EP0663819A1 - Ibuprofen-caffeine combinations - Google Patents
Ibuprofen-caffeine combinationsInfo
- Publication number
- EP0663819A1 EP0663819A1 EP93922264A EP93922264A EP0663819A1 EP 0663819 A1 EP0663819 A1 EP 0663819A1 EP 93922264 A EP93922264 A EP 93922264A EP 93922264 A EP93922264 A EP 93922264A EP 0663819 A1 EP0663819 A1 EP 0663819A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- ibuprofen
- lysine
- caffeine
- salt
- enhancement
- 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.)
- Withdrawn
Links
- 229960001948 caffeine Drugs 0.000 title claims abstract description 40
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 claims abstract description 76
- IHHXIUAEPKVVII-PTKYJSHISA-N [(5s)-5-amino-5-carboxypentyl]azanium;(2s)-2-[4-(2-methylpropyl)phenyl]propanoate Chemical group NCCCC[C@H](N)C(O)=O.CC(C)CC1=CC=C([C@H](C)C(O)=O)C=C1 IHHXIUAEPKVVII-PTKYJSHISA-N 0.000 claims abstract description 41
- 208000002193 Pain Diseases 0.000 claims abstract description 40
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 claims abstract description 38
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 claims abstract description 38
- 230000036407 pain Effects 0.000 claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 239000000203 mixture Substances 0.000 claims abstract description 29
- HEFNNWSXXWATRW-JTQLQIEISA-N dexibuprofen Chemical compound CC(C)CC1=CC=C([C@H](C)C(O)=O)C=C1 HEFNNWSXXWATRW-JTQLQIEISA-N 0.000 claims abstract description 28
- HEFNNWSXXWATRW-SNVBAGLBSA-N levibuprofen Chemical compound CC(C)CC1=CC=C([C@@H](C)C(O)=O)C=C1 HEFNNWSXXWATRW-SNVBAGLBSA-N 0.000 claims abstract description 20
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 13
- 206010061218 Inflammation Diseases 0.000 claims abstract description 12
- 230000004054 inflammatory process Effects 0.000 claims abstract description 12
- IHHXIUAEPKVVII-PYTFSAHDSA-N (2r)-2,6-diaminohexanoic acid;(2s)-2-[4-(2-methylpropyl)phenyl]propanoic acid Chemical compound NCCCC[C@@H](N)C(O)=O.CC(C)CC1=CC=C([C@H](C)C(O)=O)C=C1 IHHXIUAEPKVVII-PYTFSAHDSA-N 0.000 claims abstract description 10
- 241000124008 Mammalia Species 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 21
- 229960001680 ibuprofen Drugs 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 3
- 230000004044 response Effects 0.000 claims description 3
- 230000002708 enhancing effect Effects 0.000 claims 1
- 235000002639 sodium chloride Nutrition 0.000 description 25
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 238000013268 sustained release Methods 0.000 description 7
- 239000012730 sustained-release form Substances 0.000 description 7
- 230000008901 benefit Effects 0.000 description 6
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 6
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 5
- -1 Amino acid salts Chemical class 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- IHHXIUAEPKVVII-APFIOPMWSA-N (2s)-2,6-diaminohexanoic acid;(2r)-2-[4-(2-methylpropyl)phenyl]propanoic acid Chemical compound NCCCC[C@H](N)C(O)=O.CC(C)CC1=CC=C([C@@H](C)C(O)=O)C=C1 IHHXIUAEPKVVII-APFIOPMWSA-N 0.000 description 4
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 4
- 206010019233 Headaches Diseases 0.000 description 4
- 229920003091 Methocel™ Polymers 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 231100000869 headache Toxicity 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 229940097964 caffeine 65 mg Drugs 0.000 description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229940095534 caffeine 200 mg Drugs 0.000 description 2
- 229940124827 caffeine tablet Drugs 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 2
- 229940038472 dicalcium phosphate Drugs 0.000 description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 2
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- 239000003814 drug Substances 0.000 description 2
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- 230000009467 reduction Effects 0.000 description 2
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- 239000002904 solvent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
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- 239000004475 Arginine Substances 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
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- 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 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010033372 Pain and discomfort Diseases 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 206010062519 Poor quality sleep Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000026137 Soft tissue injury Diseases 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 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 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
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- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-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
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
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- 230000000172 allergic effect Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
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- 229940092782 bentonite Drugs 0.000 description 1
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- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 229940026622 caffeine 20 mg Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
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- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
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- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
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- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
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- 229910052749 magnesium Inorganic materials 0.000 description 1
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- DKXULEFCEORBJK-UHFFFAOYSA-N magnesium;octadecanoic acid Chemical compound [Mg].CCCCCCCCCCCCCCCCCC(O)=O DKXULEFCEORBJK-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- NSAID non-steroidal anti-inflammatory drugs
- NSAIDs have been utilized in the treatment of pain/inflammation and a number of other symptoms including stiffness that are associated with painful conditions affecting muscles, bones, and joints.
