WO2015188005A1 - Nouvelles compositions de (r)-isometheptène et utilisations - Google Patents

Nouvelles compositions de (r)-isometheptène et utilisations Download PDF

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WO2015188005A1
WO2015188005A1 PCT/US2015/034292 US2015034292W WO2015188005A1 WO 2015188005 A1 WO2015188005 A1 WO 2015188005A1 US 2015034292 W US2015034292 W US 2015034292W WO 2015188005 A1 WO2015188005 A1 WO 2015188005A1
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salt
isometheptene
pain
headache
pharmaceutical composition
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Seth Lederman
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Seth Lederman
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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
    • A61K31/13—Amines
    • A61K31/131—Amines acyclic
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/20—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
    • C07C211/21—Monoamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • Racemic isometheptene (( RS) ⁇ isometheptene) is a non-ergot vasoconstrictor agent that has been used in the treatment of tension headache, vascular headache and migraine headache either alone or in a combination drug product. Racemic isometheptene is believed to be a cerebrovascular constrictor and may act by reducing pressure on the pain producing areas surrounding blood vessels. Racemic isometheptene has been shown to increase heart, rate and diastolic blood pressure, which are properties associated with sympathomimetic agents.
  • the heart rate increase has been shown to be blocked by propranolol, a non-selective ⁇ -adrenergic receptor antagonist, while the diastolic blood pressure increase has been shown to be blocked by prazosin, an «i -adrenergic receptor antagonist.
  • prazosin an «i -adrenergic receptor antagonist.
  • Moxonidine is believed to function as an agonist of the imidazoiine-Ii receptor.
  • known imidazoline dmgs with a postulated high affinity to the imidazoline-I j receptor are AGN 192403, riimenidine, and clonidine.
  • Specific ligands of the imidazoline-]] receptor are 2-BF1 and BU239.
  • the putative natural ligand for imidazoline Ii, , and h receptors is agmatine.
  • Idazoxan is believed to function as antagonist of the It and receptors. (Radwanska A, Dlugokecka J, Wasilewski R, aliszan R. J Physiol Pharmacol.
  • the invention provides an (R)-isometheptene salt, wherein the (R)-isometheptene salt is characterized by a differential scanning caiorimetry heating curve which shows an endothermic heat flow peak between 45 °C and 145 °C, In some embodiments, the (R)-isometheptene salt is characterized by a differential scanning caiorimetry heating curve which shows an endothermic heat flow peak between 45 °C and 130 °C.
  • the invention provide an ( )-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt.
  • the (R)-isometheptene salt is a maleate salt
  • the (R)- isometheptene maleate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 1 12 °C and 120 °C.
  • the (R)-isometheptene maleate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6.3, 19.1 , 24.2, 25.5, and 32.1 degrees two theta when measured using a Cu X-ray source
  • the (R)-isometheptene maleate salt is characterized by an X-ray powder diffraction pattern with peaks at 6.3, 19.1 , 24.2, 25.5, and 32.1 degrees two theta when measured using a Cu X-ray source.
  • the (R)-isometheptene maleate salt is characterized by the X-ray powder diffraction pattern of Figure 2 when measured using a Cu X- ray source.
  • the (R)-isometheptene salt is a L-malate salt
  • the (R.)- isometheptene L-malate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 74° C and 83° C.
  • the (R)-isometheptene malate salt is characterized by an X-ray powder diffraction pattern with peaks at about 5.9, 6.1 , 14.8, 16.0, 17.1 , 18.1 , 18.3, 20.8, 21.2, and 25.4 degrees two theta when measured using a Cu X-ray source
  • the (R)-isometheptene malate salt is characterized by an X-ray powder diffraction pattern with peaks at 5.9, 6.1 , 14.8, 16.0, 17.1 , 1 8.1 , 1 8.3, 20.8, 21 ,2, and 25.4 degrees two theta when measured using a Cu X-ray source.
  • the (R)-isometheptene malate salt is characterized by the X-ray powder diffraction pattern of Figure 4 when measured using a Cu X-ray source.
  • the (R)-isometheptene salt is a L-tartrate salt
  • the (R.)- isometheptene L-tartrate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 83 °C and 89 °C.
  • the (R)-isometheptene L-tartrate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6.1 , 12.1 , 14.2, 17.3, 17.7, 22.3, 24.3, and 26.5 degrees two theta when measured using a Cu X-ray source.
  • the (R ' )-isometheptene L-tartrate salt is characterized by an X-ray powder diffraction pattern with peaks at 6.1 , 12. 1 , 14.2, 17.3, 17.7, 22.3, 24.3, and 26.5 degrees two theta when measured using a Cu X-ray source.
  • the (R)-isometheptene L-tartrate salt is characterized by the X-ray powder diffraction pattern of Figure 6 when measured using a Cu X-ray source.
  • the (R)-isometheptene salt is a citrate salt
  • the (R) ⁇ isometheptene citrate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 65 °C and 75 °C.
  • the (R)-isomemeptene citrate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6.5, 16.0, 19.2, 19.6, 21.0, 21.4, 26.3, and 31.3 degrees two theta when measured using a Cu X-ray source.
  • the (R)-isometheptene citrate salt is
  • the (R)-isometheptene citrate salt is characterized by the X-ray powder diffraction pattern of Figure 8 when measured using a Cu X-ray source.
  • the (R)-isometheptene salt is the cyclamate salt
  • the (Rj- isometheptene cyclamate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 71 °C and 81 °C.
  • the (R)-isometheptene cyclamate salt is characterized by an X-ray powder diffraction pattern with peaks at about 5.4, 5.9, 16.4, 16.9, 20.2, and 21.9 degrees two theta when measured using a Cu X-ray source.
  • the (R)-isometheptene cyclamate salt is characterized by an X-ray powder diffraction pattern with peaks at 5.4, 5.9, 16.4, 16.9, 20.2, and 21.9 degrees two theta when measured using a Cu X-ray source.
  • the (R)-isometheptene cyclamate salt is characterized by the X-ray powder diffraction pattern of Figure 10 when measured using a Cu X-ray source.
  • the (R)-isomethept.ene salt is a fumarate salt
  • the (Rj- isometheptene fumarate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 105 °C and 115 °C.
  • the (R)-isometheptene fumarate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6.2, 6.3, 19.1, 20.6, 24.1, 25.2, 25.6, and 32.2 degrees two theta when measured using a Cu X-ray source.
  • the (R -isometheptene fumarate salt is characterized by an X-ray powder diffraction pattern with peaks at 6.2, 6.3, 19.1, 20.6, 24.1 , 25.2, 25.6, and 32,2 degrees two theta when measured using a Cu X-ray source.
  • the (R ' )-isometheptene fumarate salt is characterized by the X-ray powder diffraction pattern of Figure 12 when measured using a Cu X-ray source.
  • the (R)-isometheptene salt is a hippurate salt
  • the (R)- isometheptene hippurate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 107 °C and 117 °C.
  • the (R)-isometheptene hippurate salt is characterized by an X-ray powder diffraction pattern with peaks at about 5.2, 10.4, 15.7, 19.4, and 26.4 degrees two theta when measured using a Cu X-ray source.
  • the (R)-isometheptene hippurate salt is characterized by an X-ray powder diffraction pattern with peaks at 5.2, 10.4, 15.7, 19.4, and 26.4 degrees two theta when measured using a Cu X-ray source
  • the ( )-isometheptene hippurate salt is characterized by the X-ray powder diffraction pattern of Figure 14 when measured using a Cu X-ray source.
  • the (R)-isometheptene salt is the phosphate salt
  • the (R)- isometheptene phosphate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 123 °C and 133 °C.
  • the (R)-isometheptene phosphate salt is characterized by an X-ray powder diffraction pattern with peaks at about 7,2, 14, 4, 14.9, 20.7, 22.7, and 23.4 degrees two theta when measured using a Cu X-ray source.
  • the (R)-isometheptene phosphate salt is characterized by an X-ray powder diff action pattern with peaks at 7.2, 14.4, 14.9, 20.7, 22.7, and 23.4 degrees two theta when measured using a Cu X-ray source.
  • the (R -isometheptene phosphate salt is characterized by the X-ray powder diffraction pattern of Figure 16 when measured using a Cu X-ray source.
  • the (R)-isometheptene salt is the succinate salt
  • the 01)- isometheptene succinate salt is characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 48 °C and 58 °C.
  • the (R)-isometheptene succinate salt is characterized by an X-ray powder diffraction pattern with peaks at about 6.2, 18.5, 18.7, 21.1, 22.6, 23.9, 24.7, and 25.0 degrees two theta when measured using a Cu X-ray source
  • the (R)-isometheptene succinate salt is characterized by an X-ray powder diffraction pattern with peaks at 6,2, 18,5, 18.7, 21.1, 22.6, 23.9, 24.7, and 25,0 degrees two theta when measured using a Cu X-ray source
  • the (R)-isometheptene succinate salt is characterized by the X-ray powder diffraction pattern of Figure 18 when measured using a Cu X-ray source
  • the (R)-isometbeptene salt is in a crystalline form.
  • the invention provides a phannaceutical composition comprising an (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyciamate, fumarate, hippurate, phosphate or succinate salt, and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising a crystalline (R)-isometheptene maleate salt.
  • the invention provides a pharmaceutical composition comprising a crystalline (R)-isometheptene L-malate salt.
  • the invention provides a pharmaceutical composition comprising a crystalline (R)-isometheptene L-tartrate salt.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline (R)-isometheptene citrate salt, a crystalline (R)-isometheptene cyciamate salt, a crystalline (R)-isometheptene fumarate salt, a crystalline (R)-isometheptene hippurate salt, a crystalline (R)-isometheptene phosphate salt, or a crystalline (R)-isometheptene succinate salt.
  • the pharmaceutical composition comprises a crystalline (R)- isometheptene salt described herein, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises any one of the crystalline (R)- isometheptene salts listed in Tables 1-6 or a combination thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises any one of the crystalline (R)-isometheptene salts of Figures 1-18 or a combination thereof, and a pharmaceutically acceptable carrier. [0023 J In some embodiments, the invention provides a method for treating or preventing a condition selected from the group consisting of pain; central sensitization; centralization;
  • nociceptive pain nociceptive pain; post-operative pain; orthopedic injuiy pain; phantom limb pain; pain associated with cancer; pain associated with post-traumatic stress disorder (PTSD); a headache; an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; depression;
  • isometheptene salt wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyciamate, fumarate, hippurate, phosphate or succinate salt, or a therapeutically effective amount of a pharmaceutical composition comprising a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyciamate, fumarate, hippurate, phosphate or succinate salt.
  • the (R ' )-isometheptene salts described herein or pharmaceutical compositions comprising the (R)-isometheptene salts described herein are used in these methods.
  • the (R)-isometheptene salt used in these methods comprises any one of the (R) ⁇ isometheptene salts listed in Tables 1-6 or a combination thereof. In some embodiments, the (R.)-isometheptene salt used in these methods comprises any one of the (R)-isometheptene salts of Figures 1-18 or a combination thereof, in some embodiments, the (R)-isometheptene salt used in these methods is in a crystalline form. In some embodiments, the condition is a headache. In some embodiments, the condition is a migraine headache. In some embodiments, the condition is an episodic tension-type headache. In some embodiments, the condition is hypertension. In some embodiments, the salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine,
  • the invention provides a method of sedating a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a (R)- isometheptene salt, wherein the salt is a maleate, L-maiate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a therapeutically effective amount of a pharmaceutical composition comprising a (R)-isorneiheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt.
  • the (R)-isometheptene salts described herein or pharmaceutical compositions comprising the (R)-isometheptene salts described herein are used in these methods.
  • the (R)-isometheptene salt used in these methods comprises any one of the (R)- isometheptene salts listed in Tables 1 -6 or a combination thereof.
