WO2009045985A1 - Treatment of drug-induced nausea with opioid antagonists - Google Patents

Treatment of drug-induced nausea with opioid antagonists Download PDF

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Publication number
WO2009045985A1
WO2009045985A1 PCT/US2008/078229 US2008078229W WO2009045985A1 WO 2009045985 A1 WO2009045985 A1 WO 2009045985A1 US 2008078229 W US2008078229 W US 2008078229W WO 2009045985 A1 WO2009045985 A1 WO 2009045985A1
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WIPO (PCT)
Prior art keywords
opioid antagonist
constipation
methylnaltrexone
lubiprostone
opioid
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PCT/US2008/078229
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English (en)
French (fr)
Inventor
Chu-Su Yuan
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The University Of Chicago
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Priority to JP2010528062A priority Critical patent/JP5905198B2/ja
Publication of WO2009045985A1 publication Critical patent/WO2009045985A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to methods of treating drug-induced gastrointestinal side effects such as nausea while enhancing treatment of constipation.
  • narcotic analgesics such as morphine and related opiates, meperidine, methadone and the like, which are given to ease pain, also produce nausea and emesis.
  • drugs commonly used for the treatment gastrointestinal disorders such as constipation, inflammatory bowel disease, irritable bowel syndrome and post-operative bowel dysfunction, are often associated with the development of nausea and emesis.
  • Such side effects often limit the usefulness of the drug and may even render the drug unacceptable for use.
  • compositions While numerous antinausea and antiemetic compositions exist, these compositions often produce their own undesired patient side-effects. The result is often that the patient is put in the position of choosing between the condition she or he seeks to alleviate and the side effect of the therapy.
  • the inventor has discovered effective antinausea and antiemetic formulations which have few side effects and permit use of therapeutic agents to effectively treat a condition or illness.
  • methods are provided for relieving gastrointestinal side effects, such as nausea and emesis, associated with the administration of certain drugs, specifically ion channel modulators, especially chloride channel activators, for the treatment of, e.g., constipation.
  • An illustrated embodiment of the invention provides methods of relieving, e.g., alleviating, inhibiting, attenuating, or reducing, nausea, including that associated with constipation treatment, by administering opioid antagonists, including, but not limited to, those that are peripherally restricted antagonists.
  • the invention provides methods of treating gastrointestinal disorders by co-administering a chloride channel activator and an opioid antagonist.
  • Such co-administered treatments may enhance laxation as well as treat nausea and other side effects.
  • synergy of the co-administered chloride channel activator and the opioid antagonist is contemplated as another aspect of the invention.
  • Chloride channel activators useful for the treatment of gastrointestinal disorders include type 2 chloride channel activators, such as lubiprostone.
  • nausea induced by treatment of gastrointestinal disorders with lubiprostone is alleviated by administering an opioid antagonist, such as the peripheral opioid antagonist methylnaltrexone.
  • Suitable chloride channel activators include prostaglandin derivatives.
  • one class suitably is derivatives and analogs of prostaglandin E1 (PGE 1 ), e.g., derivatives that are bicyclic fatty acids.
  • PGE 1 prostaglandin E1
  • Lubiprostone is a PGE 1 metabolite analog and is a chloride channel activator of particular value for the treatments of constipation.
  • Suitable opioid antagonists generally include heterocyclic amine compounds that belong to several different classes of compounds.
  • one class is suitably tertiary derivatives of morphinan, and in particular, tertiary derivatives of noroxymorphone.
  • the tertiary derivative of noroxymorphone is, e.g., naloxone or naltrexone.
  • the opioid antagonist is a peripheral opioid antagonist.
  • Suitable peripheral opioid antagonists are generally heterocyclic amine compounds that may belong to several different classes of compounds.
  • one class is suitably quaternary derivatives of morphinan, and in particular, quaternary derivatives of noroxymorphone.
  • the quaternary derivative of noroxymorphone is, e.g., N-methylnaltrexone (or simply methylnaltrexone), N-methylnaloxone, N-methylnalorphine, N-diallylnormorphine, N- allyllevallorphan, or N-methylnalmefene.
  • Another class is N-substituted piperidines.
  • the N-piperidine is a piperidine-N-alkylcarbonylate, such as, e.g., alvimopan.
