WO2005002566A1 - Antipyretic medicine containing dexibuprofen as an effective component - Google Patents
Antipyretic medicine containing dexibuprofen as an effective component Download PDFInfo
- Publication number
- WO2005002566A1 WO2005002566A1 PCT/KR2003/002386 KR0302386W WO2005002566A1 WO 2005002566 A1 WO2005002566 A1 WO 2005002566A1 KR 0302386 W KR0302386 W KR 0302386W WO 2005002566 A1 WO2005002566 A1 WO 2005002566A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dexibuprofen
- hyperthermia
- antipyretic
- antipyretic medicine
- ibuprofen
- Prior art date
Links
- HEFNNWSXXWATRW-JTQLQIEISA-N dexibuprofen Chemical compound CC(C)CC1=CC=C([C@H](C)C(O)=O)C=C1 HEFNNWSXXWATRW-JTQLQIEISA-N 0.000 title claims abstract description 55
- 229960003428 dexibuprofen Drugs 0.000 title claims abstract description 51
- 230000001754 anti-pyretic effect Effects 0.000 title claims abstract description 35
- 239000003814 drug Substances 0.000 title claims abstract description 24
- 239000002221 antipyretic Substances 0.000 title claims abstract description 19
- 206010020843 Hyperthermia Diseases 0.000 claims abstract description 22
- 230000036031 hyperthermia Effects 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 15
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 5
- 239000000654 additive Substances 0.000 claims abstract description 4
- 239000002671 adjuvant Substances 0.000 claims abstract description 4
- 239000007788 liquid Substances 0.000 claims abstract description 4
- 239000007787 solid Substances 0.000 claims abstract description 4
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 3
- 239000000969 carrier Substances 0.000 claims abstract description 3
- 230000002458 infectious effect Effects 0.000 claims abstract description 3
- 201000009240 nasopharyngitis Diseases 0.000 claims abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 5
- 239000003086 colorant Substances 0.000 claims description 5
- 239000012153 distilled water Substances 0.000 claims description 5
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 4
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 4
- 235000013681 dietary sucrose Nutrition 0.000 claims description 4
- 229960004793 sucrose Drugs 0.000 claims description 4
- 230000000954 anitussive effect Effects 0.000 claims description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- 229940124584 antitussives Drugs 0.000 claims description 3
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 239000003755 preservative agent Substances 0.000 claims description 3
- 230000002335 preservative effect Effects 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229940127230 sympathomimetic drug Drugs 0.000 claims description 3
- 239000000739 antihistaminic agent Substances 0.000 claims description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 26
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 24
- 229960001680 ibuprofen Drugs 0.000 description 23
- 230000036760 body temperature Effects 0.000 description 20
- 241000700159 Rattus Species 0.000 description 14
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- 229960005489 paracetamol Drugs 0.000 description 13
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- 239000000463 material Substances 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
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- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000150 Sympathomimetic Substances 0.000 description 2
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- 229920006173 natural rubber latex Polymers 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 230000004526 pharmaceutical effect Effects 0.000 description 2
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229960003101 pranoprofen Drugs 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- 239000011787 zinc oxide Substances 0.000 description 2
- ZLGIZCLYTDPXEP-LQDNOSPQSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-[4-(2-methylpropyl)phenyl]propanoic acid;hydrate Chemical compound O.NCCCC[C@H](N)C(O)=O.CC(C)CC1=CC=C([C@H](C)C(O)=O)C=C1 ZLGIZCLYTDPXEP-LQDNOSPQSA-N 0.000 description 1
- FPXKNYVSOKOLKD-BTJKTKAUSA-N (z)-but-2-enedioic acid;n-chloroaniline Chemical compound OC(=O)\C=C/C(O)=O.ClNC1=CC=CC=C1 FPXKNYVSOKOLKD-BTJKTKAUSA-N 0.000 description 1
- DYXBSXBXZNSAPO-UHFFFAOYSA-M 1,1-dimethylpyrrolidin-1-ium;iodide Chemical compound [I-].C[N+]1(C)CCCC1 DYXBSXBXZNSAPO-UHFFFAOYSA-M 0.000 description 1
- FLNXBVJLPJNOSI-UHFFFAOYSA-N 1-[2-[(4-chlorophenyl)-phenylmethoxy]ethyl]piperidine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)OCCN1CCCCC1 FLNXBVJLPJNOSI-UHFFFAOYSA-N 0.000 description 1
- UYHNNWQKLGPQQX-UHFFFAOYSA-N 2-[2-(2-methylpropyl)phenyl]propanoic acid Chemical compound CC(C)CC1=CC=CC=C1C(C)C(O)=O UYHNNWQKLGPQQX-UHFFFAOYSA-N 0.000 description 1
- MGWGWNFMUOTEHG-UHFFFAOYSA-N 4-(3,5-dimethylphenyl)-1,3-thiazol-2-amine Chemical compound CC1=CC(C)=CC(C=2N=C(N)SC=2)=C1 MGWGWNFMUOTEHG-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- HVUMOYIDDBPOLL-IIZJTUPISA-N [2-[(2r,3s,4r)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@@H](O)[C@@H]1O HVUMOYIDDBPOLL-IIZJTUPISA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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- 229960001012 codeine hydrochloride Drugs 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- IRVLBORJKFZWMI-JQWIXIFHSA-N etafedrine Chemical compound CCN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 IRVLBORJKFZWMI-JQWIXIFHSA-N 0.000 description 1
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- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-SNVBAGLBSA-N levibuprofen Chemical compound CC(C)CC1=CC=C([C@@H](C)C(O)=O)C=C1 HEFNNWSXXWATRW-SNVBAGLBSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
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- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Definitions
- the present invention relates to an antipyretic medicine containing dexibuprofen as an effective component.