  • the (R)-isometheptene salt used in these methods comprises any one of the (R)-isometheptene salts of Figures 1-18 or a combination thereof.
  • the (R)-isometheptene salt used in these methods is in a crystalline form.
  • the salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichloralphenazone, naproxen, or sumatriptan succinate.
  • the salt or the pharmaceutical composition is used with a CYP2.D6 inhibitor.
  • the subject is a human,
  • the invention provides a method of inducing analgesia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a (R -isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a therapeutically effective amount of a pharmaceutical composition comprising a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt.
  • the (R -isometheptene salts described herein or pharmaceutical compositions comprising the ( R)-isometheptene salts described herein are used in these methods.
  • the (R)-isometheptene salt used in these methods comprises any one of the (R)-isometheptene salts listed in Tables 1-6 or a combination thereof, in some embodiments, the (R)-isometheptene salt used in these methods comprises any one of the (R)-isometheptene salts of Figures 1-18 or a combination thereof.
  • the (R)-isometh.eptene salt used in these methods is in a crystalline form.
  • the salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dic frequentlyaiphenazone, naproxen, or sumatriptan succinate, in some embodiments, the salt or the pharmaceutical composition is used with a CYP2D6 inhibitor.
  • the subject is a human.
  • a (R)-isometheptene salt wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a
  • composition comprising a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, is used in treating or preventing a condition selected from the group consisting of: pain; central sensitization; centralization; regional pain syndrome; lower back pain; visceral pain; neuropathic pain; sickle cell pain; nociceptive pain; post-operative pain; orthopedic injury pain; phantom limb pain; pain associated with cancer; pain associated with post-traumatic stress disorder (PTSD); a headache; an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular,
  • the (R)-isometheptene salts described herein or pharmaceutical compositions comprising the (R)-isometheptene salts described herein are used in these uses of treatment or prevention.
  • the (R)-isometheptene salt used in these uses comprises any one of the (R)-isometheptene salts listed in Tables 1 -6 or a combination thereof.
  • the (R)-isometheptene salt used in these uses comprises any one of the (R) ⁇ isometheptene salts of Figures 1-18 or a combination thereof. In some embodiments, the (R)-isometheptene salt used in these uses is in a crystalline form. In some embodiments, the condition is a headache. In some embodiments, the condition is a migraine headache. In some embodiments, the condition is an episodic tension-type headache. In some embodiments, the condition is hypertension.
  • the (R)- isometheptene salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dic trendaiphenazone, naproxen, or sumatriptan succinate.
  • the (R)-isometheptene salt or the pharmaceutical composition is used with a CYP2D6 inhibitor,
  • a (R)-isometheptene salt wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a
  • composition comprising a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succmate salt, is used as a sedative.
  • compositions comprising the (R)-isometheptene salts described herein are used in these uses.
  • the (R)-isometheptene salt used in these uses comprises any one of the (R)-isometheptene salts listed in Tables 1-6 or a combination thereof.
  • the (R)-isometheptene salt used in these uses comprises any one of the 01)- isometheptene salts of Figures 1-18 or a combination thereof.
  • the 0)- isometheptene salt used in these uses is in a crystalline form.
  • the (R) ⁇ isometheptene salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichioralphenazone, naproxen, or sumatriptan succinate.
  • the (R)-isometheptene salt or the pharmaceutical composition is used with a CYP2D6 inhibitor,
  • a (R)-isometheptene salt wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a
  • compositions comprising a (R)-isometlieptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succmate salt, is used as an analgesic.
  • the (R)-isometheptene salts described herein or pharmaceutical compositions comprising the (R)-isometheptene salts described herein are used in these uses.
  • the (R)-isometheptene salt used in these uses comprises any one of the (R)-isometlieptene salts listed in Tables 1-6 or a combination thereof.
  • the (R)-isometheptene salt used in these uses comprises any one of the 01)- isometheptene salts of Figures 1-18 or a combination thereof.
  • the 01)- isometheptene salt used in these uses is in a crystalline form.
  • the (R) ⁇ isometheptene salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichloralphenazone, naproxen, or sumatriptan succinate.
  • the (R)-isometheptene salt or the pharmaceutical composition is used with a CYP2D6 inhibitor,
  • the invention provides for use of a (R) ⁇ isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a pharmaceutical composition comprising a (Rj-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, for the manufacture of a medicament for treating or preventing a condition selected from the group consisting of: pain; central sensitization; centralization;
  • nociceptive pain nociceptive pain; post-operative pain; orthopedic injur ⁇ ' pain; phantom limb pain; pain associated with cancer; pain associated with post-traumatic stress disorder (PTSD); a headache; an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; a headache from mild to moderate hypertension; depression;
  • the (R) ⁇ isometheptene salts described herein or pharmaceutical compositions comprising the (R)- isometheptene salts described herein are used in these uses.
  • the (R) ⁇ isometheptene sal t used in these uses comprises any one of the (R)-isometheptene salts l isted in Tables 1-6 or a combination thereof.
  • the (R)-isometheptene salt used in these uses comprises any one of the (R)-isometheptene salts of Figures 1-18 or a combination thereof. In some embodiments, the (R) ⁇ isometheptene salt used in these uses is in a crystalline form.
  • the condition is a headache, in some embodiments, the condition is a migraine headache. In some embodiments, the condition is an episodic tension-type headache, in some embodiments, the condition is hypertension.
  • the (Rj- isometheptene salt or the pharmaceutical composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichloralphenazone, naproxen, or sumatriptan succinate.
  • the ( Visometheptene salt is used with a CYP2D6 inhibitor.
  • the invention provides for use of a (R) ⁇ isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a pharmaceutical composition comprising a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, for the manufacture of a medicament for sedation.
  • the (R)-isometheptene salts described herein or pharmaceutical compositions comprising the (R -isometheptene salts described herein are used in these uses of treatment or prevention.
  • the (R)-isometheptene salt used in these uses comprises any one of the (R)-isometheptene salts listed in Tables 1 -6 or a combination thereof.
  • the (R)-isometheptene salt used in these uses comprises any one of the (R)- isometheptene salts of Figures 1 -18 or a combination thereof.
  • the (R)- isometheptene salt used in these uses is in a crystalline form.
  • the condition is a headache. In some embodiments, the condition is a migraine headache. In some embodiments, the condition is an episodic tension-type headache. In some embodiments, the condition is hypertension. In some embodiments, the (R)-isometheptene salt or the
  • composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichloralphenazone, naproxen, or sumatriptan succinate.
  • additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichloralphenazone, naproxen, or sumatriptan succinate.
  • the (R)-isometheptene salt or the pharmaceutical composition is used with a CYP2D6 inhibitor.
  • the invention provides for use of a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, or a pharmaceutical composition comprising a (R)-isometheptene salt, wherein the salt is a maleate, L-malate, L-tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate salt, for the manufacture of a medicament for analgesia.
  • the (R)-isometheptene salts described herein or pharmaceutical compositions comprising the (R)-isometheptene salts described herein are used in these uses of treatment or prevention.
  • the (R)-isometheptene salt used in these uses comprises any one of the ( )-isometheptene salts listed in Tables 1 -6 or a combination thereof.
  • the (R)-isometheptene salt used in these uses comprises any one of the (R)- isometheptene salts of Figures 1 -18 or a combination thereof
  • the (R)- isometheptene salt used in these uses is in a crystalline form.
  • the condition is a headache. In some embodiments, the condition is a migraine headache. In some embodiments, the condition is an episodic tension-type headache. In some embodiments, the condition is hypertension. In some embodiments, the (R)-isometheptene salt or the
  • composition is used with one or more additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichloralplieiiazone, naproxen, or sumatriptan succinate.
  • additional therapeutics selected from acetaminophen, ibuprofen, aspirin, caffeine, dichloralplieiiazone, naproxen, or sumatriptan succinate.
  • the (R)-isometheptene salt or the pharmaceutical composition is used with a CYP2D6 inhibitor.
  • Fig. 1 Differential scanning calorimetry (DSC) heating curve of (R)-isometheptene maleate.
  • Fig. 2 X-ray powder diffraction (XRPD) pattern of (R)-isometheptene maleate.
  • Fig. 3 DSC heating curve of (R)-isometheptene L-malate.
  • Fig. 4 XRPD pattern of (R)-isometheptene L-malate.
  • Fig. 5 DSC heating curve of (R)-isometheptene L-tartrate. [ ⁇ 038]
  • Fig. 6 XRPD pattern of (R)-isometheptene L-tartrate.
  • Fig. 7 DSC heating curve of (R)-isometheptene citrate.
  • Fig. 8 XRPD pattern of (R)-isometheptene citrate.
  • Fig. 9 DSC heating curve of (R)-isometheptene cyclamate.
  • J Fig. 10 XRPD pattern of (R)-isometheptene cyclamate.
  • J Fig. 1 1 DSC heating curve of (R)-isornetheptene fumarate.
  • J Fig. 12 XRPD pattern of (R)-isometheptene fumarate.
  • Fig. 13 DSC heating curve of (R)-isometheptene hippurate.
  • Fig. 14 XRPD pattern of (R)-isometheptene hippurate.
  • Fig. 15 DSC heating curve of (R)-isometheptene phosphate.
  • Fig. 16 XRPD pattern of (R)-isometheptene phosphate.
  • Fig. 17 DSC heating curve of (R)-isometheptene succinate.
  • Fig. 18 XRPD pattern of (R)-isometheptene succinate.
  • a “patient”, “subject”, or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
  • Treating" a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms associated with a disease or condition as described herein.
  • administering or "administration of a substance, a salt or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
  • a salt or an agent can be administered sublingual iy or intranasal!', by inhaiation into the lung or rectaliy.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or 20 more extended periods, in some aspects, the adm stration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug.
  • a physician who instructs a patient to self- administer a drug, or to have the drug administered by another and/or who provides a patient with a prescription for a drug is administering the drug to the patient.
  • the term ''therapeutic treatment is art-recognized and includes administration to the host of one or more of the subject compositions or salts. Treatment is therapeutic if it is administered after manifestation of the unwanted condition (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the tenns "preventing” or “prevention” are art-recognized and include stopping a disease, disorder, or condition from occurring in a subject, which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it. Preventing a condition related to a disease includes stopping the condition from occurring after the disease has been diagnosed but before the condition has been diagnosed.
  • therapeutic agent drug
  • immediate release drug drug
  • bioactive substance include molecules and other agents that are biologically, physiological iy, or pharmacologically active substances that act locally or systemically in a patient or subject to treat a disease or condition.
  • terapéuticaally effective amount or "pharmaceutically effective amount” is an art-recognized term.
  • the term refers to an amount of a therapeutic agent that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the term refers to that amount necessary or sufficient to eliminate, reduce or maintain a target of a particular therapeutic regimen.
  • the effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject or the severity of the disease or condition.
  • One of ordinary skill in the art may empirically determine the effective amount of a particular composition or salt without necessitating undue experimentation.
  • a therapeutically effective amount of a therapeutic agent for in vivo use will likely depend on a number of factors, including: the identity of the agent and the mode and method of administration,
  • the term "therapeutically effective dose” refers to a dose that produces the desired effect for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).
  • US patent application Serial No. 14/158,735 (US Patent Application Publication No. US20140212486) describes and claims the synthesis, purification and both structural and biological characterization of the ( )-isomer of isometheptene, and in particular its mucate salt.
  • the patent application describes the uti lity of the compound for the treatment or prevention of a headache and/or hypertension among other disorders.
  • the above -referenced patent application is herein incorporated by reference in its entirety.
  • racemic isometheptene refers to pharmaceutically acceptable racemic isometheptene.
  • (R)-isometheptene refers to pharmaceutically acceptable (R)- isometheptene.
  • the structure of (R)-isometheptene is:
  • (S)-isometheptene refers to pharmaceutically acceptable (S)- isometheptene.
