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EP0550668A1 - Ibuprofen-antihistamine combinations - Google Patents

Ibuprofen-antihistamine combinations

Info

Publication number
EP0550668A1
EP0550668A1 EP91918783A EP91918783A EP0550668A1 EP 0550668 A1 EP0550668 A1 EP 0550668A1 EP 91918783 A EP91918783 A EP 91918783A EP 91918783 A EP91918783 A EP 91918783A EP 0550668 A1 EP0550668 A1 EP 0550668A1
Authority
EP
European Patent Office
Prior art keywords
antihistamine
ibuprofen
substantially free
composition
stereoisomers
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Withdrawn
Application number
EP91918783A
Other languages
German (de)
French (fr)
Other versions
EP0550668A4 (en
Inventor
Thomas N. Gates
Robert T. Sims
King Chiu Kwan
William Slivka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kenvue Brands LLC
Merck and Co Inc
Original Assignee
McNeil PPC Inc
Merck and Co 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 McNeil PPC Inc, Merck and Co Inc filed Critical McNeil PPC Inc
Publication of EP0550668A1 publication Critical patent/EP0550668A1/en
Publication of EP0550668A4 publication Critical patent/EP0550668A4/en
Withdrawn legal-status Critical Current

Links

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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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

  • NSAID NSAID
  • Ibuprofen (2-(4-isobutylphenyl)propionic acid) is a well known and commonly employed NSAID.
  • S-ibuprofen single enantiomer
  • racemic ibuprofen see for example U.S. Patent 4,877,620.
  • Antihistamines useful for the treatment of cold and flu symptoms, may be categorized into conventional and non-sedating antihistamines.
  • the conventional antihistamines exhibit an anticholinergic effect which may be advantageous to the cold/allergy sufferer.
  • the conventional antihistamine may also have an advantage for the subject who wishes to induce drowsiness.
  • Non-sedating antihistamines have significant benefits to the cold/allergy sufferer who needs to maintain alertness.
  • compositions for use in the treatment of pain and inflammation and the relief of allergy and cold symptoms in a mammalian organism comprising:
  • This invention is also directed to a method of treating pain and inflammation and the relief of allergy and cold symptoms in a mammalian organism in need of such treatment, comprising administering to such organism:
  • This invention is also directed to a method of eliciting an onset enhanced and enhanced response for the treatment of pain and inflammation and the relief of allergy and cold symptoms in a mammalian organism in need of such treatment, comprising administering to such organism:
  • Substantially free of (R)-ibuprofen should be taken to mean that the ratio of (S)-ibuprofen to (R)-ibuprofen is at least 90:10.
  • Substantially free with respect to an antihistamine stereoisomer should be taken to mean that the ratio of that stereoisomer to all other stereoisomers of the antihistamine is at least 90:10.
  • Salts of (S)-ibuprofen include salts with alkali metals, such as sodium or potassium, salts with alkaline earth metals, such as calcium, or salts with other metals such as magnesium, aluminum, iron, zinc, copper, nickel or cobalt.
  • Salts of (S)-ibuprofen further include the amino acid salts, particularly the basic amino acids such as lysine or arginine. Specifically included within the above composition is (S)-ibuprofen- (S)-lysine and (S)-ibuprofen-(R)-lysine.
  • (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.
  • compositions of the present invention are useful in the treatment of pain and inflammation and the symptoms such as runny nose, sneezing, sniffles and itchy watering eyes that accompany allergies and colds.
  • (S)-ibuprofen provides a faster onset of pain relief and an enhanced degree of relief compared to racemic ibuprofen. These benefits are increased in an (S)-ibuprofen/antihistamine combination as the antihistamine potentiates the action of (S)-ibuprofen. This has not heretofore been observed because the art has not proposed the combination of the (S)-ibuprofen enantiomer, absent (R)-ibuprofen, with an antihistamine. The presence of the (R)-ibuprofen may blur the potentiated effect.
  • the absence of (R)-ibuprofen provides significant benefits particularly to the subject in the weakened state of a cold or flu condition.