  • Yet another class of compounds which may be of value in the methods of the present invention is quaternary derivatives of benzomorphans.
  • Another class of compounds suitable for the methods of the invention is normorphinan derivatives.
  • the normorphinan derivative is a 6-carboxy-normorphinan derivative.
  • the opioid antagonist may be a ⁇ - opioid antagonist. In other embodiments, the opioid antagonist may be a ⁇ -opioid antagonist.
  • the invention also encompasses administration of more than one opioid antagonist, including combinations of ⁇ -antagonists, combinations of ⁇ -antagonists, and combinations of ⁇ - and ⁇ -antagonists, for example, a combination of methylnaltrexone and alvimopan, or a combination of naltrexone and methylnaltrexone.
  • FIG. 1 is a graph demonstrating dose-dependent effects of pretreatment with methylnaltrexone (MNTX) on kaolin intake induced by lubiprostone (LBP).
  • MNTX methylnaltrexone
  • the invention provides methods of relieving, e.g., alleviating, inhibiting, attenuating, or reducing, gastrointestinal side effects, such as nausea and emesis, associated with the administration of certain drugs, specifically ion channel modulators, especially chloride channel activators, for the treatment of, e.g., constipation.
  • a polymer is stated as having 7 to 300 linked monomers, it is intended that values such as 7 to 25, 8 to 30, 9 to 90, or 50 to 300, as well as individual numbers within that range, for example 25, 50, and 300, are expressly enumerated in this specification.
  • Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc.
  • each range discussed herein can be readily broken down into a lower third, middle third, and upper third, etc.
  • compositions or methods may include additional ingredients and/or steps, but only if the additional ingredients and/or steps do not materially alter the basic and novel characteristics of the claimed composition or method.
  • Subject refers to mammals, e.g., humans, mice, dogs, cats.
  • Alkyl refers to a univalent aliphatic hydrocarbon group which is saturated and which may be straight, branched, or cyclic having from 1 to about 10 carbon atoms in the chain, and all combinations and subcombinations of chains therein.
  • exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • “Lower alkyl” refers to an alkyl group having 1 to about 6 carbon atoms.
  • Alkenyl refers to a univalent aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having from 2 to about 10 carbon atoms in the chain, and all combinations and subcombinations of chains therein.
  • exemplary alkenyl groups include, but are not limited to, vinyl, propenyl, butynyl, pentenyl, hexenyl, and heptnyl.
  • Alkynyl refers to a univalent aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and having from 2 to about 10 carbon atoms in the chain, and combinations and subcombinations of chains therein.
  • Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
  • Alkylene refers to a divalent aliphatic hydrocarbon group having from 1 to about 6 carbon atoms, and all combinations and subcombinations of chains therein.
  • the alkylene group may be straight, branched, or cyclic. There may be optionally inserted along the alkylene group one or more oxygen, sulfur, or optionally substituted nitrogen atoms, wherein the nitrogen substituent is an alkyl group as described previously.
  • alkenylene refers to a divalent alkylene group containing at least one carbon-carbon double bond, which may be straight, branched, or cyclic.
  • Cycloalkyl refers to a saturated monocyclic or bicyclic hydrocarbon ring having from about 3 to about 10 carbons, and all combinations and subcombinations of rings therein.
  • the cycloalkyl group may be optionally substituted with one or more cycloalkyl-group substituents.
  • Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • acyl means an alkyl-CO group wherein alkyl is as previously described.
  • exemplary acyl groups include, but are not limited to, acetyl, propanoyl, 2- methylpropanoyl, butanoyl, and palmitoyl.
  • Aryl refers to an aromatic carbocyclic radical containing from about 6 to about 10 carbons, and all combinations and subcombinations of rings therein.
  • the aryl group may be optionally substituted with one or two or more aryl group substituents.
  • Exemplary aryl groups include, but are not limited to, phenyl and naphthyl.
  • Aryl-substituted alkyl refers to a linear alkyl group, preferably a lower alkyl group, substituted at a terminal carbon with an optionally substituted aryl group, preferably an optionally substituted phenyl ring.
  • exemplary aryl-substituted alkyl groups include, for example, phenylmethyl, phenylethyl, and 3(4-methylphenyl)propyl.