  • the structure of (S)-isometheptene is: (R -Lsomeiheptene Salts
  • the invention provides novel ( R)-isometheptene salts and crystal line forms thereof.
  • the invention further provides using the novel (R)-isometheptene salts and crystalline forms thereof for the treatment or prevention of pain, a headache, depression, ailodynia, fibromyalgia, fibromyalgia-ness, central sensitization, centralization, temporomandibular joint syndrome (TMJ), Gulf War syndrome, osteoarthritis, rheumatoid arthritis, or hypertension.
  • pain a headache, depression, ailodynia, fibromyalgia, fibromyalgia-ness, central sensitization, centralization, temporomandibular joint syndrome (TMJ), Gulf War syndrome, osteoarthritis, rheumatoid arthritis, or hypertension.
  • Examples of pain include, but are not limited to, regional pain syndrome, lower back pain, visceral pain, neuropathic pain, sickle cell pain, nociceptive pain, post-operative pain, orthopedic injury pain, phantom limb pain, pain associated with cancer, or pain associated with post-traumatic stress disorder (PTSD),
  • Examples of headache include, but are not limited to, an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; or a headache from mild to moderate hypertension.
  • the (R)-isometheptene salts and their crystalline forms of th e invention are used as analgesics. In some embodiments, the (R)-isometheptene salts and their crystalline forms of the invention are used as sedatives.
  • the invention provides a novel salt formed from (R)-isometheptene and citric acid, cyclamic acid, fumaric acid, hippuric acid, hydrochloric acid, maleic acid, L-malic acid, phosphoric acid, succinic acid or L-tartaric acid.
  • the invention provides a novel salt formed from (R)-isometheptene and salts that are selected from acetic acid, adipic acid, aspartic acid, benzoic acid, glutaric acid, glycolic acid, and sulfuric acid, or from
  • the salts of the invention are in a crystalline form.
  • the novel salt may be one from which a crystalline solid with a desired characteristic may be formed.
  • the salt may form a crystalline solid and may be characterized by a differential scanning calorimetry heating curve which shows an endothermic heat flow peak between 45 °C and 145 °C.
  • the invention provides (R)-isometheptene maleate, (R)- isornetheptene L-malate, (R)-isometheptene L-tartrate, (R)-isometheptene citrate, (R) ⁇ isometheptene cyclamate, (R)-isometheptene fumarate, (R)-isometheptene hippurate, (R)- isometheptene phosphate or (R)-isometheptene succinate.
  • the invention provides (R)-isometheptene maleate, (R)-isometheptene L-malate, or (R)-isometheptene L- tartrate.
  • the invention provides (R)-isometheptene maleate. In some embodiments, the invention provides (R)-isometheptene L-malate. In some embodiments, the invention provides (R)-isometheptene L-tartrate.
  • the salts of the invention may be equal to or greater than 0% crystalline, equal to or greater than 10% crystalline, equal to or greater than 20% crystalline, equal to or greater than 30%) crystalline, equal to or greater than 40% crystalline, equal to or greater than 50%
  • the salt may be 10% crystalline, 20% crystalline, 30% crystalline, 40% crystalline, 50% crystalline, 60% crystalline, 70% crystalline, 80% crystalline, 90% crystalline, or 100% crystalline.
  • (R)-isomethepteiie salts are those that form crystal line salts characterized by a differential scanning calorimetry heating curve which shows a maximum endothermic heat flow (or peak) between 45 °C and 145 °C, or between 70 °C and 145 °C, or between 90 °C and 145 °C, or between 70 °C and 125 °C, or between 90 °C and 125 °C, or between 110 °C and 145 °C, or between 45 °C and 70 °C, or between 45 °C and 90 °C, or between 45 °C and 130 °C, or between 45 °C and 125 °C, or between 45 °C and 110 °C, or between 1 12 °C and 120 °C, or between 74° C and 83° C, or between 83 °C and 89 "C, or between 65 °C and 75 °C, or between 71 °C and 81 °C
  • the (R)-isometheptene salt is substantial!' free of the (S) ⁇ isometheptene salt.
  • substantially free means that the (R)-isometheptene salt makes up more than 75%, or more than 80%, or more than 85%, or more than 90%, or more than 95%, or more than 96%, or more than 97%, or more than 98%, or more than 99%, or more than 99.5%, or 100% as compared to the amount of (S)-isometheptene salt in the salt. These amounts are not meant to be limiting, and increments between the recited percentages are specifically envisioned as part of the invention.
  • substantially free means that the (R)-isornetheptene salt makes up more than 90% as compared to the amount of (S)-isometheptene salt in the salt.
  • substantial!)' free means that the (R)- isometheptene salt makes up more than 91% as compared to the amount of (S)-isometheptene salt in the salt.
  • substantially free means that the (R ' )-isometheptene salt makes up more than 92% as compared to the amount of (S)-isometheptene salt in the salt. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 93% as compared to the amount of (S)-isometheptene salt in the salt. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 94% as compared to the amount of (S)-isometheptene salt in the salt.
  • substantially free means that the (R)-isometheptene salt makes up more than 95% as compared to the amount of (S)- isometheptene salt in the salt. In some embodiments, substantially free means that the (R) ⁇ isometheptene salt makes up more than 96% as compared to the amount of (S)-isometheptene salt in the salt. In some embodiments, substantially free means that the (R ' )-isometheptene salt makes up more than 97% as compared to the amount of (S)-isometheptene salt in the salt.
  • substantially free means that the (R)-isometheptene salt makes up more than 98% as compared to the amount of (S)-isometheptene salt in the salt. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 99% as compared to the amount of (S)-isometheptene salt in the salt, in some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 99.5% as compared to the amount of (S)- isometheptene salt in the salt. In some embodiments, substantially free means that the (R) ⁇ isometheptene salt makes up 100%) as compared to the amount of (S)-isometheptene salt in the salt.
  • (R)-isometheptene may be the predominant form of
  • isometheptene present in the salt For example, 100%) of the isometheptene present in the salt may be (R)-isometheptene, or 99% of the isornetheptene present in the salt may be (R) ⁇ isometheptene, or 95% of the isornetheptene present in the salt may be (R)-isometheptene, or 90% of the isornetheptene present in the salt may be (R)-isometheptene, or 85% of the isometheptene present in the salt may be (R)-isometheptene, or 80% of the isometheptene present in the salt may be (R)-isometheptene, or 75% of the isometheptene present in the salt may be (R)-isometheptene, or 70% of the isometheptene present in the salt may be (R)- iso netheptene, or 65% of the isornetheptene present in the salt
  • (R)-isometheptene of the present invention may be the nonpredominant form of isometheptene present in the salt, i.e. 50% of the isometheptene in the salt may be (R)-isometheptene, or 45%) of the isometheptene in the salt may be (R)- isometheptene, or 40% of the isometheptene in the salt may be the (R -isometheptene, or 35% of the isometheptene in the salt may be (R)-isometheptene, or 30% of the isometheptene in the salt may be (R)-isometheptene, or 25% of the isometheptene in the salt may be (R)-isometheptene, or 20% of the isometheptene in the sal t may be ( R)-isometheptene, or 15% of the isometheptene in the salt may be (R)--
  • the salts of the invention further include all pharmaceutically acceptable isotopically labelled salts (e.g., salts of (R)-isometheptene).
  • isotopically e.g., salts of (R)-isometheptene.
  • radio-labeled salt is a salt where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • the salts e.g., salts of (R)-isometheptene
  • hydrogen atoms are replaced or substituted by one or more deuterium or tritium (e.g., hydrogen atoms on a C 1-6 alkyl or a Ci. 6 alkoxy are replaced with deutrium, such as i3 ⁇ 4-methoxy or l,l 5 2,2-c/ 4 -3-methylbutyl).
  • Isotopically labeled compounds e.g., salts of (R)-isometheptene
  • prodrugs can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
  • Suitable isotopes that may be incorporated in salts described herein include but are not limited to Z H (also written as D for deuterium), 3 H (also written as T for tritium), n C, 13 C, 1 C, 1J N, 15 N, ' '' Q, 18 0, 18 F, 35 8, ⁇ ' ( : , 82 Br, 75 Br, 76 Br, 77 Br, ⁇ 23 ⁇ , n % 125 I, and , 3J I.
  • Certain isotopically labeled salts e.g., salts of (R)-isometheptene), in the inventions, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • radioactive isotopes tritium, i.e. ⁇ , and carbon 14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection, (0080]
  • Substitution with positron emitting isotopes, such as C, ' F, O, and 'N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • the isotopically labeled salt comprises (R)-isometheptene-N-CD 3 , 6 -D 6 - (R)-isometheptene, or 6,7-D 6 -(Tt)-isometheptGne-N-CD 3 .
  • the (R)-isometheptene salts of the invention can also exist as various polymorphs, pseudopolymorphs, or in amorphous state.
  • polymorph refers to different crystalline forms of (R)-isometheptene and other solid state molecular forms including pseudo-polymorphs, such as hydrates, solvates, or salts of (R)-isometheptene.
  • pseudo-polymorphs such as hydrates, solvates, or salts of (R)-isometheptene.
  • Different crystalline polymorphs have different crystal structures due to a different packing of molecules in the lattice, as a result of changes in temperature, pressure, or variations in the crystallization process.
  • Polymorphs differ from each other in their physical properties, such as X-ray diffraction characteristics, stability, melting points, solubility, or rates of dissolution in certain solvents. Thus crystalline polymorphic forms are important aspects in the development of suitable dosage forms in pharmaceutical industry.
  • Racemic isometheptene (6-methylamino-2-methylheptene) was first prepared according to the process described in U.S. Pat. No. 2,230,753. We have previously developed methods for synthesizing either (R)-or (S) isomers substantially free of the other isomer. See, for example, US patent application Serial No. 14/158,735 (US Patent Application Publication No.
  • the present application provides a novel method to synthesize (R)-isometheptene, wherein the (R)-isometheptene is synthesized at greater than 90% enantiomeric purity, greater than 95% enantiomeric purity, greater than 96% enantiomeric purity, greater than 97%
  • enantiomeric purity greater than 98%) enantiomeric purity, greater than 99% enantiomeric purity, or at 100% enantiomeric purity.
  • an R-IMH mucate salt is eventually formed, but any other of the R-IMH salts described herein (e.g., maleate, L-malate, L- tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate) may be formed following this scheme.
  • R-IMH salts described herein e.g., maleate, L-malate, L- tartrate, citrate, cyclamate, fumarate, hippurate, phosphate or succinate
  • compositions ami Modes of Administration
  • the present invention provides pharmaceutical composition comprising a salt formed from (Rj-isometheptene.
  • the pharmaceutical composition comprises (R)- isometheptene maleate, (R)-isometheptene L-malate, (R)-isometheptene L-tartrate, (R)- isometheptene citrate, (R)-isometheptene cyclamate, (R)-isometheptene fumarate, (R)- isometheptene hippurate, (R)-isometheptene phosphate or (R)-isometheptene succinate.
  • the pharmaceutical composition comprises (R)-isometheptene maleate, (R)- isometheptene L-malate, or (R)-isometheptene L-tartrate.
  • the pharmaceutical composition comprises (R)-isometheptene maleate, (R)- isometheptene L-malate, or (R)-isometheptene L
  • the pharmaceutical composition comprises (R)-isometheptene maleate. In some embodiments, the pharmaceutical composition comprises (R)-isometheptene L-malate. In some embodiments, the pharmaceutical composition comprises (R)-isometheptene L-tartrate. In some embodiments, the pharmaceutical composition comprises any one of the (R)-isornetheptene salts described herein or a combination thereof. In some embodiments, the pharmaceutical composition comprises any one of the isometheptene salts listed in Tables 1-6 or a combination thereof. In some embodiments, the pharmaceutical composition comprises any one of the ( R)-isometheptene salts of Figures 1-18 or a combination thereof. In some embodiments, the (R)-isometheptene salt contained in these pharmaceutical compositions is in a crystalline form.