  • the allergic contraindications sometimes associated with ibuprofen administration, and which may be particularly detrimental to the cold/allergy sufferer, are absent or reduced in a composition wherein the (R)-ibuprofen is absent.
  • the subject will no longer need to divert metabolic energy to the inversion of the (R)-enantiomer or the removal of this enantiomer.
  • the absence of inversion reduces or eliminates the formation and incorporation into fatty tissue of hybrid-ibuprofen containing triglycerides .
  • the renal burden and renal toxicities sometimes associated with ibuprofen therapy are reduced or absent in a substantially (R)-ibuprofen free composition.
  • the absence of the inactive substances in the present composition avoids undesirable toxic interactions and clearly avoids the metabolism necessary to remove the nonactive entity.
  • the absence of inactive enantiomers, particularly (R)-ibuprofen provides for significant size and weight advantages in a 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 reduces the weight to 650 to 800 mg, and provides for a more practical size tablet for an ibuprofen/antihistamine combination.
  • EPO publication 348,683 discloses that the combination of a piperidinoalkanol, such as terfenadine, with ibuprofen results in_ a hardened mixture rather than a flowable powder. This was attributed to an incompatability between the substances and the mixture to further processing to form a pharmaceutical dosage having acceptable bioavailability characteristics.
  • the present invention in employing a salt of ibuprofen, particularly the lysine or arginine salt, overcomes the incompatability problem and results in a pharmaceutically acceptable dosage formulation.
  • An effective amount of (S)-ibuprofen, or a salt thereof, for use in an unit dose composition of this invention may range from 50 to 800 mg (S)-ibu- profen.
  • 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.
  • the antihistamine employed herein is selected from the conventional and the non-sedating types.
  • the conventional antihistamines competitively antagonize those pharmacological effects of histamine which are mediated through activation of histamine H 2 -receptor sites on effector cells.
  • the conventional antihistamines also exhibit an anticholinergic (drying) effect.
  • the conventional antihistamine is selected from: chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbrompheniramine, triprolidine, hydroxyzine, doxylamine, tripelennamine, cyproheptadine, carbinoxamine, bromodiphenhydramine, phenindiamine, pyrilamine, azatadine or diphenhydramine or a pharmaceutically acceptable salt
  • the non-sedating antihistamine is selected from: acrivastine, A ⁇ R-11325, astemizole, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine or terfenadine.
  • any diastereomers and/or enantiomers of each antihistamine are any diastereomers and/or enantiomers of each antihistamine. Where a particular therapeutically active stereoisomer is not commercially available it may be prepared following standard resolution chemistry from the available racemic mixture.
  • the amount of the antihistamine useful in the practice of the present invention may vary from about 1 mg to 100 mg depending on the specific antihistamine.
  • compositions may be administered in the form of tablets, capsules, elixirs, syrups or a suspension.
  • active components 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 alcohol.
  • 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 components.
  • lubricants such as magnesium stearic acid talc, and disintegrators such as starch, methylcellulose, agar, bentonite and guar gum and super disintegrators such as docusate sodium, sodium starch glycollate or cross linked PVP may also be included.
  • disintegrators such as starch, methylcellulose, agar, bentonite and guar gum and super disintegrators such as docusate sodium, sodium starch glycollate 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 forms also include layered formulations which provide for distinct release ratio and thus may be more beneficial in allowing for short and long term relief.
  • sustained release forms also include layered formulations which provide for distinct release ratio and thus may be more beneficial in allowing for short and long term relief.

