JP2015178462A - Oral rinsing agent of ibuprofen - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition that reduces the pain and/or inflammation caused by oral disease comprising oral injury, stomatitis, periodontitis, tooth pain, pain after tooth extraction, or pain after oral surgical procedure, a method for preparing the composition, and a therapeutic method using the composition.SOLUTION: This invention provides a topical oral composition comprising ibuprofen ((2RS)-2(4-(2-methylpropyl)phenylpropanoic acid) or pharmacologically acceptable salt thereof and at least one carrier acceptable for an oral cavity, wherein the composition is in the form of aqueous solution, gel, or patch, and provides a method for preparing the composition, and a therapeutic method using the composition.

Description

  The present invention relates to a topical oral composition for reducing pain and / or inflammation caused by an oral disease containing ibuprofen or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for producing the composition, and a method for treating and / or preventing the composition using the composition.

  Ibuprofen is a propionic acid compound discovered by the research group of the British company Booth (now Abbott Laboratories) in the 1960s and classified as a non-steroidal anti-inflammatory analgesic (hereinafter sometimes referred to as NSAIDs). The Prostaglandin biosynthesis inhibitory action exerts anti-inflammatory, analgesic and antipyretic effects and is widely used as a medical and OTC drug.

  In general, when ibuprofen drug substance is included in the mouth, there is a strong irritation bitterness. Various devices have been made to mask the pungent bitterness. For example, a commercially available soft capsule in which ibuprofen is dissolved / suspended in a liquid is devised so that the content liquid does not leak in the mouth when it is taken. Moreover, the sugar-coated tablet containing ibuprofen reduces the bitter taste by coating the surface of a tablet with sugar. In either case, the ibuprofen solution, which is an active ingredient, and the drug substance itself are not processed to remove bitterness. Therefore, when the soft capsule is cut out and taken out from the capsule, and the experiment is performed in the mouth, irritation and stinging pain and bitterness are felt. In addition, when a sugar-coated tablet is bitten in the mouth, the throat coughs and the mouth feels tingling.

  The method of use described in the package inserts for oral preparations such as ibuprofen soft capsules and sugar-coated tablets is described as oral administration, administration, and use, all of which are active ingredients when taken orally It is assumed that ibuprofen is absorbed and put into the body. In the prior art, therapeutic doses of ibuflofen, when taken into the body, reach the expected blood concentration and exert drug efficacy according to pharmacokinetic behavior.

  Therefore, as disclosed in the present invention, it keeps in the mouth and operates to spread over the whole or part of the mouth and exhales it from the mouth after a while (referred to herein as “mouth rinse” The method of use (sometimes simply referred to as “rinsing”) is a method that does not assume that the component ibuprofen is administered to the oral cavity and ingested into the body, and is not assumed as a conventional ibuprofen preparation.

  The following are mentioned as a prior art of the non-steroidal anti-inflammatory analgesic and the local administration method to stomatitis and an oral disease.

  That is, examples of intractable stomatitis treatment (Non-patent Document 1) and cancer treatment-induced oral mucositis treatment (Non-patent Document 2) in indomethacin spray (0.25%, 1.25%); ball) (Non-patent document 9); Azulene, an example of prevention of stomatitis with voltarene-containing water (0.05%) (Non-patent document 1); In oral cleaning of diclofenac, pain after oral surgery An example of anti-inflammatory analgesic effect (Non-patent Document 3), an example of effective combination with ibuprofen tablets for pain relief after oral surgery (Non-patent Document 4), and periodontal disease (Gingivitis) In non-patent document 5: ibuprofen oral cleansing (ibuprofen D body: 1.5%), there was no significant difference from placebo for the treatment of periodontal disease , Prevention of plaque formation and adhesion (Non-patent document 6): In oral cleaning using ibuprofen, diphenhydramine, and aluminum MgS, there is no significant difference in pain relief compared with placebo, and there is no effect (non-patent document) 7); and an example of a patent (Patent Document 1) relating to a high-dose ibuprofen lozenge by masking bitterness.

  Regarding the relationship between ibuprofen and stomatitis, it is a well-known fact that it causes stomatitis as a side effect in patients who have been orally administered ibuprofen (Non-patent Document 8).

  As mentioned above, there is prior information on local administration methods for stomatitis and oral diseases with NSAIDs such as indomethacin and diclofenac sodium. However, NSAIDs, the most widely used and safest in the world, can be applied locally to the oral cavity with ibuprofen for oral stomatitis, other oral diseases, dental diseases, and pain relief after trauma and oral surgery. There is no literature or patent information that shows its effectiveness. This can be understood from the common technical knowledge that stomatitis is caused as a side effect in patients who have been orally administered ibuprofen. In addition, ibuprofen is naturally safer than indomethacin and diclofenac, and is less effective and more natural.

