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
  • 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
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• compositions containing caffeine and S(+)-1buprofe ⁇ or S(+)-flurb1profen or S(+)-ketoprofen are included in compositions containing caffeine and S(+)-1buprofe ⁇ or S(+)-flurb1profen or S(+)-ketoprofen.
• the present invention relates to compositions and methods for providing improved analgesic and/or antl-Inflammatory effect by administering a safe and effective amount of a composition comprising an analgesic agent substantially free or of Its R(-) antipode selected from the group consisting of S(+)-1buprofen, S(+) flurbiprofen and
• the 20 response can be triggered by any of a number of causative factors, including certain bacteria, radiation, hypersensitivity to chemical agents, arthritis-like conditions, and the like.
• the inflammatory response is generally believed to be a primary defense mechanism in the body, but, unchecked, can become excessive and can result in
• non-steroidal anti-inflammatory, anti-pyretic and analgesic drugs especially the salicylates, which include aspirin and aspirin derivatives, to combat inflammation and attendant pain 1s accepted medical practice.
• salicylates which include aspirin and aspirin derivatives, to combat inflammation and attendant pain 1s accepted medical practice.
• the non-steroidals are commonly employed
• a great variety of drugs have been developed to reduce pain in man and other animals; some directed to eliminating pain at its source, and others directed to blocking the perception of pain by the brain.
• drugs that are designed to blo the sensation of pain, are the analgesics, which generally relie pain without causing unconsciousness.
• Analgesics can be furth classified into two main categories: opioid analgesics, includi morphine, codeine, levorphanol, and the morphine-like analgesi meperidine, and ethadone; and antipyretic analgesics, such aspirin, ibuprofen, phenacetin, acetaminophen, phenylbutazone, a indomethacin.
• opioid analgesics are weak analgesics, with much of their effect in the peripher nervous system, so that behavioral changes do not usually occu Generally, these analgesics relieve only pain originating from mus cles, joints, tendons and fasciae, and are ineffective against de visceral pain.
• opioid analgesics are quite effectiv against all types of pain, with broad-based action in the centra nervous system. Aside from potent analgesia, the opioids, also kno as narcotics, often produce effects on mood and other behaviora changes. Perhaps the most notable side effect of opioid analgesics i the fact that their repeated use is associated with tolerance, as wel as psychic and physical dependence.
• Ibuprofen or (+) 2-(p-isobutylphenyl)propionic acid, i well-known as a nonsteroidal anti-inflammatory drug having analgesi and antipyretic activity.
• Ibuprofen is currently marketed prescription in the United States generically, as well as und tradenames such as Motrin ® , which is available in 400, 600 and 800 tablets for oral administration.
• Ibuprofen has recently also beco available in this country in non-prescription strength (200 mg) und a variety of tradenames, including Advil ® and Nuprirr*, as well as i generic form.
• For the treatment of mild to moderate pain 400 every 4 to 6 hours, not to exceed 3200 mg daily, is generall recommended for Motrin*.
• the lower dose over-the-counter products a generally recommended for minor aches and pains, to be used orally the 200 to 400 mg level, every 4 to 6 hours, not to exceed 1200 daily unless directed by a physician.
• Flurbiprofen or (+) [l,l'-biphenyl]-4-acetic acid, 2-fluoro-alphamethyl , is also well-known as a nonsteroidal anti- inflammatory drug having analgesic and antipyretic activity. Flurbiprofen is currently marketed by prescription in the United States under the tradena e Ansaid ® , which 1s available in 50 and 100 mg tablets for oral administration.
• Ketoprofen or (+) 2-(3-benzoylphenyl)propionic acid
• Orudis* another well-known nonsteroidal anti-inflammatory drug having analgesic and antipyretic activity
• Orudis* 1s available in 25, 50 and 75 mg capsules for oral administration.
• 25-50 mg every 6 to 8 hours, not to exceed 300 g daily, is generally recommended for 0rud1s # .
• Physician 's Desk Reference 46th edition, 1992, publisher Edward R. Barnhart, Medical Economics Company, Inc., Oradell, N.J. 07649, pp. 2351-54, 2319-20 and 2488-90, the disclosure of which is incorporated herein.