  • the pharmaceutical composition comprising the (R)- isometheptene sal t is substantially free of the (S)-isometheptene salt.
  • substantially free means that the (R)-isometheptene salt makes up more than 75%, or more than 80%, or more than 85%, or more than 90%, or more than 95%, or more than 96%. or more than 97%, or more than 98%, or more than 99%, or more than 99.5%, or 100% as compared to the amount of (S)-isometheptene salt in the composition.
  • substantially free means that the (R)-isometheptene salt makes up more than 90% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 91% as compared to the amount of (S)-isomet eptene salt in the composition. In some embodiments, substantially free means that the (R ' )-isometheptene salt makes up more than 92% as compared to the amount of (S)-isometheptene salt in the composition.
  • substantial ly free means that the (R)-isometheptene salt makes up more than 93% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt- makes up more than 94% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 95%) as compared to the amount of (S)-isometheptene salt in the composition.
  • substantially free means that the (R)-isometheptene salt makes up more than 96% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 97% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 98% as compared to the amount of (S)-isometheptene salt in the composition.
  • substantially free means that the (R)-isometheptene salt makes up more than 99% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt makes up more than 99.5% as compared to the amount of (S)-isometheptene salt in the composition. In some embodiments, substantially free means that the (R)-isometheptene salt makes up 100% as compared to the amount of (S)-isometheptene salt in the composition.
  • compositions of the invention are administered to a subject suffering from pain, a headache, depression, allodynia, fibromyalgia, fibromyalgia-ness, central sensitization, centralization, temporomandibular joint syndrome (TMJ), Gulf War syndrome, osteoarthritis, rheumatoid arthritis, or hypertension.
  • pain include, but are not limited to, regional pain syndrome, lower back pain, visceral pain, neuropathic pain, sickle cell pain, nociceptive pain, post-operative pain, orthopedic injur pain, phantom limb pain, pain associated with cancer, or pain associated with post-traumatic stress disorder (PTSD).
  • headache examples include, but are not limited to, an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; or a headache from mild to moderate hypertension.
  • the pharmaceutical compositions of the invention are administered to a patient as sedatives or as analgesics.
  • compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will general ly be that amount of the salt which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • the (R)-isometheptene salt or the pharmaceutical composition comprising the (R)-isometheptene salt may be combined with one or more other pharmaceutical substances, including compounds known to relieve headaches, such as acetaminophen, ibuprofen, aspirin, caffeine, dichloralphenazone, naproxen, or sumatriptan succinate.
  • the salts or the pharmaceutical compositions are with these other pharmaceutical substances in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for eac of the therapeutic agents.
  • the effective daily dose of the salt or the active salt or the pharmaceutical composition comprising the salt or the active salt may be administered as one, two, three, four, five, six, or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the salt or the active salt or the pharmaceutical composition comprising the salt or the active salt is administered two or three times daily.
  • the salt or the active salt or the pharmaceutical composition comprising the salt or the active salt is administered once daily.
  • the pharmaceutical compositions of the invention are in a variety of forms, including, but not limited to, a composition that is enterically coated, a composition that is a controlled release or sustained release formulation, a composition that is an immediate release formulation, a composition that is a solution, a composition that is a tablet or capsule, a composition that is a topical formulation, a composition that is a suppository, a composition that is a transdermal patch, a composition that is lyophilized, a composition that is in an inhaler, a composition that is in a prefilled syringe, a composition that is in a nasal spray device, and the like.
  • the pharmaceutical compositions of the invention are formulated for oral administration, parenteral administration, mucosal administration, nasal administration, topical administration, ocular admin stration, local admin stration, rectal administration, or intrathecal administration. If parenteral, the administration can be subcutaneous, intravenous, intradermal, intraperitoneal, intrathecal, among others.
  • the pharmaceutical compositions of the invention may be in a packaged unit dosage or multi-unit dosage.
  • Additional routes of administration of the pharmaceutical compositions of the invention may include, without limitation, intramuscular, intrarticular, intrabronchial, intraabdominal, intracapsular, mtracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, mtracervical, intragastric, intrahepatic, intramyocardial, intraosteal, mtrapelvic, mtrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, buccal, sublingual, intranasal, and transdermal.
  • compositions of the present invention may include, or may he diluted into, a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid, gel, or liquid fillers, diluents or encapsulating substances which are suitable for administration to a human or other mammal such as a non-human primate, a dog, cat, horse, cow, sheep, pig, or goat.
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the carriers are capable of being commingled with the compositions, salts and preparations of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy or stability.
  • Carrier formulations suitable for oral administration, for suppositories, and for parenteral administration, among others, can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.
  • An exemplary type of carrier may include alpha-cyclodextrin, beta cyclodextrin, hydroxyethyl-beta-cyclodextrin, and hydroxyethyl-alpha- cyclodextrin.
  • excipients for oral and sublingual formulations of isometheptene mucate, isometheptene malate, isometheptene maleate, isometheptene tartrate and other salts of isometheptene include alpha-cyclodextrin and hydroxypropyl-beta cyclodextrin.
  • Excipients for intravenous, intramuscular and subcutaneous formulations include hydroxypropyl-beta cyclodextrin.
  • the isometheptene salt is dissolved with at least 1 molar equivalent of cyclodextrin in water or a suitable mixed aqueous solvent prior to removal of solvent to ensure complete complexation.
  • the cyclodextrin may increase solubility and stability of the isometheptene through complexation of the isometheptene cation inside the tube-shaped cyclodextrin molecule.
  • excipients for oral and sublingual formulations of (R)- isometheptene mucate, (R)-isometheptene malate, (R)-isometheptene maleate, (R)- isometheptene tartrate and other salts of (R)-isometheptene include alpha-cyclodextrin and hydroxypropyl-beta cyclodextrin.
  • Excipients for intravenous, intramuscular and subcutaneous formulations include hydroxypropyl-beta cyclodextrin.
  • the (R)- isometheptene salt is dissolved with at least 1 molar equivalent of cyclodextrin in water or a suitable mixed aqueous solvent prior to removal of solvent to ensure complete complexation.
  • the cyclodextrin may increase solubility and stabili ty of the (R)-isometheptene through complexation of the (R)-isometheptene cation inside the tube-shaped cyclodextrin molecule.
  • a composition of the invention is administered internally.
  • the compositions can be formulated as a solution or a suspension in an aqueous-based medium, such as isotonicaily buffered saline or are combined with a biocompatible support or bioadhesive intended for internal administration.
  • an aqueous-based medium such as isotonicaily buffered saline or are combined with a biocompatible support or bioadhesive intended for internal administration.
  • the pharmaceutical compositions of the invention are aqueous formulations.
  • Such aqueous formulations may include a chelating agent, a buffering agent, an anti-oxidani and, optionally, an isotonicitv agent.
  • Chelating agents include, for example, but are not limited to ethylenediaminetetraacetic acid (EDTA) as a free acid, salt or various
  • citric acid and derivatives thereof citric acid and derivatives thereof, niacinamide and derivatives thereof, sodium desoxycholate and derivatives thereof, and L-glutamic acid, N,N ⁇ diacetic acid and derivatives thereof.
  • buffering agents include, but are not limited to, citric acid, sodium citrate, sodium acetate, acetic acid, sodium phosphate and phosphoric acid, sodium ascorbate, tartaric acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, imidazoline, sodium bicarbonate and carbonic acid, sodium succinate and succinic acid, histidine, and sodium benzoate and benzoic acid, or combinations thereof.
  • antioxidants include, but are not limited to, an ascorbic acid derivative, butylated hydroxy anisole, butylated hydroxy toluene, alkyl gallate, sodium meta-bisulfite, sodium bisulfite, sodium dithionite, sodium thioglycollate acid, sodium formaldehyde sulfoxylate, tocopheral and derivatives thereof monothioglycerol, or sodium sulfite or combinations thereof.
  • the antioxidant is monothioglycerol.
  • isotonicity agents include, but are not limited to, sodium chloride, mannitol, lactose, dextrose, glycerol, or sorbitol, or combinations thereof.
  • the pharmaceutical compositions of the invention further comprise preservatives.
  • preservatives that can be used with the present invention
  • compositions include without limitation benzyl alcohol, parabens, thimerosal, chlorobutanol and benzalkonium chloride.
  • the preservative is present in the pharmaceutical composition in a concentration of up to about 2% by weight. The exact concentration or weight percentage of the preservative, however, will vary depending upon the intended use and can be easily ascertained by one skil led in the art.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without a resulting or excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues, such as amines, alkali or organic salts of acidic residues, such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic
  • physiologically acceptable salts are prepared by methods known in the art, e.g., by dissolving the free amine bases with an excess of the acid in aqueous alcohol, or neutralizing a free carboxylic acid with an alkali metal base such as a hydroxide, or with an amine.
  • Certain acidic or basic compounds of the present invention may exist as zwitterions. All forms of the compounds, including free acid, free base and zwitterions, are contemplated to be within the scope of the present invention. It is well known in the art that compounds containing bot amino and carboxyl groups often exist in equilibrium with their zwitterionie forms. Thus, any of the compounds described herein that contain, for example, both amino and carboxyl groups, also include reference to their corresponding zwitterions.
  • a product containing a therapeutic salt(s) of the invention and, optionally, one or more other active agents can be configured as an oral dosage.
  • the oral dosage may be a liquid, a semisolid or a solid.
  • the oral dosage may be configured to release the therapeutic salt(s) of the invention before, after or simultaneously with the other agent.
  • the oral dosage may be configured to have the therapeutic salt(s) of the invention and the other agents release completely in the stomach, release partially in the stomach and partially in the intestine, in the intestine, in the colon, partially in the stomach, or wholly in the colon.
  • the oral dosage also may be configured whereby the release of the therapeutic salt(s) of the invention is confined to the stomach or intestine while the release of the other active agent is not so confined or is confined differently from the therapeutic salt(s) of the invention.
  • the therapeutic salt(s) of the invention may be an enterically coated core or pel lets contained within a pill or capsule that releases the other agent first and releases the therapeutic salt(s) of the invention only after the therapeutic salt(s) of the invention passes through the stomach and into the intestine.
  • the therapeutic sait(s) of the invention also can be in a sustained release material, whereby the therapeutic salt(s) of the invention is released throughout the gastrointestinal tract and the other agent is released on the same or a different schedule.
  • therapeutic salt(s) of the invention release can be achieved with immediate release of therapeutic salt(s) of the invention combined with enteric coated therapeutic salt(s) of the invention.
  • the other compound or agent could be released immediately in the stomach, throughout the gastrointestinal tract or only in the intestine.
  • the therapeutic salt(s) of the invention could be coated on the surface of the controlled release formulation in any pharmaceutically acceptable carrier suitable for such coatings and for permitting the release of the therapeutic sait(s) of the invention, such as in a temperature sensitive pharmaceutically acceptable carrier routinely used for controlled release.
  • any pharmaceutically acceptable carrier suitable for such coatings and for permitting the release of the therapeutic sait(s) of the invention such as in a temperature sensitive pharmaceutically acceptable carrier routinely used for controlled release.
  • Other coatings, which dissol ve when placed in the body are well known to those of ordinary skill in the art.
  • Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s).
  • Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired.
  • Bioadhesive polymers of particular interest include bioerodible hydrogeis described by H.S. Sawhney, CP. Pathak and J.A. Hubell in Macromolecules, ( 1993) 26:581 -587, the teachings of which are incorporated herein.
  • polyhyaluronic acids casein, gelatin, giutin, polyanhydrides, polyacryiic acid, alginate, chitosan, poly(methyi methacrylates), poly(ethyl methacrylates), poly(butylmethaciylate), polyfisobutyl methacrylate),
  • the therapeutic agent(s) may be contained in a controlled release formulation or controlled release systems.
