US 20100129443A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0129443 A1 Pettersson (43) Pub. Date: May 27, 2010 (54) NON-ABUSABLE PHARMACEUTICAL Publication Classification COMPOSITION COMPRISING OPODS (51) Int. Cl. A69/20 (2006.01) (76) Inventor: Anders Pettersson, Uppsala (SE) A6IR 9/14 (2006.01) Correspondence Address: 3. ?t C RYAN KROMHOLZ & MANION, S.C. (2006.01) POST OFFICE BOX 266.18 A6IP 25/00 (2006.01) MILWAUKEE, WI 53226 (US) (52) U.S. Cl. ......... 424/465; 424/489: 514/329; 514/282: 424/464 (21) Appl. No.: 12/312,995 (57) ABSTRACT (22) PCT Filed: Dec. 3, 2007 There is provided pharmaceutical compositions for the treat ment of pain comprising a pharmacologically-effective (86). PCT No.: PCT/GB2OOTFOO4627 amount of an opioid analgesic, or a pharmaceutically-accept S371 (c)(1) able salt thereof, presented in particulate form upon the sur (2), (4) Date: Jan. 12, 2010 faces of carrier particles comprising a pharmacologically s e -la?s effective amount of an opioid antagonist, or a O O pharmaceutically-acceptable Salt thereof, which carrier par Related U.S. Application Data ticles are larger in size than the particles of the opioid anal (60) Provisional application No. 60/872,496, filed on Dec. gesic. The compositions are also useful in prevention of 4, 2006. opioid abuse by addicts. US 2010/0129443 A1 May 27, 2010 NON-ABUSABLE PHARMACEUTICAL ing opioid analgesics, which may be administered by a con COMPOSITION COMPRISING OPODS Venient route, for example transmucosally, particularly, as is usually the case, when such active ingredients are incapable of being delivered perorally due to poor and/or variable bio 0001. This invention relates to new, fast acting, non-abus availability. able pharmaceutical compositions that are useful in the treat 0013 However, a perennial problem with potent opioid ment of pain, which compositions may be administered trans analgesics such as fentanyl is one of abuse by drug addicts. mucosally and in particular Sublingually. Addicts normally abuse pharmaceutical formulations by 0002 Opioids are widely used in medicine as analgesics. extracting a large quantity of active ingredient from that for Indeed, it is presently accepted that, in the palliation of more mulation into Solution, which is then injected intravenously. severe pain, no more effective therapeutic agents exist. With most commercially-available pharmaceutical formula 0003. The term “opioid' is typically used to describe a tions, this can be done relatively easily, which renders them drug that activates opioid receptors, which are found in the unsafe or “abusable'. Thus, there also is a need for a fast brain, the spinal cord and the gut. Three classes of opioids acting, non-abusable pharmaceutical formulation comprising exist: opioid analgesics. 0004 (a) naturally-occurring opium alkaloids. These 0014 Naloxone is a selective opioidantagonist that is used include morphine and codeine; to reverse the pharmacological effects of opioids. Naloxone 0005 (b) compounds that are similar in their chemical may therefore be used to treat narcotic drug overdose or to structure to the naturally-occurring opium alkaloids. diagnose Suspected opioid addiction. Naloxone has poor bio These so-called semi-synthetics are produced by chemi availability when administered transmucosally but has good cal modification of the latter and include the likes of diamorphine (heroin), oxycodone and hydrocodone; bioavailability when administered by injection. and 0015. A simple mixture combination of the opioid partial 0006 (c) truly synthetic compounds such as fentanyl agonist buprenorphine and naloxone for Sublingual adminis and methadone. Such compounds may be completely tration is available under the trademark SuboxoneR). This and different in terms of their chemical structures to the other abuse-resistant opioid-containing formulations are naturally-occurring compounds. reviewed by Fudula and Johnson in Drug and Alcohol Depen 0007 Of the three major classes of opioid receptors (u, K dence, 83S, S40 (2006). See also US patent applications US and Ö), opioids analgesic and sedative properties mainly 2003/O124061 and US 2003/0191147. derives from agonism at the LL receptor. (0016 International patent applications WO 00/16750, 0008 Opioid analgesics are used to treat the severe, WO 2004/067004 and WO 2006/103418, all disclose drug chronic pain of terminal cancer, often in combination with delivery systems for the treatment of e.g. acute pain by Sub non-steroid anti-inflammatory drugs (NSAIDs), as well as lingual administration in which the active ingredient in acute pain (e.g. during recovery from Surgery). Further, their microparticulate form and is adhered to the Surface of larger use is increasing in the management of