  • Heterocyclic refers to a monocyclic or multicyclic ring system carbocyclic radical containing from about 4 to about 10 members, and all combinations and subcombinations of rings therein, wherein one or more of the members of the ring is an element other than carbon, for example, nitrogen, oxygen, or sulfur.
  • the heterocyclic group may be aromatic or nonaromatic.
  • Exemplary heterocyclic groups include, for example, pyrrole and piperidine groups.
  • Halo refers to fluoro, chloro, bromo, or iodo.
  • Peripheral in reference to opioid antagonists, designates opioid antagonists that act primarily on physiological systems and components external to the central nervous system. In other words, they exhibit reduced or substantially no central nervous system (CNS) activity. For example, they do not readily cross the blood- brain barrier in an amount effective to inhibit the central effects of opioids, i.e., they do not effectively inhibit the analgesic effects of opioids when administered peripherally, that is, they do not reduce the analgesic effect of the opioids.
  • the peripheral opioid antagonist compounds employed in the methods of the invention suitably exhibit less than about 5-15% of their pharmacological activity in the CNS, with about 0% (i.e., no) CNS activity, being most suitable.
  • peripheral opioid antagonists are often related to charge, polarity, and/or size of the molecule or species.
  • peripherally-acting quaternary amine opioid antagonists as described herein are positively charged while the central-acting tertiary amine opioid antagonists are neutral molecules.
  • the peripheral opioid antagonists useful in the present invention are typically mu and/or kappa opioid antagonists.
  • phrases "pharmaceutically acceptable” or “pharmacologically acceptable” are meant to refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a subject such as a human.
  • the opioid antagonists in accordance with the invention may be formulated as a free base, neutral or in a salt form.
  • a “pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts are non-toxic conventional salts and quaternary ammonium salts of the compounds in accordance with the invention that have properties acceptable for therapeutic use.
  • Such salts may be prepared, e.g., from inorganic or organic bases or acids.
  • acid addition salts may include acetate, ascorbate, benzoate, bisulfate, chloride, citrate, lactate, maleate, oxalate, sulfonate, tartrate and the like.
  • Base salts may include alkali metal salts such as potassium and sodium salts, alkaline earth metals such as calcium and magnesium salts and ammonium salts with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like.
  • basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides, as well as long chain halides, and dialkyl or diamyl sulfates.
  • lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides, as well as long chain halides, and dialkyl or diamyl sulfates.
  • potency is meant to refer to the ability or capacity of a chloride channel activator to relieve constipation, i.e., to induce laxation, in a subject suffering from constipation. Potency may also be expressed as the dose of a drug required to produce a specific effect of a given intensity.
  • side effect is meant to refer to an effect other than the purpose or desired effect of a drug.
  • Side effects may be beneficial or undesirable, i.e., adverse.
  • undesirable effects often occur after the administration of a chloride channel activator such as lubiprostone.
  • Such undesirable side effects include gastrointestinal side effects such as nausea, emesis, diarrhea, and abdominal distention and pain.
  • treating or “treatment” used herein include any means of control of a medical condition such as prevention, care, relief of the condition, attenuation, alleviation, a reduction of the condition, and inhibition or arrest of progression of the pathological condition.
  • compositions and methods utilizing a combination of a chloride channel activator, for example, a type 2 chloride channel activator such a lubiprostone, and an opioid antagonist.
  • a chloride channel activator for example, a type 2 chloride channel activator such a lubiprostone
  • an opioid antagonist such as methylnaltrexone
  • unexpectedly treated the gastrointestinal side effects of lubiprostone and may also have value in enhancing the anti-constipation (i.e., laxative) potency of lubiprostone.
  • the invention also provides methods of treating a gastrointestinal disorder which may include chronic idiopathic constipation, opioid-induced bowel dysfunction, opioid-induced constipation, postoperative ileus, irritable bowel syndrome, irritable bowel syndrome with constipation, gastrointestinal motility disorder, functional gastrointestinal disorder, gastroesophageal reflux disease, duodenogastric reflux, functional heartburn, dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, or colonic pseudo-obstruction, by co-administering a chloride channel activator and an opioid antagonist.
  • the co-administered treatment may enhance laxation as well as treat side effects of the chloride channel activator such as nausea, and thus give rise to a synergy of the chloride channel activator and the opioid antagonist, when coadministered.
