KR20230130691A - Oral rinse composition for relieving dry mouth containing polyethylene glycol derivatives as an active ingredient - Google Patents

Abstract

The present invention relates to an oral rinse composition for alleviating dry mouth comprising a polyethylene glycol derivative as an active ingredient.
In addition, the oral rinse composition for alleviating dry mouth according to the present invention not only increases oral moisturizing sustainability by forming a covalent bond with the oral mucosa without irritation using polyethylene glycol derivatives as an active ingredient, but also has a granular formulation, making it easy to manufacture and package. It is not only easy but also convenient for storage and use.

Description

Oral rinse composition for relieving dry mouth containing polyethylene glycol derivatives as an active ingredient

The present invention relates to an oral rinse composition for alleviating dry mouth comprising a polyethylene glycol derivative as an active ingredient.

Xerostomia is a disease in which the oral mucosa becomes dry due to a decrease in saliva secretion due to various causes. Saliva plays an important role in smoothly maintaining the main functions of the oral cavity and protecting the oral mucosa, so when salivary secretion is reduced and dry mouth occurs, very serious disorders occur, mainly complaints of abnormalities in chewing and speech functions, severe bad breath, and Cavities occur, and depending on the severity, severe pain may be experienced due to a burning sensation in the oral mucosa or ulcers in the oral mucosa.

Causes of dry mouth include congenital malformations such as salivary gland agenesis, autoimmune diseases such as Sjogren syndrome and chronic graft-versus-host disease, and Psychiatric abnormalities, diabetes, complications of radiation therapy, hepatitis C virus, chronic renal failure, acquired immune deficiency syndrome, primary biliary cirrhosis, use of other drugs, stress and mental illness, severe high fever or diarrhea, dehydration due to large amounts of diuresis, salivary glands. When the duct is blocked by a stone or cancer, physical abnormalities such as infectious lesions in the salivary glands such as mumps can cause temporary or long-term dry mouth. In addition, as a cause of human aging and menopausal disorders, saliva secretion increases due to various stimuli while awake and active, but saliva secretion significantly decreases during sleep, and the proportion of patients who complain of discomfort due to hyposalivation that occurs during sleep is 23%. %, and most of them were geriatric (Thie et al., 2002).

Dry mouth is treated with parasympathomimetic drugs, including cholinergic drugs (pilocarpine (Salagen, MGI Pharmaceuticals., Minneapolis), Cevimeline (Evoxac); taken 3-4 times a day after meals, the effect lasts 2-4 hours). It promotes the secretion of saliva, but it can also affect other parts of the body, increasing the secretion of tears or runny nose or increasing the secretion of sweat. It is contraindicated in patients with asthma, acute iritis, narrow angle, and glaucoma, and there is a possibility of side effects in patients with cardiovascular disease, chronic bronchitis, and chronic obstructive disease. Additionally, sugar-free gum and candy containing xylitol, lactoperoxidase, or glucose oxidase, which promote saliva secretion, are being sold. Chewing gum containing a mucus component had a long-term effect in stimulating saliva secretion (Aagaard et al., 1992), and a spray containing a mucus component had a significant effect on geriatric dry mouth (Momm and Guttenberger, 2002).

In the prior art, an oral rinse composition that can prevent and improve oral diseases by containing eugenol and bamboo salt is disclosed (Korean Patent Publication No. 10-2020-0050801), and that it can relieve bad breath by containing seaweed extract. A composition that can be used is disclosed (Korean Patent Registration No. 10-2313830).

However, since the above-mentioned conventional technologies are proposed for the main purpose of killing harmful bacteria in the oral cavity and removing bad breath, they are accompanied by some irritation in the oral cavity or show a temporary moisture supply effect, so there is a problem in that the sustainability of alleviating dry mouth is low and it is difficult to expect an improvement effect. .

In addition, in a previous study by the present inventors (Korean Patent No. 10-1526258), polyethylene glycol derivatives modified with various reactors were used as active ingredients as a composition for preventing, treating or improving dry mouth that can bind to the oral mucosa. Disclosed contents including. Based on this, an oral rinse composition for relieving dry mouth was completed by confirming whether it can be applied to the human body based on the efficacy and safety results of each derivative for actual commercialization.

1. Republic of Korea Patent Publication No. 10-2020-0050801 2. Republic of Korea Patent No. 10-2313830 3. Republic of Korea Patent No. 10-1526258

Against the above background, the present inventors have developed a granule-type oral moisturizer that not only increases oral moisturizing power through covalent bonding of the oral mucosa without irritation by using polyethylene glycol derivatives as an active ingredient, but is also portable and easy to use. As a result, an oral rinse composition for relieving dry mouth was completed.

Accordingly, the object of the present invention relates to an oral rinse composition for alleviating dry mouth comprising a polyethylene glycol derivative as an active ingredient.

As a means to solve the above problems, the present invention provides an oral rinse composition for alleviating dry mouth comprising a polyethylene glycol derivative as an active ingredient.

Hereinafter, the configuration of the present invention will be described in detail.

The present invention relates to an oral rinse composition for alleviating dry mouth comprising a polyethylene glycol derivative as an active ingredient.