US Patent Publication Number: US2007 / 00 98789A1

Hospital pharmacy preparation casebook (Japan Hospital Pharmacists Association: Yakuji Nippo) Hyaku Kenji, Pharmacology 72 (1) 15-19, 2012. Agarwal S. et al., Efficacy and acceptability of 0.074% diclofenac-containing mouthwash after periodontal surgery; a crinical study, Indian J. Dent. Res. 2010, Jul-Sept. 21 (3); 408-412 Jaber Yaghini et al. (Isfahan Univ., Iran), The effect of Diclofenac mouthwash (0.01%) on periodontal postoperative pain, Dent. Res. J (Isfahan), 2011, Summer, 8 (3); 146-149. Serafini Giampiero et al., Therapeutic efficacy and tolerability of the topical treatment of inflammatory conditions of the oral cavity with a mouthwash containing Diclofenac Epolamine (0.103%) (Controlled P3 study by IBSA), Clinical Drug Investigation, 32 (1), 41- 49, 2012. Rosin M., et al., The effect of a dexibuprofen mouth rinse on experimental gingivitis in human, J. Clin. Periodontol, 2005, Jun; 32 (6), 617-621. Katayoun Borhan-Mojabi et al., Therpeutic effects of “Ibupurofen, Diphenhydramin and Aluminum MgS” on Recurrent Aphthous Stomatitis, Jounal of Dentistry, Teheran University of Medical Sciences, Teheran, Iran, 2014, 11 (2), 167-171 Brufen interview form p.22, safety-related items (3) Other side effects (Kaken Pharmaceutical, revised May 2012 (7th edition)) Suzuki, prevention of stomatitis by chemical therapy-Japanese Nursing Society Proceedings 2 Adult Nursing, 34,21-23,2003.

  It was an object of the present invention to develop a topical oral composition containing ibuprofen or a pharmaceutically acceptable salt thereof for reducing pain and / or inflammation caused by oral diseases. Another object of the present invention is to find a method for producing the composition and a method for treating and / or preventing the composition using the composition.

  As mentioned in the background of the research, there is common technical knowledge that taking ibuprofen causes stomatitis. However, on the other hand, ibuprofen is also the fact that it is the world's most versatile and safe NSAIDs. Therefore, the present inventors have started research on whether or not this ibuprofen can be used as a means for reducing pain and / or inflammation caused by oral disease, and have conducted extensive studies. As a result, a topical oral composition using ibuprofen to reduce pain and / or inflammation caused by oral disease was found, and the invention described below was completed.

The inventors disclose the technical idea of the present specification. That is, the present invention
[1] A topical oral composition containing ibuprofen or a pharmaceutically acceptable salt thereof and at least one oral acceptable carrier for preventing or reducing pain and / or inflammation caused by oral disease;
[2] Aqueous solution, suspension, semi-solid (cream, gel, ointment), spray, dissolving solid (tablet, granule, powder, foam, etc.) or patch [1] The composition according to [1];
[3] The composition according to [1] or [2], wherein the pharmaceutically acceptable salt of ibuprofen is a sodium salt, potassium salt or magnesium salt;
[4] The composition according to any one of [1] to [3], wherein the oral disease is oral trauma, stomatitis, periodontal disease, toothache, pain after extraction, or pain after oral surgery;
[5] A solution or suspension with reduced irritation or bitterness, characterized in that the final form to be administered into the oral cavity contains ibuprofen, a pH adjuster, and water, [4] The composition according to any one of the above;
[6] The composition according to [1], which is a mouth rinse.
[7] The composition according to any one of [1] to [6], wherein ibuprofen or a pharmaceutically acceptable salt thereof and at least one orally acceptable carrier are mixed. A method for preparing the composition;
[8] A method for treating and / or preventing an oral disease, comprising administering the composition according to any one of [1] to [6] to an animal including a human;
[9] A method for treating and / or preventing an oral disease according to [8], wherein mouth rinse is performed; and [10] A patch-like preparation is attached, [8] ] The treatment method and / or prevention method of an oral cavity disease as described in any one of the above;
Is disclosed.

  The technical idea of the present invention described above is surprising considering the technical common knowledge that ibuprofen causes stomatitis.

  The ibuprofen used in the present invention is a pharmaceutically acceptable salt, stereoisomer, optical isomer and a mixture of these isomers, solvate, amorphous form, Including forms, isotope-labeled compounds and the like.

  Ibuprofen contains a carboxyl group, and the counter ion can be selected not only from an inorganic salt selected from sodium, potassium, lithium, calcium, magnesium, aluminum, but also from a salt with an organic base. These salts should be pharmaceutically acceptable. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salt.

  As used herein, the term “oral disease” is typified by oral trauma, as well as periodontal disease, gingivitis, periodontitis, periodontitis, adult and juvenile periodontitis, and stomatitis. Other inflammatory conditions in the oral tissues, caries, necrotizing ulcerative gingivitis, conditions such as oral malodor or bad breath caused by these diseases, other conditions such as herpes lesions, as well as bone surgery, tooth extraction, teeth Includes infections that can occur after dental procedures such as periodontal curettage surgery, dental implants and tartar removal and root curettage. In particular, alveolar infections, dental abscesses (eg jaw cellulitis; jaw osteomyelitis), acute necrotizing ulcerative gingivitis (ie Vincent's infection), infectious stomatitis (ie acute inflammation of the oral mucosa) And water cancer (ie, gangrenous stomatitis or oral gangrene lesions). Also included are intraoral trauma, pain and / or inflammation after oral surgery. For oral and dental infections, see Finegold, “Anaerobic Bacteria in Human Diseases” (Chapter 4, pages 78-104, and Chapter 6, pages 115-154). Academic Press, Inc., New York, 1977). The compositions and treatment methods of the present invention are particularly effective in the treatment and prevention of oral trauma, stomatitis, periodontal disease, toothache, post-extraction pain, or pain and / or inflammation after oral surgery. In addition, non-steroidal anti-inflammatory drugs (NSAIDs) can be orally administered and used in combination with other compositions such as propylacetylurea and anhydrous caffeine, and treatment methods.