• these analgesic agents are racemic mixtures. It 1s only the racemic mixture of these agents which have in fact ever been marketed. There have, however, been some studies of the individual S(+) and R(-) enantiomer of ibuprofen. In the body, some of the R(-) enantiomer is converted to the S(+) enantiomer, which is the pharmacologically active form of ibuprofen.
• the present invention relates to a method of eliciting a sus ⁇ tained, enhanced analgesic response in a human or lower animal in need of such treatment, comprising administering to such human or lower animal a safe and effective amount of a composition comprising: a. an analgesically and anti-inflammatory effective amount of an analgesic agent substantially free or of its R(-) antipode selected from the group consisting of S(+) ibuprofen, S(+) flurbiprofen and S(+) ketoprofen, pharmaceutically-acceptable salt thereof, and mixtures thereof; and b. an amount of caffeine sufficient to hasten the onset of and enhance the analgesic response.
• the present invention relates to a method of eliciting a sustain ⁇ ed, enhanced analgesic response in a human or lower animal in need of such treatment, comprising administering to such human or lower animal a safe and effective amount of a composition comprising an analgesically and anti-inflammatory effective amount of an analgesic agent substantially free or of its R(-) antipode selected from the group consisting of S(+) ibuprofen, S(+) flurbiprofen and S(+) ketoprofen, pharmaceutically-acceptable salt thereof, and mixtures thereof, and an amount of caffeine sufficient to hasten the onset of and enhance the analgesic response.
• a composition comprising an analgesically and anti-inflammatory effective amount of an analgesic agent substantially free or of its R(-) antipode selected from the group consisting of S(+) ibuprofen, S(+) flurbiprofen and S(+) ketoprofen, pharmaceutically-acceptable salt thereof, and mixtures
• S(+) as applied to the analgesic agents herein is intended to encompass not only the dextrorotatory or S(+) isomer of these agents but also any pharmaceutically acceptable, analgesically effective salt thereof.
• the expression “substantially free of the R(-) antlpopde” as used in conjunction with the term “S(+)” means that the S(+) enantiomer is sufficiently free of its R(-) antipode to exert the desired onset-hastened and enhanced analgesic effect. Practically speaking, this means that the active ingredient should contain at least 90% by weight of the S(+) enantiomer and 10% or less weight R(-) enantiomer.
• the weight ratio of S(+) enantiomer to R(-) enantiomer is greater than 20:1, more preferabl greater than 97:3.
• the S(+) enantiomer is 99 or more % by weight free of R(-) enantiomer, i.e.., the weight ratio of S to R is approximately equal to or greater than 99:1.
• the safe and effective amount of S(+) ibuprofen used in the compositions of the present invention generally ranges from about 50 to about 800 mg, preferably from about 50 to about 400 mg, more preferably from about 50 to about 200 mg and most preferably from about 50 to about 100 mg.
• the safe and effective amount of S(+) flurbiprofen used in the compositions of the present invention generally ranges from about 12.5 to about 300 mg, preferably from about 12.5 to about 200 mg, more preferably from about 12.5 to about 100 mg and most preferably from about 12.5 to about 50 mg.
• the safe and effective amount of S(+) ketoprofen used in the compositions of the present invention generally ranges from about 5 to about 100 mg, preferably from about 5 to about 75 mg, more preferably from about 5 to about 50 mg and most preferably from about 5 to about 25 mg.
• the amount of caffeine used in the compositions of the present invention generally ranges from about 20 to about 200 mg, preferably from about 32 to about 200 mg, more preferably from about 32 to about 150 mg and most preferably from about 32 to about 100 mg.
• salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from nonorganic bases include sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, zinc, manganous, aluminum, ferric, manganic salts and the like.
• Salts derived from pharmaceutically acceptable organic non- toxic bases include salts of primary, secondary, tertiary and quater ⁇ nary amines, substituted amines including naturally occurring substi ⁇ tuted amines, cyclic amines and basic ion exchange resins, such as triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylamino- ethanol, lysine, arginine, histidine, caffeine, procaine, N-ethylpip- eridine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglycamine, theobro ine, purines, piperazine, piperidine, poly- amine resins and the like.