Polyethylene glycol is well known for its moisturizing effect. However, since it is applied to the oral mucosa and is easily washed off with water or saliva, the effectiveness of relieving dry mouth is low.

Accordingly, in the present invention, as shown in the following formula 1, the terminal reactive group of polyethylene glycol is modified to form a covalent bond with the oral mucosal epithelial cells, thereby allowing the polyethylene glycol derivative to adhere to the oral mucosal epithelial cells for a long time. The problem has been resolved.

Through the applicant's previous research, among various PEG derivatives, various PEG derivatives with reactive groups capable of forming covalent bonds with amine groups on oral mucosal epithelial cells have been developed. In the process of developing and researching products suitable for oral application using various PEG derivatives, the present inventors used halogen, amine (NH2), epoxide, and maleimide reactive groups to interact with the amine groups of cells. It was discovered that the time required for the amide binding reaction was long and that there was a problem in that the oral application time had to be extended accordingly. In addition, it was also revealed that the use of toxicants and by-products may remain during the reactor synthesis process of PEG derivatives, and that the scent caused by chemical synthesis remains due to the odor characteristics of the final finished PEG derivative, making it unsuitable for oral application. In addition, the aldehyde (CHO) reactor requires a reducing agent (Sodium cyanoborohydride) for the amide binding reaction, and the nitrophenyl carbonate (NPC) reactor reduces harmful by-products (nitrophenol) during the amide reaction. It was confirmed that it was not suitable for oral application.

Accordingly, the present inventors found that by using a branched modified polyethylene glycol derivative having an -NHS (N-Hydroxysuccinimide) reactive group of Formula 1, the amide reaction rate is fast when applied intraorally, and the reagents and by-products required before and after the reaction are reduced. After confirming that there was no discomfort and that it was safe when applied intraorally, the present invention was completed.

The present invention includes a polyethylene glycol derivative of Formula 1, an acidity regulator, and a flavoring agent as active ingredients,

The polyethylene glycol derivative has a molecular weight of 8,000 to 15,000 Da,

An oral rinse composition for alleviating dry mouth, having a granular formulation, is provided.

As can be seen in the examples below, it was confirmed that the polyethylene glycol derivative of Formula 1 has a higher moisture absorption rate compared to the linear PEG derivative, which means that the polyethylene glycol derivative can capture more water molecules when combined with the oral mucosa. This can enhance the moisturizing effect.

In addition, the oral rinse composition for alleviating dry mouth according to the present invention is manufactured in a granular formulation to improve storage stability such as moisture absorption and static electricity.

In one embodiment of the present invention, the granules may have a particle size of 200 to 1500 ㎛. For example, the granules may have a particle size of 300 to 1000 ㎛. For manufacturing (production) and single-use packet packaging, and for stability during manufacturing and storage, the particle size of the granules is preferably 200 to 1500 ㎛.

When the composition of the granule formulation of the present invention is used, it is dissolved in water and reconstituted in the form of a solution.

When 1 g of the granular composition according to the present invention is quickly dissolved in 20 ml of water and applied intraorally, the polyethylene glycol derivative of Formula 1 forms a moisture layer tightly bound to the oral mucosa on the dry oral mucosa, similar to the temporary moisture layer of existing products. Compared to other products, it has the characteristic of maintaining moisture for a long time. Therefore, when the composition of the granule formulation of the present invention feels dry in the mouth, especially for dry mouth patients, the elderly, and the general public before going to bed, mix the amount used once with 20 ml of water and reconstitute it as a solution for about 30 to 60 seconds. It is a product that is held in the mouth and then spit out. Effects include moisturizing the oral cavity, cavity prevention function, and cleansing effect.

In the composition of the present invention, the acidity regulator is included in an amount of 1 to 10 parts by weight, for example, 2 to 8 parts by weight, or 3 to 7 parts by weight, based on 100 parts by weight of the composition. Preferably, the acidity regulator is included in an amount of 4 to 6 parts by weight.

Meanwhile, when the composition is dissolved in water and reconstituted in the form of a solution when used, the viscosity of the solution may be 0.001 Pas to 0.01 Pas. The viscosity of the solution may affect user convenience, oral application, feeling of use, etc., so the above range is appropriate. This viscosity not only improves palatability when applied orally, but also prevents cytotoxicity and irritation that occurs when granules are administered directly. Alternatively, when the composition is dissolved in water and reconstituted in the form of a solution when used, the concentration of the solution may be 4 to 5%.

Due to the inclusion of an acidity regulator, the composition is preferably dissolved in water at the time of use and reconstituted in solution form to have a pH of 7 to 8. According to the research results of the present inventors, pH 7 to 8 is a favorable condition for covalent bonding between the PEG derivative according to the present invention and oral amine. Furthermore, the salivary pH of patients with dry mouth is as low as 6.4 or less, and since dry mouth symptoms and salivary pH show a significant negative correlation, the pH of the composition for alleviating dry mouth symptoms is preferably pH 7 to 8.

As a flavoring agent, for example, powdered food flavorings suitable for oral application, such as citrus, fruit, berry, vanilla, mint, etc., can be used. There are no particular restrictions. The flavoring agent may be used in an amount of 1 to 10 parts by weight, for example, 4 to 10 parts by weight, based on 100 parts by weight of the composition, but is not limited thereto.