  As used herein, a “topical oral composition” refers to the activity of the oral cavity, rather than intentionally swallowed for the purpose of systemic administration of a particular therapeutic agent, in the normal course of use. By product is meant a product that is retained in the oral cavity for a time sufficient to substantially contact all or part of the tooth surface and / or oral tissue. Alternatively, the present invention may be referred to as an oral rinse, a mouthwash, or a liquid preparation to be applied locally such as the oral cavity.

  If the topical oral composition of the present invention can be rinsed by being discharged at a desired stage, it may be a liquid such as an aqueous solution, a gel, a mouth spray, a mousse, a foam, a gum, Or various forms, such as a patch shape, may be sufficient. An aqueous solution, gel shape, or patch shape is particularly preferable.

  When the topical oral composition is in gel form, a thickener or the like can be used to achieve the desired consistency of the composition. Moreover, it can adjust by a method well-known to those skilled in the art, such as a moisturizing agent being added in order to maintain a gel state. Such a topical oral composition in the form of a gel can be rinsed by being discharged at a desired stage in the same manner as other forms of the topical oral composition. The use of the present invention Included in embodiments.

  When the topical oral composition is in the form of a patch, an adhesive oral patch that gradually erodes and dissolves as the molecule hydrates is preferable, rather than being attached to the affected area and finally peeled off. Such intraoral patches are added with a binder to hold and release ibuprofen. Examples of binders for this purpose include gelatin, carrageenan, xanthan gum, konjac gum, locust bean gum, guar gum, agar, gum arabic, cellulose derivatives such as HPMC, HPC, CMC-Na, polyacrylic acid, polyvinyl alcohol, and pectin. Is mentioned. The patch-like preparation includes a tape preparation, a patch, a poultice, an adhesive troche, and a plaster, as long as it has adhesiveness that gradually erodes and dissolves as the molecule hydrates. It is contained in the composition for topical oral cavity which is the patch shape of this invention. Such a topical oral composition in the form of a patch can be rinsed by being discharged at a desired stage in the same manner as other types of topical oral compositions. Included in embodiments.

  Even when the topical oral composition is in the form of a mouth spray, mousse, foam, or gum, it can be prepared by methods well known to those skilled in the art. The topical oral composition having such a shape can be rinsed by being discharged at a desired stage, and is included in the use mode of the present invention.

  The term “orally acceptable carrier” as used herein includes safe and effective substances for use in the compositions of the present invention. Such substances are conventional additives in oral care compositions, including water, gelling agents, pH adjusting agents, solubilizers, humectants, thickeners, flavoring agents (fragrances), sweeteners. , Flavoring agents, coloring agents, preservatives, surfactants, and stabilizers. In addition, if desired, for the purpose of dental health, a fluoride ion source, an anticalculus agent or an anticalculus agent, an abrasive such as silica, a bleaching agent such as a peroxide source, a wetting agent, titanium dioxide may be added. However, it is not limited to these. In particular, attention must be paid to the safety of the carrier that is acceptable to the oral cavity. Therefore, for example, cetylpyridinium chloride may cause symptoms that may worsen oral diseases, such as mouth and throat irritation, mouth sores, tongue blackening, glossitis, stomatitis, and gingival bleeding. As such, it is not necessarily a carrier acceptable for the oral cavity.

  The water used for the preparation of the oral composition of the present invention is based on, for example, purified water, distilled water for injection, etc., and in some cases, water suitable for drinking such as tap water is preferable. Should not contain impurities. In the oral composition of the present invention, the water content depends on the shape of the intended oral composition, but is 1% to about 99% by weight of the composition, preferably about 3% to about It may account for 97% by weight. The amount of water includes water introduced with a carrier such as other additives in addition to the added water.

Examples of the base used in the gel include gelling agents, lower alcohols, polyhydric alcohols, hydrogenated oil, and purified water. The gelling agent may be a chemical substance that gels and solidifies a liquid, and a high-concentration micelle of a surfactant or a polymer gel that is a polymer solution is used.
Examples of lower alcohols include ethanol, propanol, isopropanol, butanol, and benzyl alcohol.
Examples of the polyhydric alcohol include glycerin, ethylene glycol, butylene glycol, propylene glycol, macrogol, and polypropylene glycol.

When preparing gels, it may be necessary to provide a desired consistency of the composition, provide desirable active agent release characteristics in use, provide storage stability, provide stability of the composition, etc. It is necessary to add some thickener. Preferred thickeners are carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose, laponite, and water soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural rubbers such as Karaya gum, xanthan gum, gum arabic, and tragacanth can also be used. To further improve the texture, colloidal magnesium aluminum silicate or ultrafine silica can be used as part of the thickener.
The content of the gelling agent is preferably 0.01 to 5% by weight, preferably 0.1 to 5% by weight, particularly 0.25 to 3% by weight, based on the total amount of the anti-inflammatory analgesic external preparation.

  The pH adjuster may be a carrier for adjusting the pH to a desired value using a buffer, an alkali metal hydroxide, or the like. In the present invention, the composition of the present invention can be used to adjust the pH in the range of about 3.0 to about pH 10, more preferably in the range of about pH 5.0 to about pH 8.5. Preferred pH adjusters and / or buffers include alkali metal hydroxides, alkali metal oxides, carbonates, sesquicarbonates, borates, silicates, phosphates, and organic acids, organic acid salts, organic Examples include bases. Specific pH adjusters and / or buffers include monosodium phosphate, trisodium phosphate, sodium benzoate, benzoic acid, salicylic acid, sodium salicylate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, alkali metal carbonate. Salt (sodium carbonate, potassium carbonate, magnesium carbonate), alkali metal bicarbonate (potassium bicarbonate, sodium bicarbonate), pyrophosphate, boric acid, citric acid, and sodium citrate, malic acid, tartaric acid, sodium tartrate, Examples include lactic acid, imidazole, triethanolamine, diethanolamine, diisopropanolamine, and lidocaine. Preferably, alkali metal hydroxides, alkali metal bicarbonates such as potassium bicarbonate and sodium bicarbonate (hereinafter sometimes referred to as sodium bicarbonate), phosphates, organic acids, organic acid salts, lidocaine, etc. Can be mentioned.

