US20010056098A1 - Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid - Google Patents
Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid Download PDFInfo
- Publication number
- US20010056098A1 US20010056098A1 US09/885,096 US88509601A US2001056098A1 US 20010056098 A1 US20010056098 A1 US 20010056098A1 US 88509601 A US88509601 A US 88509601A US 2001056098 A1 US2001056098 A1 US 2001056098A1
- Authority
- US
- United States
- Prior art keywords
- group
- acid
- optionally substituted
- nitrogen atom
- atom
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 0 C*1C(=O)C2=C(*(C)=[Y](C)*(C)~C2C)N(C)C~1C.II Chemical compound C*1C(=O)C2=C(*(C)=[Y](C)*(C)~C2C)N(C)C~1C.II 0.000 description 14
- RYYVLZVUVIJVGH-UHFFFAOYSA-N CN1C=NC2=C1C(=O)N(C)C(=O)N2C Chemical compound CN1C=NC2=C1C(=O)N(C)C(=O)N2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 7
Classifications
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0046—Ear
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
Definitions
- the present invention relates to a method for stabilizing arylcarboxylic acid, which is an acidic compound and which has an antiinflammatory activity, or a pharmacologically acceptable salt thereof, a stabilizer thereof and an aqueous solution containing a stabilized arylcarboxylic acid.
- Arylcarboxylic acid and pharmacologically acceptable salts thereof have been known to be extremely superior antiinflammatory agents.
- said arylcarboxylic acids particularly pranoprofen, diclofenac and bromfenac, are associated with a problem that they become unstable in an aqueous solution.
- Arylcarboxylic acid and pharmacologically acceptable salts thereof have been also known to be stabilized by adding an antioxidant, by adjusting the pH, concentration and ionic strength thereof, by shutting out the light, and the like. These methods, nevertheless, cannot provide sufficient stability at lower temperatures.
- an aqueous solution which contains an arylcarboxylic acid or a pharmacologically acceptable salt thereof, particularly pranoprofen, dicrofenac or bromfenac, and which has sufficient stability at lower temperatures.
- Another object of the present invention is to provide a stabilizer of an arylcarboxylic acid and a pharmacologically acceptable salt thereof, which contains a heterocyclic base.
- Yet another object of the present invention is to provide an aqueous solution containing a solubilized arylcarboxylic acid and a heterocyclic base.
- the present invention provides the following. (1) A method for stabilizing an arylcarboxylic acid or a pharmacologically acceptable salt thereof, which comprises adding a heterocyclic base of the formula (II):
- a and A′ are each a carbon atom or a nitrogen atom
- X is a carbon atom or a nitrogen atom
- Y and Z are each a carbon atom or Y and Z may combinedly form CH;
- L 1 is an optionally substituted heterocyclic group or aryl group having not more than 14 carbon atoms
- R 1 is an optionally substituted alkyl group having not more than 4 carbon atoms or a single bond
- R 9 , R 10 and R 11 may be the same or different and each is a hydrogen atom or an optionally substituted alkyl group, or a pharmacologically acceptable salt thereof.
- X is as defined above;
- R 12 , R 13 , R 14 and R 15 may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;
- R 12 and R 13 may form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X
- R 14 and R 15 may form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R 13 is void, or a pharmacologically acceptable salt thereof.
- pyridonecarboxylic acid is at least one compound selected from the group consisting of lomefloxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin and tosufloxacin.
- arylcarboxylic acid is at least one compound selected from the group consisting of ibuprofen, diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyacetic acid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal, ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen, mefenamic acid, niflumic acid, metiazinic acid, protizinic acid, clonixin, indomethacin and fenclozic acid.
- a and A′ are each a carbon atom or a nitrogen atom
- X is a carbon atom or a nitrogen atom
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,
- R 4 and R 5 may form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X
- R 6 and R 7 may form a 4- to 6-membered heterocyclic group with the adjacent Y and Z, provided that when X is a nitrogen atom, R 5 is void; and is a single bond or a double bond, provided that when A is a carbon atom, Y and Z are each CH and is a double bond, and when A is a nitrogen atom, Y and Z combinedly form CH and is a single bond.
- R 9 , R 10 and R 11 may be the same or different and each is a hydrogen atom or an optionally substituted alkyl group, or a pharmacologically acceptable salt thereof.
- X is as defined above;
- R 12 , R 13 , R 14 and R 15 may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;
- R 12 and R 13 may form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X
- R 14 and R 15 may form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R 13 is void, or a pharmacologically acceptable salt thereof.
- arylcarboxylic acid is at least one compound selected from the group consisting of ibuprofen, diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyacetic acid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal, ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen, mefenamic acid, niflumic acid, metiazinic acid, protizinic acid, clonixin, indomethacin and fenclozic acid.
- a and A′ are each a carbon atom or a nitrogen atom
- X is a carbon atom or a nitrogen atom
- Y and Z are each a carbon atom or Y and Z may combinedly form CH;
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,
- R 4 and R 5 may form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X
- R 6 and R 7 may form a 4- to 6-membered heterocyclic group with the adjacent Y and Z, provided that when X is a nitrogen atom, R 5 is void; and is a single bond or a double bond, provided that when A is a carbon atom, Y and Z are each CH and is a double bond, and when A is a nitrogen atom, Y and Z combinedly form CH and is a single bond.
- R 9 , R 10 R 11 may be the same or different and each is a hydrogen atom or an optionally substituted alkyl group, or a pharmacologically acceptable salt thereof.
- X is as defined above;
- arylcarboxylic acid is at least one compound selected from the group consisting of ibuprofen, diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyacetic acid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal, ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen, mefenamic acid, niflumic acid, metiazinic acid, protizinic acid, clonixin, indomethacin and fenclozic acid.
- an arylcarboxylic acid and a heterocyclic base are dissolved in water and the pH thereof is adjusted with boric acid, acetic acid, phosphoric acid and the like, which is followed by lyophilization where necessary.
- Said heterocyclic base may be any as long as it has the following formula (II):
- a and A′ are each a carbon atom or a nitrogen atom
- Y and Z are each a carbon atom or Y and Z may combinedly form CH;
- R 4 and R 5 may form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X
- R 6 and R 7 may form a 4- to 6-membered heterocyclic group with the adjacent Y and Z, provided that when X is a nitrogen atom, R 5 is void; and is a single bond or a double bond, provided that when A is a carbon atom, Y and Z are each CH and is a double bond, and when A is a nitrogen atom, Y and Z combinedly form CH and is a single bond.
- the alkyl of the “optionally substituted lower alkyl group” has 1 to 6 carbon atoms, and may be a linear or branched one, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, neohexyl and the like.
- the cycloalkyl of the “optionally substituted cycloalkyl group” has 3 to 9 carbon atoms, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
- the substituents of the above-mentioned lower alkyl group and cycloalkyl group include lower alkyl group, halogen and the like.
- the lower acyl of the “optionally substituted lower acyl group” may be, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, benzoyl group, naphthoyl group, toluoyl group, salicyloyl group and the like.
- acyl may be substituted by suitable substituents which may be the same or different, such as
- lower alkyl e.g., methyl, ethyl, propyl, etc.
- lower alkoxy e.g., methoxy, ethoxy, propoxy, etc.