- Dexibuprofen (S (+) -ibuprofen) is an S(+)- stereoisomer of ibuprofen (2-4 (isobutylphenyl) propionic acid) having the following formula:
- Ibuprofen is one of the propionic acid-based nonsteroidal anti-inflammatory drugs (NSAIDs) .
- Ibuprofen is excellent in pharmaceutical effects and stability, and is thus widely used for treating hyperthermia induced by a cold, inflammatory diseases and the like, and inflammatory diseases such as rheumatism and arthritis (referred to as "Cox SR, Gall EP et al . , J. Clin. Pharmacol. 1991, 31, 88-94" and "Rudy AC, Bradley
- Ibuprofen has pharmaceutical effects such as antipyretic, anti-inflammatory and analgesic activity, since it inhibits a biosynthesis of prostaglandin, which is pro-inflammatory material in vivo, by inhibiting an activity of cyclooxygenase (referred to as "Eller N,
- Ibuprofen ordinarily exists in the form of racemate including two stereoisomers of R (-) -ibuprofen and S (+) -ibuprofen at a rate of 1:1 (referred to as
- dexibuprofen is more effective and preferable than the currently used ibuprofen in terms of its reduced side effects, and its development as an antipyretic medicine, arthritis therapeutic agent and its relating therapeutic agent.
- the pharmaceutical research and therapeutic development for dexibuprofen are still unsatisfactory rather than ibuprofen (referred to as "Eur . J. Clin. Pharmacol. 1995, 48, 505-511").
- an excellent antipyretic medicine can be obtained by using dexibuprofen.
- the object of the present invention is to provide an excellent antipyretic medicine comprising a dexibuprofen as an effective component.
- the present invention provides a pharmaceutical composition which comprises ibuprofen in the form of its S-enantiomer (dexibuprofen) , substantially free of its R-enantiomer, or a pharmacologically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
- Examples of such a salt or solvate include dexibuprofen lysine; and a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a zinc salt of dexibuprofen.
- the present invention also provides the use of a composition which comprises in dexibuprofen NSAIDs
- the present invention also provides a method for preparing an antipyretic medicine by adding dexibuprofen to a mixture of carboxy-methyl-cellulose, saccharose, colorant, preservative and distilled water.
- Dexibuprofen is available from "Shasun Chemical & Drugs Ltd.” In order to prepare an antipyretic medicine according to the present invention, dexibuprofen may be mixed with well known other active components; inert solid, .liquid and gaseous carriers; additives; ' and/or, adjuvants .
- NSAIDs acetaminophen, aspirin, pranoprofen and the like
- sympathomimetic drugs phenylpropanolamine, ethylephedrine hydrochloride, etc.
- anti-inflammatory agents serratiopeptidase, streptokinase and the like
- antihistaminic drug chlorophenylamine maleate, cetirizine, etc.
- antitussive cloperastine hydrochloride, codeine hydrochloride, theophylline, etc.
- the examples of the inert solid, liquid and gaseous ingredients used in the present invention include magnesium stearate, carbxymmethyl cellulose calcium, carnauba wax, nitrogen dioxide, carbonic acid gas and the like.