Each of the above ingredients included in the oral rinse composition according to the present invention may be included in the oral rinse composition of the present invention within a range that does not exceed the maximum usage amount specified in the food safety standards of each country.

The present invention also provides a method for alleviating dry mouth comprising applying the oral rinse composition for alleviating dry mouth to a subject in need thereof.

The application includes administering and rinsing the oral rinse composition for relieving xerostomia reconstituted in solution form.

For example, when 1 g of the granular oral rinse composition according to the present invention is quickly dissolved in 20 ml of water and applied intraorally, the polyethylene glycol derivative of Formula 1 forms a moisture layer tightly bound to the oral mucosa on the dry oral mucosa. Moisturization is maintained for a long time compared to the temporary moisture layer of existing products. Therefore, it can be useful for subjects or patients with dry mouth. The application may be performed once to three times a day, but is not limited thereto. You can apply it at any time when your mouth feels dry, and it is especially advantageous to apply it before going to bed.

Additionally, the present invention provides a method for producing an oral rinse composition for alleviating dry mouth.

Hereinafter, the configuration of the manufacturing method of the present invention will be described in detail.

In the production method of the present invention, preparing a polyethylene glycol derivative powder of Formula 1 having a molecular weight of 8,000 to 15,000 Da; Containing an acidity regulator and a flavoring agent in the polyethylene glycol derivative powder, then transferring the polyethylene glycol derivative powder to an airtight container and liquefying it at high temperature; When the liquefaction is complete, transferring the airtight container to a low temperature and solidifying it; And when the solidification is completed, it may include grinding to produce granules.

In the production of the polyethylene glycol derivative of Formula 1 according to the present invention, -NHS was used as a reactor, which is suitable for mass production because the half-life of the NHS ester is relatively long, the number of production processes is small, it is simple, and the risk in the production process is low.

In the step of preparing the polyethylene glycol derivative powder of Formula 1, the polyethylene glycol derivative preferably has a molecular weight of 8,000 to 15,000 Da. If the molecular weight is less than 8,000 Da, if the molecular weight is more than 15,000 Da, not only is the moisture absorption rate lowered, but the crystallization and powdering processes during the production process become complicated, and the production yield is lowered.

In the step of selecting the polyethylene glycol derivative, a branched structure is more advantageous than a linear structure. In the case of the branched structure, the moisture absorption rate was higher, and since there are a large number of derivative reactors that bind to the oral mucosa, it can retain a lot of moisture for a longer period of time and maintain a moist oral cavity when bound to the oral mucosa.

In the production method of the present invention, the step of adding an acidity regulator to adjust pH to 7 to 8 may be included.

The liquefaction step may be performed at 50°C to 70°C for 1 hour. At this time, if the temperature is less than 50°C, liquefaction is not sufficiently achieved, and if it exceeds 70°C, some of the derivative molecules are decomposed and the effect is reduced.

The solidifying step includes primary hardening at room temperature for 1 hour; And it may include secondary hardening at -20°C (freezing).

In the step of manufacturing the granules, the particle size of the granules is preferably 200 to 1500 ㎛ for storage stability and reduction of static electricity during product packaging.

The present invention also provides a product for alleviating dry mouth, comprising a container capable of measuring 15 ml to 30 ml of water for a single use, and a packet packaged with a composition for alleviating dry mouth in a granular formulation with a single use amount of 1 g to 1.5 g. provides.

The product includes an instruction sheet containing instructions to pour the composition for relieving dry mouth in a granular form packaged in a single-use amount into a container with water measured for one-time use, mix and dissolve, apply it to the dry mouth, gargle, and then spit it out. can do.

The oral rinse composition for alleviating dry mouth according to the present invention not only increases the oral moisturizing power by forming a covalent bond with the oral mucosa without irritation using the polyethylene glycol derivative of Chemical Formula 1 as an active ingredient, but also has a granule formulation, so it is manufactured and Not only is it easy to package, but it is also convenient for storage and use.

Figures 1a and 1b show the results of NMR (Nuclear Magnetic Resonance) analysis of the powder formulation and granule formulation of the oral rinse composition for alleviating dry mouth according to the present invention.
Figure 2 is a comparison result of surface static electricity according to the formulation of the oral rinse composition for alleviating dry mouth according to the present invention.

Hereinafter, the present invention will be explained in detail by the following examples. However, the following examples only illustrate the present invention, and the content of the present invention is not limited to the following examples.

Experimental Example 1. Test to confirm the moisture absorption rate of PEG derivatives for oral moisture absorption

In order to identify and determine the PEG-OH structure with high oral moisture absorption rate, the moisture absorption rate of PEG derivatives with different structures was tested.

Test material: As a PEG derivative for the moisture absorption test, dry powder with a molecular weight of 3,000 Da or more was used rather than liquid (wax-type) PEG. PEG (Formula A) with a linear structure as shown below has a molecular weight of 3,400 Da and 10,000 Da, and branches. The test was conducted using PEG powders of 4arm PEG (Formula B) and 6arm PEG (Formula C) with a molecular weight of 10,000 Da.