  • controlled release is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations.
  • sustained release also referred to as " ⁇ extended release” is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that in some embodiments, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.
  • delayed release is used in its conventional sense to refer to a drag formulation in which there is a time del ay between administration of the formulation and the release of the drug therefrom. "Delayed release” may or may not involve gradual release of drag over an extended period of time, and thus may or may not be “sustained release.” These formulations may be for any mode of administration.
  • Deliver ⁇ ' systems specific for the gastrointestinal tract are roughly divided into three types: the first is a delayed release system designed to release a drug in response to, for example, a change in pH; the second is a timed-release system designed to release a drag after a predetermined time; and the third is a microflora enzyme system making use of the abundant enterobacteria in the lower part, of the gastrointestinal tract (e.g., in a colonic site-directed release formulation).
  • An example of a delayed release system is one that uses an acrylic or ceilulosic coating material and dissolves on pH change.
  • an enteric coating is one which passes through the stomach without releasing substantial amounts of drug in the stomach (i.e., less than 10% release, 5% release and even 1% release in the stomach) and sufficiently disintegrating in the intestinal tract (by contact with approximately neutral or alkaline intestine juices) to allow the transport (active or passive) of the active agent through the walls of the intestinal tract.
  • the enteric coating is typically, although not necessarily, a polymeric material.
  • Enteric coating materials comprise bioerodible, gradually hydroiyzabie and/or gradually water-soluble polymers.
  • the "coating weight,” or relative amount of coating material per capsule, generally dictates the time interval between ingestion and drug release. Any coating should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the practice of the present invention.
  • enteric coating material will depend on the following properties: resistance to dissolution and disintegration in the stomach; impermeability to gastric fluids and drug/carrier/enzyme while in the stomach; ability to dissolve or disintegrate rapidly at the target intestine site; physical and chemical stability during storage; non-toxicity; ease of application as a coating (substrate friendly); and economical practicality.
  • Suitable enteric coating materials include, but are not limited to: ceilulosic polymers such as cellulose acetate phthalate, cellulose acetate trirnellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropyhm ethyl cellulose succinate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, formed from acrylic acid, methacryiic acid, methyl acryiate, ammonium rnethylaerylate, ethyl acryiate, methyl methacrylate and/or ethyl meth acryiate (e.g., those copolymers sold under the trade name EUDRAGIT); vinyl polymers and copolymers such as polyvinyl acetate, polyvinyl acetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymers; and shellac (purified lac). Combinations of different coating materials may also
  • the coating can, and usually does, contain a plasticizer to prevent the formation of pores and cracks that would permit the penetration of the gastric fluids.
  • Suitable plasticizers include, but are not limited to, triethyl citrate (Citroflex 2), triacetin
  • a coating comprised of an anionic carboxylic acrylic polymer will usually contain approximately 10% to 25% by weight of a plasticizer, particularly dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin.
  • the coating can also contain other coating excipients such as detackifiers, antifoaming agents, lubricants (e.g., magnesium stearate), and stabilizers (e.g., hydroxypropylcellulose, acids and bases) to solubilize or disperse the coating material, and to improve coating performance and the coated product.
  • detackifiers e.g., detackifiers, antifoaming agents, lubricants (e.g., magnesium stearate), and stabilizers (e.g., hydroxypropylcellulose, acids and bases) to solubilize or disperse the coating material, and to improve coating performance and the coated product.
  • lubricants e.g., magnesium stearate
  • stabilizers e.g., hydroxypropylcellulose, acids and bases
  • the coating can be applied to particles of the therapeutic agent(s), tablets of the therapeutic agent(s), capsules containing the therapeutic agent(s) and the like, using conventional coating methods and equipment.
  • an enteric coating can be applied to a capsule using a coating pan, an airless spray technique, fiuidized bed coating equipment, or the like.
  • Detailed information concerning materials, equipment and processes for preparing coated dosage forms may be found in Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al. (New York: Marcel Dekker, Inc., 1989), and in Ansel et al.. Pharmaceutical Dosage Forms and Drug
  • the coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the lower intestinal tract is reached,
  • compositions also can be administered as a nasal spray, nasal drop, suspension, gel, ointment, cream or powder.
  • administration of a composition can also include using a nasal tampon or a nasal sponge containing or impregnated with a composition of the present invention.
  • the nasal delivery systems that can be used with the present invention can take various forms including aqueous preparations, non-aqueous preparations and combinations thereof.
  • Aqueous preparations include, for example, aqueous gels, aqueous suspensions, aqueous liposomal dispersions, aqueous emulsions, aqueous microemulsions and combinations thereof.
  • Non-aqueous preparations include, for example, non-aqueous gels, non-aqueous suspensions, non-aqueous liposomal dispersions, non-aqueous emulsions, non-aqueous microemulsions and combinations thereof.
  • the various forms of the nasal deliv er ⁇ ' systems can include a buffer to maintain pH, a pharmaceutically acceptable thickening agent and a humectant.
  • the pH of the buffer can be selected to optimize the absorption of the therapeutic agent(s) across the nasal mucosa.
  • suitable forms of buffering agents can be selected such that when the formulation is delivered into the nasal cavity of a mammal, selected pH ranges are achieved therein upon contact with, e.g., a nasal mucosa.
  • the pH of the compositions should be maintained from about 2.0 to about 6.0. It is desirable that the pH of the compositions is one which does not cause significant irritation to the nasal mucosa of a recipient upon administration.
  • An aerosol or spray device may be used in conj unction with the n asal delivery systems of the invention.
  • the viscosity of the compositions of the present invention can be maintained at a desired level using a pharmaceutically acceptable thickening agent.
  • Thickening agents that can be used in accordance with the present invention include methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyi cellulose, earhomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.
  • concentration of the thickening agent will depend upon the agent selected and the viscosity desired. Such agents can also be used in a powder formulation discussed above.
  • compositions of the present invention can also include a humectant to reduce or prevent drying of the mucus membrane and to prevent irritation thereof.
  • suitable humectants that can be used in the present invention include sorbitol, mineral oil, vegetable oil and glycerol; soothing agents; membrane conditioners; sweeteners; and combinations thereof.
  • concentration of the humectant in the present compositions will vary depending upon the agent selected.
  • compositions are formulated for topical administration.
  • A. composition formulated for topical administration may be liquid or semi-solid (including, for example, a gel, lotion, emulsion, cream, ointment, spray or aerosol) or may be provided in combination with a "finite" carrier, for example, a non-spreading material that retains its form, including, for example, a patch, bioadhesive, dressing or bandage. It may be aqueous or nonaqueous; it may be formulated as a solution, emulsion, dispersion, a suspension or any other mixture.
  • modes of administration for topical administration include application to the skin, eyes or mucosa.
  • typical vehicles are those suitable for topical administration.
  • compositions provided herein may be applied topically or locally to various areas in the body of a patient.
  • topical application is intended to refer to application to the tissue of an accessible body surface, such as, for example, the skin (the outer integument or covering) and the mucosa (the mucous-producing, secreting and/or containing surfaces).
  • Exemplar ⁇ ' mucosal surfaces include the mucosal surfaces of the eyes, mouth (such as the lips, tongue, gums, cheeks, sublingual and roof of the mouth), larynx, esophagus, bronchial, nasal passages, vagina and rectum/anus; in some embodiments, the mouth, larynx, esophagus, vagina and rectum/anus; in other embodiments, the eyes, larynx, esophagus, bronchial, nasal passages, and vagina and rectum/anus.
  • local application refers to application to a discrete intemai area of the body, such as, for example, a joint, soft tissue area (such as muscle, tendon, ligaments, intraocular or other fleshy internal areas), or other internal area of the body.
  • a discrete intemai area of the body such as, for example, a joint, soft tissue area (such as muscle, tendon, ligaments, intraocular or other fleshy internal areas), or other internal area of the body.
  • soft tissue area such as muscle, tendon, ligaments, intraocular or other fleshy internal areas
  • local application refers to applications to discrete areas of the body.
  • suitably prepared solutions and suspensions may also be topically applied to the eyes.
  • Solutions particularly those intended for ophthalmic use, may be formulated as 0.01 %- 10% isotonic solutions, pH about 5-7, with appropriate salts, and in some embodiments, containing one or more of the salts herein at a concentration of about 0.1%, in some embodiments, greater than 1%, up to 50% or more.
  • Suitable ophthalmic solutions are known (see, e.g., U.S. Pat. No. 5, 1 16,868, which describes typical compositions of ophthalmic irrigation solutions and solutions for topical application).
  • Such solutions which have a pH adjusted to about 7.4, contain, for example, 90-100 mM sodium chloride, 4-6 mM dibasic potassium phosphate, 4-6 mM dibasic sodium phosphate, 8-12 mM sodium citrate, 0.5-1.5 mM magnesium chloride, 1 .5-2.5 mM calcium chloride, 15-25 mM sodium acetate, 10-20 mM D,L ⁇ sodium, ⁇ -hydroxybutyrate and 5-5.5 mM glucose.
  • the salts or pharmaceutical compositions of the invention are formulated as a lotion.
  • Lotions which, for example, may be in the form of a suspension, dispersion or emulsion, contain an effective concentration of one or more of the salts. In some embodiments, the effective concentration is that which will deliver an effective amount, typically at a concentration of between about 0.1-50%, by weight, or more of one or more of the salts provided herein.
  • the lotions also contain by weight from 1 % to 50% of an emollient and the balance water, a suitable buffer, and other agents as described above. Any emollients known to those of skill in the art as suitable for application to skin, e.g., human skin, may be used.
  • the lotions further contain, by weight, from 1% to 10%, or from 2% to 5%, of an emulsifler.
  • the emulsifiers can be noiiioiiic, anionic or cationic.
  • suitable nonionic emulsifiers include, but are not limited to, fatty alcohols having 10 to 20 carbon atoms, fatty alcohols having 10 to 20 carbon atoms condensed with 2 to 20 moles of ethylene oxide or propylene oxide, alkyl phenols with 6 to 12 carbon atoms in the alkyl chain condensed with 2 to 20 moles of ethylene oxide, mono- and di-fatty acid esters of ethylene oxide, mono- and di-fatty acid esters of ethylene glycol where the fatty acid moiety contains from 10 to 20 carbon atoms, diethylene glycol, polyethylene glycols of molecular weight 200 to 6000, propylene glycols of molecular weigh 200 to 3000, glycerol, sorbitol, sorbit
  • Suitable anionic emulsifiers include, but are not limited to, the fatty acid soaps, e.g., sodium, potassium and triethanolamine soaps, where the fatty acid moiety contains from 10 to 20 carbon atoms.
  • Other suitable anionic emulsifiers include, but are not limited to, the alkali metal, ammonium or substituted ammonium alkyl sulfates, alkyl arylsu!fonates, and alkyl ethoxy ether sulfonates having 10 to 30 carbon atoms in the alkyl moiety.
  • the alkyl ethoxy ether sulfonates contain from 1 to 50 ethylene oxide units.
  • cationic emulsifiers are quaternary ammonium, rnorpholinium and pyridinium compounds.
  • an additional ernuisifter is not needed, though it can be included in the composition.
  • the balance of the lotion is water or a C 2 or € alcohol, or a mixture of water and the alcohol.
  • the lotions are formulated by simply admixing all of the components together.
  • the salt is dissolved, suspended or otherwise uniformly dispersed in the mixture.
  • ком ⁇ онент is a thickening agent at a level from 1% to 10% by weight of the composition.
  • suitable thickening agents include, but are not limited to: cross-linked carboxypolymethylene polymers, ethyl cellulose, polyethylene glycols, gum tragacanth, gum kharaya, xanthan gums and bentonite, hydroxyethyl cellulose, and hydroxypropyl cellulose.