- the examples of the additives and adjuvants used in the present invention include paraoxy benzoic acid, oleosaccharum, colorant, flavorings and the like.
- dexibuprofen is also effective for treating hyperthermia accompanied by infectious and inflammatory diseases; aspecific hyperthermia; - and hyperthermia caused by a cold. According to the present invention, dexibuprofen exerts the same antipyretic effect as ibuprofen even though a half dosage of ibuprofen is administered.
- Fig. 1 is a graph showing the time course of the body weight of a rat administered with Brewer's yeast (hereafter, referred to as 'yeast") to induce hyperthermia, wherein the reduction of the body weight is basically caused by hyperthermia and fast;
- Fig. 2 is a graph showing time course of the antipyretic effect of dexibuprofen in each concentration after yeast-induced hyperthermia; and Fig.
- FIG. 3 is a graph showing time course of the antipyretic effects of dexibuprofen, acetaminophen and ibuprofen (R (-) /S (+) -ibuprofen) in each concentration after yeast-induced hyperthermia.
- the symbols have the following meanings : ' .
- Control Case that only yeast is administered to induce hyperthermia.
- AAP acetaminophen
- PreYeast before administration of yeast
- PostYeast after administration of yeast
- Example 1 (Preparation of Dexibuprofen, Acetaminophen and Ibuprofen) 150.2 g of agar (Agar Powder, produced by Showa Co., Ltd., Japan) and 5,032.0 mg of glycerin (Glycerol, produced by Aldrich Co., Ltd., USA) were added to 100 ml of 0.5% carboxymethyl cellulose sodium salt solution (CMC, produced by DaeJung Co., Ltd., Korea) to obtain a solution.
- CMC carboxymethyl cellulose sodium salt solution
- test materials 100.0 mg of dexibuprofen, 1,000 mg of acetaminophen and 1,000 mg of ibuprofen were melted, respectively, in the solutions in three vehicles. Two kinds of solutions for each test material having concentrations of 1 mg/ml and 10 mg/ml, respectively, were made with the said solutions. These two kinds of solution were diluted to prepare the test materials having various concentrations.
- Example 2 (Hyperthermia-Inducing Experiment) Body temperature of 144 rats (body weight 250 ⁇ 260 g) was measured before administering the yeast. Among them 120 rats having a body temperature of about 37.5 ° C were selected and divided into 12 groups with 10 rats in each group. The average body temperature of each group was 37.4 ° C, and no difference of the average body temperature in each group was found. 20% yeast suspension (produced by Sigma Co., Ltd., USA) was hypodermically injected into the necks of the rats in each group at a dose of 20 ml/kg to induce hyperthermia (referred to as w Journal of Ethnopharmacology 2001, 75(2-3), 283-286").
- the rats were fasted for 19 hours after hypodermical injection. But, water was freely supplied.
- the rats were weighed twice shortly before administration of the yeast and test materials. In twice weighing, the body weight was slightly reduced. But, this reduction did not affect the experimental result of the present invention, since it naturally appeared on account of hyperthermia and fast.
- Example 3 (Experiment on Antipyretic Activity) After 19 hours from the yeast-administration, the body temperature of the rats in each group was measured to confirm the hyperthermia of the rats. Dexibuprofen (dosages: 1, 5, 10, 25 and 50 g/kg) as a test material, and acetaminophen (dosages: 100, 200 and 400 mg/kg) and ibuprofen (dosages: 10, 50 and 100 mg/kg) as controls were orally administered to the rats. The change of body temperature of the rats was observed after 30, 60, 180 and 360 minutes from the administration of the test material and two controls. The body temperature measured at this time and the body temperature measured during the acclimation period as a standard body temperature evaluated antipyretic activity.
- the body temperature was measured before 2 hours from the administration of the test materials to confirm the' hyperthermia of the rats.
- ' Average body temperature in each group was 39.0 ⁇ 39.23 °C . No difference of the average body temperature in each group was found.
- dexibuprofen was administered at each dosage of 1, 5, 10, 25 and 50 mg/kg.
- the body temperature was measured in time intervals of 30, 60, 180 and 360 minutes from the administration.
- an antipyretic effect appeared at a dosage of 10 mg/kg.
- 60 minutes from the administration the same antipyretic effect appeared in each group.
- the same effect could be obtained in each group except for 360 minutes at a dosage of 10 mg/kg and 180 minutes and 360 minutes at a dosage of 1 mg/kg.
