WO2023100836A1

WO2023100836A1 - Pharmaceutical composition

Info

Publication number: WO2023100836A1
Application number: PCT/JP2022/043861
Authority: WO
Inventors: 和洋前田; 雄也梶浦
Original assignee: マルホ株式会社
Priority date: 2021-11-30
Filing date: 2022-11-29
Publication date: 2023-06-08
Also published as: TW202333659A

Abstract

The present invention addresses the problem of providing a pharmaceutical composition that is for local use and that is appropriate for the alleviation of pain in the oral cavity and/or the pharynx.　This pharmaceutical composition for local use contains N,N-dimethyl-2-oxo-N-(2-oxo-2-(phenylamino)ethyl)-2-(phenylamino)ethan-1-aminium and/or a pharmaceutically acceptable salt thereof as the active ingredient. Preferably the pharmaceutical composition contains at least one selected from the group consisting of hydrochloric acid, lactic acid, tartaric acid, and C4 or higher sugar alcohols.

Description

Pharmaceutical composition

The present invention provides N,N-dimethyl-2-oxo-N-(2-oxo-2-(phenylamino)ethyl)-2-(phenylamino)ethane-1-aminium (hereinafter referred to as compound A) and/or or a pharmaceutically acceptable salt thereof as an active ingredient, particularly to a pharmaceutical composition for relieving pain in the oral cavity and/or pharynx.

Stomatitis is known as inflammation that occurs in the mucous membranes in and around the mouth (e.g., the inside of the cheeks, gums, tongue, lips, and palate). and may even interfere with speech. Such severe stomatitis often occurs in patients who have undergone cancer treatment such as anti-cancer drug treatment and radiation therapy, and the pain greatly affects the patient's QOL (quality of life). undermine. In addition, simultaneous chemoradiotherapy to the head and neck is known to cause severe oropharyngeal mucositis. Severe dysphagia occurs.

Oral analgesics are administered to alleviate the intense pain caused by such stomatitis and/or pharyngitis, and when the pain is particularly severe, analgesics and medical narcotics (such as morphine) are used in combination. ing. However, since oral drugs can affect the whole body, safer topical formulations are desired.

As a topical preparation that can be used to directly relieve pain caused by stomatitis, Patent Document 1 discloses an oral or pharynx preparation containing a local anesthetic (such as lidocaine) and a weak acid (such as citric acid or phosphoric acid). is disclosed, and Patent Document 2 discloses a jelly containing phosphoric acid or a pharmaceutically acceptable salt thereof and a local anesthetic. However, there is still a need for topical pain relief agents suitable for relieving oral and/or pharyngeal pain.

JP 2005-015479 A Japanese Patent Application Laid-Open No. 2006-160607

Thus, an object of the present invention is to provide a topical pharmaceutical composition suitable for relieving pain in the oral cavity and pharynx. In particular, an object of the present invention is to provide a topical pharmaceutical composition capable of stably maintaining an active ingredient.

The present inventors focused on compound A (especially the chloride of compound A), which is a local anesthetic, and locally applied compound A and / or a salt thereof to the oral cavity and pharynx to relieve pain in the oral cavity and pharynx. It has been found that not only can it be improved, but also the sanitary conditions in the oral cavity can be improved due to its antibacterial action. Furthermore, since compound A exhibits different properties from lidocaine, it was not possible to provide a stable formulation by the same approach as in Patent Documents 1 and 2. We also found a component that can keep the