  • Chloride channel activators of particular interest in accordance with the present invention are prostaglandin E 1 (PGE 1 ) derivatives or metabolites. See, e.g., U.S. Patents 7,064,148, 6,982,283, and 7,253,295, each of which is hereby incorporated by reference.
  • PGE 1 prostaglandin E 1
  • Lubiprostone which is a PGE 1 metabolite analog.
  • Lubiprostone is a bicyclic fatty acid, shown in formula (A) below, which activates type 2 chloride channels in the lining of the small intestine. This leads to an increase in intestinal fluid secretion and improves the passage of stool. The result is the alleviation of the symptoms due to constipation including abdominal discomfort and pain, and bloating.
  • Lubiprostone is approved for marketing in the United States for the indications chronic idiopathic constipation and irritable bowel syndrome with constipation.
  • Lubiprostone has undesirable side effects which include nausea and emesis as well as abdominal distention and pain, diarrhea, headache and sinusitis.
  • the opioid antagonists in accordance with the present invention include both centrally and peripherally acting opioid antagonists. It is contemplated that those antagonists of particular value are suitably the peripherally restricted opioid antagonists. Especially suitable may be a ⁇ opioid antagonist, especially a peripheral ⁇ opioid antagonist.
  • Opioid antagonists form a class of compounds that can vary in structure while maintaining their peripherally restrictive properties. These compounds include tertiary and quaternary morphinans, in particular noroxymorphone derivatives, N-substituted piperidines, and in particular, piperidine-N-alkylcarboxylates, tertiary and quaternary benzomorphans, and normorphinan derivatives, in particular 6-carboxy-normorphinan derivatives.
  • Peripherally restricted antagonists while varied in structure, are typically charged, polar, and/or of high molecular weight, each of which impedes their crossing the blood-brain barrier.
  • opioid antagonists that cross the blood-brain barrier and are centrally (and peripherally) active, include, e.g., naloxone, naltrexone (each of which is commercially available from Baxter Pharmaceutical Products, Inc.), and nalmefene (available, e.g., from DuPont Pharma). These may have value in treating nausea, such as drug-induced nausea, as well as other adverse effects in patients being treated for constipation.
  • a peripheral opioid antagonist useful for the present invention may be a compound which is a quaternary morphinan derivative, and in particular, a quaternary noroxymorphone of formula (I): wherein R is alkyl, alkenyl, alkynyl, aryl, cycloalkyl-substituted alkyl, or arylsubstituted alkyl, and X " is the anion, for example, a chloride, bromide, iodide, or methylsulfate anion.
  • the noroxymorphone derivatives of formula (I) can be prepared, for example, according to the procedure in U.S. Patent No. 4,176,186, which is incorporated herein by reference; see also, U.S.
  • a compound of formula (I) of particular value is N-methylnaltrexone (or simply methylnaltrexone), wherein R is cyclopropylmethyl as represented in formula (II):
  • Methylnaltrexone is a quaternary derivative of the opioid antagonist naltrexone. Methylnaltrexone exists as a salt, and "methylnaltrexone” or “MNTX”, as used herein, therefore embraces salts. "Methylnaltrexone” or “MNTX” specifically includes, but is not limited to, bromide salts, chloride salts, iodide salts, carbonate salts, and sulfate salts of methylnaltrexone.
  • names used for the bromide salt of MNTX include: methylnaltrexone bromide; N-methylnaltrexone bromide; naltrexone methobromide; naltrexone methyl bromide; SC-37359; MRZ-2663-BR; and N- cyclopropylmethylnoroxy-morphine-methobromide.
  • Methylnaltrexone is commercially available from, e.g., Mallinckrodt Pharmaceuticals, St. Louis, Mo. Methylnaltrexone is provided as a white crystalline powder, freely soluble in water, typically as the bromide salt. The compound as provided is 99.4% pure by reverse phase HPLC, and contains less than 0.011 % unquaternized naltrexone by the same method. Methylnaltrexone can be prepared as a sterile solution at a concentration of, e.g., about 5 mg/mL.