- the antipyretic effect is dependent on the concentration of the dexibuprofen after 60 minutes from the administration.
- the same antipyretic effect appeared at dosages of acetaminophen (100, 200 and 400 mg/kg) in each group after 30 minutes and 60 minutes from the administration.
- antipyretic effect could not be found in the rats of the group administered at a dosage of 100 mg/kg after 180 s minutes and 360 minutes -from the administration, and at a dosage of 200 mg/kg after 360 minutes from the administration.
- an antipyretic effect was found at a dosage of 400 mg/kg until 360 minutes from the administration. And low body temperature was found at an excessive dosage due to its side effect.
- the same effect could be obtained in all the groups except for the group administered at a dosage of 50 mg/kg (30 minutes).
- the antipyretic effect was dependent on the concentration. Comparing the body temperature of the rats when administrating dexibuprofen and acetaminophen at their excessive dosages, low body temperature symptom was not found in case of dexibuprofen, but low body temperature symptom was found in case of acetaminophen.
- Formulation Example 1 (tablet, per tablet) dexibuprofen 300g diethylene glycol monoehtylether 20g oleosaccharum 40g macrocrystalline cellulose 70g magnesium stearate 2g colloidal silicon dioxide 60g polyethylene glycol 6000 lg
- This suspension was poured into 100 pieces of a cooled suppository mold to contain 500 mg of an active component .
- Formulation Example 4 (hard capsule, per capsule) dexibuprofen 350g poly-vinyl-pyrolidone 200g talc 60mg magnesium stearate 60g sodium-starch-glycolate lOOg
- Formulation Example 5 (soft capsule, per capsule) dexibuprofen 300g fractionated coconut oil 175g gellatine 80g concentrated glycerin 30g disorbitol solution lOg titanium oxide adequate amount
- dexibuprofen 400 mg was mixed with concentrated glycerin, natural rubber latex, gelatin, flowable paraffin, sodium polyacrylate, propylene glycol, carboxymethylene cellulose sodium, zinc oxide, sorbitan monosterate, dibutylhydroxytoluene, citric acid and paraoxy benzoic acid, and then sufficiently stirred to give an adhesive solution containing dexibuprofen.
- the obtained adhesive solution was applied to non-woven textile using a knife doctor. The textile was dried by gradually heating it from 60 ° C, covered with polypropylene film, and then cut into a size of 20 cm 2 to obtain a final product of a patch.
- dexibuprofen has more excellent antipyretic effect than positive controls, ibuprofen and acetaminophen.
- the antipyretic effect of dexibuprofen at 25 and 50 mg/kg is substantially the same as that of the two positive controls, 50 and 100 mg/kg of ibuprofen and 400 mg/kg of acetaminophen .
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Abstract
The present invention relates to an antipyretic medicine containing dexibuprofen (S(+)-ibuprofen) as an active component useful for treating hyperthermia accompanied by infectious and inflammatory diseases, aspecific hyperthermia, and hyperthermia induced by common cold. The dexibuprofen is used in a mixture with well-known active components; inert solid, liquid and gaseous carriers; additives; and/or adjuvants.
Description
Antipyretic Medicine Containing Dexibuprofen As An Effective Component
Technical Field
The present invention relates to an antipyretic medicine containing dexibuprofen as an effective component. Dexibuprofen (S (+) -ibuprofen) is an S(+)- stereoisomer of ibuprofen (2-4 (isobutylphenyl) propionic acid) having the following formula:
Background Art
Ibuprofen is one of the propionic acid-based nonsteroidal anti-inflammatory drugs (NSAIDs) . Ibuprofen is excellent in pharmaceutical effects and stability, and is thus widely used for treating hyperthermia induced by a cold, inflammatory diseases and the like, and inflammatory diseases such as rheumatism and arthritis (referred to as "Cox SR, Gall EP et al . , J.
Clin. Pharmacol. 1991, 31, 88-94" and "Rudy AC, Bradley
JD et al., Ther. Drug. Monit. 1992, 14, 464-470"). Ibuprofen has pharmaceutical effects such as antipyretic, anti-inflammatory and analgesic activity, since it inhibits a biosynthesis of prostaglandin, which is pro-inflammatory material in vivo, by inhibiting an activity of cyclooxygenase (referred to as "Eller N,
Kollenz CJ et al . , Int. J. Clin. Pharmacol. Ther. 1998,
36, 414-417") . Ibuprofen ordinarily exists in the form of racemate including two stereoisomers of R (-) -ibuprofen and S (+) -ibuprofen at a rate of 1:1 (referred to as
"Zohmann A, Hawel R et al . , Inflammopharmaciolgy, 1998,
6, 75-79") . It is considered that dexibuprofen is more effective and preferable than the currently used ibuprofen in terms of its reduced side effects, and its development as an antipyretic medicine, arthritis therapeutic agent and its relating therapeutic agent. However, the pharmaceutical research and therapeutic development for dexibuprofen are still unsatisfactory rather than ibuprofen (referred to as "Eur . J. Clin. Pharmacol. 1995, 48, 505-511"). Particularly, it has not been reported that an excellent antipyretic medicine can be obtained by using dexibuprofen.