[Formula A]

[Formula B]

[Formula C]

The test material was purchased from Daechang Chemical, and for the test, the powder particles were uniformly pretreated through an extraction and powdering process using an organic solvent before the test was conducted.

Hygroscopicity measurement method : Hygroscopicity was determined by the weight of water vapor absorbed per mass of PEG (polyethylene glycol). After preprocessing the PEG by drying it in a desiccator at a temperature of 25 ± 1℃, it was left in moisture-absorbing conditions of a temperature of 25 ± 1℃ and a relative humidity of 60 ± 2% for 24 hours, and the weight increase (mg) per gram of PEG was measured by the PEG. It was defined as the moisture absorption of . The moisture absorption rate of each PEG was determined by calculating the percentage by comparing the weight difference before and after being left in the above moisture absorption conditions. The results are shown in Table 1 below.

As shown above, linear Di-PEG-OH molecular weight of 3,400 Da (Comparative Example 1) was found to be the lowest at 10.14%, 10,000 Da (Comparative Example 2) was confirmed to be the lowest at 12.31%, and branched 4-arm PEG-OH molecular weight of 10,000 Da was confirmed to be the lowest. (Example 1) showed the highest moisture absorption rate at 15.48%.

As a result of checking the moisture absorption rate of PEG-OH with linear and branched structures, the linear PEG-OH of solid powder had a higher moisture absorption rate as the molecular weight increased (i.e., the molecular weight was 10,000 Da (Comparative Example 1) rather than 3,400 Da (Comparative Example 1). 2) has a high moisture absorption rate), when comparing the moisture absorption rates of linear and branched PEG structures based on the same molecular weight of 10,000 Da, the moisture absorption rate of branched PEG was high. In particular, compared to 6-arm PEG-OH (Comparative Example 3), the 4-arm PEG-OH (Example 1) structure showed the highest moisture absorption rate, making 4arm-PEG-OH (Example 1) the main raw material of the present invention. was selected.

In addition to branched 4arm-PEG-OH, 6arm-PEG-OH and 8arm-PEG-OH can be used for oral moisturizing purposes, but they are superior to 4arm-PEG-OH in terms of synthesis/manufacturing process for PEG derivatives and moisturizing effect. There was none.

Experimental Example 2. Test to confirm moisture content by molecular weight of 4arm-PEG-OH for oral moisture absorption

According to the results of Experimental Example 1, it was confirmed that the branched 4arm-PEG-OH structure had a high moisture absorption rate, and to confirm the moisture absorption power according to the molecular weight of the same structure, 4arm PEG-OH 10,000 Da, 20,000 Da, and 30,000 Da were used according to the molecular weight. A moisture content confirmation test was performed. The test method is to determine the amount of moisture contained in each test substance before and after exposing the 4arm-PEG-OH test substance for each molecular weight to moisture absorption conditions of temperature 25±1°C and relative humidity 60±2% for 4 hours. It was analyzed using a moisture meter (MS-70; METTLER TOLEDO, 400W straight halogen lamp heating system with SRA filter and SHS weighting technology). That is, the moisture absorption capacity was confirmed using the difference in moisture content before and after exposure to moisture absorption conditions.

As shown in the table below, the moisture content and moisture absorption amount were measured according to the molecular weight of 10,000 Da, 20,000 Da, and 30,000 Da of the 4arm-PEG-OH structure. 4arm-PEG-OH PEG derivatives with a molecular weight of less than 5,000 Da (e.g., 2,000 Da and 5,000 Da) were excluded from this test material because they were not easy to powder in the production/synthesis process. 4arm-PEG-OH of each molecular weight was purchased from Daechang Chemical, and for testing, the powder particles were uniformly pretreated through an extraction and powdering process using an organic solvent and then tested. The results are shown in Table 2 below.

As shown in the results above, the smaller the molecular weight, the greater the difference in moisture content before and after exposure for 4 hours at 60% relative humidity. In other words, the larger the molecular weight of 4arm-PEG-OH, the lower the moisture absorption.

In other words, among the molecular weights of 10,000 Da, 20,000 Da, and 30,000 Da, 4arm-PEG-OH (Example 1) of 10,000 Da showed the largest difference in moisture content (A-B) before and after exposure to 60% relative humidity. It was confirmed that it absorbs a lot of moisture.

As previously explained, 4arm-PEG-OH molecular weight of 2,000 Da or 5,000 Da was excluded due to the difficulty of the final powder manufacturing process for PEG derivatives and the resulting low production yield. In the overall reaction process for PEG derivatization, the crystallization and powder manufacturing process affects the production yield in the crystallization and recrystallization process using organic solvents after the chemical reaction process and filtration/concentration. In addition, it is an essential consideration because the production yield is lowered in the washing/recrystallization process of removing impurities with an organic solvent and the powdering process of the final selected particles after drying. According to the results of Experimental Example 2, 4arm-PEG-OH molecular weights of 20,000 Da and 30,000 Da were not suitable for use as intraoral moisturizers due to low moisturizing effect due to increased molecular weight.