  The pH adjuster is defined in an amount such as a buffer that can achieve the desired pH, but by weight, the composition is about 0.01% to about 50% by weight of the oral composition, preferably about 0.01% to about 40% by weight, more preferably about 0.03% to about 30% by weight, and most preferably about 0.03% to about 25% by weight of alkali bicarbonate. Good.

  Moisturizers prevent paste-like compositions such as toothpaste from curing when exposed to air, and give the composition a moisturizing feeling. With certain moisturizers, toothpaste compositions Helps to impart a desirable sweet flavor. The humectant generally constitutes from about 0% to about 70%, preferably from about 5% to about 25%, by weight of the composition herein, based on pure humectant. Preferred humectants for use in the compositions of the present invention include edible polyhydric alcohols such as glycerin, sorbitol, xylitol, butylene glycol, polyethylene glycol and propylene glycol, particularly sorbitol and glycerin.

  Examples of flavoring agents (perfumes) include winter green oil, peppermint oil, spearmint oil, clove bud oil, menthol, anethole, methyl salicylate, eucalyptol, cassia, 1-menthyl acetate, sage, eugenol, parsley oil, oxanone ( oxanone, α-irisone, marjoram, lemon, orange, propenyl guetol, cinnamon, vanillin, thymol, linalool, and cinnamaldehyde glycerol acetal known as CGA, etc. Flavoring agents are about the composition of the present invention. Used at a concentration of 0.001% to about 5% by weight.

  Sweetening agents include, for example, sucrose, glucose, saccharin, glycyrrhizic acid and its salts, dextrose, fructose, lactose, mannitol, sorbitol, fructose, maltose, xylitol, saccharin salt, thaumatin, aspartame, D-tryptophan, dihydrochalcone Acesulfame and cyclamate, especially sodium cyclamate and saccharin sodium. Sweetening agents are used in concentrations of about 0.1% to about 10%, preferably about 0.05% to about 3% by weight of the composition of the invention.

  Examples of the corrigent include, for example, ascorbic acid (salt), asenyaku, amacha, fennel, erythritol, sodium chloride, magnesium chloride, eugenol, oat extract, auren, orange (oil), cacao, caramel, carbachol, licorice, camphor, 5 '-Guanylic acid, citric acid (salt), glycyrrhizic acid (salt), glutamic acid (salt), chlorella extract, cinnamon extract, cinnamon oil, succinic acid (salt), saffron, methyl salicylate, salamander, peonies extract, tartaric acid (Salt), shrimp, cinnamaldehyde, stevia extract, assembly, D-sorbitol, soybean oil, taiso extract, taurine, tannic acid, clove oil, spruce extract, nigaki extract, plum extract, honey, mint water, mint oil, Fumaric acid Salt), l-menthol, povidone, d-borneol, malt extract, eucalyptus oil, green tea powder, malic acid (salt), lemon oil, rose oil, and royal jelly and the like. The corrigent is used at a concentration of about 0.05% to about 30%, preferably about 0.2% to about 20% by weight of the composition.

  The colorant may be in the form of an aqueous solution, for example, food blue 1, food yellow 4, food yellow 5, food red 2, food red 3, and food red 102, safe for pharmaceuticals or food The well-known thing used for is mentioned. A 1% aqueous colorant solution may be preferable. The coloring solution is generally used at a concentration of about 0.01% to about 5% by weight of the composition.

  Preservatives include benzoic acid, sodium benzoate, sodium edetate, agar, chlorhexidine, paraoxybenzoate (methyl, ethyl, propyl, isopropyl, and butyl esters), benzalkonium chloride, and benzethonium chloride . Preservatives generally constitute from about 0.01% to about 5% by weight of the composition.

  Surfactants are those that are reasonably stable and foamable over a wide pH range. Surfactants can be anionic, nonionic, amphoteric, zwitterionic, or cationic.

  Anionic surfactants useful herein include water-soluble salts of alkyl sulfates having 8 to 20 carbon atoms in the alkyl residue (eg, sodium alkyl sulfate), and 8 to 20 carbons. Water-soluble salts of sulfonated monoglycerides of fatty acids having atoms. Sodium lauryl sulfate and sodium coconut monoglyceride sulfonate are examples of this type of anionic surfactant. Other preferred anionic surfactants are sarcosinates such as sodium lauroyl sarcosinate, taurate, sodium lauryl sulfoacetate, sodium laureuylisethionate, sodium laurethcarboxylate, and sodium dodecylbenzene sulfonate. Mixtures of anionic surfactants can also be used. Many preferred anionic surfactants are disclosed in US Pat. No. 3,959,458 (Agricola et al., Issued May 25, 1976).