The present invention has the following configurations.
[1] N,N-dimethyl-2-oxo-N-(2-oxo-2-(phenylamino)ethyl)-2-(phenylamino)ethane-1-aminium (hereinafter referred to as compound A) and/or its A topical pharmaceutical composition for application to the oral cavity and/or pharynx, comprising a pharmaceutically acceptable salt as an active ingredient.
[2] The pharmaceutical composition of [1], containing at least one selected from the group consisting of hydrochloric acid, lactic acid, tartaric acid, and sugar alcohols having 4 or more carbon atoms.
[3] The pharmaceutical composition of [1] or [2], comprising at least one sugar alcohol having 4 or more carbon atoms.
[4] The pharmaceutical composition of any one of [1] to [3], comprising at least one acidic component selected from the group consisting of hydrochloric acid, lactic acid, and tartaric acid.
[5] At least one acidic component selected from the group consisting of hydrochloric acid, lactic acid, and tartaric acid, and at least one basic component selected from the group consisting of sodium hydroxide, potassium hydroxide, diisopropanolamine, and sodium tartrate The pharmaceutical composition according to any one of [1] to [4], comprising the component.
[6] The pharmaceutical composition according to any one of [2] to [4], wherein the at least one sugar alcohol is selected from the group consisting of xylitol, mannitol and sorbitol.
[7] The pharmaceutical composition according to any one of [1] to [6], which contains a chloride of Compound A as the active ingredient.
[8] The pharmaceutical composition of any one of [1]-[7], which has a pH of 3-7.
[9] Any one of [1] to [8], further comprising at least one selected from the group consisting of sucralose, sucrose, stevia extract, purified stevia extract, thaumatin, and acesulfame potassium pharmaceutical composition of
[10] The pharmaceutical composition of any one of [1] to [9], further comprising at least one polyhydric alcohol selected from glycerin and propylene glycol.
[11] a chloride of compound A,
at least one acidic component selected from the group consisting of hydrochloric acid, lactic acid and tartaric acid, optionally at least one basic component selected from the group consisting of sodium hydroxide, potassium hydroxide, diisopropanolamine and sodium tartrate ,
at least one sugar alcohol selected from the group consisting of xylitol, mannitol, and sorbitol;
at least one selected from the group consisting of sucralose, sucrose, stevia extract, refined stevia extract, thaumatin, and acesulfame potassium;
The medicament according to any one of [1] to [10], which contains at least one polyhydric alcohol selected from glycerin and propylene glycol, and 0 to 5% by weight of additives, the remainder being water. Composition.

1A and 1B are graphs showing the effect of an acidic or basic component on the hydrolysis of the chloride of Compound A. FIG. The lower the stability of compound A, the higher the amount of hydrolyzate produced. FIG. 2 is a graph showing the effect of sugar alcohol (sorbitol or xylitol) on the hydrolysis of the chloride of Compound A. FIG. 3 is a graph showing the effect of sugar alcohol (mannitol or erythritol) on the hydrolysis of the chloride of compound A. FIG.

The composition of the present invention is a pharmaceutical composition. As a pharmaceutical composition, it falls under ethical drugs, guidance-required drugs, over-the-counter drugs, or quasi-drugs as stipulated in the "Act on Securing Quality, Efficacy and Safety of Pharmaceuticals and Medical Devices, etc." compositions.

The composition of the present invention contains at least one selected from compound A and pharmaceutically acceptable salts thereof as an active ingredient. In particular, a composition containing a chloride of compound A represented by the following structural formula as an active ingredient is preferred.

The content of compound A and/or a salt thereof is preferably 0.1 to 5% by weight, more preferably 0.5 to 2.5% by weight, and 1 to 2% by weight. Especially preferred.
As used herein, the content of each component contained in the composition of the present invention means the weight ratio of each component when the total weight of the composition is 100.

Compound A and its salts have local anesthetic action. Furthermore, it has been clarified that Compound A and its salts have antimicrobial activity against multiple bacteria and fungi. Patients who have pain in the oral cavity or pharynx due to stomatitis, pharyngitis, etc. have difficulty brushing their teeth and gargling sufficiently due to the pain, and the oral cavity tends to become unsanitary. As a result, the number of bacteria increases, and it has been reported that the bacteria enter the trachea together with saliva and cause pneumonia. There have also been reports of cases in which bacteria enter blood vessels from ulcers of stomatitis, spread throughout the body through the blood vessels, and cause high fever. Therefore, a composition comprising Compound A/a salt thereof, which has antibacterial activity in addition to local anesthetic activity, can relieve pain and prevent diseases caused by bacteria. Very suitable for topical application to the larynx. For this reason, the composition of the present invention is particularly suitable for alleviating pain caused by stomatitis and/or pharyngitis caused by cancer treatment using anticancer drugs or radiation, It is suitable for relieving pain caused by oropharyngeal mucositis caused by chemoradiotherapy.

In addition, since the composition of the present invention has a local anesthetic effect, it can also be used as a topical composition for anesthetizing the oral cavity, pharynx, and/or nasal cavity, etc. when performing gastroscopy.

For pharmaceutical compositions, it is important to stably maintain the active ingredients in the composition (to suppress the decomposition of the active ingredients) in order to suppress the decline in efficacy during storage. The present inventors found that the addition of citric acid, phosphoric acid, etc., which are widely used as pH adjusters, to a composition containing compound A and/or a salt thereof promotes hydrolysis of compound A or a salt thereof. Therefore, it has been found that it is difficult to keep the active ingredient stable. On the other hand, the present inventors have found that some acidic components and basic components are less likely to accelerate the hydrolysis of compound A and salts thereof. Such a phenomenon was not observed with lidocaine and its salts, which are representative drugs used as local anesthetics, and the phenomenon that the rate of hydrolysis differs greatly depending on the type of acidic component/basic component added was not observed. , which is believed to be characteristic of compound A and its salts.