- lower alkylamino e.g., methylamino, ethylamino, propylamino and the like
- cyclo(lower)alkyl such as cyclo(C 3 -C 6 )alkyl (e.g., cyclopentyl, cyclohexyl and the like);
- cyclo(lower)alkenyl such as cyclo (C 3 -C 6 )alkenyl (e.g., cycloxenyl, cyclohexadienyl and the like);
- halogen e.g., fluorine, chlorine, bromine and iodine
- amino(lower)alkyl e.g., aminomethyl, aminoethyl and the like
- carbamoyloxy e.g., hydroxymethyl, 1- or 2-hydroxyethyl, 1- or 2- or 3-hydroxypropyl and the like
- hydroxy(lower)alkyl e.g., hydroxymethyl, 1- or 2-hydroxyethyl, 1- or 2- or 3-hydroxypropyl and the like
- aryl of the “optionally substituted aryl group” is exemplified by phenyl, naphthyl and the like, with preference given to naphthyl.
- the heterocyclic group of the optionally substituted heterocyclic group may contain, besides the carbon atom, at least one hetero atom selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, as the atom constituting the ring, and may be a saturated or unsaturated, heteromonocyclic or heteropolycyclic group.
- unsaturated heteropolycyclic group having 1 to 5 nitrogen atoms such as indolyl, isoindolyl, 3H-indolyl, indolizinyl, benzoimidazolyl, quinolyl, isoquinolyl, indazolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazolyl, tetrazolo-pyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl and the like), pteridinyl, carbazolyl, phenanthrinidyl, acridinyl, perimidyl, and the like;
- 3- to 6-membered unsaturated heteromonocyclic group having 1 to 3 nitrogen atoms and 1 or 2 oxygen atoms such as oxazolyl, isooxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl and the like), and the like;
- unsaturated condensed heterocyclic group having 1 to 3 nitrogen atoms and 1 or 2 oxygen atoms such as benzofurazanyl, benzoxazolyl, benzoxazinyl, benzoxadiazolyl, and the like;
- 3- to 6-membered unsaturated condensed heterocyclic group having 1 to 3 nitrogen atoms and 1 or 2 sulfur atoms such as thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and the like), and the like;
- unsaturated condensed heterocyclic group having 1 to 3 nitrogen atoms and 1 or 2 sulfur atoms, such as benzothiazolyl, benzothiadiazolyl, and the like;
- unsaturated condensed heterocyclic group having 1 or 2 sulfur atoms such as benzothienyl and the like; and the like.
- the 4- to 6-membered ring formed by R 4 and R 5 with the adjacent nitrogen atom and X, and the 4- to 6-membered heterocyclic ring formed by R6 and R 7 with the adjacent Y and Z may be, for example, thienyl group, furyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isooxazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, triazinyl group, dithiazolyl group, dioxolanyl group (e.g., 1,3-dioxolanyl group), dithiolyl group, pyrrolidinyl group, thiaziadinyl group, dithiazi
- the above-mentioned heterocyclic base is specifically exemplified by a purine base having a purine skeleton and a pyridonecarboxylic acid having a pyridine skeleton or pyridazine skeleton.
- the purine base is a compound of the formula (II) wherein A is a nitrogen atom, Y and Z may combinedly form CH and is a single bond. It is represented by the formula (III):
- R 9 , R 10 and R 11 may be the same or different and each is a hydrogen atom or an optionally substituted alkyl group, and exemplified by caffeine, theobromine, theophylline and salts thereof.
- the pyridonecarboxylic acid is a compound of the formula (II) wherein A is a carbon atom, Y and Z are each CH and is a double bond. It is represented by the formula (IV):
- X is as defined above;
- R 12 and R 13 may form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X
- R 14 and R 15 may form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R 13 is void.
- Examples of the pyridonecarboxylic acid include norfloxacin: [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid], ofloxacin: [( ⁇ )-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid], enoxacin: [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid], cinoxacin: [1-ethyl-1,4-dihydro-4-oxo-[1,3]-dioxolo[4,5-g]cinnoline-3-
- the arylcarboxylic acid to be used for the stabilization of the present invention may be any compound as long as it has the following formula (I):
- L 1 is an optionally substituted heterocyclic group or aryl group having not more than 14 carbon atoms
- R 1 is an optionally substituted alkyl group having not more than 4 carbon atoms or a single bond.
- heterocyclic group in the optionally substituted heterocyclic group having not more than 14 carbon atoms may be exemplified by those mentioned above, and the substituents of said heterocyclic group are also exemplified by those mentioned above.
- arylcarboxylic acid examples include naphthoic acid-related compounds, salicylic acid-related compounds, phenylacetic acid-related compounds, pyrazolone-related compounds, anthranilic acid-related compounds, indoleacetic acid-related compounds, fenclozic acid-related compounds and salts thereof and the like.
- salicylic acid-related compounds examples include salicylic acid, aspirin, flufenisal, ethenzamide, benorylate and the like.
- phenylacetic acid-related compounds examples include ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen, ibuprofen, bromfenac, pranoprofen, namoxylate, fenoprofen and the like.
- Examples of the pyrazolone-related compounds include aminopyrine, phenylbutazone, azapropazone, cinopentazone and the like.
- anthranilic acid-related compounds examples include mefenamic acid, niflumic acid, diclofenac, metiazinic acid, protizinic acid, clonixin, flufenamic acid, ketoprofen and the like.
- indoleacetic acid-related compounds examples include indomethacin, intrazole and the like.
- the stabilizer of the arylcarboxylic acid and a pharmacologically acceptable salt thereof contains a heterocyclic base as an active ingredient, and the amount thereof is about the same as the amount mentioned above.
- the solvent to be used for the aqueous solution of the present invention may be, for example, purified water, particularly distilled water for injection.
- concentration of the active ingredient of the aqueous solution i.e. arylcarboxylic acid, can be markedly increased by a heterocyclic base, preferably to 0.1-10 (w/v)%.
- heterocyclic base to be used for the aqueous solution of the present invention may be those mentioned above.
- Said aqueous solution may contain various additives as appropriate, such as buffer, isotonizing agent, solubilizer, antiseptic, thickener, chelating agent, aromatic and the like.
- buffer examples include phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer, amino acid and the like.
- Examples of the isotonizing agent include sugars such as sorbitol, glucose, mannitol and the like, polyhydric alcohols such as glycerol, propylene glycol and the like, salts such as sodium chloride and the like, and the like.
- solubilizer examples include non-ionic surfactants such as polyoxyethylenesorbitan monoolate, polyoxyethyleneoxystearic acid triglyceride, polyethylene glycol, polyoxyethylene hydrogenated castor oil and the like, and the like.
- antiseptic examples include quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride and the like, p-hydroxybenzoates such as methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate and the like, benzyl alcohol, phenethyl alcohol, sorbic acid, salts thereof, thimerosal, chlorobutanol, sodium dehydroacetate and the like.
- quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride and the like
- p-hydroxybenzoates such as methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate and the like
- Examples of the thickener include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, salts thereof and the like.
- Examples of the chelating agent include sodium edetate, citric acid and the like.
- aromatic examples include 1-menthol, borneol, camphor, eucalyptus oil and the like.
