US 2013 0195981A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0195981 A1 Pettersson (43) Pub. Date: Aug. 1, 2013 (54) NON-ABUSABLE PHARMACEUTICAL Publication Classification COMPOSITION COMPRISING OPODS (51) Int. Cl. (71) Applicant: Orexo AB, Uppsala (SE) A619/16 (2006.01) A613 L/4468 (2006.01) (72) Inventor: Anders Pettersson, Kode (SE) A613 L/485 (2006.01) (52) U.S. Cl. (73) Assignee: Orexo AB, Uppsala (SE) CPC ............... A61K 9/167 (2013.01); A61 K3I/485 (2013.01); A61 K3I/4468 (2013.01) USPC ........................................... 424/490; 514/282 (21) Appl. No.: 13/799,117 (57) ABSTRACT 1-1. There is provided pharmaceutical compositions for the treat (22) Filed: Mar 13, 2013 ment of pain comprising a pharmacologically-effective amount of an opioid analgesic, or a pharmaceutically-accept Related U.S. Application Data able salt thereof, presented in particulate form upon the sur (63) Continuation of application No. 12/312.995, filed on faces of carrier particles comprising a pharmacologically OO4627Jan 2, On2010, Dec. ?ilication 3, 2007 No. PCT GE2007, pharmaceutically-acceptableelective amount of n Saltpioidantagonist thereof, which carrier or par a • - s 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 2013/0195981 A1 Aug. 1, 2013 NON-ABUSABLE PHARMACEUTICAL lar injection). However, injections are an unpopular mode of COMPOSITION COMPRISING OPODS administration, often being regarded as inconvenient and painful. RELATED APPLICATIONS 0013. In view of the above, there is a real and growing 0001. This application is a continuation of U.S. applica clinical need for fast-acting orally-delivered drug composi tion Ser. No. 12/312,995, filed Jan. 12, 2010, which is the tions comprising opioid analgesics. In particular, a need national stage of PCT/GB2007/0004627, filed Dec. 3, 2007, exists for further or better fast-acting formulations compris which claims priority to U.S. Provisional Application Ser. ing opioid analgesics, which may be administered by a con No. 60/872,496, filed Dec. 4, 2006, the disclosures of which Venient route, for example transmucosally, particularly, as is are each incorporated herein by reference in their entireties. usually the case, when such active ingredients are incapable 0002 This invention relates to new, fast acting, non-abus of being delivered perorally due to poor and/or variable able pharmaceutical compositions that are useful in the treat 0014. 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 0003) 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 0004. 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. 0005 (a) naturally-occurring opium alkaloids. These 0015 Naloxone is a selective opioidantagonist that is used include morphine and codeine; to reverse the pharmacological effects of opioids. Naloxone 0006 (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 bioavailability when administered by injection. diamorphine (heroin), oxycodone and hydrocodone; 0016 A simple mixture combination of the opioid partial and agonist buprenorphine and naloxone for Sublingual adminis 0007 (c) truly synthetic compounds such as fentanyl tration is available under the trademark SuboxoneR). This and and methadone. Such compounds may be completely other abuse-resistant opioid-containing formulations are different in terms of their chemical structures to the reviewed by Fudula and Johnson in Drug and Alcohol Depen naturally-occurring compounds. dence, 83S, S40 (2006). See also US patent applications US 0008 Of the three major classes of opioid receptors (u, K 2003/O124061 and US 2003/0191147. and Ö), opioids analgesic and sedative properties mainly (0017 International patent applications WO 00/16750, derives from agonism at the LL receptor. WO 2004/067004 and WO 2006/103418, all disclose drug 0009 Opioid analgesics are used to treat the severe, delivery systems for the treatment of e.g. acute pain by Sub chronic pain of terminal cancer, often in combination with lingual administration in which the active ingredient in non-steroid anti-inflammatory drugs (NSAIDs), as well as microparticulate form and is adhered to the Surface of larger acute pain (e.g. during recovery from Surgery). Further, their carrier particles in the presence of a bioadhesive and/or use is increasing in the management of chronic, non-malig mucoadhesive promoting agent. Specific combinations of nant pain. opioid analgesics and opioidantagonists are not mentioned or 0010 Opioid-requiring cancer patients are usually given Suggested anywhere in these documents. slow-release opiates (slow-release morphine or ketobemi 0018. In endeavouring to solve the above-mentioned prob done, or transdermal fentanyl). A characteristic feature of lems, and to provide an improved, effective, fast-acting, non Such treatments is periods of inadequate analgesia (so-called abusable bioadhesive formulation comprising a potent opioid “breakthrough' pain). Such periods are thought to be due to analgesic, such as fentanyl, in combination with a sufficient increased physical activity of the patient. However, treatment dose of an opioidantagonist. Such as naloxone, we have found of breakthrough pain by administration of increased time that it is not possible to provide both active ingredients upon contingent doses of long-acting analgesic formulations is the surfaces of inert carrier particles as disclosed in the afore known to cause adverse side effects, including excess seda mentioned patent documents. We have therefore devised an tion, nausea, and constipation. elegant Solution to this problem by providing particles of 0011 Presently-available oral, rectal and sublingual opioid analgesic drug upon the Surfaces of carrier particles opioid analgesic formulations have relatively lengthy onset comprising an opioid antagonist, Such as naloxone. times and/or erratic absorption characteristics, which makes 0019. According to a first aspect of the invention there are then not entirely suitable for the control of acute and/or break provided particulate pharmaceutical compositions for the through pain. treatment of pain comprising a pharmacologically-effective 0012. In order to obtain rapid onset of analgesia in the amount of an opioid analgesic, or a pharmaceutically-accept treatment of other types of acute pain, including operative able salt thereof, presented in particulate form upon the sur pain, post-operative pain, traumatic pain, post-traumatic faces of carrier particles comprising a pharmacologically pain, and pain caused by severe diseases, such as myocardial effective amount of an opioid antagonist, or a infarction, nephrolithiasis, etc., opioid analgesics are often pharmaceutically-acceptable Salt thereof, which carrier par administered parenterally (e.g. by intravenous or intramuscu ticles are larger in size than the particles of the opioid anal US 2013/0195981 A1 Aug. 1, 2013 gesic, which compositions are referred to hereinafter as “the nalmefene, opioid antagonist compounds having the same compositions of the invention”. pentacyclic nucleus as nalmefene, naltrexone, methylmaltrex 0020 Compositions of the invention may further com one, nalorphine, nalbuphine, thebaine, levallorphon, penta prise a bioadhesion and/or a mucoadhesion promoting agent, Zocine, oxymorphine, butorphanol, bupremorphine, levor which agent is, at least in part, presented on the Surfaces of the phanol, meptazinol, dezocine, or pentazocine or their carrier particles. pharmacologically effective salts or esters such as, but not 0021. 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 0025. 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