  • peripheral opioid antagonists may include N-substituted piperidines, and in particular, piperidine-N-alkylcarboxylates as represented by formula (III):
  • R 1 is hydrogen or alkyl
  • R 2 is hydrogen, alkyl, or alkenyl
  • R 3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl- substituted alkyl, or aryl-substituted alkyl
  • R 4 is hydrogen, alkyl, or alkenyl
  • R 7 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycl
  • R 8 is hydrogen or alkyl
  • R 9 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aryl- substituted alkyl or together with the nitrogen atom to which they are attached, R 8 and R 9 form a heterocyclic ring selected from pyrrole and piperidine
  • W is OR 10 , NR 11 R 12 , or OE; wherein R 10 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl- substituted alkyl, cycloalkenyl-substituted alkenyl, or aryl-substituted alkyl;
  • R 11 is hydrogen or alkyl;
  • R 12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
  • R 17 is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R 16 and R 17 form a heterocyclic ring selected from the group consisting of pyrrole or piperidine;
  • Y is OR 18 or NR 19 R 20 ; wherein R 18 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R 19 is hydrogen or alkyl; R 20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkylsubstituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or, together with the nitrogen atom to which they are attached, R 19 and R 20 form a heterocyclic ring selected from pyrrole and piperidine; R 21 is hydrogen or alkyl; and n is 0 to 4. Particular piperidine-N-alkylcarbonylates which may be of value are N
  • Suitable N-substituted piperidines may be prepared as disclosed in U.S.
  • Patent Nos. 5,270,328; 6,451 ,806; 6,469,030 all of which are hereby incorporated by reference.
  • Alvimopan is available from Adolor Corp., Exton, PA.
  • Such compounds have moderately high molecular weights, a zwitterion form, and a polarity, any of which may prevent penetration of the blood-brain barrier.
  • peripheral opioid antagonist compounds may include quaternary benzomorphan compounds.
  • R 1 is hydrogen, acyl, or acetoxy; and R 2 is alkyl or alkenyl; R is alkyl, alkenyl, or alkynyl and X " is an anion, for example, a chloride, bromide, iodide, or methylsulfate anion.
  • V Specific quaternary derivatives of benzomorphanium-bromide.
  • peripheral opioid anatagonists may include 6-carboxy-normorphinan derivatives, particularly N-methy-C-normorphinan derivatives, as described in U.S. Application Serial No. 1 1/888,955, entitled “6-Carboxy-Normorphinan Derivatives, Synthesis and Uses Thereof,” hereby incorporated in its entirety herein by reference.
  • compounds of the invention may suitably exist and be formulated as pharmaceutically acceptable salts.
  • prodrug is intended to include any covalently bonded carriers which release the active parent drug according to formulas (I) to (V) or other formulas or compounds employed in the methods of the present invention in vivo when such prodrug is administered to a mammalian subject. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compounds employed in the present methods may, if desired, be delivered in prodrug form. Thus, the present invention contemplates methods of delivering prodrugs. Prodrugs of the compounds employed in the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • prodrugs include, for example, compounds described herein in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or carboxylic acid, respectively.
  • Examples include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups; and alkyl, carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl, iso- propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, and phenethyl esters, and the like.
  • the compounds employed in the methods of the present invention may be prepared in a number of ways well known to those skilled in the art. All preparations disclosed in association with the present invention are contemplated to be practiced on any scale, including milligram, gram, multigram, kilogram, multikilogram, or commercial pharmaceutical scale.
  • Compounds employed in methods of the inventions may contain one or more asymmetrically-substituted carbon atoms, and may be isolated in optically active or racemic form.
  • optically active or racemic form all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare and isolate such optically active forms.
  • mixtures of stereoisomers may be separated by standard techniques including, but not limited to, resolution of racemic form, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral centers.
  • the opioid antagonist may be a ⁇ opioid antagonist. In other embodiments, the opioid antagonist may be a K opioid antagonist.
  • the invention also encompasses administration of more than one opioid antagonist, including combinations of ⁇ antagonists, combinations of K antagonists, and combinations of ⁇ and K antagonists, for example, a combination of methylnaltrexone and alvimopan.
  • the methods of this invention may be practiced using any mode of administration that is medically acceptable, e.g., any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects.
  • modes of administration include oral, rectal, topical (as by powder, ointment, drops, transdermal patch, or iontophoretic device), transdermal, sublingual, intramuscular, infusion, intravenous, pulmonary, intramuscular, intracavity, as an aerosol, aural (e.g., via eardrops), intranasal, inhalation, intraocular, or subcutaneous.