- the aqueous solution of the present invention is used as an eye drop, nasal drop or ear drop.
- its pH is generally adjusted to about 3.5-8.5, preferably about 6-7
- its pH is generally adjusted to about 3.5-8.5, preferably about 6-7
- its pH is generally adjusted to about 3.5-8.5, preferably about 6-7.
- a nasal drop having the following formulation was prepared. pranoprofen 1.0 g enoxacin 0.6 g phosphoric acid 0.1 g sodium hydroxide appropriate amount sterile purified water appropriate amount total amount 200 ml (pH 7)
- arylcarboxylic acid and pharmacologically acceptable salts thereof, particularly pranoprofen can be stabilized at every temperature range, particularly at lower temperatures, thereby making the production of an aqueous solution to be used as an eye drop, nasal drop, ear drop and the like possible.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Ophthalmology & Optometry (AREA)
- Otolaryngology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
A method for stabilizing an arylcarboxylic acid, which comprises adding a heterocyclic base to the arylcarboxylic acid or a pharmacologically acceptable salt thereof, a stabilizer thereof and an aqueous solution containing a stabilized arylcarboxylic acid. According to the stabilization method of the present invention, arylcarboxylic acid and pharmacologically acceptable salts thereof, particularly pranoprofen, can be stabilized at every temperature range, particularly at lower temperatures, thereby making the production of an aqueous solution to be used as an eye drop, nasal drop, ear drop and the like possible.
Description
- The present invention relates to a method for stabilizing arylcarboxylic acid, which is an acidic compound and which has an antiinflammatory activity, or a pharmacologically acceptable salt thereof, a stabilizer thereof and an aqueous solution containing a stabilized arylcarboxylic acid.
- Arylcarboxylic acid and pharmacologically acceptable salts thereof have been known to be extremely superior antiinflammatory agents. However, said arylcarboxylic acids, particularly pranoprofen, diclofenac and bromfenac, are associated with a problem that they become unstable in an aqueous solution.
- Arylcarboxylic acid and pharmacologically acceptable salts thereof have been also known to be stabilized by adding an antioxidant, by adjusting the pH, concentration and ionic strength thereof, by shutting out the light, and the like. These methods, nevertheless, cannot provide sufficient stability at lower temperatures.
- Thus, an aqueous solution has not been provided which contains an arylcarboxylic acid or a pharmacologically acceptable salt thereof, particularly pranoprofen, dicrofenac or bromfenac, and which has sufficient stability at lower temperatures.
- While WO9632941 A1 discloses pranoprofen combined with an organic amine, it does not disclose the heterocyclic base to be used in the present invention.
- It is therefore an object of the present invention to provide a method for stabilizing an arylcarboxylic acid and a pharmacologically acceptable salt thereof.
- Another object of the present invention is to provide a stabilizer of an arylcarboxylic acid and a pharmacologically acceptable salt thereof, which contains a heterocyclic base.
- Yet another object of the present invention is to provide an aqueous solution containing a solubilized arylcarboxylic acid and a heterocyclic base.
- According to the present invention, it has now been found that the addition of a heterocyclic base to an arylcarboxylic acid or a pharmacologically acceptable salt thereof leads to successful stabilization thereof, particularly pranoprofen, at every temperature range, particularly at low temperatures.
-
- wherein
- A and A′ are each a carbon atom or a nitrogen atom;
- X is a carbon atom or a nitrogen atom;
- Y and Z are each a carbon atom or Y and Z may combinedly form CH;
- R2, R3, R4, R5, R6, R7 and R8 may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,
-
- L1—R1COOH (I)
- wherein
- L1 is an optionally substituted heterocyclic group or aryl group having not more than 14 carbon atoms; and
- R1 is an optionally substituted alkyl group having not more than 4 carbon atoms or a single bond,
- or a pharmacologically acceptable salt thereof.
-
- wherein
- R9, R10 and R11 may be the same or different and each is a hydrogen atom or an optionally substituted alkyl group, or a pharmacologically acceptable salt thereof.
- (3) The method of (2) above, wherein the purine base is at least one compound selected from the group consisting of caffeine, theobromine and theophylline.
-
- wherein
- X is as defined above; and
- R12, R13, R14 and R15 may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;
- wherein R12 and R13 may form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R14 and R15 may form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R13 is void, or a pharmacologically acceptable salt thereof.
- (5) The method of (4) above, wherein the pyridonecarboxylic acid is at least one compound selected from the group consisting of lomefloxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin and tosufloxacin.
- (6) The method of (1) above, wherein the arylcarboxylic acid is at least one compound selected from the group consisting of ibuprofen, diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyacetic acid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal, ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen, mefenamic acid, niflumic acid, metiazinic acid, protizinic acid, clonixin, indomethacin and fenclozic acid.
- (7) The method of (1) above, wherein the heterocyclic base is added in a proportion of 0.00-5 parts by weight per 100 parts by weight of the arylcarboxylic acid.
-
- wherein
- A and A′ are each a carbon atom or a nitrogen atom;
- X is a carbon atom or a nitrogen atom;
- Y and Z are each a carbon atom or Y and Z may combinedly form CH;
- R2, R3, R4, R5, R6, R7 and R8 may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,
-
-
- wherein
- R9, R10 and R11 may be the same or different and each is a hydrogen atom or an optionally substituted alkyl group, or a pharmacologically acceptable salt thereof.
- (10) The stabilizer of (9) above, wherein the purine base is at least one compound selected from the group consisting of caffeine, theobromine and theophylline.
-
- wherein
- X is as defined above; and
- R12, R13, R14 and R15 may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;
- wherein R12 and R13 may form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R14 and R15 may form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R13 is void, or a pharmacologically acceptable salt thereof.
- (12) The stabilizer of (11) above, wherein the pyridonecarboxylic acid is at least one compound selected from the group consisting of lomefloxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin and tosufloxacin.
- (13) The stabilizer of (8) above, wherein the arylcarboxylic acid is at least one compound selected from the group consisting of ibuprofen, diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyacetic acid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal, ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen, mefenamic acid, niflumic acid, metiazinic acid, protizinic acid, clonixin, indomethacin and fenclozic acid.
- (14) The stabilizer of (8) above, wherein the heterocyclic base is contained in a proportion of 0.001-5 parts by weight per 100 parts by weight of the arylcarboxylic acid.
-
- wherein
- A and A′ are each a carbon atom or a nitrogen atom;
- X is a carbon atom or a nitrogen atom;
- Y and Z are each a carbon atom or Y and Z may combinedly form CH;
- R2, R3, R4, R5, R6, R7 and R8 may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,
-
-
- wherein
- R9, R10 R11 may be the same or different and each is a hydrogen atom or an optionally substituted alkyl group, or a pharmacologically acceptable salt thereof.
- (17) The aqueous solution of (16) above, wherein the purine base is at least one compound selected from the group consisting of caffeine, theobromine and theophylline.
-
- wherein
- X is as defined above; and
- R12, R13, R14 and R15 may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;
- wherein R12 and R 13 may form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R14 and R15 may form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R13 is void, or a pharmacologically acceptable salt thereof.
- (19) The aqueous solution of (18) above, wherein the pyridonecarboxylic acid is at least one compound selected from the group consisting of lomefloxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin and tosufloxacin.
