric acid, buffering agent, potassium dihydrogen phosphate

[0133] According to the methods of Experimental Examples 1-2 and 1-3, the changes in benzydamine hydrochloride (standard: 90% to 110%) and related substances (Unknown Max: 0.2%, Total: 2.0%) were confirmed. As a result, under slightly acidic conditions (pH 3.0 to 4.5), the total related substances increased to less than about 0.3% for up to 1 week, but from pH 5.5, each related substance increased by more than 0.5% and the benzydamine hydrochloride content decreased to about 5 to 8%, indicating a significant decrease in stability (Tables 8 and 9). As a result, it was confirmed that the stability was improved not only when benzydamine hydrochloride was used alone but also when the gargle solution containing various additives was used at a slightly acidic pH (3.0 to 4.5).

[0134] Benzidamine hydrochloride initial content, harsh 1 week change rate│harsh 1 week - initial│pH3.0101.30%97.30%-4.00%pH3.596.60%-4.70%pH4.595.70%-5.60%pH5.594.20%-7.10%pH6.092.80%-8.50%

[0135]

[0136] Flexible material initial content Severe 1 week change rate│Severe 1 week - Initial│pH3.0Unk Max0.02 %0.02 %0.00 %Total Imp0.04 %0.04 %0.00 %pH3.5Unk Max0.02 %0.03 %0.01 %Total Imp0.04 %0.09 %0.05 %pH4.5Unk Max0.02 %0.15 %0.13 %Total Imp0.04 %0.32 %0.28 %pH5.5Unk Max0.02 %0.58 %0.56 %Total Imp0.04 %0.75 %0.71 %pH6.0Unk Max0.02 %0.71 %0.69 %Total Imp0.04 %1.13 %1.09 %

[0137]

[0138] Experimental Example 4: Stability Verification of Pouch-Packaged Mouthwash Containing Benzydamine Hydrochloride_2

[0139] In Experimental Example 3, a gargle solution was manufactured and its stability according to pH was confirmed. However, since the proportions of the components and some of the materials of the pouch material vary depending on the manufacturer, the experiment of Experimental Example 3 was repeated using a pouch material different from that used in Experimental Example 3. The pouch material used was PET12 / AL9 / PE40 (manufacturer: Amcor).

[0140] According to the methods of Experimental Examples 1-2 and 1-3, the changes in benzydamine hydrochloride (standard: 90% to 110%) and related substances (Unknown Max: 0.2%, Total: 2.0%) were confirmed. As a result, under slightly acidic conditions (pH 3.0 to 4.0), the total related substances increased to less than 0.1% for up to 1 week, and the benzydamine hydrochloride content also decreased to less than 5%. However, the stability decreased further as the pH increased. Specifically, under pH 7.0 conditions, related substances increased to 0.23%, and the benzydamine hydrochloride content showed a large decrease of about 23% (Tables 10 and 11).

[0141] pH Benzidamine Hydrochloride Initial Content Harsh 1 Week Harsh 2 Weeks Change Rate│Harsh 2 Weeks - Initial│pH 3.0 10 1.30% 97.30% 96.50% - 4.80%pH 4.0 96.60% 96.70% - 4.60%pH 5.0 95.70% 95.80% - 5.50%pH 6.0 94.20% 91.90% - 9.40%pH 7.0 92.80% 78.20% - 23.10%

[0142]

[0143] pH Initial Harsh 1 week Harsh 2 weeks Change rate│Harsh 2 weeks - Initial│pH3.0Unk Max0.05%0.05%0.05%0.00%Total Imp0.07%0.08%0.08%0.01%pH4.0Unk Max0.05%0.05%0.04%-0.01%Total Imp0.07%0.07%0.05%-0.02%pH5.0Unk Max0.05%0.06%0.04%-0.01%Total Imp0.07%0.09%0.10%0.03%pH6.0Unk Max0.05%0.02%0.09%0.04%Total Imp0.07%0.08%0.20%0.13%pH7.0Unk Max0.05%0.71%0.14%0.09%Total Imp0.07%0.15%0.30%0.23%

[0144]

[0145] Through the results obtained so far, it was confirmed that the stabilizing effect of benzydamine hydrochloride was observed under slightly acidic conditions (pH 3.0 to 4.5) even when there were differences in some of the components of the pouch material.