  • the compounds of the invention are given in pharmaceutically acceptable amounts and in pharmaceutically acceptable compositions or preparations.
  • Such preparations may routinely contain salts, buffering agents, preservatives, and optionally other therapeutic ingredients.
  • the salts When used in medicine, the salts should be pharmaceutically acceptable, but non- pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention.
  • pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluenesulfonic, tartaric, citric, methanesulfonic, formic, succinic, naphthalene-2- sulfonic, pamoic, 3-hydroxy-2-naphthalenecarboxylic, and benzene sulfonic.
  • Suitable buffering agents include, but are not limited to, acetic acid and salts thereof (1-2% w/v); citric acid and salts thereof (1-3% w/v); boric acid and salts thereof (0.5-2.5% w/v); and phosphoric acid and salts thereof (0.8-2% w/v).
  • Suitable preservatives include, but are not limited to, benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v); and thimerosal (0.004-0.02% w/v).
  • a pharmaceutical composition of the peripheral opioid antagonist may also contain one or more pharmaceutically acceptable excipients, such as lubricants, diluents, binders, carriers, and disintegrants.
  • auxiliary agents may include, e.g., stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, coloring, flavoring, and/or aromatic active compounds.
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type.
  • suitable pharmaceutically acceptable carriers, diluents, solvents, or vehicles include, but are not limited to, water, salt (buffer) solutions, alcohols, gum arabic, mineral and vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, vegetable oils, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxyl methylcellulose, polyvinyl pyrrolidone, etc.
  • Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • Prevention of the action of microorganisms may be ensured by the inclusion of various antimicrobial, e.g., antibacterial and antifungal, agents such as paraben, chlorobutanol, phenol, sorbic acid and the like.
  • the dosage form of the compounds suitable for use in methods of the invention may be tablets, capsules, powders, suppositories, or lozenges. If a liquid carrier is used, soft gelatin capsules, transdermal patches, aerosol sprays, topical cream, syrups or liquid suspensions, emulsions, or solutions may be the dosage form.
  • injectable, sterile solutions preferably nonaqueous or aqueous solutions, as well as dispersions, suspensions, emulsions, or implants, including suppositories.
  • Ampoules are often convenient unit dosages.
  • injectable depot-form may also be suitable and may be made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide- polyglycolide, poly(orthoesters), and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled.
  • Suitable enteral application particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules such as soft gelatin capsules.
  • a syrup, elixir, or the like can be used wherein a sweetened vehicle is employed.
  • kits may include time-release, delayed-release, or sustained-release delivery system. Such systems can avoid repeated administrations of the compounds of the invention, increasing convenience to the patient and the physician and maintain sustained plasma levels of compounds.
  • Many types of controlled-release delivery systems are available and known to those of ordinary skill in the art.
  • Sustained- or controlled-release compositions can be formulated, e.g., as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc.
  • the opioid antagonists in accordance with the invention may be administered as an enterically coated tablet or capsule.
  • the opioid antagonist is administered by a slow infusion method or by a time-release or controlled-release method or as a lyophilized powder.
  • compounds in accordance with the invention may be combined with pharmaceutically acceptable sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.
  • sustained-release matrix is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid-base hydrolysis or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids.
  • a sustained-release matrix may be desirably chosen from biocompatible materials such as liposomes, polymer-based system such as polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid), polyanhydrides, poly(ortho)esters, polysaccharides, polyamino acids, hyaluronic acid, collagen, chondroitin sulfate, polynucleotides, polyvinyl propylene, polyvinyl pyrrolidone, and silicone; nonpolymer systems such as carboxylic acids, fatty acids, phospholipids, amino acids, lipids such as sterols, hydrogel release systems; silastic systems; peptide-based systems; implants and the like.
  • biocompatible materials such as liposomes
  • polymer-based system such as polylactides (polylactic acid), polyglycolide (polymer of glycolic acid),
  • aqueous formulations may include a chelating agent, a buffering agent, an anti-oxidant and, optionally, an isotonicity agent, preferably pH adjusted to between 3.0 and 3.5.
  • a chelating agent preferably a chelating agent, a buffering agent, an anti-oxidant and, optionally, an isotonicity agent, preferably pH adjusted to between 3.0 and 3.5.