- (20) The aqueous solution of (15) above, wherein the arylcarboxylic acid is at least one compound selected from the group consisting of ibuprofen, diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyacetic acid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal, ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen, mefenamic acid, niflumic acid, metiazinic acid, protizinic acid, clonixin, indomethacin and fenclozic acid.
- (21) The aqueous solution of any one of the above (15) to (20), which is an eye drop.
- (22) The aqueous solution of any one of the above (15) to (20), which is a nasal drop.
- (23) The aqueous solution of any one of the above (15) to (20), which is an ear drop.
- The stabilizing method of the present invention comprises the addition of a stabilizer containing a heterocyclic base as an active ingredient to an arylcarboxylic acid, which is an acidic compound and which has an antiinflammatory activity, or a pharmacologically acceptable salt thereof. For example, a heterocyclic base is added to an arylcarboxylic acid or a pharmacologically acceptable salt thereof.
- To be specific, an arylcarboxylic acid and a heterocyclic base are dissolved in water and the pH thereof is adjusted with boric acid, acetic acid, phosphoric acid and the like, which is followed by lyophilization where necessary.
- While the pH varies depending on the kind of arylcarboxylic acid, it is generally 5-9, preferably about 6-8.
-
- wherein
- A and A′ are each a carbon atom or a nitrogen atom;
- X is a carbon atom or a nitrogen atom;
- Y and Z are each a carbon atom or Y and Z may combinedly form CH;
- R2, R3, R4, R5, R6, R7 and R8 may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,
-
- The alkyl of the “optionally substituted lower alkyl group” has 1 to 6 carbon atoms, and may be a linear or branched one, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, neohexyl and the like.
- The cycloalkyl of the “optionally substituted cycloalkyl group” has 3 to 9 carbon atoms, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
- The substituents of the above-mentioned lower alkyl group and cycloalkyl group include lower alkyl group, halogen and the like.
- The lower acyl of the “optionally substituted lower acyl group” may be, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, benzoyl group, naphthoyl group, toluoyl group, salicyloyl group and the like.
- The above-mentioned acyl may be substituted by suitable substituents which may be the same or different, such as
- lower alkyl (e.g., methyl, ethyl, propyl, etc.);
- lower alkoxy (e.g., methoxy, ethoxy, propoxy, etc.);
- lower alkylthio (e.g., methylthio, ethylthio, etc.);
- lower alkylamino (e.g., methylamino, ethylamino, propylamino and the like);
- cyclo(lower)alkyl such as cyclo(C3-C6)alkyl (e.g., cyclopentyl, cyclohexyl and the like);
- cyclo(lower)alkenyl such as cyclo (C3 -C6 )alkenyl (e.g., cycloxenyl, cyclohexadienyl and the like);
- halogen (e.g., fluorine, chlorine, bromine and iodine);
- amino; amino protecting group; hydroxy; protected hydroxy; cyano; nitro; carboxy; protected carboxy; sulfo; sulfamoyl; imino; oxo;
- amino(lower)alkyl (e.g., aminomethyl, aminoethyl and the like), carbamoyloxy, hydroxy(lower)alkyl (e.g., hydroxymethyl, 1- or 2-hydroxyethyl, 1- or 2- or 3-hydroxypropyl and the like); and the like.
- The aryl of the “optionally substituted aryl group” is exemplified by phenyl, naphthyl and the like, with preference given to naphthyl.
- The heterocyclic group of the optionally substituted heterocyclic group may contain, besides the carbon atom, at least one hetero atom selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, as the atom constituting the ring, and may be a saturated or unsaturated, heteromonocyclic or heteropolycyclic group.
- The preferable heterocyclic groups are the following:
- 3- to 6-membered unsaturated heteromonocyclic group having 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl and the like), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl and the like), triazinyl (e.g., 1,2,4-triazinyl and the like), and the like;
- 3- to 7-membered saturated heteromonocyclic group having 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, homopiperazinyl, and the like;
- saturated heteropolycyclic group having 1 to 4 nitrogen atoms, such as quinuclidinyl and the like;
- unsaturated heteropolycyclic group having 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, 3H-indolyl, indolizinyl, benzoimidazolyl, quinolyl, isoquinolyl, indazolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazolyl, tetrazolo-pyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl and the like), pteridinyl, carbazolyl, phenanthrinidyl, acridinyl, perimidyl, and the like;
- 3- to 6-membered unsaturated heteromonocyclic group having 1 to 3 nitrogen atoms and 1 or 2 oxygen atoms, such as oxazolyl, isooxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl and the like), and the like;
- 3- to 6-membered saturated heteromonocyclic group having 1 to 3 nitrogen atoms and 1 or 2 oxygen atoms, such as morpholinyl, sydnolyl, and the like;
- unsaturated condensed heterocyclic group having 1 to 3 nitrogen atoms and 1 or 2 oxygen atoms, such as benzofurazanyl, benzoxazolyl, benzoxazinyl, benzoxadiazolyl, and the like;
- 3- to 6-membered unsaturated condensed heterocyclic group having 1 to 3 nitrogen atoms and 1 or 2 sulfur atoms, such as thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and the like), and the like;
- 3- to 6-membered saturated heteromonocyclic group having 1 to 3 nitrogen atoms and 1 or 2 sulfur atoms, such as thiazolidinyl and the like;
- unsaturated condensed heterocyclic group having 1 to 3 nitrogen atoms and 1 or 2 sulfur atoms, such as benzothiazolyl, benzothiadiazolyl, and the like;
- 3- to 6-membered unsaturated heteromonocyclic group having 1 oxygen atom, such as furyl, pyranyl and the like;
- 3- to 6-membered unsaturated heteromonocyclic group having 1 or 2 sulfur atoms, such as thienyl, dihydrothienyl, and the like;
- unsaturated condensed heterocyclic group having 1 or 2 sulfur atoms, such as benzothienyl and the like; and the like.
- The aryl group and heterocyclic group are optionally substituted by one or more substituents selected from the group consisting of hydroxyl group, halogen atom, aliphatic alkyl group, aromatic alkyl group, aliphatic carboxylic acid group, aromatic carboxylic acid group, aliphatic carboxylate group, aromatic carboxylate group, aliphatic ether group, aromatic ether group, aliphatic alcohol group, aromatic alcohol group, aliphatic aldehyde group, aromatic aldehyde group, aliphatic amino group, aromatic amino group and the like, which are optionally substituted by halogen atom.
- The 4- to 6-membered ring formed by R4 and R5 with the adjacent nitrogen atom and X, and the 4- to 6-membered heterocyclic ring formed by R6 and R7 with the adjacent Y and Z may be, for example, thienyl group, furyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isooxazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, triazinyl group, dithiazolyl group, dioxolanyl group (e.g., 1,3-dioxolanyl group), dithiolyl group, pyrrolidinyl group, thiaziadinyl group, dithiaziadinyl group, morpholinyl group, oxazinyl group, thiazinyl group, piperazinyl group, piperidinyl group, pyranyl group, thiopyranyl group and the like.
- The above-mentioned heterocyclic base is specifically exemplified by a purine base having a purine skeleton and a pyridonecarboxylic acid having a pyridine skeleton or pyridazine skeleton.