- NSAIDs have been prescribed to relieve back pain, gout, menstrual pain, headaches, mild pain following surgery, and pain from soft tissue injuries such as sprains and strains.
- NSAIDs are within the broader class of non- narcotic analgesics which also includes acetylsahcyclic acid (aspirin) and acetaminophen.
- NSAIDs, except for acetaminophen are generally considered to exert their effect by blocking the production of prostaglandins at the site of pain, irritation or injury so that the pain signal does not reach the brain.
- Ibuprofen (2-(4-isobutylphenyl)propionic acid) is a well known and commonly employed NSAID.
- Amino acid salts of racemic ibuprofen Including the lysine or arginine salt are also known pain relievers. See U.S. Pat. No. 4,279,926.
- S-ibuprofen also known as (-f-)-ibuprofen or dexibuprofen
- Caffeine is a well known xanthine alkaloid and is used in a number of foods and medicines.
- the Xanthines including caffeine, are known to stimulate the central nervous system, induce relaxation of smooth muscle constrictions of the smaller bronchi and other smooth muscles, cause dilation of the small pulmonary arteries, and induce stimulation of cardiac muscle with increased cardiac output and the promotion of mild diuresis. It has been postulated that these actions may be related to the antagonism of adenosine receptors.
- compositions for use in the treatment of pain and inflammation comprising:
- This invention is also directed to a method of treating pain and inflammation in mammals, including humans, in need thereof, comprising administering to such organism:
- This invention is further directed to a method of eliciting an onset hastened and enhanced response for the treatment of pain and inflammation in mammals, including humans, in need thereof, comprising administering to such organism: (i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)- lysine; and (ii) an amount effective in enhancement of pain relief of caffeine.
- Substantially free of (R)-ibuprofen means that the ratio of (S)-ibuprofen to (R)-ibuprofen is at least 90:10.
- Salts of (S)-ibuprofen include pharmaceutically acceptable salts such as alkali metals (sodium or potassium), alkaline earth metals (calcium), or salts with other metals such as magnesium, aluminum, iron, zinc, copper, nickel or cobalt.
- compositions of the instant invention further include the amino acid salts, particularly the basic amino acids such as lysine or arginine.
- amino acid salts particularly the basic amino acids such as lysine or arginine.
- Specifically included within the composition of the instant invention is (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)- lysine.
- mammals or mammalian organism includes but is not limited to man, dog, cat, horse and cow.
- (S)-ibuprofen may be prepared following the procedures disclosed in U.S. Patent 4,877,620.
- Metal salts of ibuprofen may be obtained by contacting a hydroxide, or carbonate with ibuprofen.
- Amino acid salts of ibuprofen may be obtained by contacting an amino acid in solution with ibuprofen.
- 4,994,604 describes a process for the formation and resolution of (S)-ibuprofen-(S)-lysine that employs preferential crystallization to separate a pair of diastereomeric salts, (S)-ibuprofen-(S)-lysine and (R)-ibuprofen-(S)-lysine.
- the basic procedure involves (a) contacting (R),(S)-ibuprofen and (S)-lysine in an aqueous-organic solvent mixture; (b) separating any suspended solid from the mixture; and (c) cooling the clear mixture until the mixture is supersaturated with respect to each of the (S)-ibuprofen-(S)-lysine and (R)-ibuprofen-(S)-lysine salts; (d) contacting the supersaturated mixture with a slurry of (S)-ibuprofen-(S)-lysine in an aqueous-organic solvent; and (e) separating the formed crystalline (S)-ibuprofen-(S)-lysine.