More specifically, when the decomposition product (hydrolyzate) resulting from the hydrolysis of compound A or a salt thereof was measured, hydrochloric acid (HCl), lactic acid, tartaric acid, sodium hydroxide, potassium hydroxide, diisopropanolamine, or When sodium tartrate hydrate or the like was added, a small amount of decomposition products was obtained (that is, compound A and its salt were stable), but citric acid, phosphoric acid, sodium dihydrogen phosphate, sodium hydrogen carbonate, Or when other acidic or basic components such as sodium acetate were added, the degradants increased significantly. Therefore, when adjusting the pH of the composition of the present invention, it is preferable to select a component that does not easily accelerate the decomposition of compound A or its salt. For example, at least one of hydrochloric acid (HCl), lactic acid, and tartaric acid. alone, or at least one of hydrochloric acid (HCl), lactic acid, tartaric acid and sodium hydroxide, potassium hydroxide, diisopropanolamine, sodium tartrate (including hydrates) It is preferable to use together with at least 1 or more basic components among these to adjust pH.

The pH of the composition of the present invention is preferably 3-7, more preferably 3-6, and particularly preferably 4.5-5.5. Thus, the pH of the composition of the present invention is preferably more acidic, so the pH of the composition of the present invention is selected from hydrochloric acid (HCl), lactic acid, tartaric acid and monosodium fumarate. It is preferably adjusted using at least one of the acidic components (more preferably an acidic component selected from hydrochloric acid, lactic acid and tartaric acid, particularly preferably hydrochloric acid). In addition, when a basic component is used in addition to the above acidic component, the basic component includes sodium hydroxide, potassium hydroxide, diisopropanolamine, sodium tartrate (including hydrates), and disodium succinate (water (more preferably a basic component selected from sodium hydroxide, potassium hydroxide, diisopropanolamine and sodium tartrate, particularly preferably sodium hydroxide, and/or or potassium hydroxide). In particular, it is preferable to use hydrochloric acid, and it is more preferable to use hydrochloric acid and sodium hydroxide in combination. As used herein, hydrochloric acid means an aqueous solution of hydrogen chloride (HCl), and the concentration of hydrogen chloride is not particularly limited. , dilute hydrochloric acid (containing 9.5 to 10.5 w/v% hydrogen chloride).

When one or more of the aforementioned acidic/basic components are used, the total concentration of said acidic/basic components in the composition is preferably 0.001-1% by weight, preferably 0.005-0. 0.1% by weight is more preferred, and 0.008-0.05% by weight is particularly preferred.

Furthermore, the present inventors have found that sugar alcohols have the effect of suppressing the hydrolysis of compound A and its salts. Therefore, the composition of the invention preferably contains a sugar alcohol. Examples of the sugar alcohol include sugar alcohols having 4 to 12 carbon atoms such as erythritol, xylitol, sorbitol, mannitol, maltitol and reduced palatinose. Sugar alcohols having 4 to 6 carbon atoms (erythritol [C4], xylitol [C5], sorbitol [C6], or mannitol [C6]) are preferred, sugar alcohols having 5 or 6 carbon atoms are more preferred, and sugars having 6 carbon atoms are preferred. Alcohols are particularly preferred. In particular, sorbitol (D-sorbitol) and mannitol have a high hydrolysis inhibitory effect on compound A, so the composition of the present invention preferably contains sorbitol and/or mannitol (especially sorbitol).

The total content of the sugar alcohols contained in the composition of the present invention is preferably 0.4 to 20% by weight, more preferably 1 to 15% by weight, particularly preferably 2 to 10% by weight, and 3 to 7% by weight. % by weight is more preferred.

Since compound A and its salt have a strong bitterness, the composition of the present invention may further contain a sweetener other than the sugar alcohol in order to reduce the bitterness. Among sweeteners, saccharin sodium hydrate and dipotassium glycyrrhizinate were found to reduce the solubility of the active ingredient (Compound A and/or its salt) in the composition. Therefore, when using a sweetener, it is particularly preferable to select a sweetener that does not reduce the solubility of the active ingredient even in situations where the active ingredient is expected to precipitate easily (for example, when the composition is stored at low temperatures). .