-
- wherein
- R9, R10 and R11 may be the same or different and each is a hydrogen atom or an optionally substituted alkyl group, and exemplified by caffeine, theobromine, theophylline and salts thereof.
-
- wherein
- X is as defined above; and
- R12R13, R14 and R15 may be the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;
- wherein R12 and R13 may form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R14 and R15 may form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R13 is void.
- Examples of the pyridonecarboxylic acid include norfloxacin: [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid], ofloxacin: [(±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid], enoxacin: [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid], cinoxacin: [1-ethyl-1,4-dihydro-4-oxo-[1,3]-dioxolo[4,5-g]cinnoline-3-carboxylic acid], ciprofloxacin: [1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline-carboxylic acid], sparfloxacin: [5-amino-1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid], tosufloxacin: [(±)-7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1-naphthyridine-3-carboxylic acid], fleroxacin: [6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid], levofloxacin: [(-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid], lomefloxacin: [1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid], 5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidinecarboxylic acid, 7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1-cyclopropyl-6-fluoro-7-(3-methyl-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and the like, and salts thereof and the like.
- The pharmacologically acceptable salts of purine base and pyridonecarboxylic acid include, for example, acid addition salts with inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid and the like, organic acid such as acetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, gluconic acid and the like, or amino acid such as aspartic acid, glutamic acid and the like; metal salts such as sodium salt, potassium salt and the like; and the like.
- The arylcarboxylic acid to be used for the stabilization of the present invention may be any compound as long as it has the following formula (I):
- L1—R1COOH (I)
- wherein
- L1 is an optionally substituted heterocyclic group or aryl group having not more than 14 carbon atoms; and
- R1 is an optionally substituted alkyl group having not more than 4 carbon atoms or a single bond.
- The heterocyclic group in the optionally substituted heterocyclic group having not more than 14 carbon atoms may be exemplified by those mentioned above, and the substituents of said heterocyclic group are also exemplified by those mentioned above.
- The aryl of the “optionally substituted aryl group having not more than 14 carbon atoms” may be exemplified by those mentioned above, and the substituents of said aryl group are also exemplified by those mentioned above.
- The alkyl of the “optionally substituted alkyl group having not more than 4 carbon atoms” may be, for example, a linear or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.
- Examples of the arylcarboxylic acid include naphthoic acid-related compounds, salicylic acid-related compounds, phenylacetic acid-related compounds, pyrazolone-related compounds, anthranilic acid-related compounds, indoleacetic acid-related compounds, fenclozic acid-related compounds and salts thereof and the like.
- Examples of the naphthoic acid-related compounds include 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyacetic acid and the like.
- Examples of the salicylic acid-related compounds include salicylic acid, aspirin, flufenisal, ethenzamide, benorylate and the like.
- Examples of the phenylacetic acid-related compounds include ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen, ibuprofen, bromfenac, pranoprofen, namoxylate, fenoprofen and the like.
- Examples of the pyrazolone-related compounds include aminopyrine, phenylbutazone, azapropazone, cinopentazone and the like.
- Examples of the anthranilic acid-related compounds include mefenamic acid, niflumic acid, diclofenac, metiazinic acid, protizinic acid, clonixin, flufenamic acid, ketoprofen and the like.
- Examples of the indoleacetic acid-related compounds include indomethacin, intrazole and the like.
- The amount of the heterocyclic base to be added to the arylcarboxylic acid or a pharmacologically acceptable salt thereof is preferably about 0.001-5 parts by weight per 100 parts by weight of the arylcarboxylic acid or pharmacologically acceptable salt thereof.
- The stabilizer of the arylcarboxylic acid and a pharmacologically acceptable salt thereof contains a heterocyclic base as an active ingredient, and the amount thereof is about the same as the amount mentioned above.
- The solvent to be used for the aqueous solution of the present invention may be, for example, purified water, particularly distilled water for injection. The concentration of the active ingredient of the aqueous solution, i.e. arylcarboxylic acid, can be markedly increased by a heterocyclic base, preferably to 0.1-10 (w/v)%.
- The heterocyclic base to be used for the aqueous solution of the present invention may be those mentioned above.
- Said aqueous solution may contain various additives as appropriate, such as buffer, isotonizing agent, solubilizer, antiseptic, thickener, chelating agent, aromatic and the like.
- Examples of the buffer include phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer, amino acid and the like.
- Examples of the isotonizing agent include sugars such as sorbitol, glucose, mannitol and the like, polyhydric alcohols such as glycerol, propylene glycol and the like, salts such as sodium chloride and the like, and the like.
- Examples of the solubilizer include non-ionic surfactants such as polyoxyethylenesorbitan monoolate, polyoxyethyleneoxystearic acid triglyceride, polyethylene glycol, polyoxyethylene hydrogenated castor oil and the like, and the like.
- Examples of the antiseptic include quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride and the like, p-hydroxybenzoates such as methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate and the like, benzyl alcohol, phenethyl alcohol, sorbic acid, salts thereof, thimerosal, chlorobutanol, sodium dehydroacetate and the like.
- Examples of the thickener include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, salts thereof and the like.
- Examples of the chelating agent include sodium edetate, citric acid and the like.
- Examples of the aromatic include 1-menthol, borneol, camphor, eucalyptus oil and the like.
- The aqueous solution of the present invention is used as an eye drop, nasal drop or ear drop. When it is used as an eye drop, its pH is generally adjusted to about 3.5-8.5, preferably about 6-7, when it is used as a nasal drop, its pH is generally adjusted to about 3.5-8.5, preferably about 6-7, and when it is used as an ear drop, its pH is generally adjusted to about 3.5-8.5, preferably about 6-7.
- While the method for producing the aqueous solution of the present invention varies depending on the kind of a desired solution, a known method can be used to produce such aqueous solution.
- When the aqueous solution of the present invention is used as an eye drop, for example, the dose thereof need only be sufficient to effectively suppress an inflammation in the eye, and may vary according to symptoms, the kind of inflammation, the patients (human or animal) in need of said solution and the like. A typical dose is 20-200 μL, preferably 50-100 μL, which may be administered 1 to 12 times a day.
- The present invention is described in more detail by way of Examples and Experimental Examples, which should not be construed as limiting the invention.
- Stabilization of pranoprofen—1
- Solutions (Examples 1-3 below) of 0.5 w/v% pranoprofen were respectively charged in 5 ml colorless glass ampoules, and allowed to stand at 80° C. for 1 week and 2 weeks, at 60° C. for 1 week and 2 weeks, and at 4° C. for 1 week. The percentage of residual pranoprofen in the ampoules after standing was determined by high performance liquid chromatography. The results are shown in Table 1. The values in the Table are relative to the amount of pranoprofen when it was prepared, which was taken as 100.
TABLE 1 residual pranoprofen (%) temperature-period w/o addition norfloxacin ofloxacin enoxacin 80° C.-1W 95.4 91.0 99.5 96.7 80° C.-2W 93.0 85.0 100.4 95.9 60° C.-1W 98.7 98.0 99.8 99.2 60° C.-2W 98.5 93.8 98.8 98.4 4° C.-1W 87.5 99.8 99.9 99.2 - Stabilization of pranoprofen—2
- Solutions (Example 4) of 0.5 w/v% pranoprofen, containing boric acid (1.6 w/v%), caffeine (0.3 w/v%) and sterile purified water (appropriate amount) were respectively charged in 5 ml colorless glass ampoules, and allowed to stand at 80° C. for 2 weeks, at 60° C. for 1 week, 2 weeks and 4 weeks, and at 4° C. for 1 week and 1 month. The percentage of residual pranoprofen in the ampoules after standing was determined by high performance liquid chromatography. The results are shown in Table 2. The values in the Table are relative to the amount of pranoprofen when it was prepared, which was taken as 100.
