WO1994003209A1 - Combinaisons dexibuprofene/antacide/simethicone - Google Patents

Combinaisons dexibuprofene/antacide/simethicone Download PDF

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Publication number
WO1994003209A1
WO1994003209A1 PCT/US1993/006725 US9306725W WO9403209A1 WO 1994003209 A1 WO1994003209 A1 WO 1994003209A1 US 9306725 W US9306725 W US 9306725W WO 9403209 A1 WO9403209 A1 WO 9403209A1
Authority
WO
WIPO (PCT)
Prior art keywords
ibuprofen
treatment
antacid
simethicone
lysine
Prior art date
Application number
PCT/US1993/006725
Other languages
English (en)
Inventor
Robert T. Sims
William Slivka
Thomas N. Gates
Original Assignee
Merck & Co., Inc.
Mcneil-Ppc, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Merck & Co., Inc., Mcneil-Ppc, Inc. filed Critical Merck & Co., Inc.
Priority to AU46821/93A priority Critical patent/AU4682193A/en
Publication of WO1994003209A1 publication Critical patent/WO1994003209A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/12—Magnesium silicate

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 aspirin and acetaminophen.
  • Non-narcotic analgesics are 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. Recently, it has been found that a faster onset of pain relief and an enhanced analgesic response can be obtained by the utilization of the single enantiomer (S)-ibuprofen (also known as (+)-ibuprofen or dexibuprofen) rather than the racemic mixture of ibuprofen. See U.S. Patent 4,877,620.
  • Antacids are commonly prescribed to treat excess acid buildup in the stomach, duodenum or esophagus. Damage to the mucus lining surrounding these tissues may occur which also enables
  • antacids include aluminum hydroxide, calcium carbonate, magnesium hydroxide and sodium bicarbonate. Simethicone may optionally be used to treat flatulence.
  • the present invention provides both faster onset and enhanced relief of aches and pains associated with the head and stomach to provide broad and concurrent symptomatic relief.
  • compositions for use in the treatment of pain and inflammation and the treatment of mild stomach and esophagus disorders.
  • the composition comprises:
  • This invention is also directed to a method of treating pain and inflammation and concurrently treating indigestion, sour stomach, heartburn, and other gastrointestinal disorders in mammals,
  • This invention is further directed to a method of eliciting an onset hastened and enhanced response for the treatment of pain and inflammation and the treatment of gastrointestinal or esophagus disorders 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
  • 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
  • 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 magnesium, aluminum, iron, zinc, copper, nickel or cobalt.
  • (S)-ibuprofen further include the amino acid salts, particularly the basic amino acids such as lysine or arginine. Specifically included within the amino acid salts, particularly the basic amino acids such as lysine or arginine. Specifically included within the amino acid salts, particularly the basic amino acids such as lysine or arginine. Specifically included within the amino acid salts, particularly the basic amino acids such as lysine or arginine.
  • composition of the instant invention is
  • mammals or mammalian organism includes but is not limited to man, dog, cat, horse and cow.
  • 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 ,
  • the 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 5oC 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.
  • the (S,S) salt crystals acting as a seed, the
  • compositions of the present invention are useful in the rapid and enhanced treatment of pain and inflammation and in the treatment of various mild gastrointestinal disorders including indigestion, sour stomach, and heartburn and flatulence.
  • various mild gastrointestinal disorders including indigestion, sour stomach, and heartburn and flatulence.
  • (S)-ibuprofen-(S)-lysinate combined with an antacid such as aluminum hydroxide/magnesium hydroxide containing an anti-foaming agent such as simethicone is useful for the treatment of pain, inflammation, and the various gastrointestinal disorders such as indigestion, sour stomach, or heartburn and
  • the lysine salt of (S)-ibuprofen provides a faster onset of pain and inflammation relief and an enhanced degree of relief compared to racemic
  • 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 salt eliminates the need to excrete the (R)-ibuprofen or its metabolites. The absence of the (R)-enantiomer also reduces or eliminates the
  • composition that is substantially free of the (R) enantiomer.
  • Antacids are well known in the treatment of ulcers and other gastrointestinal disorders and may be used in combination with (S)-ibuprofen salts. Antacids used for the treatment of gastrointestinal pain and discomfort fall into four major groups:
  • Antacids are used to neutralize stomach or gastrointestinal acids and to relieve associated pain and discomfort. Antacids are well tolerated and thus advantageously may be used in the present invention in combination with
