WO1997048390A1 - Analgesiques combinant acetaminophene et meclozine - Google Patents

Analgesiques combinant acetaminophene et meclozine Download PDF

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Publication number
WO1997048390A1
WO1997048390A1 PCT/US1997/010922 US9710922W WO9748390A1 WO 1997048390 A1 WO1997048390 A1 WO 1997048390A1 US 9710922 W US9710922 W US 9710922W WO 9748390 A1 WO9748390 A1 WO 9748390A1
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WO
WIPO (PCT)
Prior art keywords
acetaminophen
meclizine
weight
composition
pharmaceutically acceptable
Prior art date
Application number
PCT/US1997/010922
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 AU35763/97A priority Critical patent/AU3576397A/en
Publication of WO1997048390A1 publication Critical patent/WO1997048390A1/fr

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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

Definitions

  • the present invention relates to analgesic compositions. More particularly, the present invention relates to analgesic compositions containing acetaminophen and meclizine.
  • Acetaminophen, N-(4-hydroxyphenyl)acetamide or herein referred to as APAP was first used in medicine by Van Mering in 1893, but only since 1949 has it gained in popularity as an effective alternative to aspirin for
  • No 4,260,629 discloses that an orally administered composition of APAP and zomepirac, a non-opioid analgesic, in a particular weight ratio range produces a superadditive relief of pain in mammals Furthermore, U.S. Pat. No. 4,132,788 discloses that 5- aroyl-1-(lower)alkylpyrrole-2-acet ⁇ c acid derivatives, non-opioid analgesics, when combined with APAP or aspirin exhibit superadditive antiarth ⁇ tic activity. Also, U.S. Pat.
  • No 5,336,691 discloses that the combination of tramadol, a centrally active analgesic analgesic, and APAP exhibits a synergistic analgesic effect when combined in certain ratios.
  • G. B. Pat. No. 1 ,442,159 teaches that combinations of APAP and diphenhydramme hydrochlo ⁇ de in certain proportions are satisfactory in the treatment of migraine headache
  • U. S. Pat. Nos. 4,401 ,665 and 4,505,862 disclose combinations of aspirin, APAP and diphenhydramme dihydrogencitrate for use as an analgesic.
  • FIG. 1 is an isobologram showing the analgesic effect of combinations of APAP and meclizine hydrochlo ⁇ de with inhibition of acetylcholine induced writhing in mice.
  • composition for use as an analgesic comprising:
  • Meclizine is an anttnauseant now sold for this use in formulations under a variety of names. It has the chemical formula:
  • meclizine is well known and a description of a suitable process for its preparation may be found in Morren, Belg. Pat. No. 502,889; Brit. Pat. No. 705,979 and U.S. Pat. No. 2,709,169.
  • the pharmaceutically acceptable salts referred to above are generally salts with strong mineral acids.
  • suitable such acids are hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, methanesulfonic or hydroxyethanesulfonic.
  • the APAP is compounded with the meclizine in a suitable carrier in the proportions recommended above.
  • a suitable carrier in the proportions recommended above.
  • the ⁇ meclizine is present only to enhance the analgesic effect of the acetaminophen. In such case, the meclizine should be present in an amount insufficient to produce substantial relief from nausea.
  • APAP and meclizine are only poorly soluble in water.
  • it is desirable to employ methods designed to improve the availability of the actives such as, grinding the the actives to a small particle size or using 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, oleic 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, oleic acid, propylene glycol alginate and triethanolamine.
  • Persons skilled in the art can easily determine how much
  • 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 principle active ingredient would be from about 10 to 2000 mg, in particular about 25 to 1000 mg or about 100 or 500 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 meclizine should not exceed about 200 mg, up to four times per day, for an average (70 kg) human.
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenterai such as intra muscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, ftavo ⁇ ng 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 earners 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 ⁇ 80 surface active agent (containing 100% polysorbate 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 mouse acetylcholine-induced abdominal constiction assay as described by Collier et al. in Brit. J. Pharmacol. Chem. Ther., 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 intrapentoneal (i.p.) injection of 5.5 mg/kg acetylcholme bromide (Matheson, Colema ⁇ 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 constnction 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 constnction and elongation passing caudally along the abdominal wall, accompanied by a twisting of the trunk and followed by extension of the hind limbs
  • ED50 that dose which would produce 50% analgesia
  • An experimental design was used which permitted the complete randomization of the separate dosage forms tested.
  • the ED50 values and their 95% fiducial limits were determined by a computer assisted probit analysis.