TABLE 2 residual pranoprofen (%) temperature-period w/o addition caffeine 80° C.-2W 91.9 94.2 60° C.-1W 100.1 101.3 60° C.-2W 99.2 100.9 60° C.-4W 96.7 99.5 4° C.-1W 95.0 100.8 4° C.-1M 93.5 97.8 - As is evident from the results shown in Table 1 and Table 2, pranoprofen was markedly stabilized against heat by the addition of ofloxacin, enoxacin and caffeine. The decomposition of pranoprofen which occurs at low temperatures was significantly suppressed by norfloxacin, ofloxacin, enoxacin and caffeine.
-
An eye drop having the following formulation was prepared. pranoprofen 1.0 g norfloxacin 0.6 g boric acid 3.2 g sodium hydroxide appropriate amount sterile purified water appropriate amount total amount 200 ml (pH 7) -
An ear drop having the following formulation was prepared. pranoprofen 1.0 g ofloxacin 0.6 g boric acid 3.2 g sodium hydroxide appropriate amount sterile purified water appropriate amount total amount 200 ml (pH 7) -
A nasal drop having the following formulation was prepared. pranoprofen 1.0 g enoxacin 0.6 g phosphoric acid 0.1 g sodium hydroxide appropriate amount sterile purified water appropriate amount total amount 200 ml (pH 7) -
An eye drop having the following formulation was prepared. pranoprofen 0.5 g caffeine 0.3 g boric acid 1.6 g sterile purified water appropriate amount total amount 100 ml (pH 7) -
An eye drop having the following formulation was prepared. pranoprofen 0.1 g ofloxacin 0.3 g boric acid 1.8 g sorbic acid 0.1 g sterile purified water appropriate amount total amount 100 ml (pH 7) -
An eye drop having the following formulation was prepared. pranoprofen 0.1 g enoxacin 0.3 g boric acid 1.8 g benzalkonium chloride 0.002 g sodium citrate 0.1 g sterile purified water appropriate amount total amount 100 ml (pH 7) -
An eye drop having the following formulation was prepared. pranoprofen 0.1 g caffeine 0.3 g boric acid 1.8 g benzalkonium chloride 0.002 g sterile purified water appropriate amount total amount 100 ml (pH 7) -
An ear drop having the following formulation was prepared. pranoprofen 1.0 g ofloxacin 0.6 g phosphoric acid 0.1 g sodium hydroxide appropriate amount sterile purified water appropriate amount total amount 200 ml (pH 7) - According to the stabilization method of the present invention, arylcarboxylic acid and pharmacologically acceptable salts thereof, particularly pranoprofen, can be stabilized at every temperature range, particularly at lower temperatures, thereby making the production of an aqueous solution to be used as an eye drop, nasal drop, ear drop and the like possible.
- This application is based on application No. 21805/1997 filed in Japan, the content of which is incorporated hereinto by reference.
Claims (23)
1. A method for stabilizing an arylcarboxylic acid or a pharmacologically acceptable salt thereof, which comprises adding a heterocyclic base of the formula (II):
wherein
A and A′ are each a carbon atom or a nitrogen atom;
X is a carbon atom or a nitrogen atom;
Y and Z are each a carbon atom or Y and Z taken together optionally form CH;
R2, R3, R4, R5, R6, R7 and R8 are the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,
wherein R4 and R5 optionally form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R6 and R7 optionally form a 4- to 6-membered heterocyclic group with the adjacent Y and Z, provided that when x is a nitrogen atom, R5 is void; and is a single bond or a double bond, provided that when a is a carbon atom, y and z are each ch and is a double bond, and when a is a nitrogen atom, y and z combinedly form CH and is a single bond, to an arylcarboxylic acid of the formula (I):
L1—R1COOH (I)
wherein
L1 is an optionally substituted heterocyclic group or aryl group having not more than 14 carbon atoms; and
R1 is an optionally substituted alkyl group having not more than 4 carbon atoms or a single bond, or a pharmacologically acceptable salt thereof.
3. The method of , wherein the purine base is at least one compound selected from the group consisting of caffeine, theobromine and theophylline.
claim 2
4. The method of , wherein the heterocyclic base is a pyridonecarboxylic acid of the formula (IV):
claim 1
wherein
X is a carbon atom or a nitrogen atom; and
R12, R13, R14 and R15 are the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;
wherein R12 and R13 optionally form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R14 and R15 optionally form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R13 is void, or a pharmacologically acceptable salt thereof.
5. The method of , wherein the pyridonecarboxylic acid is at least one compound selected from the group consisting of lomefloxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin and tosufloxacin.
claim 4
6. The method of , wherein the arylcarboxylic acid is at least one compound selected from the group consisting of ibuprofen, diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyacetic acid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal, ibufenac, alolofenac, flurbiprofen, ketoprofen, naproxen, mefenamic acid, niflumic acid, metiazinic acid, protizinic acid, clonixin, indomethacin and fenclozic acid.
claim 1
7. The method of , wherein the heterocyclic base is added in a proportion of 0.001-5 parts by weight per 100 parts by weight of the arylcarboxylic acid.
claim 1
8. A stabilizer of an arylcarboxylic acid or a pharmacologically acceptable salt thereof, which comprises, as an active ingredient, a heterocyclic base of the formula (II):
wherein
A and A′ are each a carbon atom or a nitrogen atom;
X is a carbon atom or a nitrogen atom;
Y and Z are each a carbon atom or Y and Z taken together optionally form CH;
R2 R3, R4, R5, R6, R7 and R8 are the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,
wherein R4 and R5 optionally form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R6 and R7 optionally form a 4- to 6-membered heterocyclic group with the adjacent Y and Z, provided that when X is a nitrogen atom, R5 is void; and is a single bond or a double bond, provided that when A is a carbon atom, Y and Z are each CH and is a double bond, and when A is a nitrogen atom, Y and Z combinedly form CH and is a single bond.
10. The stabilizer of , wherein the purine base is at least one compound selected from the group consisting of caffeine, theobromine and theophylline.
claim 9
11. The stabilizer of , wherein the heterocyclic base is a pyridonecarboxylic acid of the formula (IV):
claim 8
wherein
X is a carbon atom or a nitrogen atom; and
R12, R13, R14 and R15 are the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;
wherein R12 and R13 optionally form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R1 4 and R15 optionally form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R13 is void, or a pharmacologically acceptable salt thereof.