• basic ion exchange resins such as triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylamino- ethanol, lysine, arginine, his
• the pharmaceutical compositions of the presen invention comprise the S(+) enantiomer and caffeine in a ratio of S(+) enantiomerrcaffeine of from about 10:1 to about 1:10, preferably fro about 5:1 to about 1:5 and most preferably from about 2:1 to about 1:5.
• Solid oral dosage forms preferably contain from about 5% to about 95%, more preferably from about 10% to about 95%, and most preferably from about 25% to about 95% of the active compo- nent.
• Liquid oral dosage forms preferably contain from about 1% to about 50% and more preferably from about 1% to about 25% and most preferably from about 3% to about 10% of the active component.
• Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, preservatives and flow-inducing agents.
• Liquid oral dosage forms include aqueous and nonaqueous solu ⁇ tions, emulsions, suspensions, and solutions and/or suspensions reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, taste-masking agents, coloring agents, and flavoring agents.
• suitable solvents preservatives, emulsifying agents, suspending agents, diluents, sweeteners, taste-masking agents, coloring agents, and flavoring agents.
• Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms are described in U.S. Patent 3,903,297, Robert, issued Sep- tember 2, 1975, incorporated by reference herein. Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern Pharmaceutics. Vol. 7.
• aqueous-based orally acceptable pharmaceutical carrier is one wherein the entire or predominant solvent content 1s water.
• Typical carriers include simple aqueous solutions, syrups, dispersions and suspensions, and aqueous based emulsions such as the oil-in-water type.
• the most preferred carrier is a suspension of the pharma ⁇ ceutical composition in an aqueous vehicle containing a suitable suspending agent.
• suitable suspending agents include Avicel RC-591 (a microcrystalline cellulose/sodium carboxy ⁇ ethyl cellulose mixture available from FMC), guar gum and the like.
• the amount of water in the compositions of this invention can vary over quite a wide range depending upon the total weight and volume of the active component and other optional non-active ingredients, the total water content, based on the weight of the final composition, will generally range from 2 about 20 to about 75%, and, preferably, from about 20 to about 40%, by weight/volume.
• typical liquid formulations preferably contain a co-solvent, for example, propylene glycol, glycerin, sorbitol solution and the like, to assist solubilization and incorporation of water-insoluble ingredients, such as flavoring oils and the like into the composition.
• the compositions of this invention preferably contain from about 5 to about 25 volume/volume percent and, most preferably, from about 10 to about 20 volume/ volume percent, of the co-solvent.
• compositions of this invention may optionally contain one or more other known therapeutic agents, particularly those commonly utilized in cough/cold preparations, such as, for example, a cough suppressant such as dextromethorphan, chlophedianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, fominoben, their pharmaceutically-acceptable salts; an expectorant or mucolytic such as glyceryl guaiacolate, terpin, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, their pharmaceutically acceptable salts; and an antihista ine such as chlorpheniramine bromphenira ine, dexchlorpheniramine, dexbrompheniramine, triprolidine, doxylamine, tripelennaraine, cyproheptadine, carbinoxamine, bromodiphenhydramine, phenindamine
• Patent 4,783,465 to Sunshine et al . issued November 8, 1988
• U.S. Patent 4,619,934 to Sunshine et al. issued October 28, 1986
• broncho- dilators such as theophylline and albuterol
• other analgesic agents such as acetaminophen and aspirin.
• a highly preferred optional component is caffeine, which is preferably present at a level of from about 10% to about 50%.
• ingredients well known to the pharmacist's art may also be included in amounts generally known for these ingredients, for example, natural or artificial sweeteners, flavoring agents, colorants and the like to provide a palatable and pleasant looking final prod ⁇ uct, antioxidants, for example, butylated hydroxy anisole or butylated hydroxy toluene, and preservatives, for example, methyl or propyl paraben or sodium benzoate, to prolong and enhance shelf life.
• the amount of the pharmaceutical composition administered depends upon the percent of active ingredients within its formula, which is a function of the amount of the ibuprofen and caffeine and any optional components such as a decongestant, expectorant and/or antihistamine required per dose, stability, release characteristics and other pharmaceutical parameters.
• each individual dosage of the pharmaceutical compositions of the present invention range from about 1 mg/kg to about 25 mg/kg, preferably from about 2 mg/kg to about 15 mg/kg and most preferably from about 3 mg/kg to about 10 mg/kg.
