Opioid antagonist compositions and dosage forms

#The present invention relates to novel dosage forms and pharmaceutical compositions containing a low dose of an opioid antagonist. The present invention also relates to dosage forms comprising an opioid antagonist and another active pharmaceutical ingredient, such as an opioid agonist.

#The pharmacology of opioid antagonist compounds is described in Goodman and Gillman, PHARMACOLOGICAL BASIS OF THERAPEUTICS, Chapter 22, “Opioid Antagonists,” incorporated by reference herein. Opioid antagonists include, but are not limited to, naloxone, cyclazocine, opioid antagonist compounds having the same pentacyclic nucleus as nalmefene, naltrexone, nalorphine, nalbuphine, thebaine, levallorphon, pentazocine, oxymorphine, butorphanol, bupremorphine, levorphanol, meptazinol, dezocine, or pentazocine or their pharmacologically effective salts or esters such as, but not limited to, their hydrochlorides, maleates, tartrates and lactates.

#The generally accepted use for opioid antagonists has been to treat overdoses and to prevent abuse of opioid agonists such as heroin or morphine. For these conventional uses, the antagonist such as naloxone or naltrexone is used in relatively high concentrations to effectively block the activity or effects of the opioid agonist. The previously employed high concentration of an opioid antagonist is believed to act antagonistically to the opioid agonist on a biochemical level at opioid receptors on nociceptive neurons.

#The following figures form part of the present description and describe exemplary embodiments of the claimed invention. The skilled artisan will, in light of these figures and the description herein, be able to practice the invention without undue experimentation.

#FIGS. 1A-1B is a flow diagram illustrating a method of manufacturing naltrexone capsule dosage forms according to a disclosed embodiment.

#FIG. 2 depicts an embodiment of an immediate release dosage form with two different types of coated nonpareil pellets.

#The present disclosure is directed to novel pharmaceutical compositions of very low doses of opioid antagonists. Novel dosage forms of such antagonists have been manufactured for the first time and administered to human subjects with unexpected benefits. Such novel dosage forms when administered to human subjects enhance the analgesic potency of opioid agonists and/or attenuate (e.g., reduce, block, inhibit or prevent) their adverse side effects and/or attenuate tolerance, withdrawal, dependence and/or addiction. For example, such novel dosage forms simultaneously enhance the analgesic potency of an opioid agonist while attenuating side effects of the agonist, or enhance the analgesic potency of an opioid agonist without attenuating side effects of the agonist, or maintain the analgesic potency of an agonist while attenuating side effects of the agonist, while at the same time or alternatively, attenuate tolerance, withdrawal, dependence and/or addiction. For compositions and methods of the invention that attenuate (e.g., reduce, block or prevent) an adverse effect of the opioid agonist, it is advantageous that the analgesic potency is maintained without increasing or decreasing the cumulative daily dose of agonist.

#The present invention includes the manufacture and use of new dosage forms of very small amounts of an opioid antagonist. Clinical trials have yielded surprising effects and benefits in humans. For example, using novel pharmaceutical compositions or dosage forms according to the invention, it was unexpectedly demonstrated that the analgesic potency effects of opioid agonists can be dissociated from their adverse effects in humans. Thus, for the first time, the present invention provides novel pharmaceutical compositions, dosage forms, kits, and methods to dose or treat humans with opioid antagonists. An opioid antagonist is provided in an amount from at least about 0.0001 mg to about or less than about 1.0 mg, or at least about 0.001 mg to about or less than about 1.0 mg, or at least about 0.01 mg to about or less than about 1.0 mg or at least about 0.1 mg to about or less than about 1 mg. Preferred ranges of opioid antagonists also include: from about 0.0001 mg to less than 1.0 mg; from about 0.001 mg to less than 1.0 mg; from about 0.01 mg to less than 1.0 mg; or from about 0.1 mg to less than 1.0 mg. Additional preferred ranges of opioid antagonists include from about 0.0001 mg to about 0.1 mg; from about 0.001 mg to about 0.1 mg; from about 0.01 mg to about 0.1 mg; from about 0.001 mg to about 0.1 mg; from about 0.001 mg to about 0.01 mg; or from about 0.01 mg to about 0.1 mg. Further preferred ranges of opioid antagonists include: from at least about 0.0001 to less than about 0.5 mg; from at least about 0.01 to less than about 0.5 mg; or from at least about 0.1 to less than about 0.5 mg.

#The term “opioid” refers to compounds or compositions including metabolites of such compounds or compositions which bind to specific opioid receptors and have agonist (activation) or antagonist (inactivation) effects at these receptors, such as opioid alkaloids, including the agonist morphine and its metabolite morphine-6-glucuronide and the antagonist naltrexone and its metabolite and opioid peptides, including enkephalins, dynorphins and endorphins. The opioid can be present in the present compositions as an opioid base, an opioid pharmaceutically acceptable salt, or a combination thereof. The pharmaceutically acceptable salt embraces an inorganic or an organic salt. Representative salts include hydrobromide, hydrochloride, mucate, succinate, n-oxide, sulfate, malonate, acetate, phosphate dibasic, phosphate monobasic, acetate trihydrate, bi(heplafluorobutyrate); maleate, bi(methylcarbamate), bi(pentafluoropropionate), mesylate, bi(pyridine-3-carboxylate), bi(trifluoroacetate), bitartrate, chlorhydrate, fumarate and sulfate pentahydrate. The term “opiate” refers to drugs derived from opium or related natural or synthetic analogs.