  • 11/899,724 and formulations comprising particles containing methylnaltrexone are described in U.S. Patent No. 6,419,959, which is incorporated herein by reference.
  • Formulations suitable for transdermal delivery of methylnaltrexone are described in International Patent Publication No. 2007/41544, hereby incorporated by reference.
  • compounds in accordance with the invention are administered in a continuous dosing regimen of the compound to a subject, e.g., a regimen that maintains minimum plasma levels of the opioid antagonist, and preferably eliminates the spikes and troughs of a drug level with conventional regimens.
  • a continuous dose may be achieved by administering the compound to a subject on a daily basis using any of the delivery methods disclosed herein.
  • the continuous dose may be achieved using continuous infusion to the subject, or via a mechanism that facilitates the release of the compound over time, for example, a transdermal patch, or a sustained release formulation.
  • compounds of the invention are continuously released to the subject in amounts sufficient to maintain a concentration of the compound in the plasma of the subject effective to inhibit or reduce nausea induced by treatment with a chloride channel activator such as lubiprostone.
  • Compounds in accordance with the invention are provided in an anti-nausea effective amount. It will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts.
  • one technique is to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the effective daily dose may be divided into multiple doses for purposes of administration. Consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • those of ordinary skill in the art can readily optimize effective doses and co-administration regimens (as described herein) as determined by good medical practice and the clinical condition of the individual patient.
  • oral doses of the opioid antagonists will range from about 0.01 to about 80 mg/kg body weight per day. It is expected that oral doses in the range from 1 to 20 mg/kg body weight will yield the desired results.
  • parenteral administration including intravenous and subcutaneous administration, will range from about 0.001 to 5 mg/kg body weight. It is expected that doses ranging from 0.05 to 0.5 mg/kg body weight will yield the desired results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending on the mode of administration. For example, it is expected that the dosage for oral administration of the opioid antagonists in an enterically coated formulation would be from 10 to 30% of the non-coated oral dose.
  • the opioid antagonists are coadministered with a chloride channel activator, e.g., lubiprostone.
  • a chloride channel activator e.g., lubiprostone.
  • coadministration is meant to refer to a combination therapy by any administration route in which two or more agents are administered to a patient or subject. Co- administration of agents may also be referred to as combination therapy or combination treatment.
  • the agents may be in the same dosage formulations or separate formulations.
  • the active agents can be administered concurrently, or they each can be administered at separately staggered times.
  • the agents may be administered simultaneously or sequentially (e.g., one agent may directly follow administration of the other or the agents may be given episodically, e.g., one can be given at one time followed by the other at a later time, e.g., within a week), as long as they are given in a manner sufficient to allow both agents to achieve effective concentrations in the body.
  • the agents may also be administered by different routes, e.g., one agent may be administered intravenously while a second agent is administered intramuscularly, intravenously, or orally.
  • the co-administration of the opioid antagonist compound in accordance with the present invention with, e.g., lubiprostone is suitably considered a combined pharmaceutical preparation which contains an opioid antagonist and lubiprostone, the preparation being adapted for the administration of the peripheral opioid antagonist on a daily or intermittent basis, and the administration of lubiprostone on a daily or intermittent basis.
  • the opioid antagonists may be administered prior to, concomitant with, or after administration of lubiprostone. Particularly suitable is administration of the opioid antagonist prior to administration of lubiprostone.
  • Co-administrable agents also may be formulated as an admixture, as, for example, in a single formulation or single tablet. These formulations may be parenteral or oral, such as the formulations described, e.g., in U.S. Patent Nos.
  • Example 1 Animal model for nausea
  • Rats react to emetic stimuli by altered feeding habits, manifested as increased consumption of non-nutritive substances such as kaolin (a type of clay), known as pica (Mitchell et al., 1976; Takeda et al., 1993; Takeda et al., 1995).
  • kaolin a type of clay
  • pica Mitsubishi kaolin
  • Rats Male Wistar strain rats (Harlan Sprague Dawley, Indianapolis, IN) weighing between 150-300 g were used. All the animals were housed in standard isolation cages (45cm x 35cm x 25cm) in environmentally controlled conditions with a 12 hr light/12 hr dark cycle. Rats were allowed free access to water, standard laboratory rat chow (Harlan-Teklad, Madison, Wl), and kaolin (see below), placed in separated containers continuously available throughout the experiment.
