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WO1998058640A1 - Analgesique a base d'ibuprofene et de diphenhydramine - Google Patents

Analgesique a base d'ibuprofene et de diphenhydramine Download PDF

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Publication number
WO1998058640A1
WO1998058640A1 PCT/US1997/010857 US9710857W WO9858640A1 WO 1998058640 A1 WO1998058640 A1 WO 1998058640A1 US 9710857 W US9710857 W US 9710857W WO 9858640 A1 WO9858640 A1 WO 9858640A1
Authority
WO
WIPO (PCT)
Prior art keywords
ibuprofen
diphenhydramine
weight
composition
pharmaceutically acceptable
Prior art date
Application number
PCT/US1997/010857
Other languages
English (en)
Inventor
Douglas R. Hough
Edward B. Nelson
Robert B. Raffa
Original Assignee
Mcneil-Ppc
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 filed Critical Mcneil-Ppc
Priority to AU43256/97A priority Critical patent/AU4325697A/en
Priority to PCT/US1997/010857 priority patent/WO1998058640A1/fr
Publication of WO1998058640A1 publication Critical patent/WO1998058640A1/fr

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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid

Definitions

  • the present invention relates to analgesic compositions. More particularly, the present invention relates to analgesic compositions containing ibuprofen and diphenhydramine.
  • Ibuprofen a-Methyl-4-(2-methylpropyl)benzeneacetic acid
  • NSAID non-steroidal, anti-inflammatory drug
  • FIG. 1 is an isobologram showing the analgesic effect of combinations of ibuprofen and the HCL salt of diphenhydramine on the inhibition of acetylcholine induced writhing in mice.
  • composition for use as an analgesic comprising:
  • an analgesic inducing amount of ibuprofen (b) from less than 1/8 to about 1/500 parts by weight diphenhydramine or pharmaceutically acceptable salt thereof for each part by weight ibuprofen; and (c) a pharmaceutically acceptable carrier.
  • Diphenhydramine 2-diphenylmethoxy-N,N-dimethylethanamine
  • diphenhydramine The preparation of diphenhydramine is well known and a description of a suitable process for its preparation may be found in U.S. Pat. Nos. 2,421 ,714 and 2,427,878 (both 1947 to Parke Davis) and 2,399,799 (1946).
  • the pharmaceutically acceptable salts referred to above are generally salts with strong mineral acids. Representative of suitable such acids are hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, methanesulfonic or hydroxyethanesulfonic.
  • the ibuprofen is compounded with the diphenhydramine in a suitable carrier in the proportions recommended above.
  • the diphenhydramine is present only to enhance the stromsic effect of the ibuprofen. In such case, the diphenhydramine should be present in the combination product in an amount insufficient to produce a substantial antihistaminic effect and/or an amount insufficient to produce substantial drowsiness.
  • ibuprofen is only poorly soluble in water.
  • a surface active agent to stabilize the suspension and/or act as a solubilizing agent.
  • Suitable such agents include well known surfactants such as glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol, sorbitan esters, benzalkonium chloride, benzethonium chloride, cetrimide, docusate sodium and sodium lauryl sulfate.
  • Suitable such agents may also include solubilizing agents/wetting agents such as polyoxyethylene castor oil derivatives, poloxamer, polyoxyethylene stearates, polyoxyethylene alkylene ethers, stearic acid, lecithin, glyceryl monostearate, cyclodextrins and benzyl benzoate.
  • solubilizing agents/wetting agents such as polyoxyethylene castor oil derivatives, poloxamer, polyoxyethylene stearates, polyoxyethylene alkylene ethers, stearic acid, lecithin, glyceryl monostearate, cyclodextrins and benzyl benzoate.
  • Suitable such agents may also be emulsifying agents such as acacia, anionic emulsifying wax, carbomer, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, hydrous lanolin, hydroxypropyl cellulose lanolin, lanolin alcohols, methyl cellulose, mineral oil, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oieic acid, propylene glycol alginate and triethanolamine.
  • emulsifying agents such as acacia, anionic emulsifying wax, carbomer, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, hydrous lanolin, hydroxypropyl cellulose lanolin, lanolin alcohols, methyl cellulose, mineral oil, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oieic acid, propylene glycol alginate and triethanolamine.
  • Persons skilled in the art can easily determine
  • compositions of the present invention may be used to treat mild to moderately severe pain in warm-blooded animals such as humans by administration of an analgesically effective dose.
  • the dosage range, based on the ibuprofen would be from about 5 to 1000 mg, in particular about 25 to 600 mg or about 100 to 400 mg, of active ingredient 1 to 4 times per day for an average (70 kg) human although it is apparent that activity of individual compounds of the invention will vary as will the pain being treated.
  • Pharmaceutical compositions of the invention comprise the active ingredients as defined above, particularly in admixture with a pharmaceutically-acceptable carrier.
  • the dose of diphenhydramine should not exceed about 200 mg, up to four times daily, for an average (70 kg) human.
  • TABLET 1 200 mg ibuprofen and 10 mg diphenhydramine in a 300 mg tablet, 1 or 2 tablets to be administered to an average adult every 4 to 6 hours, not to exceed 6 tablets daily.
  • TABLET 2 300 mg ibuprofen and 7.5 mg diphenhydramine in a 400 mg tablet, 1 tablet to be administered to an average adult every 4 to 6 hours, not to exceed 4 tablets daily.
  • ELIXIR 1 100 mg ibuprofen and 5 mg diphenhydramine in 5 mL of liquid excipient, 1/2 to 2 teaspoons dose to be administered to a child, depending on weight, every 6 to 8 hours, not to exceed 4 doses every 24 hours.
  • the compounds of the invention are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intra muscular.
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intra muscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
  • the active ingredients instead of administering the active ingredients as a single composition, they may be administered simultaneously of sequentially as separate compositions. To obtain the advantages described herein, it is only important that the active ingredients be administered in combination, regardless of whether they are in the same tablet, capsule, powder, injection or elixir.
  • the combination products of Table I were prepared with active ingredients which were administered in distilled water containing containing one drop of Tween R 80 surface active agent (containing 100% poiysorbate 80, a monooleate of polyoxyethylenesorbitan with a fatty acid content of about 75% oleic acid and the balance linoleic, palmitic and stearic acids) per 10 ml of preparation.
  • the concentration of the active ingredients in the distilled water was such to provide a dosing volume of about 10 ml/kg.
  • the activity of the combination products of Table I as analgesic agents may be demonstrated by the mouse acetylcholine-bromide induced constriction assay as described below:
  • the mouse acetylcholine-induced abdominal constiction assay as described by Collier et al. in Brit. J. Pharmacol. Chem. Then, 32: 295-310, 1968, with minor modifications was used to assess analgesic potency of the combination products herein.
  • the test drugs and appropriate vehicle were administered orally (p.o.) and 30 minutes later the animal received an intraperitoneal (i.p.) injection of 5.5 mg/kg acetylcholine bromide (Matheson, Coleman and Bell, East Rutherford, NJ).
  • mice were then placed in groups of three into glass bell jars and observed for a ten minute observation period for the occurrence of an abdominal constriction response (defined as a wave of constriction and elongation passing caudally along the abdominal wall, accompanied by a twisting of the trunk and followed by extension of the hind limbs).
  • an abdominal constriction response defined as a wave of constriction and elongation passing caudally along the abdominal wall, accompanied by a twisting of the trunk and followed by extension of the hind limbs.
  • IBU Ibuprofen
  • DPHD HCI salt of Diphenhydramine
  • IBU DPHD writhing IBU DPHD