- racemic ibuprofen starting material is mixed with an organic solvent that is miscible with water.
- the (S)- lysine is mixed with water and the ibuprofen and lysine solutions are combined.
- the mixture is agitated for a time period sufficient to crystallize all the salts, if any, in excess of the solubility limit.
- the suspended salts are separated to obtain a clear mother liquor which is generally saturated with respect to the diastereomeric salts (S)- ibuprofen-(S)-lysine and (R)-ibuprofen-(S)-lysine. Filtration may be employed to effect the separation.
- the liquor is then cooled to a temperature at which it is supersaturated with respect to each of the diastereomeric salts. It is preferred that the liquor be cooled to the point at which maximum supersaturation is obtained with respect to each salt without nucleation of either crystallizable species.
- the temperature of the mother liquor must be lowered by about 5° C to reach maximum supersaturation without precipitation of either salt.
- the degree of cooling will depend on the particular solvent composition.
- the supersaturated liquor is then passed into a vessel containing a slurry of (S)-ibuprofen-(S)-lysine, hereafter referred to as the (S,S) salt, in the same solvent system employed above for the mixture of racemic ibuprofen and (S)-lysine.
- the (S,S) salt crystals acting as a seed the supersaturation of the (S,S)-salt in the feed liquor is released by the growth of further crystals of the (S,S)- salt.
- compositions of the present invention are useful in the rapid and enhanced treatment of pain and inflammation.
- the (S)-ibuprofen-(S)-lysine combined with caffeine is useful for the treatment of pain, and inflammation.
- the utilization of (S)-ibuprofen and in particular (S)-ibuprofen-(S)-lysine in an analgesic/caffeine combination offers significant advantages over the combination of racemic ibuprofen and caffeine or (S)-ibuprofen and caffeine.
- (S)-ibuprofen and in particular the lysine salt of (S)- ibuprofen provides a faster onset of pain and inflammation relief and an enhanced degree of relief compared to racemic ibuprofen.
- These benefits contribute to overall enhanced and faster relief of symptoms associated with headaches and other aches and pains when the (S)- ibuprofen -(S)-lysine is combined with a xanthine derivative such as caffeine.
- the absence or reduction of (R)-ibuprofen also provides significant benefits.
- the allergic contraindications sometimes associated with ibuprofen administration are absent or reduced in a (R)-ibuprofen- free or substantially -free composition.
- An additional advantage may be that less metabolic energy will be used to convert the inactive (R)- ibuprofen to the active (S)-ibuprofen.
- a reduced burden may be placed on the urogenital system since administration of the pure (S)-ibuprofen eliminates the need to excrete the (R)-ibuprofen or its metabolites.
- the absence of the (R)-enantiomer also reduces or eliminates the incorporation of this molecule into fatty tissue.
- the renal burden and renal toxicities sometimes associated with racemic ibuprofen therapy may be reduced or eliminated in a (S)-ibuprofen composition that is substantially free of the (R) enantiomer.
- Caffeine and xanthine alkaloids are known in the art and may be used in combination with (S)-ibuprofen (S)-lysine. Caffeine is well tolerated and has minimal side effects and thus advantageously may be used in the present invention in combination with (S)-ibuprofen (S)- lysine.
- the composition of (S)-ibuprofen-(S)-lysine with caffeine provides a combination which simultaneously and selectively provides enhanced relief from headaches, pain, and inflammation. This combination also has an advantage under circumstances where a mammalian organism requires enhanced pain relief and wakefulness or mental altertness.
- inactive enantiomers particularly (R)- ibuprofen provides for significant size and weight advantages in a combination dosage form, particularly a sustained release dosage form.
- a sustained release dosage of ibuprofen may have required 800 to 1000 mg
- the employment of (S)-ibuprofen-(S)-lysine reduces the weight to 400 to 500 mg, and provides for a more practical size tablet for an ibuprofen/caffeine combination.
- An effective amount of (S)-ibuprofen, or a salt thereof, for use in a unit dose composition of this invention may range from 50-800 mg of (S)-ibuprofen.
- the preferred amount of (S)-ibuprofen is about 100 to 400 mg.
- the amount of a salt such as (S)-ibuprofen-(S)-lysine is determined based on the amount of (S)-ibuprofen contained therein.
- Caffeine is advantageously used in the present invention in combination with (S)-ibuprofen-(S)-lysine.