• Typical unit dosage forms for oral administration generally comprise from about 50 mg to about 2000 mg, preferably from about 100 mg to about 600 mg and most preferably from about 100 mg to about 400 mg of the ibuprofen and from about 25 mg to about 200 mg, preferably from about 50 mg to about 200 mg and most preferably from about 50 mg to about 100 mg of caffeine. While dosages higher than the foregoing are effective to provide analgesic relief, care must be taken, as with any drug, in some individuals to prevent adverse side effects.
• a hard gelatin capsule composition for oral administration is prepared by combining the following ingredients:
• Triturate active ingredients and q.s. with lactose to selected capsule size Triturate active ingredients and q.s. with lactose to selected capsule size.
• Administration of 1 or 2 of the above capsules to a human in need of treatment provides improved analgesic and/or anti-inflammatory effect.
• a hard gelatin capsule composition for oral administration is prepared by combining the following Ingredients:
• Triturate active ingredients and q.s. with lactose to selected capsule size Triturate active ingredients and q.s. with lactose to selected capsule size.
• a liquid composition for oral administration is prepared by combining the following ingredients:
• the purified water (approximately 10% of the final batch volume) is poured into a batch container equipped with a lightnin' mixer.
• the sodium citrate, citric acid and Caffeine are added sequentially and dissolved with agitation.
• the glycerin and liquid sugar are then colorants added.
• the colorants are added to purified water (approximately 0.5% of the final batch volume).
• This colorant solution is then added to the first batch container.
• the ibuprofen is added to the alcohol while stir ⁇ ring.
• the propylene glycol and flavors are added to this alcohol premix and the resulting mixture is stirred until homogeneous and then added to the first container.
• the remaining purified water is added to the resulting mixture and stirred.
• a liquid composition for oral administration is prepared by combining the following ingredients:
• the purified water (approximately 10% of the final batch volume) is poured into a batch container equipped with a lightnin' mixer.
• the sodium citrate, citric acid, pseudoephedrine HCL and chlorpheniramine maleate are added sequentially and dissolved with agitation.
• the glycerin and liquid sugar are then added.
• the colorants are added to purified water (approximately 0.5% of the final batch volume). This colorant solution is then added to the first batch container.
• the ibuprofen is added to the alcohol while stirring.
• the propylene glycol and flavors are added to this alcohol premix and the resulting mixture is stirred until homogeneous and then added to the first container.
• the remaining purified water is added to the resulting mixture and stirred.
• a liquid composition for oral administration is prepared by combining the following ingredients:
• the purified water (approximately 10% of the final batch volume) is poured into a batch container equipped with a lightnin' mixer.
• the sodium citrate, citric acid, pseudoephedrine HC1 and chlorpheniramine maleate are added sequentially and dissolved with agitation.
• the glycerin and liquid sugar are then added.
• the colorants are added to purified water (approximately 0.5% of the final batch volume). This colorant solution is then added to the first batch container.
• the ibuprofen and dextro ⁇ methorphan HBr are added sequentially to the alcohol while stirring.
• the propylene glycol and flavors are added to this alcohol premix and the resulting mixture is stirred until homogeneous and then added to the first container. The remaining purified water is added to the resulting mixture and stirred.

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• 1993
  • 1993-12-10 AU AU58993/94A patent/AU672279B2/en not_active Ceased
  • 1993-12-10 JP JP6515225A patent/JPH08504818A/ja active Pending
  • 1993-12-10 EP EP94905364A patent/EP0674517A1/de not_active Withdrawn
  • 1993-12-10 BR BR9307697A patent/BR9307697A/pt not_active Application Discontinuation
  • 1993-12-10 CA CA002149317A patent/CA2149317A1/en not_active Abandoned
  • 1993-12-10 WO PCT/US1993/012040 patent/WO1994014449A1/en not_active Application Discontinuation
  • 1993-12-17 PE PE1993233164A patent/PE56194A1/es not_active Application Discontinuation
  • 1993-12-21 CN CN93119937A patent/CN1094615A/zh active Pending
• 1994
  • 1994-01-03 MX MX9400038A patent/MX9400038A/es unknown

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