The composition of the present invention preferably contains a sweetener selected from the group consisting of sucralose, sucrose, stevia extract, refined stevia extract, thaumatin, and acesulfame potassium, wherein sucralose, stevia extract, refined stevia extract and thaumatin, more preferably sucralose and refined stevia extract. In the present specification, the stevia extract refers to a total of 80.50 g of four steviol glycosides (stevioside, rebaudioside A, rebaudioside C, and dulcoside A) obtained by extracting from stevia leaves. It means that it contains 0% by weight or more. As used herein, the purified stevia extract is obtained by extracting stevia leaves with water and purifying them, as described in Japanese Pharmaceutical Excipients 2018, which contains steviol glycosides It means that 5 kinds (stevioside, rebaudioside A, rebaudioside C, dulcoside A, rubusoside) are contained in a total of 90.0 to 96.0% by weight. The total content of these sweeteners in the composition is preferably 0.01 to 3% by weight, more preferably 0.05 to 2% by weight, particularly preferably 0.1 to 1% by weight, and 0.2% by weight. ~0.6% by weight is more preferred.

The composition of the present invention preferably contains glycerin (including concentrated glycerin) and a polyhydric alcohol selected from propylene glycol, and particularly preferably contains glycerin. As used herein, polyhydric alcohols do not include sugar alcohols having 4 or more carbon atoms. The total content of polyhydric alcohols in the composition is preferably 2 to 30% by weight, more preferably 3 to 20% by weight, and particularly preferably 5 to 15% by weight.

The composition of the present invention preferably contains water (preferably purified water). The water content in the composition is preferably 50% by weight or more, more preferably 60% by weight or more, particularly preferably 70 to 95% by weight, and even more preferably 80 to 90% by weight.

The composition of the present invention may or may not contain additives (preservatives, thickeners, etc.) other than the components described above. The content of the additive in the composition of the present invention is preferably 0 to 5% by weight, more preferably 0 to 3% by weight, and particularly preferably 0 to 1% by weight.

Examples of preservatives include, but are not limited to, thymol, dibutylhydroxytoluene, citric acid hydrate, boric acid, parahydroxybenzoic acid, paraoxybenzoic acid esters (methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, , butyl p-oxybenzoate), sodium benzoate, phenoxyethanol, chlorobutanol, chlorocresol, benzyl alcohol, salicylic acid, sodium edetate hydrate, tetrasodium edetate, sodium dehydroacetate, sorbic acid, potassium sorbate, benzethonium chloride, Benzalkonium chloride, dry sodium sulfite, and the like can be mentioned, and one or more of them may be used. Since Compound A and its salts exhibit antibacterial activity against bacteria and fungi, the composition of the present invention may be free of preservatives.

Examples of thickening agents include, but are not limited to, sodium alginate, gelatin, carboxyvinyl polymer, sodium polyacrylate, methylcellulose, glycerin monooleate, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, polyvinyl Alcohol, xanthan gum, etc. may be mentioned, and only one may be used, or two or more may be used. The compositions of the invention may be free of such thickening agents.

The composition of the present invention is preferably a topical formulation that is particularly applied to the mucous membranes of internal cavities such as the oral cavity, pharynx, and nasal cavities. Dosage forms include liquid preparations (including solutions, elixirs, suspensions, emulsions, limonades, syrups, lotions, etc.), gel preparations (including jelly), sprays, etc. A form that is easy to contact with is preferred. For example, the composition of the present invention may be a spray for the oral and/or pharyngeal mucosa, or an oral gargle or mouthwash. Moreover, after the composition of the present invention is applied to the mucous membranes of the oral cavity and pharynx, it is preferable not to wash it off by gargling or the like. For example, a patient with stomatitis or pharyngitis can apply the composition to the oral cavity before eating or drinking and eat or drink as it is. Since the composition of the present invention has an antibacterial effect in addition to a local anesthetic effect, it is expected that by using it without rinsing off, it will not only alleviate pain due to the anesthetic effect, but also keep the oral cavity sanitary due to the antibacterial effect. .

A preferred example of the composition of the present invention is a liquid composition. The liquid composition has low viscosity, and the viscosity is usually 3000 mPa·s or less, preferably 2000 mPa·s or less, more preferably 500 mPa·s or less, and most preferably 300 mPa·s or less. The liquid composition may be free of thickening agents. In the present invention, the viscosity means the viscosity after 60 seconds from the start of rotation with a cone plate type viscometer (modular compact rheometer) at a measurement temperature of 25 ° C., cone plate No. 50-1, rotation speed of 5 rpm. do.