chronic, non-malig carrier particles in the presence of a bioadhesive and/or nant pain. mucoadhesive promoting agent. Specific combinations of 0009 Opioid-requiring cancer patients are usually given opioid analgesics and opioidantagonists are not mentioned or slow-release opiates (slow-release morphine or ketobemi Suggested anywhere in these documents. done, or transdermal fentanyl). A characteristic feature of 0017. In endeavouring to solve the above-mentioned prob Such treatments is periods of inadequate analgesia (so-called lems, and to provide an improved, effective, fast-acting, non “breakthrough' pain). Such periods are thought to be due to abusable bioadhesive formulation comprising a potent opioid increased physical activity of the patient. However, treatment analgesic, such as fentanyl, in combination with a sufficient of breakthrough pain by administration of increased time dose of an opioidantagonist. Such as naloxone, we have found contingent doses of long-acting analgesic formulations is that it is not possible to provide both active ingredients upon known to cause, adverse side effects, including excess seda the surfaces of inert carrier particles as disclosed in the afore tion, nausea, and constipation. mentioned patent documents. We have therefore devised an 0010 Presently-available oral, rectal and sublingual elegant Solution to this problem by providing particles of opioid analgesic formulations have relatively lengthy onset opioid analgesic drug upon the Surfaces of carrier particles times and/or erratic absorption characteristics, which makes comprising an opioid antagonist, Such as naloxone. then not entirely suitable for the control of acute and/or break 0018. According to a first aspect of the invention there are through pain. provided particulate pharmaceutical compositions for the 0011. In order to obtain rapid onset of analgesia in the treatment of pain comprising a pharmacologically-effective treatment of other types of acute pain, including operative amount of an opioid analgesic, or a pharmaceutically-accept pain, post-operative pain, traumatic pain, post-traumatic able salt thereof, presented in particulate form upon the sur pain, and pain caused by severe diseases, such as myocardial faces of carrier particles comprising a pharmacologically infarction, nephrolithiasis, etc., opioid analgesics are often effective amount of an opioid antagonist, or a administered parenterally (e.g. by intravenous or intramuscu pharmaceutically-acceptable Salt thereof, which carrier par lar injection). However, injections are an unpopular mode of ticles are larger in size than the particles of the opioid anal administration, often being regarded as inconvenient and gesic, which compositions are referred to hereinafter as “the painful. compositions of the invention. 0012. In view of the above, there is a real and growing 0019 Compositions of the invention may further com clinical need for fast-acting orally-delivered drug composi prise a bioadhesion and/or a mucoadhesion promoting agent, tions comprising opioid analgesics. In particular, a need which agent is, at least in part, presented on the Surfaces of the exists for further or better fast-acting formulations compris carrier particles. US 2010/0129443 A1 May 27, 2010 0020. The compositions of the invention are interactive limited to, their hydrochlorides, maleates, tartrates and lac mixtures. The term “interactive” mixture will be understood tates. Preferred opioid antagonists include nalmefene, pref by those skilled in the art to denote a mixture in which par erably methylmaltrexone, more preferably naltrexone and, ticles do not appear as single units, as in random mixtures, but particularly, naloxone. rather where Smaller particles (of for example, opioid anal 0024. Any of the active ingredients mentioned in the above gesic and/or bioadhesion and/or mucoadhesion promoting groupings may also be used in combination as required. agent) are attached to (i.e. adhered to or associated with) the Moreover, the above active ingredients may be used in free Surfaces of larger opioid antagonist-containing, or opioid form or, if capable of forming salts, in the form of a salt with antagonist-based, carrier particles. Such mixtures are charac a suitable acid or base. If the drugs have a carboxyl group, terised by interactive forces (for example van der Waals their esters may be employed. Active ingredients can be used forces, electrostatic or Coulombic forces, and/or hydrogen as racemic mixtures or as single enantiomers. bonding) between carrier and Surface-associated particles 0025. The term “pharmacologically effective amount (see, for example, Staniforth, Powder Technol., 45, 73 refers to an amount of an active ingredients, which is capable (1985)). In