It has now been surprisingly discovered that use of ibuprofen in the form of S-stereoisomer, substantially free of its R-stereoisomer exerts an excellent antipyretic medicine rather than ibuprofen. The present invention has been accomplished on the basis of these findings . Therefore, the object of the present invention is to provide an excellent antipyretic medicine comprising a dexibuprofen as an effective component.
Disclosure of the Invention The present invention provides a pharmaceutical composition which comprises ibuprofen in the form of its S-enantiomer (dexibuprofen) , substantially free of its R-enantiomer, or a pharmacologically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
Examples of such a salt or solvate include dexibuprofen lysine; and a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a zinc salt of dexibuprofen. The present invention also provides the use of a composition which comprises in dexibuprofen NSAIDs
(acetaminophen, aspirin, pranoprofen and the like) , antitussive, antihista inic drug, sympathomimetic and/or
anti-inflammatory agent for manufacturing of a medicament for use as an antipyretic agent. The present invention also provides a method for preparing an antipyretic medicine by adding dexibuprofen to a mixture of carboxy-methyl-cellulose, saccharose, colorant, preservative and distilled water. Dexibuprofen is available from "Shasun Chemical & Drugs Ltd." In order to prepare an antipyretic medicine according to the present invention, dexibuprofen may be mixed with well known other active components; inert solid, .liquid and gaseous carriers; additives; 'and/or, adjuvants . The examples of the other active components to be used in the present invention include NSAIDs (acetaminophen, aspirin, pranoprofen and the like) , sympathomimetic drugs (phenylpropanolamine, ethylephedrine hydrochloride, etc.), anti-inflammatory agents (serratiopeptidase, streptokinase and the like) , antihistaminic drug (chlorophenylamine maleate, cetirizine, etc.), antitussive (cloperastine hydrochloride, codeine hydrochloride, theophylline, etc.) and the like.
The examples of the inert solid, liquid and gaseous ingredients used in the present invention include magnesium stearate, carbxymmethyl cellulose calcium, carnauba wax, nitrogen dioxide, carbonic acid gas and the like. The examples of the additives and adjuvants used in the present invention include paraoxy benzoic acid, oleosaccharum, colorant, flavorings and the like. According to the present invention, dexibuprofen is also effective for treating hyperthermia accompanied by infectious and inflammatory diseases; aspecific hyperthermia; - and hyperthermia caused by a cold. According to the present invention, dexibuprofen exerts the same antipyretic effect as ibuprofen even though a half dosage of ibuprofen is administered.
Brief Description of the Drawings
The above object, other features and advantages of the present invention will become more apparent by describing the preferred embodiment thereof with reference to the accompanying drawings, in which: Fig. 1 is a graph showing the time course of the body weight of a rat administered with Brewer's yeast
(hereafter, referred to as 'yeast") to induce hyperthermia, wherein the reduction of the body weight is basically caused by hyperthermia and fast; Fig. 2 is a graph showing time course of the antipyretic effect of dexibuprofen in each concentration after yeast-induced hyperthermia; and Fig. 3 is a graph showing time course of the antipyretic effects of dexibuprofen, acetaminophen and ibuprofen (R (-) /S (+) -ibuprofen) in each concentration after yeast-induced hyperthermia. In the drawings, the symbols have the following meanings : '.
Control : Case that only yeast is administered to induce hyperthermia.
Ibu : ibuprofen
AAP : acetaminophen
Dexibu : dexibuprofen
PreYeast: before administration of yeast PostYeast: after administration of yeast
Postl9hr: 19 hours after administration of yeast
Post-Drug: after administration of test materials and control
Best Mode for Carrying Out the Invention
The present invention is described in more detail by referring to the following examples without limiting the scope of the invention in any way.
