WO2023100836A1 - 医薬組成物 - Google Patents

医薬組成物 Download PDF

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WO2023100836A1
WO2023100836A1 PCT/JP2022/043861 JP2022043861W WO2023100836A1 WO 2023100836 A1 WO2023100836 A1 WO 2023100836A1 JP 2022043861 W JP2022043861 W JP 2022043861W WO 2023100836 A1 WO2023100836 A1 WO 2023100836A1
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pharmaceutical composition
compound
group
weight
composition according
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PCT/JP2022/043861
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English (en)
French (fr)
Japanese (ja)
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和洋 前田
雄也 梶浦
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マルホ株式会社
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Priority to JP2023513124A priority Critical patent/JP7273257B1/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • 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.
  • 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.
  • 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.
  • a local anesthetic such as lidocaine
  • a weak acid such as citric acid or phosphoric acid
  • Patent Document 2 discloses a jelly containing phosphoric acid or a pharmaceutically acceptable salt thereof and a local anesthetic.
  • JP 2005-015479 A Japanese Patent Application Laid-Open No. 2006-160607
  • an object of the present invention is to provide a topical pharmaceutical composition suitable for relieving pain in the oral cavity and pharynx.
  • 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.
  • 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.
  • 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.
  • [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.
  • 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.
  • FIG. 1A and 1B are graphs showing the effect of an acidic or basic component on the hydrolysis of the chloride of Compound A.
  • 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.
  • composition of the present invention is a pharmaceutical composition.
  • 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.
  • composition of the present invention contains at least one selected from compound A and pharmaceutically acceptable salts thereof as an active ingredient.
  • 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.
  • 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.
  • compositions 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.
  • Compound A/a salt thereof which has antibacterial activity in addition to local anesthetic activity, can relieve pain and prevent diseases caused by bacteria.
  • 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.
  • composition of the present invention 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • the basic component 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).
  • hydrochloric acid it is preferable to use hydrochloric acid, and it is more preferable to use hydrochloric acid and sodium hydroxide in combination.
  • 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).
  • 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.
  • the composition of the invention preferably contains a sugar alcohol.
  • 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 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.
  • sorbitol D-sorbitol
  • mannitol have a high hydrolysis inhibitory effect on compound A
  • 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.
  • the composition of the present invention may further contain a sweetener other than the sugar alcohol in order to reduce the bitterness.
  • a sweetener other than the sugar alcohol
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition of the present invention may be a spray for the oral and/or pharyngeal mucosa, or an oral gargle or mouthwash.
  • composition of the present invention 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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 - optional
  • 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.
  • 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 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%
  • 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
  • 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.
  • 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.
  • HPLC high performance liquid chromatography
  • Acidic components include hydrochloric acid, citric acid, phosphoric acid, lactic acid, tartaric acid, or sodium dihydrogen phosphate
  • basic components include sodium hydroxide, sodium citrate, sodium hydrogen carbonate, and aqueous sodium hydrogen phosphate. hydrate, or trisodium phosphate was 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.
  • a basic component sodium hydroxide, potassium hydroxide, sodium acetate, sodium tartrate hydrate ( C4H4Na2O6.2H2O ), or diisopropanolamine
  • 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 saccharin Na hydrate
  • acesulfame potassium or dipotassium glycyrrhizinate
  • 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.
  • 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
  • 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.
  • 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.
  • 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).
  • 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.
  • NSDA Spbouraud dextrose agar
  • 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.
  • 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.
  • SCDLPA sey bean casein digest agar with lecithin and polysorbate 80 added
  • NSDLPA Sabouraud glucose agar with lecithin and polysorbate 80 added
  • 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.
  • 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.
  • 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. .
  • 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.

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2752393A (en) * 1950-04-21 1956-06-26 Variapat Ag Trifluoromethyl-imino-bisacetanilide ammonium salts
JP2001514216A (ja) * 1997-09-03 2001-09-11 ノートラン ファーマシューティカルス インコーポレーテッド 痛み治療における塩化ｎ，ｎ−ビス（フェニルカルバモイルメチル）ジメチルアンモニウムおよび誘導体
JP2005015479A (ja) * 2003-06-03 2005-01-20 Medorekkusu:Kk 局所麻酔薬を含有する口中用または咽頭部用製剤
US20110237611A1 (en) * 2008-05-19 2011-09-29 Massachusetts Institute of Technology Massachusett s Chemical permeation enhancers enhance nerve blockade by toxins

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2752393A (en) * 1950-04-21 1956-06-26 Variapat Ag Trifluoromethyl-imino-bisacetanilide ammonium salts
JP2001514216A (ja) * 1997-09-03 2001-09-11 ノートラン ファーマシューティカルス インコーポレーテッド 痛み治療における塩化ｎ，ｎ−ビス（フェニルカルバモイルメチル）ジメチルアンモニウムおよび誘導体
JP2005015479A (ja) * 2003-06-03 2005-01-20 Medorekkusu:Kk 局所麻酔薬を含有する口中用または咽頭部用製剤
US20110237611A1 (en) * 2008-05-19 2011-09-29 Massachusetts Institute of Technology Massachusett s Chemical permeation enhancers enhance nerve blockade by toxins

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CREVELING, C. R. ET AL.: "Batrachotoxin-Induced Depolarization and [3H]Batrachotoxinin-A 20α-Benzoate Binding in a Vesicular Preparation from Guinea Pig Cerebral Cortex", MOLECULAR PHARMACOLOGY, vol. 23, 1983, pages 350 - 358, XP009546726 *
RAZAVI BIBI MARJAN; FAZLY BAZZAZ BIBI SEDIGHEH: "A review and new insights to antimicrobial action of local anesthetics", EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES, SPRINGER, WIESBADEN, DE, vol. 38, no. 6, 24 January 2019 (2019-01-24), DE , pages 991 - 1002, XP036783215, ISSN: 0934-9723, DOI: 10.1007/s10096-018-03460-4 *

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