  Nonionic surfactants that can be used in the compositions of the present invention include condensation of alkylene oxide groups (hydrophilic in nature) with organic hydrophobic compounds that may be aliphatic or alkyl-aromatic in nature. Can be broadly defined as a compound produced by Examples of preferred nonionic surfactants include poloxamer (sold under the trade name Pluronic), polyoxyethylene, polyoxyethylene sorbitan ester (sold under the trade name Tweens), polyoxyl 40 hydrogenated castor oil , Aliphatic alcohol ethoxylates, polyethylene oxide condensates of alkylphenols, products obtained from the condensation of ethylene oxide with the reaction products of propylene oxide and ethylenediamine, ethylene oxide condensates of aliphatic alcohols, long chain tertiary amine oxides, long chains Tertiary phosphine oxide, long chain dialkyl sulfoxide and the like can be mentioned. Nonionic surfactant poloxamer 407 is the most preferred surfactant since poloxamer can also function as an emulsifier, binder, stabilizer and reduce the astringency of metal ions such as stannous and zinc. One. Poloxamers are bifunctional block polymers terminated with primary hydroxyl groups with molecular weights ranging from 1,000 to over 15,000. Poloxamers are marketed by BASF under the trade names Pluronics and Pluraflo. Preferred poloxamers for the present invention are poloxamer 407 and pullulafro L4370.

  Amphoteric surfactants useful in the present invention can be broadly described as derivatives of aliphatic secondary and tertiary amines, wherein the aliphatic residue can be linear or branched. And one of the aliphatic substituents contains from about 8 to about 18 carbon atoms, and one contains an anionic water-soluble group such as a carboxylate, sulfonate, sulfate, phosphate, or phosphonate. Another preferred amphoteric surfactant is betaine, especially cocamidopropyl betaine. Mixtures of amphoteric surfactants can also be used. Many of this preferred nonionic and amphoteric surfactants are disclosed in US Pat. No. 4,051,234 (Gieske et al., Issued September 27, 1977). The composition is typically about 0.25% to about 12%, preferably about 0.5% to about 8%, most preferably about 1% to about 6% by weight of the composition. One or more surfactants at each concentration of%.

  Examples of the stabilizer include adipic acid, ascorbic acid, sodium sulfite, sodium hydrogen sulfite, dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, sodium chloride, citric acid, and cysteine.

  The oral composition of the present invention may optionally include a soluble fluoride source that can provide biologically available and effective fluoride ions. Soluble fluoride ion sources include sodium fluoride, stannous fluoride, indium fluoride, amine fluoride, and sodium monofluorophosphate.

  The composition may contain a soluble fluoride ion source that can provide from about 50 ppm to about 3500 ppm, preferably from about 500 ppm to about 3000 ppm free fluoride ions. In order to deliver the desired amount of fluoride ions, the fluoride ion source is included in the total oral composition in an amount of about 0.1% to about 5% by weight of the total composition delivered to the oral cavity, preferably It may be present in an amount from about 0.2% to about 1%, more preferably from about 0.3% to about 0.6% by weight.

  The present invention may include a peroxide source in the composition. In addition to whitening, peroxides also provide other benefits to the oral cavity. Hydrogen peroxide and other peroxygen compounds can cause caries, dental plaque, gingivitis, periodontitis, bad breath, chronic recurrent after ulcers, denture inflammation, orthodontic appliance damage, after tooth extraction and after periodontal surgery It has long been recognized as effective for therapeutic and / or prophylactic treatment of traumatic oral lesions, as well as mucosal infections, herpes stomatitis and the like. Peroxide-containing agents in the oral cavity exert a chemical-mechanical action that produces thousands of small oxygen bubbles resulting from interaction with tissues and salivary enzymes. The swishing action of the mouth rinse enhances this unique chemical mechanical action. Such action has been recommended for delivering other agents to infected gingival crevasses. Thus, peroxide is one of the preferred antimicrobial agents for use herein, preventing the colonization and growth of anaerobic bacteria known to be associated with periodontal disease.

  The peroxide source is selected from the group consisting of hydrogen peroxide, calcium peroxide, and urea peroxide. The following amounts indicate the amount of peroxide source material, but the peroxide source may contain components other than the peroxide source material. The composition is about 0.01% to about 10%, preferably about 0.1% to about 5%, more preferably about 0.2% to about 3% by weight of the oral composition. Most preferably from about 0.3% to about 0.8% by weight of a peroxide source.

  The composition is optionally a substance having chelating activity and may contain an anticalculus agent effective to reduce mineral deposition associated with calculus formation. Such chelating agents can complex calcium found in the bacterial cell wall, and can further degrade plaque by removing calcium from calcium bridges that help keep this biomass intact. However, using a chelating agent that has too high an affinity for calcium can result in tooth demineralization and is undesirable. Preferred chelating agents improve cleaning and reduce plaque and calculus formation. Chelating agents can also complex with metal ions and can therefore be used to stabilize stannous when present in the composition.

Such chelating agents useful for anticalculus activity include pyrophosphates, tripolyphosphates and diphosphonates such as EHDP and AHP. Pyrophosphate salts useful as pyrophosphate ion sources in the present compositions include dialkali metal pyrophosphate salts and tetraalkali metal pyrophosphate salts. Non-hydrated and hydrated forms, disodium dihydrogen pyrophosphate (Na ₂ H ₂ P ₂ O ₇ ), tetrasodium pyrophosphate (Na ₄ P ₂ O ₇ ), and tetrapotassium pyrophosphate (K ₄ P ₂ O ₇ ) is preferred. In the compositions of the present invention, the pyrophosphate salt is one of three forms: predominantly dissolved form, predominantly undissolved form, or a mixture of dissolved and undissolved form of pyrophosphate. May exist in one.