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des compositions comprenant de l'acétaminophène (APAP) et de la méclozine et des procédés pour leur emploi en analgésie. L'acétaminophène et la méclozine ont un effet suradditif lorsqu'ils sont administrés ensemble.
PCT/US1997/010922 1996-06-20 1997-06-20 Analgesiques combinant acetaminophene et meclozine WO1997048390A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU35763/97A AU3576397A (en) 1996-06-20 1997-06-20 Analgesics combining acetaminophen with meclizine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US66783496A 1996-06-20 1996-06-20

Publications (1)

Publication Number Publication Date
WO1997048390A1 true WO1997048390A1 (fr) 1997-12-24

Family

ID=24679844

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/010922 WO1997048390A1 (fr) 1996-06-20 1997-06-20 Analgesiques combinant acetaminophene et meclozine

Country Status (3)

Country Link
AU (1) AU3576397A (fr)
WO (1) WO1997048390A1 (fr)
ZA (1) ZA975444B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103543231A (zh) * 2012-07-11 2014-01-29 北大方正集团有限公司 一种盐酸美克洛嗪中氯仿残留量的分离分析方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1442159A (en) * 1973-08-03 1976-07-07 Restien H Pharmaceutical compositions containing paracetamol
US4017614A (en) * 1969-12-05 1977-04-12 Henry Wild Compositions for the relief of migraine
WO1991001132A1 (fr) * 1989-07-24 1991-02-07 Fertin Laboratories Ltd. (Dansk Tyggegummi Fabrik A/S) Composition de chewing-gum a liberation reglee et acceleree des agents actifs
EP0426479A1 (fr) * 1989-11-02 1991-05-08 McNEIL-PPC, INC. Utilisation d'une compostition pour la fabrication d'un médicament destiné à traiter les symptômes de l'intempérance
WO1993004675A1 (fr) * 1991-09-06 1993-03-18 Mcneilab, Inc. Composition renfermant une matiere a base de tramadol et de l'acetaminophene, et son utilisation
WO1995019759A1 (fr) * 1994-01-24 1995-07-27 The Procter & Gamble Company Procede pour solubiliser des agents pharmaceutiques difficilement solubles

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4017614A (en) * 1969-12-05 1977-04-12 Henry Wild Compositions for the relief of migraine
GB1442159A (en) * 1973-08-03 1976-07-07 Restien H Pharmaceutical compositions containing paracetamol
WO1991001132A1 (fr) * 1989-07-24 1991-02-07 Fertin Laboratories Ltd. (Dansk Tyggegummi Fabrik A/S) Composition de chewing-gum a liberation reglee et acceleree des agents actifs
EP0426479A1 (fr) * 1989-11-02 1991-05-08 McNEIL-PPC, INC. Utilisation d'une compostition pour la fabrication d'un médicament destiné à traiter les symptômes de l'intempérance
WO1993004675A1 (fr) * 1991-09-06 1993-03-18 Mcneilab, Inc. Composition renfermant une matiere a base de tramadol et de l'acetaminophene, et son utilisation
WO1995019759A1 (fr) * 1994-01-24 1995-07-27 The Procter & Gamble Company Procede pour solubiliser des agents pharmaceutiques difficilement solubles

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103543231A (zh) * 2012-07-11 2014-01-29 北大方正集团有限公司 一种盐酸美克洛嗪中氯仿残留量的分离分析方法
CN103543231B (zh) * 2012-07-11 2015-09-16 北大方正集团有限公司 一种盐酸美克洛嗪中氯仿残留量的分离分析方法

Also Published As

Publication number Publication date
AU3576397A (en) 1998-01-07
ZA975444B (en) 1998-12-21

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