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(19) TZZ ZZ_¥_T (11) EP 2 089 013 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/167 (2006.01) A61K 31/192 (2006.01) 27.09.2017 Bulletin 2017/39 A61K 45/06 (2006.01) A61P 29/00 (2006.01) (21) Application number: 07854106.7 (86) International application number: PCT/US2007/081589 (22) Date of filing: 17.10.2007 (87) International publication number: WO 2008/051759 (02.05.2008 Gazette 2008/18) (54) COMBINATION OF ACETAMINOPHEN WITH IBUPROFEN FOR THE TREAMENT OF PAIN KOMBINATION VON ACETAMINOPHEN MIT IBUPROFEN ZUR BEHANDLUNG VON SCHMERZEN. COMBINAISON DE ACÉTAMINOPHÈNE ET IBUPROFÈNE POUR LE TRAITEMENT DE DOULEUR (84) Designated Contracting States: (74) Representative: Kirsch, Susan Edith et al AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Carpmaels & Ransford LLP HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE One Southampton Row SI SK TR London WC1B 5HA (GB) (30) Priority: 20.10.2006 US 853509 P (56) References cited: EP-A- 0 012 621 EP-A- 0 109 281 (43) Date of publication of application: WO-A-2006/004449 US-A- 5 409 709 19.08.2009 Bulletin 2009/34 • MIRANDA ET AL: "Synergism between (73) Proprietor: Johnson & Johnson Consumer Inc. paracetamol and nonsteroidal anti-inflammatory Skillman, NJ 08558 (US) drugs in experimental acute pain" PAIN, ELSEVIER SCIENCE PUBLISHERS, (72) Inventors: AMSTERDAM, NL, vol. 121, no. 1-2, March 2006 • SWANN, Jim (2006-03), pages 22-28, XP005330893 ISSN: Waterloo, ON N2L 5Y8 (CA) 0304-3959 • CUMMINS, Peter Guelph, ON N1L 1B4 (CA) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 089 013 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 089 013 B1 Description BACKGROUND OF THE INVENTION 5 Field of the Invention [0001] This invention relates to dosage forms comprising non-steroidal anti-inflammatory agents and acetaminophen. Methods for their use are also disclosed. More specifically, this invention relates to dosage forms comprising synergistic combinations of ibuprofen and acetaminophen. 10 Description of the Related Art [0002] Numerous antipyretic and analgesic products are frequently used and/or widely prescribed. One type of antipyretic/analgesic combination product includes salicylic acid derivatives such as aspirin with acetaminophen. Disadvan- 15 tageously, dosage forms that include salicylic acid derivatives often cause gastric disorders. Gastric disorders such as, for example, nausea, gastralgia, and stomach discomfort, have also been associated with other non-steroidal anti- inflammatory -containing products, such as those containing ibuprofen, although to varying degrees and frequency. [0003] One approach for suppressing these negative side effects has been the inclusion of an antacid into the dosage form. See, e.g., United States Patent No. 5,409,709. Disadvantageously, the manufacture of such dosage forms has 20 been complicated by the need to overcome the incompatibility of these ingredients. [0004] In view of such side effects, it would therefore be beneficial to reduce the single dose or maximum daily dose of such active ingredients contained in dosage forms, while providing equal or better analgesic and/or antipyretic effect than the full single dose or full daily dose of either of the active ingredients contained therein. [0005] It an object of the present invention to reduce the likelihood of any negative side effects that may be associated 25 with the use of such analgesic or antipyretic ingredients by reducing the levels of such ingredients in the dosage form to an amount that is below the full single dose or full daily dose of each respective active ingredient alone, but which provides the desired or improved antipyretic and/or analgesic effects. Other objects, features and advantages of the invention will be apparent to those skilled in the art from the detailed description set forth below. [0006] Document WO 2006/004449 describes a combination pharmaceutical for the treatment of pain including about 30 125 mg to about 150 mg ibuprofen and about 475 mg to about 500 mg acetaminophen. [0007] Document EP 0012621 describes a pharmaceutical composition for reducing pain comprising diclofenac, sulin- dac, fenbufin, naproxen, kotoprofen, indoprofen, or fenoprofen together with acetaminophen. SUMMARY OF THE INVENTION 35 [0008] The present invention is as defined in the appended claims. [0009] The present invention is directed to a preparation comprised of, consisting of, and/or consisting essentially of