Polymeric polycarboxylates are also used as anticalculus agents. They include maleic anhydride or a copolymer of maleic acid and another polymerizable ethylenically unsaturated monomer such as methyl vinyl ether (methoxyethylene), styrene, isobutylene or ethyl vinyl ether. Such materials are well known in the art and are used in the form of their free acids or partially or preferably fully neutralized water-soluble alkali metal salts (eg potassium, preferably sodium) or ammonium salts. The An example is a 1: 4 to 4: 1 copolymer of maleic anhydride and methyl vinyl ether having a molecular weight of about 30,000 to about 1 million. These copolymers are available, for example, as GAF Chemicals Corporation Gantrez AN139 (molecular weight 500,000), AN119 (molecular weight 250,000), and S-97 pharmaceutical grade (molecular weight 70,000).
Preferred amounts of these chelating agents for use in the present invention are about 0.1% to about 2.5%, preferably about 0.5% to about 2.5%, more preferably about 1.0%. ~ 2.5%.

  Abrasives useful in the topical oral carrier of the composition of the present invention include materials commonly used for dentistry. The substance chosen must be miscible in the intended composition and should not excessively scrape the dentin. Preferred abrasives include, for example, silica including gels and precipitates, insoluble sodium polymetaphosphate, hydrated alumina, calcium carbonate, dicalcium orthophosphate dihydrate, calcium pyrophosphate, tricalcium phosphate, calcium polymetaphosphate, And resinous abrasive materials such as particulate condensation products of urea and formaldehyde. Preferred resins include, for example, phenolic resins, urea, crosslinked epoxides, and crosslinked polyesters.

  The silica abrasive polishing material generally has an average particle size in the range of about 0.1 to about 30 microns, preferably about 5 to about 15 microns. The abrasive can be a silica gel such as precipitated silica or silica xerogel. Examples include W. under the trade name “Syloid”. R. Silica Xerogel commercially available from Grace & Company, W.R. Grace & Company Davison Chemical Division, and J. Org. M.M. Those marketed under the trade name Zeodent (R) from JM Huber Corporation, in particular Zeodent (R) 119, Zeodent (R) 118, Zeodent (Registered trademark) 109, and precipitated silica materials having the notation of Zeodent (registered trademark) 129.

  A mixture of abrasives, such as a mixture of the various grades of Zeodent® silica abrasive listed above, can be used. The total amount of abrasive in the dentifrice composition of the present invention is typically about 6% to about 70% by weight of the composition, and the toothpaste is preferably about 10% to about 50% by weight. Contains abrasive. The dental solutions, mouth sprays, mouthwashes, and non-abrasive gel compositions of the present invention typically contain only a small amount of abrasive or no abrasive.

  The amount of the compound of the present invention contained in the composition according to the present invention is not particularly limited, but should be a safe and effective amount. By safe and effective amount is meant a sufficient amount of active agent that is safe and provides the desired benefits to the hard and soft tissues of the oral cavity. The safe and effective amount of the active ingredient ibuprofen depends on the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of the combination therapy, the particular dosage form used, As well as the specific vehicle for applying the drug. Further, the amount to be used is appropriately adjusted depending on the purpose.

  In the case of an adult, the composition according to the present invention is usually about 100 μg to 20 g, preferably 1 mg to 10 g, more preferably 10 mg to 6 g, more preferably about 100 μg of ibuprofen or a pharmacologically acceptable salt thereof per 100 mL for an adult. It is 100 mg to 3 g, and each is used once or divided into several times. Moreover, you may use repeatedly several times.

The composition for topical oral cavity of this invention shows the effect described below at least.
1. The present invention (local administration of ibuprofen in the oral cavity) has analgesic and anti-inflammatory effects on oral diseases represented by oral trauma, stomatitis, periodontal disease, toothache, pain after tooth extraction, or pain after oral surgery . Moreover, the effect may increase by increasing the frequency | count of use.

  2. Ibuprofen is 4 to 8 times more effective than indomethacin and diclofenac, and is safer than indomethacin and diclofenac. Therefore, ibuprofen is used in a manner of `` rinsing with this agent in the oral cavity ''. There is an advantage that the upper limit of the amount of the composition in direct contact with the affected area is practically negligible.

3. Ibuprofen has an intense irritating bitter taste. Therefore, the only way to use ibuprofen for analgesia / anti-inflammation has been in the past, so it should be treated with capsules, tablets or granules to eliminate side effects such as bitterness. So we have addressed this issue.
On the other hand, this invention can reduce the intense irritation bitterness in a dissolved state. That is, the ibuprofen prescription liquid formulated with sodium hydroxide and a small amount of hydrochloric acid, which is one aspect of the present invention, hardly feels the pungent bitterness of the drug substance when it is contained in the oral cavity without swallowing. I found This is a new bitterness masking technique for ibuprofen in the oral cavity. Furthermore, since it can contain a carrier acceptable to the oral cavity, water, gelling agent, thickener, pH adjuster, moisturizer, flavoring agent (fragrance), sweetener, corrigent, coloring agent, preservative, surface activity By properly blending agents, stabilizers, etc., it is widely accepted by patients including children and reduces physical and psychological burdens on patients.

  4). In the case of the present invention, ibuprofen is in direct contact with the affected area in the oral cavity, so that it is fast acting. In particular, analgesic effects have been confirmed for stomatitis and mild toothache as shown in the following examples.