- the amount of caffeine used in the present invention in humans may range from 20 to 400 milligrams (mg).
- 32 to 65 mg is administered in combination with 100 to 400 mg of (S)-ibuprofen (S)-lysine.
- the combination claimed in the instant invention is advantageously admimstered orally.
- the claimed combination may be administered intravenously in a suitable dosage within the limits described for oral treatment.
- the present composition may be administered in the form of tablets, caplets, gelcaps, capsules, elixirs, syrups, or suspensions.
- the active ingredients may be admixed with a pharmaceutically acceptable diluent such as lactose, sucrose, cellulose, dicalcium phosphate, calcium sulfate, mannitol, and, in a liquid composition, ethyl alcohol.
- Acceptable emulsifying or suspending agents such as PVP, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, guar gum, agar, bentonite, carboxymethylcellulose sodium, polyethylene glycol and waxes, may also be admixed with the active components.
- lubricants such as magnesium stearic acid talc or magnesium stearate, and disintegrators or superdisintegrators such as starch, sodium starch glycolate or cross-linked PVP may also be included.
- Electrolytes such as dicalcium phosphate, sodium benzoate, sodium acetate and sodium chloride may also be used.
- the active components may also be formulated in sustained release or effervescent formulations. These formulations depending upon whether they are sustained release or effervescent may be employed in oral, dermal, rectal or vaginal administrations.
- the sustained release formulations also include layered formulations which provide for distinct release ratio and thus may be more effective in allowing for short and long term relief.
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Abstract
This invention relates to pharmaceutical compositions for use in the treatment of pain and inflammation in mammals, including humans, by administering compositions comprising (i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)-lysine; and (ii) an amount effective in the enhancement of pain relief of caffeine.
Description
TITLE OF THE INVENTION IBUPROFEN-CAFFEINE COMBINATIONS
BACKGROUND OF THE INVENTION
The non-steroidal anti-inflammatory drugs (NSAID) have been utilized in the treatment of pain/inflammation and a number of other symptoms including stiffness that are associated with painful conditions affecting muscles, bones, and joints. NSAIDs have been prescribed to relieve back pain, gout, menstrual pain, headaches, mild pain following surgery, and pain from soft tissue injuries such as sprains and strains. NSAIDs are within the broader class of non- narcotic analgesics which also includes acetylsahcyclic acid (aspirin) and acetaminophen. NSAIDs, except for acetaminophen, are generally considered to exert their effect by blocking the production of prostaglandins at the site of pain, irritation or injury so that the pain signal does not reach the brain.
Ibuprofen (2-(4-isobutylphenyl)propionic acid) is a well known and commonly employed NSAID. Amino acid salts of racemic ibuprofen Including the lysine or arginine salt are also known pain relievers. See U.S. Pat. No. 4,279,926. Recently, it has been found that a faster onset of pain relief and an enhanced analgesic response can be obtained by utilizing the single enantiomer (S)-ibuprofen (also known as (-f-)-ibuprofen or dexibuprofen) rather than the racemic mixture of ibuprofen. See U.S. Patent 4,877,620.
Caffeine is a well known xanthine alkaloid and is used in a number of foods and medicines. The Xanthines, including caffeine, are known to stimulate the central nervous system, induce relaxation of smooth muscle constrictions of the smaller bronchi and other smooth muscles, cause dilation of the small pulmonary arteries, and induce stimulation of cardiac muscle with increased cardiac output and the promotion of mild diuresis. It has been postulated that these actions may be related to the antagonism of adenosine receptors.
Combinations of ibuprofen with caffeine have been disclosed. See U.S. Pat. No. 4,851,444 which broadly discloses the
combination of (S)-ibuprofen and several additional active ingredients including caffeine; 4,587,249 discloses the combination of ibuprofen and caffeine; See also 4,567,183; 4,558,051; 4,486,436; 4,464,376; 4,656,177; 4,777,174. There is a need to employ a compound with faster acting and enhanced analgesic capability as well as enhanced solubility such as (S)-ibuprofen-(S)-lysine substantially free of (R)- ibuprofen in combination with a xanthine derivative such as caffeine to more effectively treat and prevent the pain and discomfort associated with headaches or other aches and pains. The present invention provides both faster onset and enhanced relief of aches and pains associated with the head and body.