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (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)

Abstract

L'invention concerne des compositions comprenant de l'ibuprofène et de la diphénhydramine et des procédés pour les utiliser en analgésie. Lorsque l'ibuprofène et la diphénhydramine sont présents dans certains rapports, leurs effets pharmaceutiques s'additionnent remarquablement.
PCT/US1997/010857 1997-06-23 1997-06-23 Analgesique a base d'ibuprofene et de diphenhydramine WO1998058640A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU43256/97A AU4325697A (en) 1997-06-23 1997-06-23 Ibuprofen and diphenhydramine analgesics
PCT/US1997/010857 WO1998058640A1 (fr) 1997-06-23 1997-06-23 Analgesique a base d'ibuprofene et de diphenhydramine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1997/010857 WO1998058640A1 (fr) 1997-06-23 1997-06-23 Analgesique a base d'ibuprofene et de diphenhydramine

Publications (1)

Publication Number Publication Date
WO1998058640A1 true WO1998058640A1 (fr) 1998-12-30

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/010857 WO1998058640A1 (fr) 1997-06-23 1997-06-23 Analgesique a base d'ibuprofene et de diphenhydramine

Country Status (2)

Country Link
AU (1) AU4325697A (fr)
WO (1) WO1998058640A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037054A1 (fr) * 1998-12-18 2000-06-29 Knoll Aktiengesellschaft Melange pharmaceutique contenant un profene
US6726929B1 (en) 1998-12-18 2004-04-27 Basf Aktiengesellschaft Pharmaceutical mixture comprising a profen
US10238640B2 (en) * 2004-05-25 2019-03-26 Wyeth Llc Pharmaceutical suspension composition

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985003443A1 (fr) * 1984-02-08 1985-08-15 Richardson-Vicks, Inc. Compositions analgesiques et anti-inflammatoires comprenant de la diphenhydramine et leurs procedes d'utilisation
US5024997A (en) * 1990-06-22 1991-06-18 American Home Products Corporation Palatable ibuprofen solutions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985003443A1 (fr) * 1984-02-08 1985-08-15 Richardson-Vicks, Inc. Compositions analgesiques et anti-inflammatoires comprenant de la diphenhydramine et leurs procedes d'utilisation
US5024997A (en) * 1990-06-22 1991-06-18 American Home Products Corporation Palatable ibuprofen solutions

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037054A1 (fr) * 1998-12-18 2000-06-29 Knoll Aktiengesellschaft Melange pharmaceutique contenant un profene
US6726929B1 (en) 1998-12-18 2004-04-27 Basf Aktiengesellschaft Pharmaceutical mixture comprising a profen
US10238640B2 (en) * 2004-05-25 2019-03-26 Wyeth Llc Pharmaceutical suspension composition

Also Published As

Publication number Publication date
AU4325697A (en) 1999-01-04

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