Composition comprising a tramadol material and acetaminophen and its use

a technology of acetaminophen and tramadol, which is applied in the direction of drug compositions, biocide, amide active ingredients, etc., can solve the problems of undesirable side effects, hot flushes and sweating, and certain side effects of tramadol, and achieve synergistic analgesic effects and reduce the number and degree of side effects of each

Inactive Publication Date: 2006-08-01
ORTHO MCNEIL PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]It has now been found that a tramadol material which includes various forms of tramadol as defined hereinafter can be combined with APAP to produce analgesia. The combination employs lesser amounts of both the tramadol material and APAP than would be necessary to produce the same amount of analgesia if either was used alone. By using lesser amounts of both drugs the side effects associated with each are reduced in number and degree. Surprisingly, the compositions comprising the tramadol material and APAP have been found to exhibit synergistic analgesic effects when combined in certain ratios. The compositions according to this invention may also be useful in treating tussive conditions.

Problems solved by technology

When given at a dose of 50 mg by rapid i.v. injection, tramadol may produce certain side effects unique to tramadol including hot flushes and sweating.
They, however, produce undesirable side effects and as a result cannot be given repeatedly or at high doses.
The prior art, however, does not disclose that tramadol an ‘atypical’ opioid analgesic, can or should be combined with another analgesic to lessen the side effects of each or to yield a composition comprising a tramadol material and another analgesic that exhibits superadditive analgesia.

Method used

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  • Composition comprising a tramadol material and acetaminophen and its use

Examples

Experimental program
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Effect test

example 1

Preparation of the Combined Doses of Tramadol and APAP

[0019]The preparation of different ratios of a tramadol / APAP combination is effected by first preparing a stock solution of tramadol having a concentration expressed in mgdrugs per 10 mL of distilled water. For example, 8 mg of tramadol as the free base is dissolved per 10 mL of water to yield the highest dose of tramadol stock solution. The stock solution of the tramadol is then diluted with a sufficient amount of distilled water to prepare the lower doses of the tramadol per 10 mL of distilled water. The combinations are then made by adding 10 mL of each dilution to the appropriate mg of APAP to achieve the desired ratio of tramadol to APAP. For the 1:50 example: 400 mg of APAP as the free base is suspended with 10 mL of the 8 mg tramadol solution and 2 drops of TWEEN 80, a pharmacological dispersant, manufactured by Fisher Scientific Company, to yield the 1:50 ratio, i.e. (8 mg:400 mg) combination per 10 mL of water. Each rati...

example 2

Preparation of the Combined Doses of Tramadol N-oxide and APAP

[0020]First, tramadol N-oxide was prepared as set forth hereinafter. Tramadol hydrochloride (0.5 mol) was converted to its free base in basified water (pH>9) and then extracted with ether. The ether was evaporated to yield the crystalline hydrate of tramadol. The solid was then heated with steam under a high vacuum to remove as much water as possible to yield 131.5 g of material. The material was dissolved in methanol (500 mL) and 65 g of 30% H2O2 was added. The solution was stirred for 3 hours and then an additional 65 g of the 30% H2O2 was added. The reaction was stirred for 2.5 days at room temperature. Approximately 10 mg of PtO2 on carbon (use of Pt / C is suggested for its ease of removal) was added to the reaction mixture, and very gentle foaming took place. An additional 10 mg of PtO2 was added and the reaction mixture was stirred overnight and then filtered thru a filter aid. The filtrate was concentrated under vac...

example 3

(−) and (+) Enantiomers of O-Desmethyl Tramadol: Their Syntheses and the Preparation of Doses of O-Desmethyl Tramadol-with APAP

[0023]First, O-desmethyl tramadol was prepared as set forth hereinafter. Diethylene glycol (125 mL) was added with cooling to potassium hydride (9.5 g) with the temperature being maintained at D25=−32.9 (C=1, EtOH).

[0024]C15H23NO2.HCl Theor.: C, 63.04; H, 8.46; N, 4.90 Found: C, 63.00; H, 8.51; N, 4.94

[0025]To prepare the (+) enantiomer of the title compound, the reaction was run under the same conditions except that (+)-tramadol as the free base was used instead of the (−)-tramadol to yield 2.8 g of the (+) enantiomer of O-desmethyl tramadol (mp. 242°-3° C.) [α]D25=+32.2 (C=1, EtOH).

[0026]C15H23NO2.HCl Theor.: C, 63.04; H, 8.46; N, 4.90 Found: C, 63.14; H, 8.49; N, 4.86

[0027]The preparation of different ratios of a O-desmethyl / APAP combination is effected by first preparing a stock solution of O-desmethyl tramadol having a concentration expressed in mgdrugs...

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Abstract

This invention relates to a composition comprising a tramadol material and acetaminophen, and its use. As used herein tramadol refers to various forms of tramadol. The compositions are pharmacologically useful in treating pain and tussive conditions. The compositions are also subject to less opioid side-effects such as abuse liability, tolerance, constipation and respiratory depression. Furthermore, where the components of the compositions are within certain ratios the pharmacological effects of the compositions are superadditive (synergistic).

Description

CROSS REFERENCE[0001]This case is related to application Ser. Nos. 7 / 759,259, filed Sep. 13, 1991, now U.S. Pat. No. 5,223,541 and 07 / 785,137, filed Oct. 30, 1991, now abandoned, and is a continuation-in-part of application serial No. 07 / 755,924, filed Sep. 6, 1991, now abandoned. Claims priority, application Germany, filed Apr. 2, 1963, C29547 IV b / 12o and application Germany, filed Apr. 2, 1963, C29548 IVd / 12p.BACKGROUND OF THE INVENTION[0002]U.S. Pat. No. 3,652,589 discloses a class of analgesic cycloalkanol-substituted phenol esters having a basic amine group in the cycloalkyl ring. The compound (1RS, 2RS)-[(dimethylamino)-methyl]-1-(3-methoxy-phenyl)cyclohexanol, commonly known as tramadol, is specifically disclosed therein. A series of articles pertaining to the pharmacology, toxicology and clinical studies of tramadol are found in Arzneim. Forsch, (Drug Res.), 28(I), 114(1978). Driessen et al., Arch. Pharmacol., 341, R104 (1990) disclose that tramadol produces its analgesic e...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/16A61K31/135A61K31/165A61K31/166A61K31/167A61P25/04A61P29/00
CPCA61K31/165A61P25/04A61P29/00A61K31/135A61K2300/00
Inventor RAFFA, ROBERT B.VAUGHT, JEFFREY L.
Owner ORTHO MCNEIL PHARM INC
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