DETAILED DESCRIPTION OF THE INVENTION
This invention claims pharmaceutical compositions for use in the treatment of pain and inflammation. The composition comprises:
(i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)- lysine; and
(ii) an amount effective in enhancement of pain relief of caffeine.
This invention is also directed to a method of treating pain and inflammation in mammals, including humans, in need thereof, comprising administering to such organism:
(i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)- lysine; and(ii) an amount effective in enhancement of pain relief of caffeine.
This invention is further directed to a method of eliciting an onset hastened and enhanced response for the treatment of pain and inflammation in mammals, including humans, in need thereof, comprising administering to such organism:
(i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)- lysine; and (ii) an amount effective in enhancement of pain relief of caffeine.
Substantially free of (R)-ibuprofen means that the ratio of (S)-ibuprofen to (R)-ibuprofen is at least 90:10.
Salts of (S)-ibuprofen include pharmaceutically acceptable salts such as alkali metals (sodium or potassium), alkaline earth metals (calcium), or salts with other metals such as magnesium, aluminum, iron, zinc, copper, nickel or cobalt.
Pharmaceutically acceptable salts of (S)-ibuprofen further include the amino acid salts, particularly the basic amino acids such as lysine or arginine. Specifically included within the composition of the instant invention is (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)- lysine.
The term mammals or mammalian organism includes but is not limited to man, dog, cat, horse and cow.
The term treatment encompasses the complete range of therapeutically positive effects associated with pharmaceutical medication including reduction of, alleviation of and relief from the symptoms or illness which affect the organism. (S)-ibuprofen may be prepared following the procedures disclosed in U.S. Patent 4,877,620. Metal salts of ibuprofen may be obtained by contacting a hydroxide, or carbonate with ibuprofen. Amino acid salts of ibuprofen may be obtained by contacting an amino acid in solution with ibuprofen. U.S. Patent No. 4,994,604 describes a process for the formation and resolution of (S)-ibuprofen-(S)-lysine that employs preferential crystallization to separate a pair of diastereomeric salts, (S)-ibuprofen-(S)-lysine and (R)-ibuprofen-(S)-lysine. The basic procedure involves (a) contacting (R),(S)-ibuprofen and (S)-lysine in an aqueous-organic solvent mixture; (b) separating any suspended solid from the mixture; and (c) cooling the clear mixture until the mixture is supersaturated with respect to each of the (S)-ibuprofen-(S)-lysine and
(R)-ibuprofen-(S)-lysine salts; (d) contacting the supersaturated mixture with a slurry of (S)-ibuprofen-(S)-lysine in an aqueous-organic solvent; and (e) separating the formed crystalline (S)-ibuprofen-(S)-lysine.
Specifically, the racemic ibuprofen starting material is mixed with an organic solvent that is miscible with water. The (S)- lysine is mixed with water and the ibuprofen and lysine solutions are combined.
The mixture is agitated for a time period sufficient to crystallize all the salts, if any, in excess of the solubility limit. The suspended salts are separated to obtain a clear mother liquor which is generally saturated with respect to the diastereomeric salts (S)- ibuprofen-(S)-lysine and (R)-ibuprofen-(S)-lysine. Filtration may be employed to effect the separation. The liquor is then cooled to a temperature at which it is supersaturated with respect to each of the diastereomeric salts. It is preferred that the liquor be cooled to the point at which maximum supersaturation is obtained with respect to each salt without nucleation of either crystallizable species. Typically the temperature of the mother liquor must be lowered by about 5° C to reach maximum supersaturation without precipitation of either salt. However, the degree of cooling will depend on the particular solvent composition. The supersaturated liquor is then passed into a vessel containing a slurry of (S)-ibuprofen-(S)-lysine, hereafter referred to as the (S,S) salt, in the same solvent system employed above for the mixture of racemic ibuprofen and (S)-lysine. In the presence of the (S,S) salt crystals acting as a seed, the supersaturation of the (S,S)-salt in the feed liquor is released by the growth of further crystals of the (S,S)- salt. Conversely, there is little or no change in the (R)-ibuprofen-(S)- lysine supersaturation because the growth rate of the (R,S) crystals is essentially zero in the absence of any initial (R,S) salt seed. The (S,S) crystals are then separated by filtration or centrifugation and washed with aqueous-organic solvent to yield (S)-ibuprofen-(S)-lysine of purity approximating 98%.