The liquid composition is contained in a spray container with a nozzle (a container that can discharge or spray the liquid composition in the container by a pump without using a propellant), and is discharged or sprayed into the oral cavity from the discharge hole at the tip of the nozzle. may The nozzle-equipped spray container has, for example, a container body and a dispenser attached to the top thereof, and the dispenser is provided with a horizontally extending nozzle that pushes the top of the dispenser downward toward the container body. Accordingly, it is possible to use a container capable of discharging or spraying the liquid composition in the container main body from the discharge hole at the tip of the nozzle. By using such a container, the liquid composition can hit the affected area. In addition, when the liquid composition is discharged or sprayed toward the back of the throat, the fluidity of the liquid composition allows it to flow from the oral cavity to the hypopharynx, thereby alleviating pain not only in the oral cavity but also in the pharynx. can.

As a preferred example of the composition of the present invention,
- compound A and/or a pharmaceutically acceptable salt thereof (especially a chloride of compound A),
- at least one acidic component (particularly dilute hydrochloric acid) selected from the group consisting of dilute hydrochloric acid, lactic acid and tartaric acid, optionally selected from the group consisting of sodium hydroxide, potassium hydroxide, diisopropanolamine and sodium tartrate at least one basic component,
- at least one sugar alcohol having 5 or 6 carbon atoms (more preferably a sugar alcohol selected from the group consisting of xylitol, sorbitol and mannitol, especially sorbitol);
- at least one sweetener selected from the group consisting of sucralose, sucrose, stevia extract, refined stevia extract, thaumatin, and acesulfame potassium (especially sucralose and/or refined stevia extract);
- at least one polyhydric alcohol (especially glycerin); and - optionally at least one additive, the balance being water (especially purified water). This composition is preferably a pain-relieving or local anesthetic composition, especially for oral, pharynx and/or nasal cavity application, in particular an oral and/or pharynx pain-relieving composition. Preferably. The pH of this composition is preferably between 3 and 7 (more preferably between 3 and 6, especially between 4.5 and 5.5).

Among the preferred examples,
- The content of compound A and/or a pharmaceutically acceptable salt thereof is 0.1 to 3% by weight (more preferably 0.5 to 2.5% by weight, particularly 1 to 2% by weight) ,
- The total content of the at least one acidic component and any at least one basic component is 0.001 to 1% by weight (more preferably 0.005 to 0.1% by weight, particularly preferably 0.008 ~ 0.05% by weight),
- the content of the at least one sugar alcohol is 0.4 to 20% by weight (more preferably 1 to 15% by weight, particularly 2 to 10% by weight, or 3 to 7% by weight);
0.01 to 3% by weight of the at least one sweetener (more preferably 0.05 to 2% by weight, particularly preferably 0.1 to 1% by weight, more preferably 0.2 to 0.6% by weight) ) and
- the content of the at least one polyhydric alcohol is 2 to 30% by weight (more preferably 3 to 20% by weight, particularly 5 to 15% by weight);
A composition in which the content of the additive is 0 to 5% by weight (more preferably 0 to 3% by weight, especially 0 to 1% by weight) is particularly preferred.

As a more preferable example of the composition of the present invention,
- 0.1 to 3 wt% (more preferably 0.5 to 2.5 wt%, especially 1 to 2 wt%) of a chloride of compound A;
0.001 to 1% by weight (more preferably 0.005 to 0.1% by weight, particularly preferably 0.008 to 0.05% by weight) of dilute hydrochloric acid and optionally sodium hydroxide (especially dilute hydrochloric acid and Sodium hydroxide),
0.4-20% by weight (more preferably 1-15% by weight, especially 2-10% by weight, or 3-7% by weight) of sorbitol and/or xylitol (especially sorbitol),
0.01 to 3% by weight (more preferably 0.05 to 2% by weight, particularly preferably 0.1 to 1% by weight, still more preferably 0.2 to 0.6% by weight) of sucralose and/or purified stevia extracts (particularly sucralose and purified stevia extracts),
2 to 30% by weight (more preferably 3 to 20% by weight, especially 5 to 15% by weight) of glycerol, and 0 to 5% by weight (more preferably 0 to 3% by weight, especially 0 to 1% by weight). ) and the remainder is water (especially purified water). Preferably, the composition is an oral and/or pharynx pain relief composition. The pH of this composition is preferably between 3 and 7 (more preferably between 3 and 6, especially between 4.5 and 5.5).