  5. In the present invention, when ibuprofen is used as a mouth rinse, since ibuprofen is not taken, systemic side effects due to the drug are considered to hardly occur, so the present invention is an epoch-making composition, There are significant advantages in usage. Therefore, if the amount of ibuprofen as an oral rinse is less than that of the oral agent, if the patient is applying the composition of the present invention, some or all of the drug is accidentally swallowed. However, it is the same as the method of use for the analgesia of ibuprofen that has been approved / applied conventionally, and it can be said that the safety is high because there is no problem beyond the side effects pointed out there.

  6). Due to the high safety of ibuprofen, the daily use frequency and amount of the topical oral composition of the present invention can be increased or decreased as desired by the patient. This is because the composition of the present invention has a great advantage that directly leads to the patient's benefit in consideration of the fact that the use amount of NSAIDs such as indomethacin and diclofenac is severely limited.

  The most common side effect of cancer chemotherapy and radiation therapy is said to be stomatitis. In clinical settings, there are currently no over-the-counter drugs that promote appropriate and effective pain relief, and there are no appropriate and effective treatments. In-house preparations such as indomethacin sprays and voltalen gargles are being used in some hospitals. It is only used in some hospitals. (Non-Patent Documents 1 and 2) The present invention can be used quickly, simply and safely for various medical requirements including this example.

  Next, the present invention will be described with specific implementations, but the present invention is not limited to these examples. It will be apparent to those skilled in the art that many modifications, both in materials and methods, can be made without departing from the scope of the invention.

  The materials, reagents and the like used in the present invention can be prepared using commercially available products or methods known in the art.

[Example 1] Confirmation test 1 for irritation bitterness of ibuprofen
When 150 mg of 4 ibuprofen commercially available soft capsules were placed in only 100 mL of tap water and left for 3 hours, they disintegrated to obtain a pale bluish milky white suspension in which the content liquid was dispersed (the color is considered to be derived from the colorant of the soft capsules). When this solution was thoroughly stirred and about 10 mL was contained in the mouth for about 30 seconds, everyone felt a slight numbness / irritating bitterness (burning sensation) in the mouth. (n = 3: A range that can be tolerated by normal adults)

[Example 2] Confirmation test 2 for irritation bitterness of ibuprofen
1. When 150 mg of ibuprofen commercially available soft capsules were cut and the contents were removed from the capsules and included in the mouth, irritation stinging and some bitterness were felt. (n = 1)

[Example 3] Confirmation test 3 for irritation bitterness of ibuprofen
When about 150 mg of sodium bicarbonate was added to and stirred with 100 mg of tap water in 4 mL of commercially available ibuprofen commercially available soft capsules for 3 hours, it became clear. When the same person who participated in the above Example 1 contained this solution in their mouth, none of them felt the irritating bitterness or numbness that was felt with the sodium hydrogencarbonate-free suspension (Example 1). (n = 3)

[Example 4] Confirmation test 4 for irritation bitterness of ibuprofen
When the same person who participated in the above Example 1 chewed a commercially available ibuprofen tablet (150 mg sugar-coated tablet) in the mouth and held it for a while, all of them were more irritating than the aqueous suspension of the soft capsule content of Example 1 above. Bitterness and numbness were felt, and it was confirmed that it was practically impossible for the purpose of the present invention to be used by holding it for about 30 seconds to 1 minute. (n = 3)

  [Example 5] Formulation of ibuprofen oral rinse

注）イブプロフェン原薬（CAS.NO:15687-27-1）は、市販品を用いることができる。また、リングルアイビー200ｍｇ錠からイブプロフェンを抽出し、精製して用いることもできる。また、イブプロフェン単剤の市販製剤を使用してもよい。その場合、市販錠200ｍｇの場合は３錠、市販のソフトカプセル150ｍｇの場合は４個を、本処方では使用できる。

Note) Commercially available ibuprofen drug substance (CAS.NO:15687-27-1) can be used. In addition, ibuprofen can be extracted from Ringle Ivy 200 mg tablets, purified and used. Moreover, you may use the commercial formulation of an ibuprofen single agent. In that case, 3 tablets can be used in the case of 200 mg commercially available tablets, and 4 tablets can be used in the case of 150 mg commercially available soft capsules.

[Example 6] Preparation method example 1
Add 100 mL of tap water to a container with a lid, add 3 g of baking soda and shake gently to dissolve the baking soda (aqueous solution I: baking soda 3000 mg / 100 mL). Aqueous solution I is diluted 2.5 times (aqueous solution II: sodium bicarbonate 1200 mg / 100 mL). Aqueous solution II is diluted 5 times (aqueous solution III: sodium bicarbonate 240 mg / 100 mL). In aqueous solution III, 3 tablets for a commercially available 200 mg tablet of ibuprofen alone and 4 tablets for a 150 mg commercially available soft capsule are placed and left at room temperature for about 2 hours. Since the tablets were disintegrated and the soft capsules were partially dissolved and the contents were leaking out, they were stirred uniformly to obtain ibuprofen mouth rinse. In addition, an unnecessary thing is filtered as needed.

[Example 7] Preparation method example 2
Add 40 ml of purified water to a 100 ml beaker, add 1.5 ml of 1N sodium hydroxide prepared in advance with stirring, and add 300 mg of ibuprofen (1 g Wako Pure Chemical, for biochemistry) at room temperature to be uniform. Stir. About 10 minutes later, since undissolved ibuprofen was observed, 0.3 ml of 1N sodium hydroxide was gradually added with stirring, and the whole amount was dissolved to obtain a clear aqueous solution (pH 11.5). While stirring, 0.45 ml of 0.5N hydrochloric acid was gradually added to the obtained aqueous solution, and the volume was made up to 50 ml with purified water to obtain an ibuprofen mouth rinse (pH 7.2).