The pharmaceutical compositions of the present invention are useful in the rapid and enhanced treatment of pain and
inflammation. In particular, the (S)-ibuprofen-(S)-lysine combined with caffeine is useful for the treatment of pain, and inflammation. The utilization of (S)-ibuprofen and in particular (S)-ibuprofen-(S)-lysine in an analgesic/caffeine combination offers significant advantages over the combination of racemic ibuprofen and caffeine or (S)-ibuprofen and caffeine.
(S)-ibuprofen and in particular the lysine salt of (S)- ibuprofen provides a faster onset of pain and inflammation relief and an enhanced degree of relief compared to racemic ibuprofen. These benefits contribute to overall enhanced and faster relief of symptoms associated with headaches and other aches and pains when the (S)- ibuprofen -(S)-lysine is combined with a xanthine derivative such as caffeine.
The absence or reduction of (R)-ibuprofen also provides significant benefits. The allergic contraindications sometimes associated with ibuprofen administration are absent or reduced in a (R)-ibuprofen- free or substantially -free composition. An additional advantage may be that less metabolic energy will be used to convert the inactive (R)- ibuprofen to the active (S)-ibuprofen. In addition, a reduced burden may be placed on the urogenital system since administration of the pure (S)-ibuprofen eliminates the need to excrete the (R)-ibuprofen or its metabolites. The absence of the (R)-enantiomer also reduces or eliminates the incorporation of this molecule into fatty tissue. The renal burden and renal toxicities sometimes associated with racemic ibuprofen therapy may be reduced or eliminated in a (S)-ibuprofen composition that is substantially free of the (R) enantiomer.
Caffeine and xanthine alkaloids are known in the art and may be used in combination with (S)-ibuprofen (S)-lysine. Caffeine is well tolerated and has minimal side effects and thus advantageously may be used in the present invention in combination with (S)-ibuprofen (S)- lysine. The composition of (S)-ibuprofen-(S)-lysine with caffeine provides a combination which simultaneously and selectively provides enhanced relief from headaches, pain, and inflammation. This combination also has an advantage under circumstances where a
mammalian organism requires enhanced pain relief and wakefulness or mental altertness.
The absence of inactive enantiomers, particularly (R)- ibuprofen provides for significant size and weight advantages in a combination dosage form, particularly a sustained release dosage form. Where a sustained release dosage of ibuprofen may have required 800 to 1000 mg, the employment of (S)-ibuprofen-(S)-lysine reduces the weight to 400 to 500 mg, and provides for a more practical size tablet for an ibuprofen/caffeine combination.
An effective amount of (S)-ibuprofen, or a salt thereof, for use in a unit dose composition of this invention may range from 50-800 mg of (S)-ibuprofen. The preferred amount of (S)-ibuprofen is about 100 to 400 mg. The amount of a salt such as (S)-ibuprofen-(S)-lysine is determined based on the amount of (S)-ibuprofen contained therein.
Caffeine is advantageously used in the present invention in combination with (S)-ibuprofen-(S)-lysine. The amount of caffeine used in the present invention in humans may range from 20 to 400 milligrams (mg). Advantageously, 32 to 65 mg is administered in combination with 100 to 400 mg of (S)-ibuprofen (S)-lysine. The combination claimed in the instant invention is advantageously admimstered orally. However, in patients with hypersecretory conditions, intractable ulcers, or in patients who are unable to take oral medication, the claimed combination may be administered intravenously in a suitable dosage within the limits described for oral treatment.
The present composition may be administered in the form of tablets, caplets, gelcaps, capsules, elixirs, syrups, or suspensions. For oral administration, the active ingredients may be admixed with a pharmaceutically acceptable diluent such as lactose, sucrose, cellulose, dicalcium phosphate, calcium sulfate, mannitol, and, in a liquid composition, ethyl alcohol. Acceptable emulsifying or suspending agents such as PVP, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, guar gum, agar, bentonite, carboxymethylcellulose sodium, polyethylene glycol and waxes, may also be admixed with the active components. Where
necessary, lubricants such as magnesium stearic acid talc or magnesium stearate, and disintegrators or superdisintegrators such as starch, sodium starch glycolate or cross-linked PVP may also be included. Electrolytes such as dicalcium phosphate, sodium benzoate, sodium acetate and sodium chloride may also be used.