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

Abstract

Cette invention se rapporte à des compositions pharmaceutiques devant être utilisées pour le traitement de douleurs et d'inflammations et le soulagement de symptômes allergiques et grippaux dans un organisme mammifère, ladite composition comprenant: (i) une quantité de (S)-ibuprofène, ou d'un sel de celui-ci, pratiquement dépourvue de (R)-ibuprofène et produisant un effet analgésique et anti-inflammatoire; et (ii) une quantité d'au moins l'un des antihistamines ou d'un stéréo-isomère thérapeutiquement actif de celui-ci, pratiquement dépourvue de ses autres stéréo-isomères et produisant un effet anti-histaminique.This invention relates to pharmaceutical compositions for use in the treatment of pain and inflammation and the relief of allergic and influenza-like symptoms in a mammalian organism, said composition comprising: (i) an amount of (S) -ibuprofen, or a salt thereof, practically devoid of (R) -ibuprofen and producing an analgesic and anti-inflammatory effect; and (ii) an amount of at least one of the antihistamines or of a therapeutically active stereoisomer thereof, practically devoid of its other stereoisomers and producing an antihistamine effect.

Description

TITLE OF THE INVENTION IBUPROFEN-ANTIHISTAMINE COMBINATIONS
BACKGROUND OF THE INVENTION The non-steroidal anti-inflammatory drugs
(NSAID) have been utilized in the treatment of pain/ inflammation and have been disclosed as useful in the treatment, management and mitigation of cold symptoms and the pain associated therewith. 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 in comparison to racemic ibuprofen, (see for example U.S. Patent 4,877,620).
Antihistamines, useful for the treatment of cold and flu symptoms, may be categorized into conventional and non-sedating antihistamines. The conventional antihistamines exhibit an anticholinergic effect which may be advantageous to the cold/allergy sufferer. The conventional antihistamine may also have an advantage for the subject who wishes to induce drowsiness. Non-sedating antihistamines have significant benefits to the cold/allergy sufferer who needs to maintain alertness.
Combinations of ibuprofen with antihistamines have been disclosed; however, despite the fact that the allergy and cold/pain sufferer is in need of quick and enhanced relief there has been no consideration given to the employment of (S)-ibuprofen, and more particularly a lysine or arginine salt thereof, in combination with an antihistamine for the treatment of pain and the relief of allergy and cold symptoms.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to pharmaceutical compositions for use in the treatment of pain and inflammation and the relief of allergy and cold symptoms in a mammalian organism, said composition comprising:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen; and
(ii) an antihistaminically effective amount of at least one of the antihistamines or a therapeutically active stereoisomer thereof substantially free of its other stereoisomers.
This invention is also directed to a method of treating pain and inflammation and the relief of allergy and cold symptoms in a mammalian organism in need of such treatment, comprising administering to such organism:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen; and
(ii) an antihistaminically effective amount of at least one of the antihistamines or a therapeutically active stereoisomer thereof substantially free of its other stereoisomers.
This invention is also directed to a method of eliciting an onset enhanced and enhanced response for the treatment of pain and inflammation and the relief of allergy and cold symptoms in a mammalian organism in need of such treatment, comprising administering to such organism:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen; and
(ii) an antihistaminically effective amount of at least one of the antihistamines or a therapeutically active stereoisomer thereof substantially free of its other stereoisomers.
Substantially free of (R)-ibuprofen should be taken to mean that the ratio of (S)-ibuprofen to (R)-ibuprofen is at least 90:10. Substantially free with respect to an antihistamine stereoisomer should be taken to mean that the ratio of that stereoisomer to all other stereoisomers of the antihistamine is at least 90:10.
Salts of (S)-ibuprofen include salts with alkali metals, such as sodium or potassium, salts with alkaline earth metals, such as calcium, or salts with other metals such as magnesium, aluminum, iron, zinc, copper, nickel or cobalt.
Salts of (S)-ibuprofen further include the amino acid salts, particularly the basic amino acids such as lysine or arginine. Specifically included within the above composition is (S)-ibuprofen- (S)-lysine and (S)-ibuprofen-(R)-lysine.
(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.
The pharmaceutical compositions of the present invention are useful in the treatment of pain and inflammation and the symptoms such as runny nose, sneezing, sniffles and itchy watering eyes that accompany allergies and colds.
The utilization of (S)-ibuprofen in an analgesic/antihistamine combination offers significant advantages over the combination of racemic ibuprofen with an antihistamine which has already been shown to have advantages over aspirin/acetaminophen combinations (see for example U.S. Patent 4,871,733).