[Example 8] Confirmation test of irritation bitterness of ibuprofen oral cleaning agent obtained in Example 7 10 ml of ibuprofen oral cleaning agent obtained in Example 7 was included in the mouth for about 30 seconds, and then vomiting irritation / bittering・ Evaluated for numbness. Slight stimulation was felt in 3 out of 6 people, but it was well tolerated, and no bitterness or numbness was observed. (N = 6)

[Example 9] Preparation method example 3
Purified water (40 ml) was placed in a 100 ml beaker, and 125 mg of sodium bicarbonate was added and dissolved with stirring. Then, 300 mg of ibuprofen (1 g of Wako Pure Chemicals, for biochemistry) was added, and the mixture was stirred uniformly at room temperature. About 10 minutes later, since undissolved ibuprofen was observed, 832 mg of sodium bicarbonate was gradually added with stirring, and further 0.6 ml of 1N sodium hydroxide was gradually added and dissolved to obtain a clear aqueous solution. (PH 8.6). The resulting aqueous solution was made up to 50 ml with purified water to obtain an ibuprofen mouth rinse (pH 7.9).

[Example 10] Confirmation test of irritation bitterness of ibuprofen oral cleaning agent obtained in Example 9 10 ml of ibuprofen oral cleaning agent obtained in Example 9 was contained in the mouth for about 30 seconds, and then vomiting irritation / bittering・ Evaluated for numbness. None of them felt irritation or numbness, 1 out of 6 felt slightly bitter but well tolerated and the remaining 5 did not feel bitter. (N = 6)

[Example 11] Preparation method example 4
Add 40 ml of purified water to a 100 ml beaker, add 1.5 ml of 1N potassium hydroxide prepared in advance with stirring, and then add 300 mg of ibuprofen (1 g of Wako Pure Chemicals, for biochemistry) at room temperature to be uniform. Stir. After about 15 minutes, undissolved ibuprofen was observed, and 0.2 ml of 1N potassium hydroxide was gradually added with stirring to dissolve the whole amount to obtain a clear aqueous solution (pH 7.6). The resulting aqueous solution was made up to 50 ml with purified water to obtain an ibuprofen mouth rinse (pH 7.2).

[Example 12] Confirmation test of irritation bitterness of ibuprofen mouth rinse obtained in Example 11 10 ml of ibuprofen mouth rinse obtained in Example 11 was contained in the mouth for about 30 seconds, and then vomiting was stimulated and bitter.・ Evaluated for numbness. All members felt slightly stronger irritation or bitterness than the sample obtained in Example 7, but they were sufficiently acceptable and no numbness was observed. (N = 6)

[Example 13] Test 1 for analgesic and anti-inflammatory effect
A cancer patient A suffering from severe painful stomatitis is asked to include in its mouth the ibuprofen mouth rinse preparation formulated as in Preparation Method Example 1. It keeps in the mouth and works to reach the whole mouth, particularly the affected area, and after 30 seconds, it is discharged from the mouth (mouth rinse).
As a result, an anti-inflammatory / analgesic effect was recognized by the ibuprofen oral cleaner formulation solution of the present invention and its method of use. Moreover, there was no complaint of irritating pain due to staying in the oral cavity.

[Example 14] Test 2 for analgesic / anti-inflammatory effect
When the same test as in Example 12 was applied to mild stomatitis patient B (before going to bed. Oral retention time: about 30 seconds), an analgesic effect was observed. There was no irritation or bitterness in the oral cavity. Furthermore, the next morning, when I confirmed the pain, the pain was considerably reduced.

[Example 15] Test 3 for analgesic / anti-inflammatory effect
When the application of the present invention was attempted to a patient C having mild toothache (toothache with tooth cracks and itching) similar to the test of Example 12 (oral retention time: about 30 seconds), An analgesic effect was observed. At the same time, there was no complaint of mouth pain or irritating bitterness. In addition, the degree of itching was also reduced immediately after washing in the mouth, and repeated application (applied twice after several minutes each time after the first application) further reduced tooth pain.

  The present invention provides a topical oral composition containing ibuprofen or a pharmaceutically acceptable salt thereof for reducing pain and / or inflammation caused by oral disease. Also provided are methods for producing the compositions and methods of treatment using the compositions. The present invention can respond to medical demands quickly, simply, and safely, and has extremely great industrial utility.

Claims (10)

  A topical oral composition for preventing or reducing pain and / or inflammation caused by an oral disease, comprising ibuprofen or a pharmaceutically acceptable salt thereof and at least one oral acceptable carrier.   The composition of claim 1, which is in the form of an aqueous solution, gel or patch.   The composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt of ibuprofen is a sodium salt or a potassium salt.   The composition according to any one of claims 1 to 3, wherein the oral disease is oral trauma, stomatitis, periodontal disease, toothache, pain after extraction, or pain after oral surgery.   The composition according to any one of claims 1 to 4, which is a solution or suspension with reduced irritation or bitterness, characterized by containing ibuprofen, a pH adjusting agent, and water.   The composition of claim 1 which is a mouth rinse.   The composition according to any one of claims 1 to 6, wherein ibuprofen or a pharmaceutically acceptable salt thereof and at least one oral acceptable carrier are mixed. Preparation method.   A method for treating an oral disease, comprising administering the composition according to any one of claims 1 to 6 to an animal including a human.   9. The method for treating an oral disease according to claim 8, wherein mouth rinsing is performed.   The method for treating an oral disease according to claim 8, wherein a patch-like preparation is applied (attached or inserted).