[0146] In Experimental Example 3, PET16 / PE15 / AL9 / PE15 / MLLD30 was used as the pouch material, and in Experimental Example 4, PET12 / AL9 / PE40 was used. Since the surface of both pouch materials that comes into contact with the drug is composed of polyethylene, it is believed that the interaction mechanism with the drug is similar.

[0147]

[0148] Manufacturing example: Benzydamine hydrochloride gargle solution for pouch packaging

[0149] Based on the results of Experimental Examples 1 to 4, the composition of benzydamine hydrochloride gargle solution for pouch packaging was determined as shown in Table 12 below.

[0150] Mixing purpose, raw material name, specification, input amount, main 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 40%, flavoring agent, L-menthol KP 0.015%, flavoring agent, peppermint oil KP 0.005%, buffer, citric acid KP 0.046%, buffer, potassium dihydrogen phosphate EP 0.05%, solvent, purified water KP, appropriate amount

[0151]

[0152] The pouch-packaged benzydamine hydrochloride mouthwash uses both L-menthol and peppermint oil to enhance the refreshing sensation of the liquid. Furthermore, to prevent layer separation, an emulsifier is used to stabilize the liquid phase. Tween 20, a widely used emulsifier, is a nonionic surfactant with a bitter taste. Therefore, tocopherol polyethylene glycol succinate was used as the emulsifier in this invention.

[0153] In addition, since leakage may occur when the gargle solution is packaged in a pouch, the inventors tested carboxymethyl cellulose sodium (CMC sodium), xanthan gum, and D-sorbitol as thickeners. Since CMC sodium and xanthan gum caused precipitation, D-sorbitol was ultimately selected as the thickener.

[0154]

[0155] Comparative Example 1: Taste Evaluation Results According to Gargle Solution Composition

[0156] Since gargles are liquids used for rinsing the mouth, improving the taste of the liquid increases compliance. Therefore, gargles were prepared and taste evaluated as shown in Table 12 below.

[0157] Comparative Example Example 123 Main ingredient Benzidamine hydrochloride Preservative Methyl paraoxybenzoate Sweetener D-sorbitol Liquid flavor Peppermint oil, L-menthol Ethanol + -- Emulsifier Tween 20 Tween 20 Tocopherol Polyethylene glycol succinate Taste 134 Refreshing 235 Overall feeling about the product 134 Total score 4913

[0158]

[0159] The evaluation results showed significant differences in taste evaluation depending on the use of ethanol and the type of emulsifier. When ethanol was added, the bitterness of ethanol made the mouthwash taste very bitter. Furthermore, the taste evaluation scores were higher when tocopherol polyethylene glycol succinate was used as an emulsifier than when Tween 20 was used, which is believed to be due to the improvement in the bitterness of Tween 20 itself.

Claims

1. A gargle containing benzydamine hydrochloride, an aqueous solvent, a preservative and a buffer, having a pH of 3.0 to 6.0, and maintaining stability in a polyethylene material packaging material.

2. A gargle according to claim 1, wherein the gargle further comprises an additive selected from the group consisting of an emulsifier, a thickener, and a flavoring agent.

3. A gargle solution according to claim 1, wherein the pH is 3.0 to 5.

0.

4. A gargle solution according to paragraph 1, wherein the preservative is a paraoxybenzoic acid preservative.

5. A gargle solution in the first paragraph, 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 bicarbonate, sodium hydroxide, potassium hydroxide, and mixtures thereof.

6. A gargle solution in the first paragraph, wherein the aqueous solvent is water.

7. A gargle solution in the second paragraph, wherein the emulsifier is tocopherol polyethylene glycol succinate.

8. A gargle solution according to claim 2, wherein the thickener is D-sorbitol.

9. In the second paragraph, the gargle liquid contains 1.2 to 1.8 mg / mL of benzydamine hydrochloride, 0.08 to 0.12 mg / mL of methyl paraoxybenzoate, 0.2 to 100 mg / mL of a buffer, 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.

10. In claim 9, the gargle solution contains 1.2 to 1.8 mg / mL of benzydamine hydrochloride, 0.08 to 0.12 mg / mL of methyl paraoxybenzoate, 0.3 to 0.6 mg / mL of citric acid, 0.4 to 0.6 mg / mL of potassium hydrogen phosphate, 0.4 to 0.6 mg / mL of tocopherol 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.