  • Kaolin was prepared based on the method previously described (Mitchell et al., 1976; Takeda et al., 1995). In brief, 99 g of pharmacological grade kaolin (or hydrated aluminum silicate; Fisher, Fair Lawn, NJ) was mixed with 1 g of acacia (Fisher), i.e., in a 99:1 ratio, with distilled water to form a thick paste. The paste was rolled on stainless steel tray and cut into pieces in the shape and size similar to regular rat chow pellets. The pellets were placed on steel trays, and completely dried at room temperature for 72 hr.
  • Vehicle, naloxone, or methylnaltrexone (MNTX) pretreatments were administered intraperitoneally, 30 min prior to each lubiprostone administration. Rats were observed immediately and at hr 2 to ensure that animals were not distressed and were comfortable. The animals did not demonstrate any signs of adverse effects such as restlessness, respiratory distress, or diarrhea following test drug administrations.
  • kaolin intake increased significantly compared to the vehicle group (P ⁇ 0.01 ), indicating that lubiprostone induces nausea.
  • This kaolin intake increase was attenuated significantly by 30 ⁇ g/kg naloxone (a non-selective opioid antagonist) administration (P ⁇ 0.01 ). 2.
  • naloxone a non-selective opioid antagonist
  • Methylnaltrexone significantly attenuated the lubiprostone-induced nausea. Methylnaltrexone, thus, may have a clinical value in decreasing lubiprostone-induced nausea when co-administered with lubiprostone.
  • naloxone may be effective in cases of idiopathic constipation (Kreek et al., 1983) and irritable bowel syndrome (Hawkes et al., 2002).
  • a prior in vitro study of the inventors demonstrated that methylnaltrexone reversed morphine-induced inhibition of contraction elicited by electrical stimulation in isolated guinea-pig ileum and human small intestine (Yuan et al., 1995).
  • An interesting observation in this study was that when methylnaltrexone alone was applied to the tissue bath, the force produced by muscle contraction was enhanced in a dose-related manner up to 27% compared to control level, suggesting an inhibitory modulation by endogenous opioids in these two species.
  • the enhancement of muscle contraction in isolated human intestine is significantly greater than that in guinea-pig ileum tissue, indicating that endogenous opioid action in the regulation of human gastrointestinal motility may be stronger.
  • opioid antagonists may have a therapeutic role.
  • methylnaltrexone acts peripherally on the gastrointestinal tract and may have potential as a prokinetic agent when endogenous opioids in the periphery contribute to human pathology.
  • methylnaltrexone can not only attenuate lubiprostone-induced nausea, but may also enhance lubiprostone's effects on chronic constipation, i.e., the agent may work synergistically.
  • the invention provides methods for relieving drug-induced gastrointestinal side effects, such as nausea induced by an anti-constipation agent, e.g., lubiprostone-induced nausea, utilizing opioid antagonists, particularly, peripherally restricted opioid antagonists, such as methylnaltrexone.
  • opioid antagonists particularly, peripherally restricted opioid antagonists, such as methylnaltrexone.
  • the opioid antagonist may enhance the anticonstipation effects of anticonstipation agents such as type 2 chloride channel activators, e.g., lubiprostone.
  • type 2 chloride channel activators may enhance the effects of opioid antagonists in the treatment of gastrointestinal disorders, including but not limited to chronic idiopathic constipation, opioid-induced bowel dysfunction, opioid-induced constipation, postoperative ileus, irritable bowel syndrome, irritable bowel syndrome with constipation, gastrointestinal motility disorder, functional gastrointestinal disorder, gastroesophageal reflux disease, duodenogastric reflux, functional heartburn, dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, or colonic pseudoobstruction.
  • opioid antagonists in the treatment of gastrointestinal disorders, including but not limited to chronic idiopathic constipation, opioid-induced bowel dysfunction, opioid-induced constipation, postoperative ileus, irritable bowel syndrome, irritable bowel syndrome with constipation, gastrointestinal motility disorder, functional gastrointestinal disorder, gastroesophageal reflux disease, duodenogastric reflux, functional heartburn, dyspepsia, gastroparesis, chronic intestinal pseudo-

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