(S)-ibuprofen provides a faster onset of pain relief and an enhanced degree of relief compared to racemic ibuprofen. These benefits are increased in an (S)-ibuprofen/antihistamine combination as the antihistamine potentiates the action of (S)-ibuprofen. This has not heretofore been observed because the art has not proposed the combination of the (S)-ibuprofen enantiomer, absent (R)-ibuprofen, with an antihistamine. The presence of the (R)-ibuprofen may blur the potentiated effect.
Furthermore, the absence of (R)-ibuprofen provides significant benefits particularly to the subject in the weakened state of a cold or flu condition. The allergic contraindications sometimes associated with ibuprofen administration, and which may be particularly detrimental to the cold/allergy sufferer, are absent or reduced in a composition wherein the (R)-ibuprofen is absent. Furthermore, the subject will no longer need to divert metabolic energy to the inversion of the (R)-enantiomer or the removal of this enantiomer. The absence of inversion reduces or eliminates the formation and incorporation into fatty tissue of hybrid-ibuprofen containing triglycerides . The renal burden and renal toxicities sometimes associated with ibuprofen therapy are reduced or absent in a substantially (R)-ibuprofen free composition.
Where only a single stereoisomer of the antihistamine is active (therapeutically active stereoisomer), the absence of the inactive substances in the present composition avoids undesirable toxic interactions and clearly avoids the metabolism necessary to remove the nonactive entity. The absence of inactive enantiomers, particularly (R)-ibuprofen provides for significant size and weight advantages in a 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 reduces the weight to 650 to 800 mg, and provides for a more practical size tablet for an ibuprofen/antihistamine combination.
EPO publication 348,683 discloses that the combination of a piperidinoalkanol, such as terfenadine, with ibuprofen results in_ a hardened mixture rather than a flowable powder. This was attributed to an incompatability between the substances and the mixture to further processing to form a pharmaceutical dosage having acceptable bioavailability characteristics. The present invention in employing a salt of ibuprofen, particularly the lysine or arginine salt, overcomes the incompatability problem and results in a pharmaceutically acceptable dosage formulation.
An effective amount of (S)-ibuprofen, or a salt thereof, for use in an unit dose composition of this invention may range from 50 to 800 mg (S)-ibu- profen. 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.
The antihistamine employed herein is selected from the conventional and the non-sedating types. The conventional antihistamines competitively antagonize those pharmacological effects of histamine which are mediated through activation of histamine H2-receptor sites on effector cells. The conventional antihistamines also exhibit an anticholinergic (drying) effect. The conventional antihistamine is selected from: chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbrompheniramine, triprolidine, hydroxyzine, doxylamine, tripelennamine, cyproheptadine, carbinoxamine, bromodiphenhydramine, phenindiamine, pyrilamine, azatadine or diphenhydramine or a pharmaceutically acceptable salt
The non-sedating antihistamine is selected from: acrivastine, AΞR-11325, astemizole, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine or terfenadine.
Included within this invention are any diastereomers and/or enantiomers of each antihistamine. Where a particular therapeutically active stereoisomer is not commercially available it may be prepared following standard resolution chemistry from the available racemic mixture.
The amount of the antihistamine useful in the practice of the present invention may vary from about 1 mg to 100 mg depending on the specific antihistamine.
The present compositions may be administered in the form of tablets, capsules, elixirs, syrups or a suspension. For oral administration the active components 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 alcohol. 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 components. Where necessary lubricants such as magnesium stearic acid talc, and disintegrators such as starch, methylcellulose, agar, bentonite and guar gum and super disintegrators such as docusate sodium, sodium starch glycollate 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 forms also include layered formulations which provide for distinct release ratio and thus may be more beneficial in allowing for short and long term relief. The following examples illustrate the compositions of the present invention and as such are not to be considered as limiting the invention set forth in the claims appended hereto.
EXAMPLE 1
(S)-ibuprofen. Conventional Antihistamine Tablet
(S)-ibuprofen-(S)-lys Dexchlorpheniramine m
PVP
Avicel PH101
Magnesium Stearate
(S)-ibuprofen. Conventional Antihistamine Sustained Release
(S)-ibuprofen 400 mg
Dexchlorpheniramine maleate 10 mg
PVP 30 mg
Avicel PH101 80 mg
Magnesium Stearate 8 mg
Methocel E10MCR 66 mg
Methocel K100MLV 200 mg
EXAMPLE 3
(S)-ibuprofen-(S)-lysine/conventional antihistamine Solution
(S)-ibuprofen-(S)-lysine 342 mg
Dexchlorpheniramine maleate 2 mg q.s . syrup 5 ml EXAMPLE 4
(S)-ibuprofen. Non-Sedating Antihistamine Tablet
(S)-ibuprofen-(S)-lysine 342 mg terfenadine 60 mg
PVP 15 mg
Avicel PH101 40 mg
Magnesium Stearate 4 mg
EXAMPLE 5
- - n tih s a s a n d
(S)-ibuprofen-(S)-lysine 342 mg terfenadine 10 mg q.s . syrup 5 ml

