US 2004.0024006A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0024006 A1 Simon (43) Pub. Date: Feb. 5, 2004 (54) OPIOID PHARMACEUTICAL May 30, 1997, now abandoned, and which is a COMPOSITIONS continuation-in-part of application No. 08/643,775, filed on May 6, 1996, now abandoned. (76) Inventor: David Lew Simon, Mansfield Center, CT (US) Publication Classification Correspondence Address: (51) Int. Cl. ................................................ A61K 31/485 David L. Simon (52) U.S. Cl. .............................................................. 514/282 P.O. Box 618 100 Cemetery Road (57) ABSTRACT Mansfield Center, CT 06250 (US) The invention is directed in part to dosage forms comprising a combination of an analgesically effective amount of an (21) Appl. No.: 10/628,089 opioid agonist analgesic and a neutral receptor binding agent or a partial mu-opioid agonist, the neutral receptor binding (22) Filed: Jul. 25, 2003 agent or partial mu-opioid agonist being included in a ratio Related U.S. Application Data to the opioid agonist analgesic to provide a combination product which is analgesically effective when the combina (63) Continuation-in-part of application No. 10/306,657, tion is administered as prescribed, but which is leSS analge filed on Nov. 27, 2002, which is a continuation-in-part Sically effective or less rewarding when administered in of application No. 09/922,873, filed on Aug. 6, 2001, excess of prescription. Preferably, the combination product now Pat. No. 6,569,866, which is a continuation-in affects an opioid dependent individual differently from an part of application No. 09/152,834, filed on Sep. 14, opioid naive individual, and has a diminished likelihood of 1998, now Pat. No. 6,271,240, which is a continua being associated with a life-threatening adverse drug reac tion-in-part of application No. 08/866,334, filed on tion, especially in the opioid dependent individual. US 2004/0024006 A1 Feb. 5, 2004 OPOD PHARMACEUTICAL COMPOSITIONS dopamine released. Selective blockade of kappa-receptors Significantly increases dopamine release. RELATED APPLICATIONS 0006 Spanagel et al. demonstrate that tonically active 0001. This patent application is a continuation-in-part of and functionally opposing mu and kappa opioid Systems co-pending U.S. patent application Ser. No. 10/306,657 filed regulate meSolimbic dopamine release in the nucleus accum Nov. 27, 2002, which is a continuation-in-part of U.S. patent bens. They report that the injection of mu-opioid agonists application Ser. No. 09/922,873, filed Aug. 6, 2001, now such as DAGO into the VTA stimulate mu-opioid receptors U.S. Pat. No. 6,569,866, which is a continuation application and increase the release of dopamine from the VTA into the of U.S. patent application Ser. No. 09/152,834, filed Sep. 14, NA. AS would be expected, administration of a mu-opioid 1998, now U.S. Pat. No. 6,271,240, which is a continuation receptor antagonist into the VTA decreases dopamine in-part of U.S. patent application Ser. No. 08/866,334, filed release. The authors further report that kappa-opioid recep May 30, 1997, abandoned on May 12, 1998, and U.S. patent tors agonists such as U-6953 infused into the NA inhibit application Ser. No. 08/643,775, filed May 6, 1996, aban dopamine release there, whereas kappa-opioid receptor doned on Sep. 22, 1998, the disclosure of each which is antagonists Such as nor-BNI increase dopamine release. An hereby incorporated by reference. “agonist' is a "like chemical with Similar action to a given drug. An “antagonist' is a chemical, often with a similar FIELD OF INVENTION chemical Structure to a given drug, which exerts a dissimilar action to the given drug, in general preventing the "like' 0002 The present invention relates to novel pharmaceu action of that given drug. With opioid receptors, in general, tical compositions for improved administration of drugs of an agonist binds to the receptor and activates it in Such a way the opioid classification to a human or animal. as to begin a cascade of chemical or pharmacological events So as to result in the end effect related to a particular opioid BACKGROUND OF THE INVENTION receptor Subtype. In contradistinction, an antagonist will 0003. An opioid agonist analgesic is a drug or pharma bind to the receptor but not activate it. An antagonist exerts ceutical agent that traditionally is used to treat pain, to its actions by blocking the receptors from agonists, by SuppreSS coughing, to treat diarrhea, and for other medicinal physically occupying the Space on the receptor where an uses. Depending upon the degree with which a particular agonist would otherwise bind. opioid agonist medication binds to specific opioid receptor 0007. The opposing mu and kappa opioid systems acting Subtypes, Such as its affinity for one opioid Subtype receptor together provide a homeostasis of dopamine levels within in preference to another, the opioid agonist analgesic may the central nervous system. Changes in these opioid systems, tend to cause euphoria, or it may tend to cause