Example 1: (Preparation of Dexibuprofen, Acetaminophen and Ibuprofen) 150.2 g of agar (Agar Powder, produced by Showa Co., Ltd., Japan) and 5,032.0 mg of glycerin (Glycerol, produced by Aldrich Co., Ltd., USA) were added to 100 ml of 0.5% carboxymethyl cellulose sodium salt solution (CMC, produced by DaeJung Co., Ltd., Korea) to obtain a solution. As test materials, 100.0 mg of dexibuprofen, 1,000 mg of acetaminophen and 1,000 mg of ibuprofen were melted, respectively, in the solutions in three vehicles. Two kinds of solutions for each test material having concentrations of 1 mg/ml and 10 mg/ml, respectively, were made with the said solutions. These two kinds of solution were diluted to prepare the test materials having various concentrations.
Example 2 : (Hyperthermia-Inducing Experiment) Body temperature of 144 rats (body weight 250~260 g) was measured before administering the yeast. Among
them 120 rats having a body temperature of about 37.5°C were selected and divided into 12 groups with 10 rats in each group. The average body temperature of each group was 37.4°C, and no difference of the average body temperature in each group was found. 20% yeast suspension (produced by Sigma Co., Ltd., USA) was hypodermically injected into the necks of the rats in each group at a dose of 20 ml/kg to induce hyperthermia (referred to as wJournal of Ethnopharmacology 2001, 75(2-3), 283-286"). The rats were fasted for 19 hours after hypodermical injection. But, water was freely supplied. The rats were weighed twice shortly before administration of the yeast and test materials. In twice weighing, the body weight was slightly reduced. But, this reduction did not affect the experimental result of the present invention, since it naturally appeared on account of hyperthermia and fast.
Example 3: (Experiment on Antipyretic Activity) After 19 hours from the yeast-administration, the body temperature of the rats in each group was measured to confirm the hyperthermia of the rats. Dexibuprofen (dosages: 1, 5, 10, 25 and 50 g/kg) as a test material, and acetaminophen (dosages: 100, 200 and 400 mg/kg) and
ibuprofen (dosages: 10, 50 and 100 mg/kg) as controls were orally administered to the rats. The change of body temperature of the rats was observed after 30, 60, 180 and 360 minutes from the administration of the test material and two controls. The body temperature measured at this time and the body temperature measured during the acclimation period as a standard body temperature evaluated antipyretic activity. As a result, after yeast-inducing hyperthermia, the body temperature was measured before 2 hours from the administration of the test materials to confirm the' hyperthermia of the rats.' Average body temperature in each group was 39.0~39.23 °C . No difference of the average body temperature in each group was found. After 19 hours from the administration of the yeast, dexibuprofen was administered at each dosage of 1, 5, 10, 25 and 50 mg/kg. The body temperature was measured in time intervals of 30, 60, 180 and 360 minutes from the administration. As a result, after 30 minutes from the administration of dexibuprofen, an antipyretic effect appeared at a dosage of 10 mg/kg. After 60 minutes from the administration, the same antipyretic effect appeared in each group. The same effect could be obtained in each group except for 360
minutes at a dosage of 10 mg/kg and 180 minutes and 360 minutes at a dosage of 1 mg/kg. However, it is confirmed that the antipyretic effect is dependent on the concentration of the dexibuprofen after 60 minutes from the administration. When measuring the body temperature in the same manner as above, the same antipyretic effect appeared at dosages of acetaminophen (100, 200 and 400 mg/kg) in each group after 30 minutes and 60 minutes from the administration. But, antipyretic effect could not be found in the rats of the group administered at a dosage of 100 mg/kg after 180s minutes and 360 minutes -from the administration, and at a dosage of 200 mg/kg after 360 minutes from the administration. However, an antipyretic effect was found at a dosage of 400 mg/kg until 360 minutes from the administration. And low body temperature was found at an excessive dosage due to its side effect. In the case of ibuprofen at dosages of 10, 50 and 100 mg/kg, the same effect could be obtained in all the groups except for the group administered at a dosage of 50 mg/kg (30 minutes). Generally, the antipyretic effect was dependent on the concentration.