  • the salts or pharmaceutical compositions of the invention are formulated in a cream.
  • Creams can be formulated to contain a concentration effective to deliver an effective amount of therapeutic agent(s) of the invention to the treated tissue, typically at between about 0.1% and 50%, in some embodiments at greater than 1% up to and greater than
  • the creams also contain from 5% to 50%, in some embodiments from 10% to 25%, of an emollient and the remainder is water or other suitable non-toxic carrier, such as an isotonic buffer.
  • the emollients as described above for the lotions, can also be used in the cream compositions.
  • the cream may also contain a suitable emulsifier, as described above.
  • the emu!sifier is included in the composition at a level from 3% to 50%, preferably from 5% to 20%.
  • the compositions that are formulated as solutions or suspensions may be applied to the skin, or, may be formulated as an aerosol or foam and applied to the skin as a spray-on.
  • the aerosol compositions typically contain, by weight, from 25% to 80%, in some embodiments from 30% to 50%, of a suitable propellaiit.
  • suitable propellants are the chlorinated, fluorinated and chlorofluorinated lower molecular weight hydrocarbons. Nitrous oxide, carbon dioxide, butane, and propane are also used as propellaiit gases. These propellants are used as understood in the art in a quantity and under a pressure suitable to expel the contents of the container.
  • the salts or pharmaceutical compositions of the invention are formulated in a gel.
  • Gel compositions can be formulated by simply admixing a suitable thickening agent to the previously described solution or suspension compositions. Examples of suitable thickening agents have been previously described with respect to the lotions.
  • the gelled compositions contain an effective amount of therapeutic agent(s) of the invention, typical ly at a concentration of between about 0.1-50% by weight or more of one or more of the salts provided herein.; from 5% to 75%, in some embodiments, from 10% to 50%, of an organic solvent as previously described; from 0.5% to 20%, in some embodiments, from 1 % to 10%) of the thickening agent; the balance being water or other aqueous or non-aqueous carrier, such as, for example, an organic liquid, or a mixture of carriers.
  • the compositions may also contain a glycol, that is, a compound containing two or more hydroxy groups.
  • the glycol for use in the compositions is propylene glycol.
  • the glycol is included in the compositions in a concentration of from greater than 0 to about 5 wi %, based on the total weight of the composition.
  • the compositions contain from about 0.1 to less than about 5 wt. % of a glycol.
  • the compositions contain from about 0.5 to about 2 wt. %, In some embodiments, the compositions contain about 1 wt. % of a glycol.
  • the formulations can be constructed and designed to create steady state plasma levels.
  • Steady state plasma concentrations can be measured using HPLC techniques, as are known to those of skill in the art. Steady state is achieved when the rate of dmg availability is equal to the rate of drug elimination from the circulation.
  • the therapeutic agent(s) of the invention will be administered to patients either on a periodic dosing regimen or with a constant infusion regimen.
  • the concentration of drug in the plasma will tend to rise immediately after the onset of administration and will tend to fall over time as the dmg is eliminated from the circulation by means of distribution into cells and tissues, by metabolism, or by excretion. Steady state will be obtained when the mean dmg concentration remains constant over time.
  • the pattern of the drag concentration cycle is repeated identically in each interval between doses with the mean concentration remaining constant.
  • the mean dmg concentration will remain constant with very little oscillation.
  • the achievemen t of steady state is determined by means of m easurin g the concentration of drag in plasma over at least one cycle of dosing such that one can verify that the cycle is being repeated identically from dose to dose.
  • maintenance of stead)' state can be verified by determining dmg concentrations at the consecutive troughs of a cycle, just prior to administration of another dose.
  • steady state can be verified by any two consecutive measurements of drag concentration.
  • the salts or pharmaceutical compositions of the invention are used in in the manufacture of a medicament.
  • the salts or pharmaceutical compositions of the invention are used in the manufacture of a medicament for the treatment of pain, a headache, depression, allodynia, fibromyalgia, fibromyalgia -ness, central sensitization, centralization, temporomandibular joint syndrome (TMJ), Gul f War syndrome, osteoarthriti s, rheumatoid arthritis, or hypertension.
  • Examples of pain include, but are not limited to, regional pain syndrome, lower back pain, visceral pain, neuropathic pain, sickle cell pain, nociceptive pain, post-operative pain, orthopedic injury pain, phantom limb pain, pain associated with cancer, or pain associ ated with post-traumati c stress disorder (PTSD).
  • Examples of headache include, but are not limited to, an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular,
  • the salts or pharmaceutical compositions the invention are used in the manufacture of a medicament for sedation or analgesia.
  • salts or pharmaceutical compositions described herein have numerous uses, including in vitro and in vivo uses.
  • In vivo uses include not only therapeutic uses but also diagnostic and research uses in, for example, any of the animal models described herein.
  • any of the salts or pharmaceutical compositions of the invention may be used as research reagents and delivered to animals to understand bioactivity, enzymatic activity, gene expression, interactions with other molecules, and impacts on animal physiology in healthy or diseased animals.
  • the salts or pharmaceutical compositions of the invention may be used as analgesics or to treat pain, a headache, depression, allodynia, fibromyalgia, fibromyalgia-ness, central sensitization, centralization, temporomandibular joint syndrome (TMJ), Gulf War syndrome, osteoarthritis, rheumatoid arthritis, or hypertension.
  • pain include, but are not limited to, regional pain syndrome, lower back pain, visceral pain, neuropathic pain, sickle cell pain, nociceptive pain, post-operative pain, orthopedic injur pain, phantom limb pain, pain associated with cancer, or pain associated with post-traumatic stress disorder (PTSD).
  • headache examples include, but are not limited to, an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; or a headache from mild to moderate hypertension.
  • the salts or pharmaceutical compositions of the invention may be used as sedatives.
  • the salts or pharmaceutical composi tions of the invention act as potent and selective pain inhibitors or analgesics to treat or prevent diseases or disorders, including, but not limited to, allodyiiia, fibromyalgia, migraine, and rheumatoid arthritis. Pain
  • the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of pain. Pain is an unpleasant feeling triggered by the nervous system, it is often classified by the region of the body involved, the system whose dysfunction may be causing the pain, the duration and pattern of occurrence, the intensity and time since onset, and the etiology. Many types of pain exist, including, but not limited to, nociceptive pain, neuropathic pain, psychogenic pain, visceral pain, and chronic pain.
  • the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of pain caused by headaches and episodic tension-type headaches.
  • a headache is pain in any region of the head, and may occur on one or both sides of the head, be isolated to a certain location, radiate across the head from one point, or have a vise- like quality. Headaches can cause shaip pain, a throbbing sensation, or a dull ache.
  • Primary headaches can be caused by problems with or overactivity of pain-sensitive structures in the head, and secondary headaches can be caused by diseases, such as brain cancer, glaucoma, and trigeminal neuralgia, which activate the pain-sensitive nerves in the head.
  • a tension-type headache is classified into subtypes based on how often it occurs:
  • ETTH episodic tension-type headache
  • An ETTH may be described as a mild to moderate constant band-like pain, tightness, or pressure around the forehead or back of the head and neck. ETTH may last from 30 minutes to several days. ETTH usually begins gradually, and often occurs in the middle of the day. The severity of a tension headache generally increases significantly with its frequency.
  • the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of migraines; tension or migraine headaches due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; or tension or migraine headaches due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode.
  • Migraine is described as a paroxysmal disorder or a recurrent, incapacitating, neurovascular disorder characterized by unilateral and throbbing headaches associated characterized by attacks of headache, nausea, vomiting, photophobia, and phonophobia.
  • Migraine affects people of ail races and both sexes with women accounting for 79% (61% between 20 and 49 years of age) of physician visits for migraines and Caucasians for 91% of the physician visits. Migraine without aura often has a strict menstrual relationship.
  • the pathogenesis of migraine headache involves a) the cranial blood vessels, b) the trigeminal innervation of these vessels, and c) the reflex connection of the trigeminovascular system in the cranial parasympathetic outflow.
  • Migraine pathophysiology is believed by genetic predisposition to involve leakage of ion channels in the brain stem such that the decreased blood flow in the brain leads to neuropeptide release from trigeminal nerves inducing dilatation of cranial extracerebral blood vessel. This condition stimulates the trigeminovascuiar system producing headache associated phonophobia and photophobia as well as nausea and vomiting.
  • Phantom limb pain In some embodiments, the salts or pharmaceutical compositions of the invention may ⁇ be used in the treatment or prevention of phantom pain. Phantom pain is pain coming from a body part that's no longer there. This pain originates in the spinal cord and brain and may be described as shooting, stabbing, boring, squeezing, throbbing or burning.
  • the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of depression.
  • Depression, clinical depression, major depression, unipolar depression, unipolar disorder, or recurrent depression in the case of repeated episodes is a psychiatric diagnosis for a mood disorder characterized by episodes of all encompassing low mood accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities (anhedonia) and disturbed sleep (typically early morning awakening).
  • depression is ambiguous and can be used to describe manic-depressive disorder, but is also used to describe other mood disorders or to lower mood states lacking clinical significance.
  • endogenous depression or the depressed phases of bipolar disorder can be associated with widespread pain or regional pain disorders.
  • Pain experienced during depression can include, but is not limited to, psychogenic pain, psychiatric pain, psychic pain, and psychological pain.
  • Psychogenic pain is pain that results from psychological mechanisms including traumatic experiences, em athic reactions or somatization. For example, loss of a loved friend or relative by death or other separation can result in widespread pain, regional pain, and other symptoms including reactive depression.
  • Psychiatric pain is pain that results from conditions that are believed to have biological causes. Psychic pain and psychological pain are caused by a non-physical origin and can lead to emotional suffering and mental agony. Allodynia
  • the salts or pharmaceut cal compositions of the invention may be used in the treatment or prevention of allodynia. Allodynia, or pain due to a stimulus that does not usually provoke pain, is a prominent symptom in patients with neuropathic pain.
  • Allodynia is seen in various peripheral neuropathies and central pain disorders, and affects 15— 50% of patients with neuropathic pain. Allodynia is classified according to the sensory modality (touch, pressure, pinprick, cold, and heat) that is used to elicit the sensation.
  • Fibromyalgia is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues. Research indicates that fibromyalgia amplifies painful sensations by affecting the way the brain processes pain signals. Symptoms of fibromyalgia sometimes begin after a physical trauma, surgery, infection, or significant psychological stress. In other cases, symptoms gradually accumulate over time with no single triggering event. Symptoms include: widespread pain on both sides of the body and above and below the waist, fatigue, cognitive difficulties, depression, headaches, and pain or cramping in the lower abdomen. In some embodiments, the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of fibromyalgia.
  • Fibromyalgia-ness is the tendency to respond to illness and psychosocial stress with fatigue and widespread pain
  • the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of fibromyalgia-ness.
  • the salts or pharmaceutical compositions of the invention may be used in treatment or prevention central sensitization.
  • Central or chronic sensitization is a condition of the nervous system that is associated with the development and maintenance of chronic pain.
  • the nervous system goes through a process called "wind-up” and gets regulated in a persistent state of high reactivity. This persistent, or regulated, state of reactivity subsequently comes to maintain pain even after the initial injury might be healed.
  • Central sensitization has two main characteristics. Both involve a heightened sensitivity to pain and the sensation of touch. They are called 'allodynia' and 'hyperalgesia.
  • Allodynia occurs when a person experiences pain with things that are normally not painful. Hyperalgesia occurs when an actual painful stimulus is perceived as more painful than it should. With allodynia and hyperalgesia, the sensation of pain travels through the nervous system, which is in a persistent state of high reactivi ty, and the pain is registered in the brain as a heightened level of pain.
  • the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of centralization.
  • the pathogenesis of fibromyalgia is believed to involve sensitization of the central nervous system (CNS) to perceiving painful stimuli, which is termed “central sensitization” or “centralization”.