The composition may be provided in the form of a concentrated solution that, when diluted with water at the time of use (for example, diluted 2 to 10 times or 2 to 5 times), will have the concentration described above.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited by the examples.

[Example 1]
Dissolve 0.2% by weight of acidic component in purified water and add sodium hydroxide to adjust the pH to 6. Alternatively, dissolve 0.2% by weight of basic component in purified water and add hydrochloric acid to adjust the pH to 6. Chloride of compound A was added to the aqueous solution adjusted to 10 mg/10 ml. After that, the aqueous solution was stored at 60° C. for 2 weeks, and the amount of hydrolyzate produced from the hydrolysis of the chloride of compound A was measured by high performance liquid chromatography (HPLC). The amount (weight) of hydrolyzate produced was divided by the weight of added Compound A chloride and multiplied by 100 to determine the % of hydrolyzate produced. Acidic components include hydrochloric acid, citric acid, phosphoric acid, lactic acid, tartaric acid, or sodium dihydrogen phosphate, and basic components include sodium hydroxide, sodium citrate, sodium hydrogen carbonate, and aqueous sodium hydrogen phosphate. hydrate, or trisodium phosphate was used.

The results are shown in Figure 1A. As evident from FIG. 1A, the amount of hydrolyzate varied greatly depending on the type of acidic/basic component added. Specifically, citric acid, phosphoric acid, sodium dihydrogen phosphate, or sodium bicarbonate greatly accelerated the hydrolysis of the chloride of Compound A (2% or more of the hydrolyzate was produced), sodium citrate, Sodium hydrogen phosphate hydrate, or trisodium phosphate also accelerated the hydrolysis of the chloride of Compound A (more than 1% hydrolyzate was produced). In contrast, when hydrochloric acid, lactic acid, tartaric acid, or sodium hydroxide was added, the amount of hydrolyzate produced was small, suggesting that hydrolysis of the chloride of Compound A is less likely to occur. On the other hand, with lidocaine hydrochloride, which has a local anesthetic effect like compound A, no event was observed in which the hydrolysis rate varied greatly depending on the type of pH adjuster used.

[Example 2]
0.2% by weight of a basic _component ₍ sodium hydroxide, potassium hydroxide, sodium acetate, sodium tartrate hydrate ( _{C4H4Na2O6.2H2O} ), or _{diisopropanolamine} ₎ is dissolved in purified water, To the aqueous solution adjusted to pH 6 by adding hydrochloric acid, the chloride of Compound A was added so as to make 10 mg/10 ml. Thereafter, the aqueous solution was stored at 60° C. for 2 weeks in the same manner as in Example 1, and the amount of hydrolyzate produced from the hydrolysis of the chloride of compound A was measured by HPLC.

The results are shown in Figure 1B. As can be seen from FIG. 1B, the amount of hydrolyzate of compound A was lower when sodium hydroxide, potassium hydroxide, sodium tartrate hydrate, and diisopropanolamine were used, but sodium acetate was used. case was high.

From the results of Examples 1 and 2, it was found that among the acidic components/basic components used for pH adjustment, there are those that easily cause the decomposition of compound A and those that do not. Furthermore, when the effect of the pH of the composition on the stability of the chloride of compound A was investigated, a pH range of 3 to 7 was more preferred, a pH range of 3 to 6 was more preferred, and a pH of about 5 was most preferred. rice field.

[Example 3]
The effect of sweeteners on the stability of Compound A chloride was investigated. Sugar alcohols having 4 or more carbon atoms (D-sorbitol, xylitol, mannitol), sucralose, purified stevia extract, saccharin Na hydrate, acesulfame potassium, or dipotassium glycyrrhizinate were used as sweeteners. To an aqueous solution prepared by adding each sweetener at the concentration shown in Table 1 to a pH 8 buffer solution consisting of boric acid, citric acid hydrate and trisodium phosphate dodecahydrate, the chloride of Compound A was added. was added at 10 mg/10 ml.

Thereafter, the aqueous solution was stored at 60° C. for 2 weeks in the same manner as in Example 1, and the amount of hydrolyzate produced from the hydrolysis of the chloride of compound A was measured by HPLC. Table 1 shows the results.