For this reason, for the synthesis and production of PEG derivatives, which are the main ingredient for oral moisturizing purposes of the present invention, 4arm-PEG-OH structure with a molecular weight of 10,000 Da (Example 1) was used as the main raw material.

Experimental Example 3. Selection of PEG derivative reactor

In order to select the reactive group of the PEG derivative that forms a covalent bond with the amine group present in the oral mucosa, the half-life of the PEG derivative according to the reactive group and the number of production steps (number of steps) required for the synthesis of the reactive group were compared and analyzed. If the half-life is short, hydrolysis occurs quickly while the composition is dissolved in water, so covalent bonding with the amine group of the oral mucosa cannot occur. Therefore, it is difficult to use a reactor with a short half-life to manufacture an oral rinse composition for alleviating dry mouth.

The half-life was measured based on the UV absorbance of the N-hydroxy succinimide (NHS) group, which is hydrolyzed in buffer conditions at 25°C and pH 8. The results are shown in Table 3 below.

As shown above, Succinimidyl Carbonate (SC) ester (Comparative Example 7) has a simple one-step production process and a relatively long half-life, but there are risks and environmental hazards in using phosgene gas in the manufacturing process. On the other hand, in the case of the derivative modified with Succinimidyl Glutarate (SG) according to the present invention (Example 2), the amide reaction rate is fast when applied intraorally, there are no reagents or by-products required before and after the reaction, and there is no inconvenience when applied intraorally. There are no problems with sensitivity or safety. In addition, compared to other reactors, the half-life of Example 2 was relatively long, the number of production processes was small, it was simple, and the risks in the production process were low. Accordingly, a derivative (Formula 1) modified with Succinimidyl Glutarate (SG) was prepared through Preparation Example 1 below and used in subsequent experiments.

<Preparation Example 1. Preparation of polyethylene glycol derivative of Chemical Formula 1>

[Formula 1]

[Scheme 1]

After dissolving the compound of Chemical Formula 2 in methylene chloride at room temperature, triethyamine was added. Add glutaric anhydride to the reaction solution and stir at room temperature for 20 to 24 hours. The reaction solution was washed with 14% ammonium chloride aqueous solution, and when the layers were separated, the lower organic solution layer was collected. The aqueous solution layer was extracted using methylene chloride. The collected organic solution layer was precipitated by removing moisture using magnesium sulfate, concentrating the solvent, and then adding it to diethyl ether. The precipitate was filtered and dried under vacuum at room temperature for 24 hours to obtain the compound of Formula 3.

The compound of Formula 3 was dissolved in methylene chloride, and N-Hydroxy succinimide (NHS) and dicyclohexyl carbodiimide (DCC) were added. The reaction solution was stirred at room temperature for 15 to 20 hours. After the reaction, dicyclohexyl urea (DCU), a by-product, was filtered using a glass filter, and the filtered solution was precipitated by concentrating the solvent and adding it to diethyl ether. After filtering the precipitate, it was dissolved in ethyl acetate at 55±5°C and recrystallized at 0-5°C for 15 to 17 hours. The recrystallized product was filtered, washed three times with diethyl ether, and dried under vacuum at room temperature for 24 hours to obtain a compound of formula 1 (n=57) with a weight average molecular weight of 10,000.

Experimental Example 4: Composition test using pH adjuster

As a result of the present inventors' research, it was found that the conditions under which the amine group of the oral mucosa and the reactive group of the PEG-SG derivative of Formula 1 form a covalent bond are pH 6.0 to 8.0.

However, when the PEG-SG derivative of Chemical Formula 1 and flavoring agent, which are used as main ingredients for oral moisturizing, were dissolved in water, they were slightly acidic (pH 4.5) and were not suitable for the above pH conditions.

In order to adjust the composition of the present invention to pH conditions suitable for covalent bonding in the oral cavity, an acidity regulator (Sodium bicarbonate) used as a food additive was added and the dosage of the acidity regulator was determined to reach pH 6.0 to 8.0.

Test substance: As shown in Table 4 below, an acidity regulator (Sodium Bicarbonate) was prepared by adding 0 (control), 1, 5, and 10% of the product content (1.5 g). A pH test was performed using three 1g samples for each composition.

Test method: In order to accurately measure the pH of the prepared samples, the pH meter calibration was performed in 3 sections (pH 4.0, 7.0, 10.0 standard buffer), with an acceptable parameter pH slope of 90 ~ 105% and 0 ± 30 mV (25%). 0.5 pH units at ℃ was confirmed. 1 g of each test substance was completely dissolved in 20 ml of distilled water, and then the pH was checked. The results are shown in Table 5 below.

As shown above, the average pH of each sample to which 1, 5, and 10% of the acidity regulator was added was 7.0, 7.5, and 7.8. As a result, it was confirmed that the acidity regulator addition amount of 1 to 10% was an appropriate dosage range for covalent pH 6.0 to 8.0 conditions.

However, as a result of the sensory evaluation, the composition (Example 5) containing more than 10% of the acidity regulator was excluded because it caused a bitter taste and irritation of the tongue when applied intraorally. In the subsequent experiment, a composition containing 5% of the acidity regulator (Example 4) was prepared and used according to Preparation Example 2 below.