  • (S)-ibuprofen A rapid acting and faster onset analgesic such as (S)-ibuprofen-(S)-lysinate with a potent or mild antacid provides a combination which simaltaneously and selectively provides relief from headaches, pain, inflammation, and discomfort and injury to the stomach, esophagus, or duodenum from excess production of gastric acid.
  • (S)-ibuprofen reduces the weight to 400 to 500 mg, and provides for a more practical size tablet for an ibuprofen/antacid combination.
  • An effective amount of an (S)-ibuprofen salt for use in a unit dose composition of this invention may range from 50-800 mg (S)-ibuprofen salt.
  • the preferred amount of (S)-ibuprofen is about 100 to 400 mg.
  • (S)-ibuprofen-(S)-lysinate is determined based on the amount of (S)-ibuprofen contained therein.
  • the antacid employed herein may be selected from any of the commercially available or known antacids or combinations thereof such as aluminum hydroxide, calcium carbonate, magnesium hydroxide or sodium bicarbonate.
  • aluminum hydroxide/magnesium hydroxide is
  • the amount of the antacid used in the present invention in humans may range from 5 mg to 1500 mg depending upon the specific antacid employed.
  • the amount of antacid may vary from about 20 to 1,500 mg per tablet/capsule.
  • composition is administered in the form of an elixir, syrup or suspension
  • amount of the antacid may vary from about 5 mg to 150 mg per mL of
  • composition if in tablet or capsule form contains about 200-400 mg aluminum hydroxide, 200-400 mg magnesium hydroxide, and 1-40 mg of simethicone and is administered in combination with 100 to 400 mg of (S)-ibuprofen.
  • a composition in elixir, syrup or suspension form advantageously comprises aluminum hydroxide in the amount of about 40-80 mg per ml of liquid and simethicone in the amount of about 4 to 8 mg.
  • the combination claimed in the instant invention is advantageously administered orally.
  • foaming agents may also be added to the composition of the instant invention.
  • Foaming agents act to relieve symptoms associated with excess gas that often accompany gastrointestinal disturbance.
  • Foaming agents such as sodium alginate may be added to create a foam that acts as a physical barrier to block stomach acids from backing up into the esophagus thereby preventing heartburn.
  • the composition of the instant invention may further comprise an
  • anti-ulcerative agent such as sucralfate, misoprostol and the like.
  • inventions may also further comprise a pro-motility agent to improve gastro/esophageal peristalsis and relieve the symptoms of indigestion.
  • a pro-motility agent to improve gastro/esophageal peristalsis and relieve the symptoms of indigestion.
  • pro-motility agent is selected from metoclopramide hydrochloride, cisapride and the like.
  • the present composition may be administered in the form of tablets, caplets, gelcaps, capsules, elixirs, syrups, or suspensions.
  • oral for oral
  • the active ingredients may be admixed with a pharmaceutically acceptable diluent such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, and, in a liquid composition, ethyl
  • a pharmaceutically acceptable diluent such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, and, in a liquid composition, ethyl
  • Acceptable binders such as PVP, starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes, may also be admixed with the active
  • lubricants such as magnesium stearic acid talc, boric acid, sodium benzoate, sodium acetate and sodium chloride, and disintegrators such as docusate sodium, sodium starch glycolate or cross-linked PVP may also be included.
  • the active components may also be formulated in sustained release formulations. These formulations may be employed in oral, dermal, rectal or vaginal administrations. Such 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention se rapporte à des compositions pharmaceutiques destinées au traitement de douleurs et d'inflammations, et au soulagement des indigestions, les aigreurs et brûleurs d'estomac et autres troubles gastro-intestinaux chez les mammifères, y compris les humains. Ce traitement consiste à administrer des compositions contenant (i) une dose analgésique et anti-inflammatoire efficace d'un sel de (S)-ibuprofène sensiblement dépourvu de (R)-ibuprofène, ce sel étant choisi entre (S)-ibuprofène-(S)-lysine et (S)-ibuprofène-(R)-lysine; et (ii) une dose d'un antacide permettant de traiter efficacement les indigestions acides, les aigreurs et brûleurs d'estomac et autres troubles gastro-intestinaux, et (iii) de la diméthicone.
PCT/US1993/006725 1992-07-29 1993-07-19 Combinaisons dexibuprofene/antacide/simethicone WO1994003209A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU46821/93A AU4682193A (en) 1992-07-29 1993-07-19 Dexibuprofen/antacid/simethicone combinations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US92188092A 1992-07-29 1992-07-29
US921,880 1992-07-29

Publications (1)

Publication Number Publication Date
WO1994003209A1 true WO1994003209A1 (fr) 1994-02-17

Family

ID=25446110

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/006725 WO1994003209A1 (fr) 1992-07-29 1993-07-19 Combinaisons dexibuprofene/antacide/simethicone

Country Status (3)