As shown in Table 1-1, when sugar alcohols with 4 or more carbon atoms were added, the amount of carboxylic acid forms after 2 weeks at 60°C decreased significantly compared to the case of buffer alone. On the other hand, as shown in Table 1-2, when sucralose, purified stevia extract, and dipotassium glycyrrhizinate were added, the amount of carboxylic acid forms decreased compared to the case of buffer alone, but the decrease was The extent was smaller than that of sugar alcohols with 4 or more carbon atoms. When saccharin sodium hydrate and acesulfame potassium were added to the buffer solution, compound A did not dissolve, making it impossible to prepare a formulation. After two weeks at 60°C, the pH value was within the range of about 5.5 to 6.5, and there was no significant difference between the addition of sugar alcohol and the addition of other sweeteners.

From these results, it was found that sugar alcohols with 4 or more carbon atoms are useful for enhancing the stability of compound A (suppressing the decomposition of compound A).

[Example 4]
Compositions (pH about 4.5 to 5.5) shown in Table 2 were prepared to test the effect of the type and concentration of sugar alcohol on the stability of compound A chloride. D-sorbitol, xylitol, erythritol, or mannitol was used as sugar alcohol. The stability of the chloride of Compound A was determined by storing the prepared composition at 50° C. for 2 weeks, and then measuring the amount of hydrolyzate produced from the hydrolysis of the chloride of Compound A in the same manner as in Example 1. tested by

The results are shown in Figures 2 and 3. As is clear from FIGS. 2 and 3, the addition of the sugar alcohol having 4 or more carbon atoms inhibited the decomposition of the chloride of Compound A. All sugar alcohols tended to have a higher inhibitory effect on decomposition as the amount added increased, but the degree of inhibition of decomposition varied depending on the type of sugar alcohol. The decomposition inhibitory action was higher in the order of D-sorbitol, mannitol, xylitol and erythritol.

[Example 5]
Since the addition of certain sweeteners reduced the solubility of Compound A chloride, the compatibility of Compound A chloride with sweeteners was investigated. More specifically, a 0.2% by weight aqueous solution was prepared for each sweetener, and while stirring the aqueous solution, the chloride of Compound A was gradually added until insoluble matter was produced. After that, the stirring was stopped, and the aqueous solution was allowed to stand overnight, and then the aqueous solution was filtered with a filter, and the concentration of the dissolved compound A chloride was measured by HPLC.
Table 3 shows the results.

As shown in Table 3, the solubility of the chloride of compound A does not decrease with nonionic sweeteners, but tends to decrease with ionic sweeteners. On the other hand, no such events were observed with lidocaine hydrochloride. Increasing the concentration of ionic sweetener further decreased the solubility of Compound A chloride. For this reason, it is preferable to use a nonionic sweetener under conditions where the chloride of compound A is expected to precipitate easily, such as when the room temperature is low.

[Example 6]
The compositions shown in Table 4 (pH about 5) were prepared to test the antimicrobial efficacy of the compositions against three types of bacteria: Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. tested.

In addition, as shown in Table 5, compositions (pH about 5) were prepared in which the concentration of the chloride of compound A was increased to 2%, and the above three types of bacteria and two types of fungi (Candida albicans) were ], and Aspergillus brasiliensis).

[Procedure of test]
Staphylococcus aureus (NBRC13276), Pseudomonas aeruginosa (NBRC13275), Escherichia coli (NBRC3972), Candida albicans (NBRC1594) and Aspergillus brasiliensis (NBRC9455) were used as test strains. Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli were cultured on SCDA (soybean-casein-digest agar) plate medium at 30-35°C for 18-24 hours. Candida albicans was cultured at 20-25°C for 48 hours on a NSDA (Sabouraud Dextrose Agar) plate medium. Aspergillus brasiliensis was cultured at 20-25°C for 6-10 days using NSDA (Sabouraud dextrose agar) plate medium. At this time, the sterility of the pre-culture medium was confirmed by the presence or absence of bacterial growth after culturing under the same conditions using one SCDA and one NSDA plate medium.
The test bacterial solution was prepared by suspending the cultured cells in physiological saline, centrifuging, and then preparing the spores of Aspergillus brasiliensis to about 10 ⁸ CFU per 1 mL. , After centrifugation, it was prepared so that it became about 10 ⁸ CFU per 1 mL, and these were used as each test bacterial solution. 20 mL of each composition was placed in a sterilized glass container and inoculated with 0.1 mL of each test bacterial solution to prepare a mixed sample. Mixed samples were protected from light and stored at 20-25°C for 28 days.
On each measurement day (after 0, 14 and 28 days), 1 mL was taken from each mixed sample.
Each mixed sample was added to 9 mL of lecithin/polysorbate 80-added soybean/casein/digest medium and stirred well to prepare a diluted sample solution. Ten-fold serial dilution was repeated using a heptone salt buffer as necessary to obtain each diluted mixed sample. Dispense 1 mL of each diluted mixed sample into two Petri dishes, SCDLPA (soy bean casein digest agar with lecithin and polysorbate 80 added) for bacteria and NSDLPA (Sabouraud glucose agar with lecithin and polysorbate 80 added) for fungi. Added and mixed. After that, SCDLPA was cultured at 30-35°C and NSDLPA was cultured at 20-25°C for 5 days, and the number of emergent colonies (CFU) was counted.

