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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• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Pain & Pain Management (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Epidemiology (AREA)
• Rheumatology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1993
  • 1993-09-21 AU AU51328/93A patent/AU5132893A/en not_active Abandoned
  • 1993-09-21 JP JP6509126A patent/JPH08501796A/ja active Pending
  • 1993-09-21 CA CA002144152A patent/CA2144152A1/en not_active Abandoned
  • 1993-09-21 EP EP93922264A patent/EP0663819A4/de not_active Withdrawn
  • 1993-09-21 WO PCT/US1993/008896 patent/WO1994007471A1/en not_active Application Discontinuation
  • 1993-09-28 MX MX9306005A patent/MX9306005A/es unknown

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