12. The stabilizer of , wherein the pyridonecarboxylic acid is at least one compound selected from the group consisting of lomefloxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin and tosufloxacin.
claim 11
13. The stabilizer of , wherein the arylcarboxylic acid is at least one compound selected from the group consisting of ibuprofen, diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyacetic acid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal, ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen, mefenamic acid, niflumic acid, metiazinic acid, protizinic acid, clonixin, indomethacin and fenclozic acid.
claim 8
14. The stabilizer of , wherein the heterocyclic base is contained in a proportion of 0.001-5 parts by weight per 100 parts by weight of the arylcarboxylic acid.
claim 8
15. An aqueous solution containing an arylcarboxylic acid or a pharmacologically acceptable salt thereof stabilized by the method of and a heterocyclic base of the formula (II):
claim 1
wherein
A and A′ are each a carbon atom or a nitrogen atom;
X is a carbon atom or a nitrogen atom;
Y and Z are each a carbon atom or Y and Z taken together optionally form CH;
R2 R3 R4, R5, R6, R7 and R8 are the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,
wherein R4 and R5 optionally form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R6 and R7 optionally form a 4- to 6-membered heterocyclic group with the adjacent Y and Z, provided that when X is a nitrogen atom, R5 is void; and is a single bond or a double bond, provided that when A is a carbon atom, Y and Z are each CH and is a double bond, and when A is a nitrogen atom, Y and Z combinedly form CH and is a single bond.
17. The aqueous solution of , wherein the purine base is at least one compound selected from the group consisting of caffeine, theobromine and theophylline.
claim 16
18. The aqueous solution of , wherein the heterocyclic base is a pyridonecarboxylic acid of the formula (IV):
claim 15
wherein
X is a carbon atom or a nitrogen atom; and
R12, R13, R14 and R15 are the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;
wherein R12 and R13 optionally form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R14 and R15 optionally form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R13 is void, or a pharmacologically acceptable salt thereof.
19. The aqueous solution of , wherein the pyridonecarboxylic acid is at least one compound selected from the group consisting of lomefloxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin and tosufloxacin.
claim 18
20. The aqueous solution of , wherein the arylcarboxylic acid is at least one compound selected from the group consisting of ibuprofen, diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyacetic acid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal, ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen, mefenamic acid, niflumic acid, metiazinic acid, protizinic acid, clonixin, indomethacin and fenclozic acid.
claim 15
21. The aqueous solution of any one of to , which is an eye drop.
claims 15
20
22. The aqueous solution of any one of to , which is a nasal drop.
claims 15
20
23. The aqueous solution of any one of to , which is an ear drop.
claims 15
20
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/885,096 US20010056098A1 (en) | 1997-02-04 | 2001-06-21 | Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid |
US10/624,674 US7320985B2 (en) | 1997-02-04 | 2003-07-23 | Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2180597 | 1997-02-04 | ||
JP21805/1997 | 1997-02-04 | ||
US09/017,626 US6274592B1 (en) | 1997-02-04 | 1998-02-02 | Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid |
US09/885,096 US20010056098A1 (en) | 1997-02-04 | 2001-06-21 | Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/017,626 Division US6274592B1 (en) | 1997-02-04 | 1998-02-02 | Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/624,674 Continuation US7320985B2 (en) | 1997-02-04 | 2003-07-23 | Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid |
Publications (1)
Publication Number | Publication Date |
---|---|
US20010056098A1 true US20010056098A1 (en) | 2001-12-27 |
Family
ID=12065276
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/017,626 Expired - Lifetime US6274592B1 (en) | 1997-02-04 | 1998-02-02 | Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid |
US09/885,096 Abandoned US20010056098A1 (en) | 1997-02-04 | 2001-06-21 | Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid |
US10/624,674 Expired - Fee Related US7320985B2 (en) | 1997-02-04 | 2003-07-23 | Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/017,626 Expired - Lifetime US6274592B1 (en) | 1997-02-04 | 1998-02-02 | Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/624,674 Expired - Fee Related US7320985B2 (en) | 1997-02-04 | 2003-07-23 | Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid |
Country Status (7)
Country | Link |
---|---|
US (3) | US6274592B1 (en) |
EP (2) | EP0856310B1 (en) |
KR (1) | KR100506484B1 (en) |
AT (2) | ATE253891T1 (en) |
CA (1) | CA2228536A1 (en) |
DE (2) | DE69832115T2 (en) |
ES (1) | ES2250814T3 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120115957A1 (en) * | 2003-01-21 | 2012-05-10 | Shirou Sawa | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUP0100051A3 (en) | 1997-09-15 | 2002-08-28 | Procter & Gamble | Antimicrobial quinolones, their compositions and uses |
US6387928B1 (en) | 1997-09-15 | 2002-05-14 | The Procter & Gamble Co. | Antimicrobial quinolones, their compositions and uses |
US6211246B1 (en) * | 1999-06-10 | 2001-04-03 | Mcneil-Ppc, Inc. | Rapidly absorbed liquid compositions |
US6894045B2 (en) | 2001-07-12 | 2005-05-17 | Bristol-Myers Squibb Pharma Company | Tetrahydropurinones and derivatives thereof as corticotropin releasing factor receptor ligands |
US6677352B1 (en) * | 2001-09-26 | 2004-01-13 | Yamin Wang | 1,6-naphthyridine derivatives and their use to treat diabetes and related disorders |
KR101084521B1 (en) | 2006-03-28 | 2011-11-18 | 워너 칠콧 컴퍼니 엘엘씨 | A coupling process for preparing quinolone intermediates |
MX2008012328A (en) | 2006-03-28 | 2008-10-09 | Procter & Gamble | Malate salts, and polymorphs of (3s,5s)-7-[3-amino-5-methyl-piper idinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecar boxylic acid. |
CA2647457C (en) | 2006-03-28 | 2011-05-24 | The Procter & Gamble Company | A hydride reduction process for preparing quinolone intermediates |
CN103379904A (en) | 2011-01-18 | 2013-10-30 | 千寿制药株式会社 | Bromfenac aqueous liquid composition having preservative efficiency |
JP6073231B2 (en) * | 2011-08-31 | 2017-02-01 | 興和株式会社 | Stable pharmaceutical composition |
WO2023078252A1 (en) | 2021-11-02 | 2023-05-11 | Flare Therapeutics Inc. | Pparg inverse agonists and uses thereof |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB873526A (en) | 1957-08-14 | 1961-07-26 | Upjohn Co | Fluid compositions comprising (acetyl-salicylic acid)-anhydride |