Table 6 shows the number of viable bacteria per 1 mL on days 0, 14, and 28 when the compositions shown in Table 4 were used.

As shown in Table 6, the composition containing the chloride of compound A showed significantly higher antibacterial effect against each bacterium from day 0 compared to the comparative composition without the chloride of compound A. . Also, the 0.8% composition showed a higher antibacterial effect than the 0.1% composition.

Table 7 shows the number of viable bacteria per 1 mL on days 0, 14, and 28 when the compositions shown in Table 5 were used.

As shown in Table 7, when the 2% composition was added to bacteria, the number of viable bacteria on day 0 was one order of magnitude less than the number of inoculated bacteria, demonstrating a high antibacterial effect. Also, for fungi, a decrease in the number of viable bacteria was observed from day 0 onwards with respect to the number of inoculated bacteria.

The composition of the present invention can relieve pain by applying it to the oral cavity of patients suffering from severe stomatitis or pharyngitis due to anticancer drugs, radiation therapy, etc. In addition, it exerts an antibacterial effect against bacteria and fungi in the mouth. Therefore, by applying it to patients who are unable to perform oral care such as tooth brushing due to pain and whose oral hygiene is deteriorating, it is thought that it will improve the oral environment and help prevent diseases caused by bacteria. .

[Example 8]
Formulation examples of the composition of the present invention are shown below. The compositions shown in the table are liquid compositions and can be used, for example, to relieve pain in the oral cavity and/or pharynx by spraying into the oral cavity from a nozzle-equipped spray bottle.

Claims

N,N-dimethyl-2-oxo-N-(2-oxo-2-(phenylamino)ethyl)-2-(phenylamino)ethane-1-aminium (hereinafter referred to as Compound A) and/or its pharmaceutically acceptable 1. A topical pharmaceutical composition for application to the oral cavity and/or pharynx, comprising as an active ingredient a salt of the present invention.
The pharmaceutical composition according to claim 1, comprising at least one selected from the group consisting of hydrochloric acid, lactic acid, tartaric acid, and sugar alcohols having 4 or more carbon atoms.
The pharmaceutical composition according to claim 1, comprising at least one sugar alcohol having 4 or more carbon atoms.
The pharmaceutical composition according to claim 1 or 3, comprising at least one acidic ingredient selected from the group consisting of hydrochloric acid, lactic acid, and tartaric acid.
at least one acidic component selected from the group consisting of hydrochloric acid, lactic acid, and tartaric acid; and at least one basic component selected from the group consisting of sodium hydroxide, potassium hydroxide, diisopropanolamine, and sodium tartrate. , the pharmaceutical composition according to claim 1 or 3.
The pharmaceutical composition according to claim 2 or 3, wherein said at least one sugar alcohol is selected from the group consisting of xylitol, mannitol and sorbitol.
The pharmaceutical composition according to any one of claims 1 to 6, which contains a chloride of compound A as the active ingredient.
The pharmaceutical composition according to any one of claims 1 to 7, which has a pH of 3 to 7.
The pharmaceutical composition according to any one of claims 1 to 8, further comprising at least one selected from the group consisting of sucralose, sucrose, stevia extract, purified stevia extract, thaumatin, and acesulfame potassium.
The pharmaceutical composition according to any one of claims 1 to 9, further comprising at least one polyhydric alcohol selected from glycerin and propylene glycol.
chloride of compound A,
at least one acidic component selected from the group consisting of hydrochloric acid, lactic acid and tartaric acid, optionally at least one basic component selected from the group consisting of sodium hydroxide, potassium hydroxide, diisopropanolamine and sodium tartrate ,
at least one sugar alcohol selected from the group consisting of xylitol, mannitol, and sorbitol;
at least one selected from the group consisting of sucralose, sucrose, stevia extract, refined stevia extract, thaumatin, and acesulfame potassium;
2. The pharmaceutical composition according to claim 1, comprising at least one polyhydric alcohol selected from glycerin and propylene glycol, and 0-5% by weight of additives, the remainder being water.