The active components may also be formulated in sustained release or effervescent formulations. These formulations depending upon whether they are sustained release or effervescent may be employed in oral, dermal, rectal or vaginal administrations. The sustained release formulations also include layered formulations which provide for distinct release ratio and thus may be more effective in allowing for short and long term relief.
The following examples illustrate the compositions of the present invention which may be readily prepared and as such are not to be considered as limiting the invention set forth in the claims.
EXAMPLE 1
(SVIbuprofen lvsine/caffeine Tablet
(S)-ibuprofen-(S)-lysine 342 mg caffeine 65 mg
PVP 15 mg
Avicel PHlOl 40 mg
Magnesium Stearate 4 mg
EXAMPLE 2 (SVIbuprofen lvsine/caffeine Tablet
(S)-ibuprofen-(S)-lysine 342 mg caffeine 20 mg
PVP 15 mg
Avicel PHlOl 40 mg
Magnesium Stearate 4 mg
EXAMPLE 3 (SVIbuprofen lvsine/caffeine Sustained Release
(S)-ibuprofen-(S)-lysine 400 mg caffeine 65 mg
PVP 30 mg
Avicel PH101 80 mg
Magnesium Stearate 8 mg
Methocel E10MCR 66 mg Methocel K100MLV 200 mg
EXAMPLE 4 (SVIbuprofen (S Vlvsine/caffeine Sustained Release
(S)-ibuprofen-(S)-lysine 400 mg caffeine 200 mg
PVP 30 mg
Avicel PHlOl 80 mg
Magnesium Stearate 8 mg
Methocel E10MCR 66 mg
Methocel K100MLV 200mg
EXAMPLE 5 (SVIbuprofen-fSVlvsine/caffeine Solution
(S)-ibuprofen-(S)-lysine 342 mg caffeine 65mg g.s. syrup 5 ml
EXAMPLE 6 (SVIbuprofen-CSVlvsine/caffeine Solution
(S)-ibuprofen-(S)-lysine 342 mg caffeine 200 mg g.s. syrup 5 ml
Claims
1. A pharmaceutical composition for use in the treatment of pain and inflammation and the enhancement of pain relief in mammals, including humans comprising:
(i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)- lysine; and
(ii) an amount effective in the enhancement of pain relief of caffeine.
2. The composition of Claim 1 comprising at least 50 mg of (S)-ibuprofen-(S)-lysine.
3. The composition of Claim 1 comprising between 20-400 mg of caffeine.
4. The composition of Claim 1 comprising 100-400 mg of (S)-ibuprofen-(S)-lysine and 32-65 mg of caffeine.
5. A method of treating pain and inflammation and enhancing pain relief in a mammalian organism in need of such treatment, comprising administering to such organism:
(i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)- lysine; and
(ii) an amount effective in the enhancement of pain relief of caffeine.
6. A method according to Claim 5 wherein the composition administered to a mammalian organism in need thereof comprises:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen-(S)-lysine substantially free of (R)-ibuprofen ; and
(ii) an amount effective in the enhancement of pain relief of caffeine.
7. A method of eliciting an onset enhanced and hastened response or the treatment of pain and inflammation and the enhancement of pain relief in a mammalian organism in need of such treatment, comprising administering to such organism:
(i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)- lysine; and
(ii) an amount effective in the enhancement of pain relief of caffeine.
8. A method according to Claim 7 wherein the composition administered to a mammalian organism in need thereof comprises:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen-(S)-lysine substantially free of (R)-ibuprofen ; and
(ii) an amount effective in the enhancement of pain relief of caffeine.
9. A method of reducing the side effects associated with the administration of a racemic ibuprofen/caffeine combination which comprises the administration of:
(i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)- lysine; and (ii) an amount effective in the enhancement of pain relief of caffeine.
10. A method according to Claim 9 wherein the composition administered to a mammalian organism in need thereof comprises:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen-(S)-lysine substantially free of (R)-ibuprofen; and
(ii) an amount effective in the enhancement of pain relief of caffeine.
11. A method of reducing the size and weight of a pharmaceutically effective amount of an ibuprofen/caffeine combination dosage form which comprises combining
(i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)- lysine; and
(ii) an amount effective in the enhancement of pain relief of caffeine.