  • Centralization leads to the perception of widespread pain. Pain of thi s type is termed, “cen tral neuropath ic pain” or “central pain”.
  • Centralization also leads and to other symptoms, including visceral pain such as irritable bowel, tension-type headache, and migraine.
  • Regional pain syndrome may be used in the treatment or prevention of regional pain syndrome.
  • Regional pain syndrome or complex regional pain syndrome is a chronic pain condition most often affecting one of the limbs (arms, legs, hands, or feet), usually after an injury or trauma to that limb.
  • CRPS is believed to be caused by damage to, or malfunction of, the peripheral and central nervous systems.
  • CRPS is characterized by prolonged or excessive pain and mild or dramatic changes in skin color, temperature, and/or swelling in the affected area.
  • Temporomandibular joint syndrome (TM J) Temporomandibular joint syndrome
  • the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of temporomandibular joint syndrome (TMJ), TMJ disorders can cause pain in the jaw joint and in the muscles that control jaw movement. Signs and symptoms of TMJ disorders may include: pain or tenderness of the jaw, aching pain in and around the ear, difficulty chewing or discomfort while chewing, aching facial pain, locking of the jaw joint, and a clicking sound or grating sensation when opening the mouth or chewing.
  • TMJ temporomandibular joint syndrome
  • Lower back pain may be dull or sharp pain in the lower back.
  • the pain may be in one small area or over a broad area and may include muscle spasms.
  • Lower back pain may be caused by overuse, strain, or injury; aging; a herniated disc; arthritis; compression fractures; illness; a congenital spine problem; or other causes.
  • the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of lower back pain.
  • a prominent condition affecting Gulf War Veterans is a cluster of medically unexplained chronic symptoms that can include fatigue, headaches, joint pain, indigestion, insomnia, dizziness, respiratory disorders, and memory problems.
  • the salts or compositions of the invention may be used in the treatment or prevention of Gulf War syndrome.
  • the salts or pharmaceuti cal composi tions of the invention may be used in the treatment or prevention of visceral pain.
  • Visceral pain is caused by the acti vation of pain receptors in the chest, abdomen, or pelvic areas.
  • Visceral pain is caused by problems with internal organs, such as the stomach, kidney, gallbladder, urinary bladder, and intestines. These problems include distension, perforation, inflammation, and impaction or constipation, which can cause associated symptoms, such as nausea, fever, malaise, and pain.
  • Visceral pain is also caused by problems with abdominal muscles and the abdominal wall, such as spasm.
  • Visceral pain is vague and not well localized and is usually described as pressure-like, deep squeezing, dull, or diffuse.
  • Neuropathic pain is vague and not well localized and is usually described as pressure-like, deep squeezing, dull, or diffuse.
  • Neuropathic pain is a complex, chronic pain state that usually is accompanied by tissue injury. With neuropathic pain, the nerve fibers themselves might be damaged, dysfunctional, or injured, and these damaged nerve fibers send incorrect signals to other pain centers.
  • the impact of a nerve fiber injury includes a change in nerve function both at the site of injury and areas around the injury, in some embodiments, the sal ts or pharmaceutical compositions of the invention may be used in the treatment or prevention of neuropathic pain.
  • the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of sickle ceil pain.
  • Sickle cel l disease causes red blood cells to form into a crescent shape, like a sickle.
  • the sickle-shaped red blood cells break apart easily, causing anemia, and the damaged sickle red blood cells clump together and stick to the wails of blood vessels, blocking blood flow. This can cause severe pain and permanent damage to the brain, heart, lungs, kidneys, liver, bones, and spleen.
  • Nociceptive pain is caused when special nerve endings— called nociceptors— are irritated.
  • Nociceptors are the nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain. The pain is typically well localized, constant, and often with an aching or throbbing quality.
  • the salts or pharmaceutical compositions of the invention may be used in treatment or prevention of noci ceptive pain. Post-operative pain
  • Post-operative pain is pain that occurs after an operation.
  • the salts or pharmaceutical compositions of the invention may be used in treatment or prevention of post-operative pain. Orthopedic injury pain
  • Orthopedic injuries are conditions involving the musculoskeletal system, and can mclude musculoskeletal trauma, sports injuries, degenerative diseases, or infections.
  • pain caused by orthopedic injury may be treated or prevented by the salts or pharmaceutical compositions of the invention. Osteoarthritis
  • Osteoarthritis is the most common form of arthritis, affecting mil lions of people worldwide. It occurs when the protective cartilage on the ends of the bones wears down over time. Symptoms include: pain, tenderness, stiffness, loss of flexibility, grating sensation, and bone spurs.
  • the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of osteoarthritis.
  • Rheumatoid arthritis ⁇ 163
  • the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of rheumatoid arthritis.
  • Rheumatoid arthritis is a chronic inflammatory disorder that typically affects the small joints in the hands and feet.
  • Rheumatoid arthritis affects the lining of the joints, causing painful swelling that can eventually result in bone erosion and joint deformity.
  • An autoimmune disorder, rheumatoid arthritis occurs when the immune system mistakenly attacks the body's own tissues.
  • rheumatoid arthritis sometimes can affect other organs of the body—such as the skin, eyes, lungs, and blood vessels.
  • Signs and symptoms of rheumatoid arthritis may include: tender, warm, swol len joints; morning stiffness; rheumatoid nodules; and fatigue, fever, and weight loss. Pain associated with post-traumatic stress disorder (PTSD)
  • PTSD post-traumatic stress disorder
  • the salts or pharmaceut cal compositions of the invention may be used in the treatment or prevention of pain associated with post-traumatic stress disorder (PTSD).
  • PTSD is a mental health condition that's triggered by a cosmic event— either experiencing it or witnessing it. Symptoms may include chronic pain, flashbacks, nightmares, and severe anxiety, as well as uncontrollable thoughts about the event.
  • the salts or pharmaceutical compositions of the invention may be used in the treatment or prevention of pain associated with cancer.
  • Cancer pain can result from the cancer itself as the cancer grows into or destroys nearby tissues. As a tumor grows, it may put pressure on nerves, bones or organs, causing pain. Cancer pain may also not just be from the physical effect of the cancer on a region of the body, but also due to chemicals that the cancer may rel ease in the region of the tumor.
  • Cancer treatments such as chemotherapy, radiation and surgery, are another potential source of cancer pain.
  • Surgery can be painful, radiation may leave behind a burning sensation or painful scars, and chemotherapy can cause many potentially painful side effects, including mouth sores, diarrhea and nerve damage.
  • Another aspect of the invention is the use of the isometheptene salts of the invention or the pharmaceutical compositions comprising the isometheptene salts of the invention as a sedative medication.
  • Another aspect of the invention is the use of a phannaceutical composition comprising an (R)-isometheptene salt as a sedative medication.
  • (R)-isometheptene like dexmedetomidine, is an ] j agonist but also interacts with adrenergic receptor a-2.
  • composition comprising one of the (R)-isometheptene salts of the invention
  • the (R)-isometheptene salt can be bolused for ease of admi istration.
  • the salts or pharmaceutical compositions of the invention may be used in the treatment and prevention of hypertension and the symptoms of hypertension.
  • High blood pressure is a common condition in which the force of the blood against the artery walls is high enough that it may eventually cause health problems, such as heart disease.
  • Hypertension puts strain on the heart, possibly leading to hypertensive heart disease and coronary artery disease, and it is a major risk factor for stroke, aneurysms of the arteries, peripheral arteri al disease, and chronic ki dney disease. Symptoms of hypertension include dull headaches and dizzy spells.
  • treatment of a migraine headache may include an improvement in any of the following symptoms or conditions associated with migraine headache (or combination thereof): pain on one side or both sides of the head, sensitivity to light and sounds, nausea and vomiting, blurred vision, allodynia, and lightheadness.
  • Treatment may include a reduction in the pain experienced by the patient.
  • Treatment of fibromyalgia may include an improvement in any of the following symptoms or conditions associated with fibromyalgia (or combination thereof): widespread pain, fatigue, and cognitive difficulties (e.g., impaired ability to focus).
  • “Treatment” of a headache or an episodic tension-type headache may include an improvement in any of the following symptoms or conditions associated with a headache or an episodic tension-type headache (or combination thereof): sharp pain, throbbing sensation, dull ache, and nausea.
  • “Treatment” of phantom limb pain may include an improvement in any of the following symptoms or conditions associated with phantom limb pain (or combination thereof): shooting, stabbing, or squeezing pain coming from the body part that is no longer there.
  • “Treatment” of depression may include an improvement in any of the following symptoms or conditions associated with depression (or combination thereof): unexplained aches and pains, concentration problems, loss of energy, and anger or irritability.
  • "Treatment” of psychic or psychological pain may include an improvement in any of the following symptoms or conditions associated with psychic or psychological pain (or combination thereof): emotional suffering and mental agony.
  • "Treatment” of psychiatric pain may include an improvement in any of the following symptoms or conditions associated with psychiatric pain (or combination thereof): widespread pain and regional pain.
  • Treatment of allodynia may include an improvement in any of the following symptoms or conditions associated with a symptom related to allodynia (or combination thereof): pain due to a stimulus that does not usually provoke pain.
  • Treatment of fibromyalgia-ness may include an improvement in any of the following symptoms or conditions associated with a symptom related to fibromyalgia-ness (or combination thereof): fatigue and widespread pain.
  • Treatment of centra! sensitization may include an improvement in any of the following symptoms or conditions associated with a symptom related to central sensitization (or combination thereof ⁇ : allodynia and hyperalgesia.
  • Treatment of centralization may include an improvement in any of the following symptoms or conditions associated with a symptom related to centralization (or combination thereof): irritable bowel, tension-type headache, and migraine.
  • Treatment of regional pain syndrome may include an improvement in any of the following symptoms or conditions associated with a symptom related to regional pain syndrome (or combination thereof): swelling and pain in the arms, legs, hands, or feet.
  • TMJ Temporomandibular joint syndrome
  • TMJ temporomandibular joint syndrome
  • symptoms or conditions associated with a symptom related to I ' M J or combination thereof: pain or tenderness of the jaw, aching pain in and around the ear, difficulty chewing or discomfort while chewing, aching facial pain, locking of the jaw joint, and a clicking sound or grating sensation when opening the mouth or chewing.
  • Treatment of lower back pain may include an improvement in any of the following symptoms or conditions associated with a symptom related to lower back pain (or combination thereof): pain in the lower back and muscles spasms in the lower back.
  • “Treatment” of Gulf War syndrome may include an improvement in any of the following symptoms or conditions associated with a symptom related to Gulf War syndrome (or combination thereof): fatigue, headaches, and joint pain.
  • “Treatment” of visceral pain may include an improvement in any of the fol lowing symptoms or conditions associated with a symptom related to visceral pain (or combination thereof): pressure-like, deep squeezing, dull, or diffuse pain in the chest, abdomen, or pel vic areas.
  • “Treatment” of neuropathic pain may include an improvement in any of the following symptoms or conditions associated with a symptom related to neuropathic pain (or combination thereof): shooting and burning pain, tingling, and numbness.
  • “Treatment” of sickle celf pain may include an improvement in any of the fol lowing symptoms or conditions associated with a symptom related to sickle ceil pain (or combmation thereof): pain in the chest, abdomen, joints, and bones.
  • “Treatment” of nociceptive pain may include an improvement in any of the following symptoms or conditions associated with a symptom related to nociceptive pain (or combmation thereof): aching or throbbing pain.
  • Treatment of post-operative pain may include an improvement in any of the following symptoms or conditions associated with a symptom related to post-operative pain (or
  • Treatment of orthopedic injur ⁇ ' pain may include an improvement in any of the following symptoms or conditions associated with a symptom related to orthopedic injur ⁇ ' pain (or combination thereof): pain, swelling, and irritation after an orthopedic injury.