dysphoria. Such as by activation or blockade of the Specific receptors, Some opioid analgesic agonists may also tend to cause would therefore be expected to modulate opioid-induced nausea by Stimulating or inhibiting areas in the brain known effects that are mediated by mesolimbic pathways. Mu and as “the Vomiting center” and “the chemotactic Zone,” kappa receptors are found elsewhere in the human body. For depending upon the degree with which specific opioid example, they have been located in the spinal cord (See receptor Subtypes are activated, and depending to Some Fujimoto, Bakshi and Behrmann, below) and in other non extent upon the ability of a particular opioid agonist anal central nervous System organs Such as the kidney and gesic to penetrate the blood-brain-barrier (BBB). Examples intestine (See Ohnishi and Kreek, below). Accordingly, the of opioid receptor Subtypes are delta-receptors, kappa-re model presented provides a neurochemical framework for ceptors, mu-receptors and Sigma receptors. These opioid understanding the adaptive changes resulting from long term receptor Subtypes may be further Subcategorized, as for use of opioids, as well as the clinical response elicited by example, mull-receptors and mu-receptors. exogenously administered opioid agonists and antagonists 0004. The opioid antagonist nalmefene has unique char having different binding profiles. acteristics which Set it apart from other opioid antagonists 0008 For example, Pan et al report modifications in Such as, for example, naloxone and naltrexone. The unique opioid-induced behavior resulting from changes in these mu opioid receptor Subtype binding profile of nalmefene enables and kappa Systems. These authors State that the effects of nalmefene alone, as compared to naloxone and naltrexone, opposing mu and kappa receptors extend to opioid action on to allow preferred antagonism of opioids at the kappa-opioid emotion, perception and drug reinforcement. While mor receptorS versus the mu-opioid receptors, which in turn phine and other mu-opioid agonists increase dopamine results in an optimal homeostatic balance of dopamine. release and produce euphoria and place preference, kappa 0005 Szekely shows a schematic representation of two opioid agonists reduce meSolimbic dopamine release and opposing opioid Systems located in the meSolimbic System produce dysphoria and aversion. of the human central nervous System. These Systems modu 0009 Scientists have shown that nalmefene, relative to late A10 dopaminergic neurons projecting in the nucleus other opioid antagonists Such as naloxone and naltrexone, is accumbens. AS illustrated in this reference, Stimulation of Significantly more kappa-receptor preferring. By way of mu-opioid receptors (the mu Subtype of opioid receptor) in example, Kreek et al. conclude that nalmefene has more the ventral tegmental area (VTA), the site of origin of the kappa binding activity than either naloxone or naltrexone. A10 neurons, increases dopamine release in the nucleus Specifically, nalmefene is more potent than either naloxone accumbens (NA). Selective blockade of this mu-receptor or naltrexone as a kappa-receptor antagonist, and therefore results in Significant decrease in dopamine release in the would block kappa agonists (e.g. the naturally occurring nucleus accumbens. In Stark contrast, Stimulation of kappa dynorphin) to a greater extent than the other antagonists. receptors (the kappa Subtype of opioid receptor) in either the 0010 Fujimoto et al. demonstrate differences between VTA or the NA results in a decrease in the amount of mu and kappa receptor effects in the Spinal cord. Specifi US 2004/0024006 A1 Feb. 5, 2004 cally, these authors report that the administration of dynor ing a third party to administer, or to observe Self-adminis phin, a potent kappa agonist, results in decreased analgesia. tration, of the opioid antagonist. For example, a "Squirt' The dynorphin causes antianalgesic effects at the level of the through the nares and onto the nasal mucosa would ensure Spinal cord. Fujimoto shows that when a kappa-opioid a delivered dose of antagonist Further, by bypassing the receptor antagonist Such as Cholera Toxin is given, the gastrointestinal tract, Such intranasal administration is much antianalgesic effect of dynorphin is inhibited. less likely to cause gastrointestinal upset. Intranasal admin istration has the further advantage, as does Sublingual 0.011 Bakshi et al. shows that kappa receptors are widely administration, of bypassing metabolism by the liver upon distributed in the Spinal cord, and that administration of initial administration. Metabolism of a drug by the liver after dynorphin causes motor impairment. These authorS also delivery to the gastrointestinal tract is generally referred to demonstrate that nalmefene is Selective for these intraspinal as “first pass metabolism,” and is a Significant disadvantage kappa receptors, and limits dynorphin induced motor dyS for per OS administration of many drugs. Nalmefene and function after Spinal cord injury.