12. A method according to Claim 11 wherein the composition administered to a mammalian organism in need thereof comprises:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen-(S)-lysine substantially free of (R)-ibuprofen ; and
(ii) an amount effective in the enhancement of pain relief of caffeine.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US95342392A | 1992-09-29 | 1992-09-29 | |
| US953423 | 1992-09-29 | ||
| PCT/US1993/008896 WO1994007471A1 (en) | 1992-09-29 | 1993-09-21 | Ibuprofen-caffeine combinations |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0663819A1 true EP0663819A1 (en) | 1995-07-26 |
| EP0663819A4 EP0663819A4 (en) | 1998-05-27 |
Family
ID=25493974
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP93922264A Withdrawn EP0663819A4 (en) | 1992-09-29 | 1993-09-21 | IBUPROFEN-COFFEINE COMBINATIONS. |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0663819A4 (en) |
| JP (1) | JPH08501796A (en) |
| AU (1) | AU5132893A (en) |
| CA (1) | CA2144152A1 (en) |
| MX (1) | MX9306005A (en) |
| WO (1) | WO1994007471A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2100037T3 (en) * | 1992-12-02 | 1997-06-01 | Knoll Ag | PROCESS TO PREPARE SUBSTANTIALLY PURE ENANTIOMERS OF PHENYLPROPIONIC ACIDS. |
| EP0717624A1 (en) * | 1993-09-07 | 1996-06-26 | The Procter & Gamble Company | Compositions containing an amino acid salt of propionic acid non-steroidal anti-inflammatory agents and caffeine |
| JPH0987174A (en) * | 1995-09-26 | 1997-03-31 | Kobayashi Pharmaceut Co Ltd | Analgesic and anti-inflammatory composition |
| US6251945B1 (en) * | 1999-01-14 | 2001-06-26 | Knoll Aktiengesellschaft | Pharmaceutical mixture comprising a combination of a profen and other active compounds |
| US20090238763A1 (en) * | 2006-07-09 | 2009-09-24 | Chongxi Yu | High penetration compositions and uses thereof |
| WO2016030092A1 (en) * | 2014-08-28 | 2016-03-03 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition for the treatment of acute tooth or jaw pain |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4420483A (en) * | 1982-07-22 | 1983-12-13 | Richardson-Vicks, Inc. | Analgesic and anti-inflammatory compositions comprising ibuprofen and methods of using same |
| WO1992005783A1 (en) * | 1990-09-28 | 1992-04-16 | Merck & Co., Inc. | Ibuprofen-antihistamine combinations |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4558051A (en) * | 1983-10-11 | 1985-12-10 | Richardson-Vicks, Inc. | Analgesic and anti-inflammatory compositions comprising xanthines and methods of using same |
| US4681897A (en) * | 1984-01-16 | 1987-07-21 | The Procter & Gamble Company | Pharmaceutical products providing enhanced analgesia |
-
1993
- 1993-09-21 CA CA002144152A patent/CA2144152A1/en not_active Abandoned
- 1993-09-21 AU AU51328/93A patent/AU5132893A/en not_active Abandoned
- 1993-09-21 WO PCT/US1993/008896 patent/WO1994007471A1/en not_active Application Discontinuation
- 1993-09-21 EP EP93922264A patent/EP0663819A4/en not_active Withdrawn
- 1993-09-21 JP JP6509126A patent/JPH08501796A/en active Pending
- 1993-09-28 MX MX9306005A patent/MX9306005A/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4420483A (en) * | 1982-07-22 | 1983-12-13 | Richardson-Vicks, Inc. | Analgesic and anti-inflammatory compositions comprising ibuprofen and methods of using same |
| WO1992005783A1 (en) * | 1990-09-28 | 1992-04-16 | Merck & Co., Inc. | Ibuprofen-antihistamine combinations |
Non-Patent Citations (1)
| Title |
|---|
| See also references of WO9407471A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0663819A4 (en) | 1998-05-27 |
| MX9306005A (en) | 1995-01-31 |
| WO1994007471A1 (en) | 1994-04-14 |
| JPH08501796A (en) | 1996-02-27 |
| AU5132893A (en) | 1994-04-26 |
| CA2144152A1 (en) | 1994-04-14 |
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