Comparing the body temperature of the rats when administrating dexibuprofen and acetaminophen at their excessive dosages, low body temperature symptom was not found in case of dexibuprofen, but low body temperature symptom was found in case of acetaminophen. In addition, reviewing the prolonged time of the effect at a concentration inducing no low body temperature symptom, it was confirmed that an antipyretic effect was sustained as long as more than 360 minutes at dosages of 25 and 50 mg/kg of dexibuprofen, but as short as less than 180 minutes at a dosage of 200 mg/kg of acetaminophen. When administering dexibuprofen and ibuprofen at the same dosages of 10 and 50 mg/kg, more excellent antipyretic effect appeared in dexibuprofen than in ibuprofen. And a dosage of 100 mg/kg of ibuprofen and a dosage 50 mg/kg of dexibuprofen represented the same antipyretic effect. The results from the experiment are shown in Table 1 below.
Table 1
Dosage change of body temperature after (mg/kg yeast-inducing hyperthermia ( °C ) ) 30 min. 60 min. 180 min. 360 min
Formulation Examples of the antipyretic medicine according to the present invention are described as follows :
Formulation Example 1 (tablet, per tablet) dexibuprofen 300g diethylene glycol monoehtylether 20g oleosaccharum 40g macrocrystalline cellulose 70g magnesium stearate 2g colloidal silicon dioxide 60g
polyethylene glycol 6000 lg
20g of diethylene glycol monoetylether was added to 300g of dexibuprofen to wet it, melted at a temperature of 60 °C, and then adsorbed in 60g of colloidal silicon dioxide while maintaining the temperature. The mixture was cooled to room temperature. 40g of oleosaccharum and 77g of macrocrystalline cellulose were added to the mixture and sufficiently mixed. 2g of magnesium stearate was added thereto and compressed into a tablet to be 500 mg.
Formulation Example 2 (syrup, in 100 ml) dexibuprofen 25g carboxy-methyl-cellulose lg aroma lg saccharose 30g colorant O.Olg preservative O.Olg distilled water (complemented up to total weight of lOOg)
40g of distilled water and saccharose were boiled and then were cooled. Aroma, colorant, and dexibuprofen suspended in swelled carboxy-methyl-cellulose were mixed
with each other, and then lOOg of distilled water were added thereto to obtain syrup. 250 mg of active component was contained in lg of the syrup.
Formulation Example 3 (suppository) dexibuprofen 50g lanolin wax 150g
Lanolin wax was melted, and an active component was added thereto, and then stirred to give a suspension.
This suspension was poured into 100 pieces of a cooled suppository mold to contain 500 mg of an active component .
Formulation Example 4 (hard capsule, per capsule) dexibuprofen 350g poly-vinyl-pyrolidone 200g talc 60mg magnesium stearate 60g sodium-starch-glycolate lOOg
All the ingredients were blended, and then granulated by a well-known method. 100 capsules were
charged with the granulates to contain 350 mg of active component in a capsule.
Formulation Example 5 (soft capsule, per capsule) dexibuprofen 300g fractionated coconut oil 175g gellatine 80g concentrated glycerin 30g disorbitol solution lOg titanium oxide adequate amount
All the, ingredients were blended, 2,000 capsules were charged with this formulation to contain 300 mg of active component per capsule.
Formulation Example 6 (patch) dexibuprofen 400 mg concentrated glycerin 3.7 g natural rubber latex 2.9 g gellatine 990 mg flowable paraffin 990 mg sodium polyacrylate 620 mg propylene glycol 495 mg carboxymethylene cellulose sodium 125 mg
zinc oxide 2.0 mg sorbitan monostearate 298.0 mg dibutylhydroxytoluene 50.0 mg citric acid 0.5 mg paraoxy benzoic acid 28.0 mg non-woven textile 1.4 g polypropylene film 500 mg
400 mg of dexibuprofen was mixed with concentrated glycerin, natural rubber latex, gelatin, flowable paraffin, sodium polyacrylate, propylene glycol, carboxymethylene cellulose sodium, zinc oxide, sorbitan monosterate, dibutylhydroxytoluene, citric acid and paraoxy benzoic acid, and then sufficiently stirred to give an adhesive solution containing dexibuprofen. The obtained adhesive solution was applied to non-woven textile using a knife doctor. The textile was dried by gradually heating it from 60°C, covered with polypropylene film, and then cut into a size of 20 cm2 to obtain a final product of a patch.
EFFECTS OF THE INVENTION
As apparent in Examples, it was found that dexibuprofen has more excellent antipyretic effect than positive controls, ibuprofen and acetaminophen. The antipyretic effect of dexibuprofen at 25 and 50 mg/kg is substantially the same as that of the two positive controls, 50 and 100 mg/kg of ibuprofen and 400 mg/kg of acetaminophen .