Claims

WHAT IS CLAIMED IS:
1. A pharmaceutical composition for use in the treatment of pain and inflammation and the relief of allergy and cold symptoms in a mammalian organism and adapted for unit dosage oral administration, said composition comprising:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen; and
(ii) an antihistiminically effective amount of at least one of the antihistamines or a therapeutically active stereoisomer thereof substantially free of its other stereoisomers.
2. A composition of Claim 1 where the ibuprofen is present as the salt (S)-ibuprofen- (S)-lysine, or (S)-ibuprofen-(R)-lysine.
3. A composition of Claim 1 comprising at least 50 mg of (S)-ibuprofen.
4. A composition of Claim 1 wherein the antihistamine is a conventional antihistamine.
5. A composition of Claim 4 wherein the conventional antihistamine is selected from: chlorpheniramine, brompheniramine, dexchlor¬ pheniramine, dexbrompheniramine, triprolidine, doxylamine, tripelennamine, cyproheptadine, carbinoxamine, bromodiphenhydramine, phenindiamine, pyrilamine, azatadine, diphenhydramine, or a therapeutically active stereoisomer thereof substantially free of its other stereoisomers, or a pharmaceutically acceptable salt.
6. A composition of Claim 4 wherein the conventional antihistamine is selected from chlorpheniramine, brompheniramine, diphenhydramine, or a therapeutically active stereoisomer thereof substantially free of its other stereoisomers, or a pharmaceutically acceptable salt.
7. A composition of Claim 1 wherein the antihistamine is a non-sedating antihistamine.
8. A composition of Claim 7 wherein the non-sedating antihistamine is selected from: acrivastine, AHR-11325, astemizole, azelastine, cetirizine, ebastine, ketotifen, lodoxa ide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine or terfenadine, or a therapeutically active stereoisomer thereof substantially free of its other stereoisomers, or a pharmaceutically acceptable salt.
9. A method of treating pain and inflammation and the relief of allergy and cold symptoms in a mammalian organism in need of such treatment, comprising administering to such organism:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuρrofen, or a salt thereof, substantially free of (R)-ibuprofen; (ii) an antihistamically effective amount of at least one of the antihistamines or a therapeutically active stereoisomer thereof substantially free of its other stereoisomers.
10.A method of Claim 9 wherein the antihistamine is a conventional antihistamine.
11. A method of Claim 9 wherein the antihistamine is a non-sedating antihistamine.
12. A method of eliciting an onset hastened and enhanced response for the treatment of pain and inflammation and the relief of allergy and cold symptoms in a mammalian, organism in need of such treatment, comprising administering to such organism.
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen; and
(ii) an antihistamically effective amount of at least one of the antihistamines or a therapeutically active stereoisomer thereof substantially free of its other stereoisomers.
13. A method of Claim 12 wherein the antihistamine is a conventional antihistamine.
14. A method of Claim 12 wherein the antihistamine is a non-sedating antihistamine.
15. A method of reducing the side effects associated with the administration of an ibuprofen/antihistamine combination which comprises the aministration of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen, and at least one of the anthistamines or a therapeutically active stereoisomer thereof substantially free of its other stereoisomers.
16. A method of Claim 15 wherein the antihistamine is a conventional antihistamine.
17. A method of Claim 15 wherein the antihistamine is a non-sedating antihistamine.
18. A method of reducing the size and weight of an ibuprofen/antihistamine combination dosage form which comprises combining (S)-ibuprofen, or salt thereof, substantially free of (R)-ibuprofen and at least one of the antihistamines or a therapeutically active stereoisomer thereof substantially free of its other stereoisomers.
19. A method of Claim 18 wherein the antihistamine is a conventional antihistamine.
20. A method of Claim 18 wherein the antihistamine is a non-sedating antihistamine.
EP19910918783 1990-09-28 1991-09-25 Ibuprofen-antihistamine combinations Withdrawn EP0550668A4 (en)

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US58924590A 1990-09-28 1990-09-28
US58924190A 1990-09-28 1990-09-28
US589241 1990-09-28
US589245 1990-09-28

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WO1995025518A1 (en) * 1994-03-18 1995-09-28 Ciba-Geigy Ag Aqueous solution of levocabastine for ophthalmic use
CA2227958A1 (en) * 1995-07-28 1997-02-13 Sekhar Mitra Compositions containing analgesics and antihistamines and methods for treating respiratory disorders
JP4614638B2 (en) * 2002-06-07 2011-01-19 第一三共株式会社 Analgesic composition
JP2010159299A (en) * 2002-07-04 2010-07-22 Daiichi Sankyo Co Ltd Antipyretic composition comprising loxoprofen and ketotifen
JP4614640B2 (en) * 2002-07-04 2011-01-19 第一三共株式会社 Antipyretic composition
AU2009204360B2 (en) * 2008-01-04 2014-12-18 Src, Inc. The use of analgesic potentiating compounds to potentiate the analgesic properties of an analgesic compound and single dose compositions thereof
KR20110017365A (en) * 2008-05-30 2011-02-21 페어필드 클리니컬 트라이얼즈 엘엘씨 Methods and compositions for skin inflammation and discoloration
EP2493465B1 (en) * 2009-10-26 2014-10-22 Sephoris Pharmaceuticals, LLC Treatment of sunburn using analgesics and antihistamines
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CA2092566A1 (en) 1992-03-29
AU8764191A (en) 1992-04-28
JPH06502166A (en) 1994-03-10
WO1992005783A1 (en) 1992-04-16

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