Preparation Example 2. Preparation of oral rinse composition for alleviating dry mouth

Oral rinse compositions for relieving dry mouth containing a polyethylene glycol derivative of Formula 1, an acidity regulator, and a flavoring agent are manufactured in various formulations, and the applicability to the human body such as cytotoxicity (safety in humans), moisturizing effect (functionality), and commercialization process are evaluated. Ease of handling, product stability, etc. were evaluated through the following experimental examples.

<Manufacturing Example 2-1. Preparation of powder-type oral rinse composition for relieving dry mouth>

89 parts by weight of polyethylene glycol derivative, 5 parts by weight of sodium bicarbonate as an acidity regulator, and 6 parts by weight of mint as a flavoring agent were added to a V-type mixer and mixed at 20 to 25 rpm for 15 minutes to prepare a finished composition in powder form. did.

<Manufacturing Example 2-2. Preparation of liquid oral rinse composition for relieving dry mouth>

A liquid composition was prepared by dissolving 1.5 g of the powder composition of Preparation Example 2-1 in 30 ml water.

<Manufacturing Example 2-3. Preparation of granular oral rinse composition for relieving dry mouth>

The airtight container containing the powder-like composition prepared in Preparation Example 2-1 was liquefied at 60°C for 1 hour. When the liquefaction was completed, the airtight container was moved to room temperature and subjected to primary hardening for 1 hour, followed by secondary hardening at -20°C to solidify. When the solidification was completed, it was pulverized to a particle size of 355-1400 ㎛.

Experimental Example 5. Cytotoxicity test

The cytotoxicity test was a test to confirm the safety of the composition according to the present invention and evaluated the presence and degree of cytotoxic reaction in cultured cells (L-929). The test was conducted by a GLP (Good Laboratory Practice) agency in accordance with each test method presented in ISO 10993.

Test substance:

As shown in Table 6 below, a powder formulation without an acidity regulator (A), a powder formulation containing an acidity regulator (B, Preparation Example 2-1), and a liquid form (C, prepared by dissolving the powder formulation (B) in 30 ml of water. Example 2-2) Each test solution was prepared with test substances.

Cytotoxicity Test Method 5-1. Powder sample test method: The powder test substance and control were dissolved at a concentration of 0.2g/ml in the extract (E-MEM +5% FBS) and dissolved for 24 ± 2 hours to prepare a test solution. The culture medium of cell L-929 was removed from the plate well, replaced with 1 mL of test solution and control medium (extract), and the cells were cultured. During incubation, microscopic examination was performed at 24, 48, and 72 ± 4 hours to evaluate cytotoxicity. Positive and negative controls were also used in the test.

5-2. Liquid sample test method: A liquid test solution was prepared by combining/diluting the diluent (2X E-MEM + 10% FBS) and the liquid test substance at a ratio of 1:1. The culture medium of cell L-929 was removed from the plate well, replaced with 1 mL of test solution and control medium (dilution solution), and the cells were cultured. During incubation, microscopic examination was performed at 24, 48, and 72 ± 4 hours to evaluate cytotoxicity. Cadmium chloride (100uM CdCl ₂ ) as a positive control and E-MEM + 5% FBS as a negative control were also used in the test.

The evaluation standard for the cytotoxicity test was to evaluate the morphological change of cells and the degree of change in viable cells due to lysis or separation and recorded with a score of 0 to 4. Scores of 3 and 4 were judged to be cytotoxic, and scores of 1 and 2 were judged to be non-cytotoxic. The results are shown in Tables 7 and 8 below.

As shown in the results above, as a result of the cytotoxicity test with each composition and two formulations, Comparative Examples 13 and 14 showed strong cytotoxicity with a cytotoxicity score of '4', and Example 6 had a cytotoxicity score of '0'. ' It did not show any cytotoxicity. Example 6 was confirmed to be a safe composition and formulation that did not affect morphological changes or survival of L-929 cells by containing an acidity regulator and dissolving the composition in 30 ml of water and applying it to cells as a liquid.

As shown in the above results, because the powder composition (Comparative Examples 13 and 14) exhibits cytotoxicity, it is not suitable to directly apply the dry powder formulation to patients with dry mouth with low salivary secretion.

Therefore, after changing the powder formulation of the present invention to a liquid formulation by adding moisture, the concentration of the test substance for the cytotoxicity test decreased from 0.2 g/ml to 0.025 g/ml (1.5 g/30 ml x 1/2), No toxicity was observed. In addition, unlike applying a composition in powder form to dry oral mucosa, which causes a foreign body sensation to sensitive mucous membranes, if the powder is reconstituted into a liquid formulation, it provides additional moisture in the oral cavity and allows patients to easily apply the product in the oral cavity. It showed the expected effect of increasing the moisturizing effect.

Experimental Example 6. Test to confirm moisturizing effect according to cell survival rate

The composition of the present invention was applied to human epithelial cells to form a moisturizing layer by covalently binding the main ingredient PEG derivative to the surface of the cells, and an in vitro test was performed to determine cell viability by exposing the cells to a dry environment.