US4339428A (en) | 1980-08-18 | 1982-07-13 | Bristol-Myers Company | Capsule product containing high dosage of aspirin in powder or granulated form and alkaline tablet or pellet comprising magnesium carbonate, calcium carbonate and a magnesium dry component |
US4559343A (en) | 1982-09-07 | 1985-12-17 | Alcon Laboratories, Inc. | Nonirritating aqueous ophthalmic compositions comfort formulation for ocular therapeutic agents |
AU573321B2 (en) | 1984-03-14 | 1988-06-02 | Jerome Corbiere | Process for solubilizing active principles and pharmaceuticalcompositions thus obtained |
IL80459A (en) | 1986-10-30 | 1991-04-15 | Abic Ltd | Water-soluble adduct of norfloxacin and nicotinic acid |
IT1226940B (en) | 1988-09-16 | 1991-02-22 | Recordati Chem Pharm | THERAPEUTIC SYSTEM WITH CONTROLLED RELEASE FOR LIQUID PHARMACEUTICAL FORMULATIONS |
CA1336687C (en) | 1989-08-23 | 1995-08-15 | Thomas M. Tencza | Process for preparing tablets containing ibuprofen, apap and caffeine, the products of this process and the use of such products |
US5296228A (en) | 1992-03-13 | 1994-03-22 | Allergan, Inc. | Compositions for controlled delivery of pharmaceutical compounds |
ES2065846B1 (en) * | 1993-04-20 | 1995-10-01 | Cusi Lab | PHARMACEUTICAL FORMULATION BASED ON A STEROID OR NON-STEROID ANTI-INFLAMMATORY AGENT AND AN ANTIBIOTIC BELONGING TO THE GIRASE DNA INHIBITORS GROUP FOR ITS TOPICAL OPHTHALMIC USE. |
EP0621036B1 (en) | 1993-04-22 | 1999-03-17 | Senju Pharmaceutical Co., Ltd. | Aqueous compositions comprising argatroban and cyclodextrin or caffeine |
AU676315B2 (en) | 1993-06-30 | 1997-03-06 | Takeda Chemical Industries Ltd. | Stabilized solid pharmaceutical preparation and method of producing the same |
JPH0797325A (en) | 1993-06-30 | 1995-04-11 | Takeda Chem Ind Ltd | Stable solid pharmaceutical and its production |
HUT72408A (en) | 1993-09-10 | 1996-04-29 | Egyt Gyogyszervegyeszeti Gyar | Process for producing tablets containing acetyl-salicylic acid |
US5641512A (en) | 1995-03-29 | 1997-06-24 | The Procter & Gamble Company | Soft gelatin capsule compositions |
JP3170619B2 (en) * | 1995-04-20 | 2001-05-28 | 参天製薬株式会社 | Planoprofen ophthalmic solution containing organic amine |
JPH08333265A (en) | 1995-06-07 | 1996-12-17 | Taisho Pharmaceut Co Ltd | Ibuprofen suspension liquid preparation |
JPH08333246A (en) | 1995-06-07 | 1996-12-17 | Taisho Pharmaceut Co Ltd | Ibuprofen suspension liquid |
JP3382076B2 (en) | 1995-12-12 | 2003-03-04 | 佐藤製薬株式会社 | Cold medicine capsule obtained by dissolving ibuprofen and method for producing the same |
GB9613457D0 (en) | 1996-06-27 | 1996-08-28 | Procter & Gamble | Pharmaceutical compositions |
US5942508A (en) * | 1997-02-04 | 1999-08-24 | Senju Pharmaceutical Co., Ltd. | Method for solubilizing pyridonecarboxylic acid solubilizer thereof and aqueous solution containing solubilized pyridonecarboxylic acid |
-
1998
- 1998-02-02 US US09/017,626 patent/US6274592B1/en not_active Expired - Lifetime
- 1998-02-03 AT AT98101804T patent/ATE253891T1/en not_active IP Right Cessation
- 1998-02-03 DE DE69832115T patent/DE69832115T2/en not_active Expired - Lifetime
- 1998-02-03 AT AT03025332T patent/ATE307610T1/en not_active IP Right Cessation
- 1998-02-03 KR KR10-1998-0002923A patent/KR100506484B1/en not_active IP Right Cessation
- 1998-02-03 ES ES03025332T patent/ES2250814T3/en not_active Expired - Lifetime
- 1998-02-03 DE DE69819569T patent/DE69819569D1/en not_active Expired - Lifetime
- 1998-02-03 CA CA002228536A patent/CA2228536A1/en not_active Abandoned
- 1998-02-03 EP EP98101804A patent/EP0856310B1/en not_active Withdrawn - After Issue
-
2001
- 2001-06-21 US US09/885,096 patent/US20010056098A1/en not_active Abandoned
-
2003
- 2003-02-05 EP EP03025332A patent/EP1389469B1/en not_active Expired - Lifetime
- 2003-07-23 US US10/624,674 patent/US7320985B2/en not_active Expired - Fee Related
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120115957A1 (en) * | 2003-01-21 | 2012-05-10 | Shirou Sawa | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
US8497304B2 (en) * | 2003-01-21 | 2013-07-30 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
US8669290B2 (en) | 2003-01-21 | 2014-03-11 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
US8754131B2 (en) | 2003-01-21 | 2014-06-17 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
US8871813B2 (en) | 2003-01-21 | 2014-10-28 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
US8927606B1 (en) | 2003-01-21 | 2015-01-06 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
US9144609B2 (en) | 2003-01-21 | 2015-09-29 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
US9561277B2 (en) | 2003-01-21 | 2017-02-07 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
Also Published As
Publication number | Publication date |
---|---|
US7320985B2 (en) | 2008-01-22 |
KR19980071023A (en) | 1998-10-26 |
ATE307610T1 (en) | 2005-11-15 |
ES2250814T3 (en) | 2006-04-16 |
EP1389469A1 (en) | 2004-02-18 |
ATE253891T1 (en) | 2003-11-15 |
EP0856310A3 (en) | 2000-01-19 |
DE69832115T2 (en) | 2006-07-13 |
EP0856310A2 (en) | 1998-08-05 |
US6274592B1 (en) | 2001-08-14 |
DE69832115D1 (en) | 2005-12-01 |
EP1389469B1 (en) | 2005-10-26 |
DE69819569D1 (en) | 2003-12-18 |
CA2228536A1 (en) | 1998-08-04 |
KR100506484B1 (en) | 2005-11-16 |
US20050075350A1 (en) | 2005-04-07 |
EP0856310B1 (en) | 2003-11-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5942508A (en) | Method for solubilizing pyridonecarboxylic acid solubilizer thereof and aqueous solution containing solubilized pyridonecarboxylic acid | |
US6274592B1 (en) | Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid | |
JPH0559893B2 (en) | ||
JP4489851B2 (en) | Method for stabilizing aryl carboxylic acid, stabilizer thereof and aqueous liquid agent comprising stabilized aryl carboxylic acid | |
EP1044688B1 (en) | Method for solubilizing pyridonecarboxylic acids and aqueous solutions containing pyridonecarboxylic acids | |
JP4707201B2 (en) | Method for solubilizing pyridonecarboxylic acid, solubilizer and aqueous liquid agent comprising solubilized pyridonecarboxylic acid | |
JP3346586B2 (en) | Pharmaceutical composition containing pyridonecarboxylic acid or salt thereof and method for stabilizing solution of pyridonecarboxylic acid or salt thereof | |
JPS63188626A (en) | Solubilizing pyridonecarboxylic acid | |
JP3668225B2 (en) | OCT formulation | |
JPH10152438A (en) | Stabilization of 1-azaxanthone derivative or its salt and 1-azaxanthone derivative-containing composition | |
CA2293008A1 (en) | Premixed alatrofloxacin injectable compositions | |
CA3196559A1 (en) | Ophthalmic composition | |
JP3008298B2 (en) | Method for solubilizing pyridonecarboxylic acid | |
JPH01175935A (en) | Freeze-dried injection | |
KR20190013535A (en) | Semisolid formulation containing ketoprofen and a process for the preparation thereof | |
US20090239894A1 (en) | Stabilized aqueous solutions of ergoline compounds | |
KR20080086850A (en) | Stabilized aqueous solutions of ergoline compounds | |
EP0639376A1 (en) | Liquid composition containing amide derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE |