WO1998058647A1 - Analgesiques a base d'acetaminophene et de cisapride - Google Patents

Analgesiques a base d'acetaminophene et de cisapride Download PDF

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Publication number
WO1998058647A1
WO1998058647A1 PCT/US1997/010858 US9710858W WO9858647A1 WO 1998058647 A1 WO1998058647 A1 WO 1998058647A1 US 9710858 W US9710858 W US 9710858W WO 9858647 A1 WO9858647 A1 WO 9858647A1
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WO
WIPO (PCT)
Prior art keywords
acetaminophen
cisapride
weight
composition
pharmaceutically acceptable
Prior art date
Application number
PCT/US1997/010858
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 AU43257/97A priority Critical patent/AU4325797A/en
Priority to PCT/US1997/010858 priority patent/WO1998058647A1/fr
Publication of WO1998058647A1 publication Critical patent/WO1998058647A1/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
    • A61K31/435—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

Definitions

  • the present invention relates to analgesic compositions. More particularly, the present invention relates to analgesic compositions containing acetaminophen and cisapride.
  • 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
  • 5,336,691 discloses that the combination of tramadol, a centrally active 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 diphenhydramine hydrochloride 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 diphenhydramine dihydrogencitrate for use as an analgesic. It is an object of the present invention to combine APAP with a second active ingredient to produce an analgesic having improved safety and efficacy.
  • FIG. 1 is an isobologram showing the analgesic effect of combinations of APAP and cisapride monohydrate with inhibition of acetyl choline induced writhing in mice.
  • composition for use as an analgesic comprising:
  • Cisapride cis-4-amino-5-chloro-N-[1 -[3-(4-fluorophenoxy)propyl]-3- methoxy-4-piperidinyl]-2-methoxy-benzamide, is a peristaltic stimulant providing relief from heart burn produced by decreased motility, now sold for this use in formulations under under the trademark Prepulsid. It has the chemical formula:
  • Cisapride may form salts with an appropriate acid and hydrates with water.
  • Its therapeutically useful acid addition salt may be formed by reaction with an appropriate acid, such as, for example, an inorganic acid such as hydrohalic acid, i.e., hydrochloric, hydrobromic or hydroiodic acid; sulfuric, nitric or thiocyanic acid; a phosphoric acid; and organic acid such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, 1 ,4-butanedioic, (Z)-2-butenedioic, (E)-2- butenedioic, 2-hydroxy-1 ,2,3-propanetricarboxylic, benzoic, 3-phenyl-2- propenoic, ⁇ -hydroxybenzeneacetic, methanesulfonic, ethanesuifonic, 2- hydroxyethanesulfonic, 4-methylbenzenesulfonic, 2-hydroxybenzoic, 4- amino-2-
  • the APAP is compounded with the cisapride in a suitable carrier in the proportions recommended above.
  • a suitable carrier in the proportions recommended above.
  • the cisapride is present only to enhance the analgesic effect of the acetaminophen. In such case, the cisapride should be present in an amount insufficient to produce substantial relief from heartburn.
  • APAP and cisapride are only slightly soluble in cold water.
  • it is desirable to employ methods designed to improve the availability of the APAP and cisapride such as, grinding the APAP 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 iauryl 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 0 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 p armaceutically-acceptable carrier.
  • the dose of cisapride should not exceed about 80 mg per day, for an average (70 kg) human.
  • 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% polysorbate 80, a monooleate of polyoxyethylenesorbitan with a fatty acid content of about 75% oieic acid and the balance linoleic, palmitic and stearic acids) per 10 mi 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 acetylchoiine-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.

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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 concerne des compositions comprenant de l'acétaminophène et du cisapride et des procédés d'utilisation en analgésie. Lorsque l'acétaminophène et le cisapride sont administrés de manière combinée, leurs effets pharmaceutiques analgésiques s'additionnent.
PCT/US1997/010858 1997-06-23 1997-06-23 Analgesiques a base d'acetaminophene et de cisapride WO1998058647A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU43257/97A AU4325797A (en) 1997-06-23 1997-06-23 Acetaminophen and cisapride analgesics
PCT/US1997/010858 WO1998058647A1 (fr) 1997-06-23 1997-06-23 Analgesiques a base d'acetaminophene et de cisapride

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1997/010858 WO1998058647A1 (fr) 1997-06-23 1997-06-23 Analgesiques a base d'acetaminophene et de cisapride

Publications (1)

Publication Number Publication Date
WO1998058647A1 true WO1998058647A1 (fr) 1998-12-30

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/010858 WO1998058647A1 (fr) 1997-06-23 1997-06-23 Analgesiques a base d'acetaminophene et de cisapride

Country Status (2)

Country Link
AU (1) AU4325797A (fr)
WO (1) WO1998058647A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BG65270B1 (bg) * 1999-03-31 2007-11-30 Zentaris Ag Фармацевтичен набор за програмирана контролирана овариална стимулация

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0057536A1 (fr) * 1981-01-26 1982-08-11 Beecham Group Plc Composés à activité pharmaceutique
EP0076530A2 (fr) * 1981-10-01 1983-04-13 Janssen Pharmaceutica N.V. Dérivés de la N-(3-hydroxy-4-piperidinyl)benzamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0057536A1 (fr) * 1981-01-26 1982-08-11 Beecham Group Plc Composés à activité pharmaceutique
EP0076530A2 (fr) * 1981-10-01 1983-04-13 Janssen Pharmaceutica N.V. Dérivés de la N-(3-hydroxy-4-piperidinyl)benzamide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BG65270B1 (bg) * 1999-03-31 2007-11-30 Zentaris Ag Фармацевтичен набор за програмирана контролирана овариална стимулация

Also Published As

Publication number Publication date
AU4325797A (en) 1999-01-04

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