Test substance:

Example 6 of the present invention, which was confirmed to be safe from cytotoxicity in Experimental Example 5, and Colgate's Hydris Oral Rinse product, a dry mouth relief product, were used as test substances. Both test substances are liquid and have the same formulation. As a negative control, PBS (phosphate-buffered saline; Gibco) was used.

Test method: Using a human pharynx epithelial cell line, the composition of the present invention, Hydris Oral Rinse from Colgate, and phosphate-buffered saline (PBS) were applied to the cells at 37°C for 15 minutes and incubated, The test substance was removed, the cells were washed with PBS, and then exposed to dry conditions at 25°C and 30% humidity, and cell viability was measured. The effect of the treated test substances on protecting cells by reducing cell death due to drying was confirmed by cell survival rate. As a positive control, cells were treated with PBS, and the survival rate of cells that were not exposed to dry conditions was set to 1 (100%), and the cell survival rate according to test substance treatment was expressed as a percentage. Cell viability was analyzed using Cell Counting Kit 8 (CCK8; Dojindo Molecular Technologies, Inc., Rockville, MD, USA). This kit is used to quantify the number of living cells by producing an orange formazan dye during bioreduction in the presence of an electron carrier using water-soluble tetrazolium salt. The results are shown in Table 10 below.

As shown above, based on the cell viability (%) of the positive control group, the mean cell viability of Example 6 of the present invention was 71.9% (median: 81.5%), showing the highest cell viability, compared to the existing GSK Hydris product. showed a relatively low survival rate with a mean value of 12.0% (median: 11.5%).

Because the moisturizing ingredient remained in the cells and maintained the effect of the moisturizing coating even after cell washing due to the covalent bond between the main ingredient PEG derivative of Example 6 and the oral cells, cell death due to drying was minimized when the cells were exposed to a dry environment after washing. Cell viability was maintained. In other words, compositions containing existing moisturizers have a limited role as moisturizers because they are washed off after being applied intraorally or through speaking or ingestion of beverages/food, etc., but the moisturizing effect is temporary, and therefore they must be applied intraorally frequently. However, the PEG derivative, the main ingredient of the present invention, is covalently bound to cells and is not washed off by physical stimulation and maintains a moisturizing effect for a long time.

Experimental Example 7. Reactor activity and electrostatic tests of main component 4arm-PEG-SG derivatives

General PEG derivatives are manufactured in the form of a final powder (powder type) through chemical reactions, synthesis, manufacturing processes, and recrystallization after crystallization and washing. These powdered PEG derivatives are mixed with additives, the recovered mixture is filled into the hopper of the equipment for packaging of quantitative (1g) packets, and then the powder is fed from a diaphragm to a scale (load cell), and the weight is measured and quantified. is filled into an aluminum packet. However, in the case of a powder-type formulation such as Preparation Example 2-1, a problem was found in that loss due to static electricity occurred during the weighing, mixing, and recovery of the mixture at the beginning of the production process, and the recovery rate was also lowered for the same reason.

Therefore, in order to solve the problem of static electricity in the manufacturing process caused by the physical form of 4arm-PEG-SG, the main ingredient PEG derivative of the present invention, that is, the powder, the physical form was changed to the granular formulation of Preparation Example 2-3 to determine whether the reactor activity changed. And the occurrence of static electricity was analyzed.

Test material: As in the previous experimental examples, 4arm-PEG-SG, a PEG derivative in powder form, and samples in granule form were prepared.

Test Methods

Prior to the electrostatic test, it was confirmed through NMR (Nuclear Magnetic Resonance) analysis that there were no problems with the reactor activity and stability of the PEG derivative even after the physical state change of 4arm-PEG-SG in powder form was melted and solidified. 1A and 1B are the results of NMR (Nuclear Magnetic Resonance) analysis of the powder formulation and granule formulation of the oral rinse composition for alleviating dry mouth according to the present invention, confirming that there are no problems with reactor activity and stability regardless of changes in physical state. did.

The electrostatic test was measured using an electrostatic meter (EYE-02) that can measure the surface electrostatic force of the PEG derivative, the main ingredient of the two formulations. 50 g and 100 g of PEG derivatives, the main component of powders and granules, were placed in PET storage packs (plastic packs) used when weighing during the manufacturing process, respectively, and the surface electrostatic force was measured and compared.

As shown in Figure 2, as a result of comparing the surface electrostatic force generated depending on the physical form of 4arm-PEG-SG, a PEG derivative, that is, powder and granule, the surface electrostatic force of the powder was approximately It was confirmed that surface static electricity was reduced by more than 50%.

As a result, the granule formulation of Preparation Example 2-3, unlike the powder formulation of Preparation Example 2-1, had reduced loss in the hopper due to static electricity and made packet filling easier.

Experimental Example 8. Stability confirmation test according to the formulation of the final finished composition

Tests to confirm product stability according to formulation were performed as follows.

Test material: Oral rinse compositions of the powder formulation of Preparation Example 2-1 (Comparative Example 15) and the granular formulation of Preparation Example 2-3 (Example 7) of the present invention were prepared and packaged in aluminum packets of 1 g each.