a) a first analgesic agent consisting of an effective amount of ibuprofen; pharmaceutically acceptable isomers, metabolites, polymorphs, and/or salts thereof; and mixtures thereof; and b) a second analgesic agent consisting of an effective 40 amount of acetaminophen, pharmaceutically acceptable isomers, metabolites, polymorphs, and/or salts thereof; and mixtures thereof; wherein the first analgesic agent and the second analgesic agent are the sole analgesic agents, and the weight ratio of the first analgesic agent (calculated as a racemic ibuprofen base) to the second analgesic agent (calculated as an acetaminophen base) is about 1 part to about 7.5 parts. Methods for its use are also disclosed. 45 BRIEF DESCRIPTION OF THE DRAWINGS [0010] Figure 1 graphically depicts the change in microvolts (uV) as an indication for the analgesic efficacy of each respective treatment studied in Example 1 using the LSEP methodology. 50 DETAILED DESCRIPTION OF THE INVENTION [0011] It is believed that one skilled in the art can, based upon the description herein, utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. 55 [0012] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. As used herein, all percentages are by weight unless otherwise specified. In addition, all ranges set forth herein are meant to include any combinations of values between the two endpoints, inclusively. 2 EP 2 089 013 B1 [0013] As used herein, the term "dosage form" applies to any ingestible forms, including confections. In one embodiment, dosage forms are solid, semi-solid, or liquid compositions designed to contain a specific pre-determined amount of a certain ingredient, for example an active ingredient as defined below. Suitable dosage forms may be pharmaceutical drug delivery systems, including those for oral administration, buccal administration, rectal administration, topical, 5 transdermal, or mucosal delivery, or subcutaneous implants, or other implanted drug delivery systems; or compositions for delivering minerals, vitamins and other nutraceuticals, oral care agents, flavorants, and the like. In one embodiment, the dosage forms of the present invention are considered to be solid; however, they may contain liquid or semi-solid components. In another embodiment, the dosage form is an orally administered system for delivering a pharmaceutical active ingredient to the gastro-intestinal tract of a human.. In another embodiment the dosage form is a tablet or a 10 simulated capsule like medicament, which may optionally contain a coating. In another embodiment the dosage form may have a portion comprised of the first analgesic agent and/or the second analgesic agent, whereby such agents are delivered in a sustained release manner. Also disclosed is a dosage form that is an orally administered "placebo" system containing pharmaceutically inactive ingredients, and the dosage form is designed to have the same appearance as a particular pharmaceutically active dosage form, such as may be used for control purposes in clinical studies to test, for 15 example, the safety and efficacy of a particular pharmaceutically active ingredient. In one embodiment, the dosage form contains all active ingredients within the same solid, semi-solid, or liquid forms. In another embodiment, the dosage form contains the active ingredients in one or more solid, semi-solid, or liquid forms. [0014] As used herein, the term "preparation" or "dose" applies to the dosage form or forms necessary to be ingested by the patient in order for the patient to receive the desired amount of each active ingredient contained therein. 20 [0015] "Tablets," as used herein, refer to compressed or molded solid dosage forms of any shape or size. [0016] As used herein, "injection molding" shall mean a process of forming a dosage form in a desired shape and size wherein a flowable material, which is in a fluid or flowable state form, enters a mold, then is solidified in the mold via a change in temperature (either positive or negative) before being removed therefrom. By contrast, "compression," as used herein, shall mean a process of forming a dosage form in a desired shape and size wherein a material is compacted 25 into a tablet between the surfaces of punches via an increase in pressure before being removed therefrom. [0017] As used herein, "racemic ibuprofen base" shall mean an equivalent mixture of the (R) and (S) stereoisomers of ibuprofen, more specifically,

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