Claims
1. An antipyretic medicine containing dexibuprofen as an effective component having the following formula:
2. An antipyretic medicine according to Claim 1,' wherein the said dexibuprofen includes its salt or complex.
3. An antipyretic medicine according to Claim 1 or 2, wherein the said dexibuprofen is mixed with well known other active components; inert solid, liquid and gaseous carriers; additives; and/or adjuvants.
4. An antipyretic medicine according to Claim 1, 2 or 3, wherein the said dexibuprofen is useful for treating hyperthermia accompanied by infectious and inflammatory diseases; aspecific hyperthermia; and hyperthermia induced by common cold.
5. An antipyretic medicine composition comprising dexibuprofen, NSAIDs, antitussive, antihistaminic drug, sympathomimetic drug and/or anti-inflammatory agent.
6. A method for preparing an antipyretic medicine by adding dexibuprofen to a mixture of carboxy-methyl- cellulose, saccharose, colorant, preservative and/or distilled water.
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| Application Number | Priority Date | Filing Date | Title |
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| AU2003276760A AU2003276760A1 (en) | 2003-07-07 | 2003-11-07 | Antipyretic medicine containing dexibuprofen as an effective component |
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| Application Number | Priority Date | Filing Date | Title |
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| KR1020030045785A KR20050005883A (en) | 2003-07-07 | 2003-07-07 | Antipyretic Medicine Containing Dexibuprofen As An Effective Component |
| KR10-2003-0045785 | 2003-07-07 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102258519A (en) * | 2011-08-19 | 2011-11-30 | 西安利君制药有限责任公司 | Application of dexibuprofen levocetrizine sustained release bilayer tablet in treating airway inflammation |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4877620A (en) * | 1986-11-14 | 1989-10-31 | MEDICE Chem.- Pharm. Fabrik Putter GmbH & Co. KG | Ibuprofen-containing medicament |
| WO1994003209A1 (en) * | 1992-07-29 | 1994-02-17 | Merck & Co., Inc. | Dexibuprofen/antacid/simethicone combinations |
| EP1175913A1 (en) * | 2000-07-28 | 2002-01-30 | SPA SOCIETA' PRODOTTI ANTIBIOTICI S.p.A. | Intramuscular pharmaceutical composition comprising dexibuprofen and uses thereof |
| US6551615B1 (en) * | 2001-10-18 | 2003-04-22 | M/S. Strides Arcolab Limited | Dexibuprofen-containing soft gelatin capsules and process for preparing the same |
-
2003
- 2003-07-07 KR KR1020030045785A patent/KR20050005883A/en not_active Application Discontinuation
- 2003-11-07 AU AU2003276760A patent/AU2003276760A1/en not_active Abandoned
- 2003-11-07 WO PCT/KR2003/002386 patent/WO2005002566A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4877620A (en) * | 1986-11-14 | 1989-10-31 | MEDICE Chem.- Pharm. Fabrik Putter GmbH & Co. KG | Ibuprofen-containing medicament |
| WO1994003209A1 (en) * | 1992-07-29 | 1994-02-17 | Merck & Co., Inc. | Dexibuprofen/antacid/simethicone combinations |
| EP1175913A1 (en) * | 2000-07-28 | 2002-01-30 | SPA SOCIETA' PRODOTTI ANTIBIOTICI S.p.A. | Intramuscular pharmaceutical composition comprising dexibuprofen and uses thereof |
| US6551615B1 (en) * | 2001-10-18 | 2003-04-22 | M/S. Strides Arcolab Limited | Dexibuprofen-containing soft gelatin capsules and process for preparing the same |
Non-Patent Citations (2)
| Title |
|---|
| DIONNE R.A. ET AL.: "Enhanced analgesia and supression of plasma beta-endorphin by the S(+)-isomer of ibuprofen", CLINICAL PHARMACOLOGY AND THERAPEUTICS, vol. 63, no. 6, 1998, pages 694 - 701 * |
| EVANS A.M.: "Comparative pharmacology of S(+)-ibuprofen and (RS)-ibuprofen", CLINICAL RHEUMATOLOGY, vol. 20, no. SUPPL.1, 2001, pages S9 - 14 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102258519A (en) * | 2011-08-19 | 2011-11-30 | 西安利君制药有限责任公司 | Application of dexibuprofen levocetrizine sustained release bilayer tablet in treating airway inflammation |
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| Publication number | Publication date |
|---|---|
| KR20050005883A (en) | 2005-01-15 |
| AU2003276760A1 (en) | 2005-01-21 |
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