Stability test method: 1g each of the finished composition in powder and granular form was filled into an aluminum packet (9 cm . The stability test was analyzed on days 0, 1, 2, 3, 4, 5, 6, 7, 8, and 10 of the stored samples. 10 mg of the analysis sample was weighed, placed in an NMR tube, and dissolved in 0.62 mL of CDCl _3. It was dissolved and analyzed by 1H-NMR (400 MHz). The analysis method was confirmed by the reactor activity of the main component 4arm-PEG-SG derivative and the succinimidyl group peak of 2.80~2.90 ppm (parts per million; Proton) in the NMR spectrum. In other words, since 4arm-PEG-SG is the main ingredient that binds to the oral mucosa and provides a moisturizing effect, the functional group (succinimidyl group) activity of 4arm-PEG-SG, which covalently binds to the amine (NH2) group of the oral mucosa, was measured using 1H-NMR. Analysis is performed to confirm the stability of the finished composition. The stability of the finished composition was judged as “stable” if the NMR activity value of the main component 4arm-PEG-SG was more than 90%, and “not stable” if it was less than 90%. The results are shown in Table 11 below.

*In the results of the 7th day, one of the three batches meets the standard (90% or more), but since the average value of the three batches is below the standard, it is judged as Not stable. As shown in the above results, the harsh conditions depending on the formulation of the finished composition As a result of a stability test at (25 ± 2 °C, relative humidity 60% ± 5%), the reactor activity of the main component 4arm-PEG-SG derivative was 92.15% and 92.19% on the 3rd day for the powder-type composition (Comparative Example 15). , 92.25% granular composition (Example 7) showed stable results of 90.26%, 90.29%, and 92.68% on the 6th day.

When the finished composition was in powder form (Comparative Example 15), it was confirmed that the granular finished composition (Example 7) was stable for 6 days, showing improved stability, compared to the results showing stability for 3 days under harsh conditions. The formulation of the composition is changed to a granular form, and compared to the powder form, the exposed area in the air is reduced, the absorption of moisture in the air is reduced due to reduced exposure, and stability appears to have increased.

Therefore, the dosage form of the final finished composition was determined to be granular. A product for relieving dry mouth was developed as the final product, including a container capable of measuring the amount of water used per time and a packet containing a composition for relieving dry mouth in the form of a granule for one use.

The oral rinse composition for alleviating dry mouth according to the present invention not only increases the oral moisturizing power by forming a covalent bond with the oral mucosa without irritation using the polyethylene glycol derivative of Chemical Formula 1 as an active ingredient, but also has a granule formulation, so it is manufactured and Not only is it easy to package, but it is also convenient for storage and use.

Claims (15)

As active ingredients, it contains a polyethylene glycol derivative of the following formula (1), an acidity regulator, and a flavoring agent,
The polyethylene glycol derivative has a molecular weight of 8,000 to 15,000 Da,
Oral rinse composition for alleviating dry mouth, having granular formulation:
[Formula 1]

The oral rinse composition for alleviating dry mouth according to claim 1, wherein the granules have a particle size of 200 to 1500 ㎛. The oral rinse composition for alleviating dry mouth according to claim 1, wherein the composition is dissolved in water and reconstituted in a solution form upon use. The oral rinse composition for alleviating dry mouth according to claim 1, wherein the acidity regulator is included in an amount of 1 to 10 parts by weight based on 100 parts by weight of the composition. The oral rinse composition for alleviating dry mouth according to claim 3, wherein the composition exhibits a pH of 7 to 8 when dissolved in water and reconstituted in a solution form upon use. The oral rinse composition for alleviating dry mouth according to claim 3, wherein the solution has a viscosity of 0.001 to 0.01 Pas. A method for alleviating dry mouth comprising applying the oral rinse composition for relieving dry mouth of claim 1 to a subject in need thereof. The method of claim 7, wherein the application comprises administering and rinsing the oral rinse composition for relieving dry mouth reconstituted in solution form. The method of alleviating dry mouth according to claim 7, wherein the application is performed once to three times a day. Preparing a polyethylene glycol derivative powder of Chemical Formula 1 having a molecular weight of 8,000 to 15,000 Da;
Mixing the polyethylene glycol derivative powder with an acidity regulator and a flavoring agent, then transferring the polyethylene glycol derivative powder to an airtight container and liquefying it at high temperature;
When the liquefaction is complete, transferring the airtight container to a low temperature and solidifying it; and
A method for producing the oral rinse composition for alleviating dry mouth according to claim 1, comprising: pulverizing the solidification upon completion of the solidification to produce granules;
[Formula 1]

The method of claim 10, comprising adding an acidity regulator to adjust the pH to 7 to 8. The method of claim 10, wherein the liquefying step is performed at 50 to 70° C. for 1 hour. The method of claim 10, wherein the solidifying step includes:
Primary hardening at room temperature for 1 hour; and
A method for producing an oral rinse composition for alleviating dry mouth comprising the step of secondary hardening at -20°C. A product for alleviating dry mouth comprising a container capable of measuring 15 to 30 ml of water for a single use and a packet packed with 1 to 1.5 g of an oral rinse composition for alleviating dry mouth of the granule formulation according to claim 1 for a single use. product. The product for alleviating dry mouth according to claim 14, wherein the amount of water used per time is 20ml, and the oral rinse composition used per time is 1g.

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