Country Link
AU (1) AU4682193A (fr)
MX (1) MX9304563A (fr)
WO (1) WO1994003209A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995025545A1 (fr) * 1994-03-18 1995-09-28 Alfred Schmidt Utilisation de dimeticone en tant que systeme vehiculaire et/ou d'apport medicamenteux
WO1996010409A2 (fr) * 1994-10-03 1996-04-11 The Procter & Gamble Company Compositions liquides antiacides contenant du carbonate de calcium et eventuellement de la simethicone comme composes actifs et du phosphate de potassium et du bicarbonate de potassium comme tampon
DE19502789A1 (de) * 1995-01-28 1996-08-01 Dirk Krischenowski Arzneimittel
US5599969A (en) * 1992-12-02 1997-02-04 The Boots Company Plc Process of resolving phenylpropionic acids using α-methylbenzylamine
US5834004A (en) * 1994-03-18 1998-11-10 Upmeyer; Hans-Juergen Enteral composition comprising dimethicone and a photosensitizer and a method of delivery
US6028062A (en) * 1995-03-15 2000-02-22 Upmeyer; Hans-Juergen Use of dimeticone for the local antibacterial therapy and/or the prevention and therapy of helicobacter pylori (Hp) associated syndromes and infectious diseases
WO2005002566A1 (fr) * 2003-07-07 2005-01-13 Ahn-Gook Pharmaceutical Co., Ltd. Medicament antipyretique contenant du dexibuprofene comme principe actif
US7705050B2 (en) * 2000-02-11 2010-04-27 Janete Peloia Barroso Gandolfi, legal representative Amides, useful in the inhibition of IL-8-induced chemotaxis of neutrophils
US8288368B2 (en) 2001-02-27 2012-10-16 Dompé Pha.R.Ma S.P.A. Omega aminoalkylamides of R-2 aryl propionic acids as inhibitors of the chemotaxis of polymorphonucleate and mononucleate cells

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4994604A (en) * 1990-01-10 1991-02-19 Merck & Co., Inc. Formation and resolution of ibuprofen lysinate
EP0465235A1 (fr) * 1990-07-03 1992-01-08 McNEIL-PPC, INC. Compositions pharmaceutiques et méthodes pour calmer les symptomes gastrointestinaux induits par les anti-inflammatoires non-stéroidaux

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4994604A (en) * 1990-01-10 1991-02-19 Merck & Co., Inc. Formation and resolution of ibuprofen lysinate
EP0465235A1 (fr) * 1990-07-03 1992-01-08 McNEIL-PPC, INC. Compositions pharmaceutiques et méthodes pour calmer les symptomes gastrointestinaux induits par les anti-inflammatoires non-stéroidaux

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5599969A (en) * 1992-12-02 1997-02-04 The Boots Company Plc Process of resolving phenylpropionic acids using α-methylbenzylamine
WO1995025545A1 (fr) * 1994-03-18 1995-09-28 Alfred Schmidt Utilisation de dimeticone en tant que systeme vehiculaire et/ou d'apport medicamenteux
US5834004A (en) * 1994-03-18 1998-11-10 Upmeyer; Hans-Juergen Enteral composition comprising dimethicone and a photosensitizer and a method of delivery
WO1996010409A2 (fr) * 1994-10-03 1996-04-11 The Procter & Gamble Company Compositions liquides antiacides contenant du carbonate de calcium et eventuellement de la simethicone comme composes actifs et du phosphate de potassium et du bicarbonate de potassium comme tampon
WO1996010409A3 (fr) * 1994-10-03 1996-07-11 Procter & Gamble Compositions liquides antiacides contenant du carbonate de calcium et eventuellement de la simethicone comme composes actifs et du phosphate de potassium et du bicarbonate de potassium comme tampon
DE19502789A1 (de) * 1995-01-28 1996-08-01 Dirk Krischenowski Arzneimittel
US6028062A (en) * 1995-03-15 2000-02-22 Upmeyer; Hans-Juergen Use of dimeticone for the local antibacterial therapy and/or the prevention and therapy of helicobacter pylori (Hp) associated syndromes and infectious diseases
US7705050B2 (en) * 2000-02-11 2010-04-27 Janete Peloia Barroso Gandolfi, legal representative Amides, useful in the inhibition of IL-8-induced chemotaxis of neutrophils
US8288368B2 (en) 2001-02-27 2012-10-16 Dompé Pha.R.Ma S.P.A. Omega aminoalkylamides of R-2 aryl propionic acids as inhibitors of the chemotaxis of polymorphonucleate and mononucleate cells
US9493402B2 (en) 2001-02-27 2016-11-15 Dompé Farmaceutici S.P.A. Omega-aminoalkylamides of R-2-aryl-propionic acids as inhibitors of the chemotaxis of polymorphonucleate and mononucleate cells
WO2005002566A1 (fr) * 2003-07-07 2005-01-13 Ahn-Gook Pharmaceutical Co., Ltd. Medicament antipyretique contenant du dexibuprofene comme principe actif

Also Published As

Publication number Publication date
AU4682193A (en) 1994-03-03
MX9304563A (es) 1994-02-28

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