  • Treatment of osteoarthritis may include an improvement in any of the following symptoms or conditions associated with a symptom related to osteoarthritis (or combination thereof): pain, tenderness, stiffness, loss of flexibility, grating sensation, and bone sp urs.
  • “Treatment” of rheumatoid arthritis may include an improvement in any of the following symptoms or conditions associated with a symptom related to rheumatoid arthritis (or combination thereof): tender, warm, swollen joints; morning stiffness; rheumatoid nodules; and fatigue, fever and weight loss.
  • “Treatment” of pain associated with post-traumatic stress disorder (PTSD) may include an improvement in any of the following symptoms or conditions associated with a symptom related to pain associated with post-traumatic stress disorder (PTSD) (or combination thereof): chronic pain and headaches.
  • Treatment of pain associated with cancer may include an improvement in any of the following symptoms or conditions associated with a symptom related to pain associated with cancer (or combination thereot): chronic pain, nerve damage, and burning sensation.
  • Treatment of hypertension may include an improvement in any of the following symptoms or conditions associated with hypertension (or combination thereof): high blood pressure, dull headaches, and dizzy spells.
  • any of the salts or pharmaceutical compositions described above or herein may be used in any of the methods described herein. Effects are not limited to those listed above and other effects may also be noted during treatment.
  • mice and rats Animal Models ⁇ 0171 j Pain, headaches, and migraines have been modeled in animals such as mice and rats.
  • Oshinsky et al. Oshinsky, M.L., et ai, Spontaneous Trigeminal Allodynia in Rats: A Model of Primary Headache, Headache, 2012, 52: 1336-1349
  • STA spontaneous trigeminal allodynia
  • the periorbital, hind-paw, and jaw- pressure thresholds for STA rats are determined by applying von Frey monofilaments. These determinations are made both before and after receiving treatments with compositions or salts of interest.
  • Analgesic activity of the compositions or salts described herein can be evaluated by determining trigeminal von Frey thresholds in STA rats, ⁇ 0172]
  • Common mouse models for pain include the Formalin Test (Wheeler- Aceto, et al.,
  • mice are given an intraplantar injection of 5% formalin into one posterior hindpaw to induce paw licking. Test compositions or salts are given to the mice before treatment with formalin and the mice are evaluated and compared to a control group.
  • the Hot Plate Test Eddy and Leimbach, J. Pharmacol. Exp. Ther., 107, 385-393, 1953
  • the Tail-flick Test D'Amour and Smith, J. Pharmacol. Exp. Ther., 1 , 74-79, 1941.
  • mice are placed onto a hot metal plate maintained at 54 °C and the latency to the first foot-lick is measured.
  • compositions or salts of interest are given to the mice before the test and the mice are evaluated and compared to a control group.
  • Tail- flick Test a mouse's tail is heated by means of a thermal light source, and the latency before the animal withdraws its tail is measured. Test compositions or salts are administered before the test, and compared with a vehicle control group.
  • the analgesic activity of the compositions or salts described herein can be identified using the mouse formalin, hot plate, and tail-flick tests.
  • Stability of the salts described herein can be assessed using pharmacokinetic studies in animals such as dogs, rats, and humans. Animals are treated with varying doses of the sal ts described herein and after specified time periods, plasma samples are drawn and then analyzed for the presence of (R)- or (S)-isometheptene.
  • the pharmaceutical compositions or salts of the invention can be used in combination with other therapeutics as analgesics or sedatives, in some embodiments, the pharmaceutical compositions or salts of the invention can be used in combination with other therapeutic agents to treat pain, a headache, depression, allodynia, fibromyalgia, fibromyalgia- ness, central sensitization, centralization, temporomandibular joint syndrome (TMJ), Gulf War syndrome, osteoarthritis, rheumatoid arthritis, or hypertension.
  • TMJ temporomandibular joint syndrome
  • pain examples include, but are not limited to, regional pain syndrome, lower back pain, visceral pain, neuropathic pain, sickle ceil pain, nociceptive pain, post-operative pain, orthopedic injury pain, phantom limb pain, pain associated with cancer, or pain associated with post-traumatic stress disorder (PT8D).
  • regional pain syndrome lower back pain
  • visceral pain neuropathic pain
  • nociceptive pain post-operative pain
  • orthopedic injury pain phantom limb pain
  • pain associated with cancer or pain associated with post-traumatic stress disorder (PT8D).
  • P8D post-traumatic stress disorder
  • headache examples include, but are not limited to, an episodic tension-type headache; a migraine headache; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; or a headache from mild to moderate hypertension.
  • the phrase "combination therapy” refers to the administration of any of the pharmaceutical compositions or salts described herein and an additional therapeutic agent as part of a specific treatment regimen intended to provide a beneficial effect from the co- action of these therapeutic agents.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “combination therapy” refers to administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time.
  • “combination therapy” refers to administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally, or by intravenous injection.
  • “combination therapy” refers to the administration of the therapeutic agents as described above in further combination with other biologically active ingredients (such as, but not limited to, a second and different therapeutic agent) and non-drug therapies (such as, but not limited to, surgery or radiation).
  • one or more pharmaceutical compositions or salts described herein can be used as part of a therapeutic regimen combined with one or more addi tional treatment modalities.
  • such other treatment modalities include, but are not limited to, dietary therapy, occupational therapy, physical therapy, ventilator supportive therapy, massage, acupuncture, acupressure, mobility aids, assistance animals, speech therapy, language therapy, educational therapy, psychological therapy, occupational therapy, and the like.
  • the combination therapy is useful for treating a mammalian disease (e.g., a human disease) including any of the conditions described herein.
  • the combination therapy is useful for veterinary treatment of companion animals, exotic and farm animals, including rodents, horses, dogs, and cats.
  • the therapeutic agents administered in combination therapy with any of the compositions or salts of the invention can comprise: acetaminophen, non-steroidal anti-inflammatory drugs ( SAJDs), ibuprofen, naprosyn, cyclooxygenase-2 inhibitors, aspirin, caffeine, dichloraiphenazone, triptans, antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRJs), or gabapentinoids, or a combination thereof.
  • SAJDs non-steroidal anti-inflammatory drugs
  • ibuprofen ibuprofen
  • naprosyn cyclooxygenase-2 inhibitors
  • aspirin caffeine, dichloraiphenazone, triptans, antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRJ
  • the therapeutic agents administered in combination therapy with any of the compositions or salts of the invention can comprise: anti-inflammatory agents, corticosteroids, CYP2D6 inhibitors, or TNF-alpha inhibitors, or combinations thereof
  • the therapeutic agents administered in combination therapy with the compositions or salts of the invention can comprise one or more opiates.
  • Anti-inflammatory agents include, but are not limited to, non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and naprosyn (naproxen); TNF-a blockers or inhibitors such as infliximab, adalimumab, and etanercept; IL-RA; azathioprine;
  • NSAIDs non-steroidal antiinflammatory drugs
  • ibuprofen and naprosyn naproxen
  • TNF-a blockers or inhibitors such as infliximab, adalimumab, and etanercept
  • IL-RA azathioprine
  • cyclophosphamide sulfasalazine
  • cyclooxygenase-2 inhibitors such as aspirin; caffeine
  • Gabapentinoids include, but are not limited to, gabapentin, pregabalin, gabapentin enacarbil, atagabalin, 4-methylpregabalin, and PD-217,014.
  • Antidepressants include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram, and escitalopram; serotonin and norepinephrine reuptake inhibitors (SNRJs) such as duioxetine, venlafaxine, desveniafaxine, tramadol, tapentadol, and levomilnacipran; norepinephrine and dopamine reuptake inhibitors (NDRJs) such as bupropion; trazodone; mirtazapine; vortioxetine; vilazodone; tricyclic antidepressants such as imipramine, nortriptyline, amitriptyline, doxepin, nimipramine, desipramine, and protriptyline; and monoamine oxidase inhibitors (MAOIs) such as tranyl
  • CYP2D6 inhibitors include, but are not limited to, fluoxetine, paroxetine, bupropion, qumidme, cmaealcet, ritonavir, sertraline, duloxetine, and terbinafme. Not to be bound by theory, but in some embodiments a salt of the invention is metabolized by CYP2D6. In such embodiments, a CYP2D6 inhibitor may slow metabolism of a salt of the invention.
  • Opiates include, but are not limited to, codeine, thebaine, hydrocodone,
  • hydromorphone hydromorphone, morphine, oxycodone, oxymorphone, and tramadol.
  • Such combination products employ the pharmaceutical compositions or salts of this invention within the dosage range described herein and the other pharmaceutically active salt or salts within approved dosage ranges and/or the dosage described in the publication reference.
  • any of the pharmaceutical compositions or salts described herein can allow the combination therapeutic agents and/or pharmaceutical compositions described herein to be administered at a low dose, that is, at a dose lower than has been conventionally used in clinical situations.
  • a low dose is a sub-therapeutic dose, which is a dose less than the therapeutic dose, that is, less than the amount/dose normally used when said therapeutic agent is administered alone (i.e., individual ly and in the absence of other therapeutic agents or compounds) for treatment of pain, a headache, depression, ailodynia, fibromyalgia, fibromyalgia-ness, central sensitization, centralization, temporomandibular joint syndrome (TMJ), Gulf War syndrome, osteoarthritis, rheumatoid arthritis, or hypertension.
  • TMJ temporomandibular joint syndrome
  • pain examples include, but are not limited to, regional pain syndrome, lower back pain, visceral pain, neuropathic pain, sickle cell pain, nociceptive pain, post-operative pain, orthopedic injury pain, phantom limb pain, pain associated with cancer, or pain associated with post-traumatic stress disorder (PTSD).
  • regional pain syndrome lower back pain
  • visceral pain neuropathic pain
  • nociceptive pain post-operative pain
  • orthopedic injury pain phantom limb pain
  • pain associated with cancer or pain associated with post-traumatic stress disorder (PTSD).
  • PTSD post-traumatic stress disorder
  • headache examples include, but are not limited to, an episodic tension-type headache; a migraine headache: a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a menstrual cycle episode; a tension or migraine headache due to a vascular, neurovascular, or neurogenic disorder or dysfunction during a migraine episode; or a headache from mild to moderate hypertension, [0188]
  • the methods and combination of the invention can also maximize the therapeutic effect at higher doses.
  • one or more of the salts or components to make the salts, of the invention are prepared from commercially available reagents by routine methods in synthetic organic chemistry.
  • reaction mixture was cooled to 5-15 °C. 10 volumes of water and 10 volumes of methyl-t-butyl ether were added to the reaction mixture and stirred for 20-30 min. Following the organic phase was separated and the aqueous extracted a second time with 10 volumes methyl-t- butyl ether. The organic phases were washed with 10 volumes water twice and once with 10 volumes brine. The ee was about 90-95%.
  • Another synthetic route may include, but not be limited to, the following steps: (a) combining (S)-methyloxirane with 3-memyl-2-buten-l-ylmagnesium chloride in THF in the presence of copper iodide; (b) neutralizing, extracting with ether, drying with magnesium sulfate, removing solvent, and distilling the (S)-6-methyl-hept-5-en-2-ol; (c) reacting (S)-6-methyl-hept- 5-en-2 ⁇ ol with methanesulfonyl chloride and DIEA in anhydrous DCM; (d) cooling the reaction mixture to about 5 °C; (e) adding mesyi chloride dropwise; (f) diluting the reaction mixture after 18 hours at room temperature; (g) washing said mixture with water, brine and drying over MgS0 4 ; (h) concentrating to oily product, (S)-methanesulfonic acid l,5-dimethyl-hex-4-
  • (R)-isometheptene was mixed with the following acids under different conditions to attempt to generate crystalline salts. Techniques used to analyze the samples were as follows. Different acids were selected and used to prepare a particular (R)-isometheptene salt. Exemplary methods are provided below, but these methods in no way should limit the invention. Preparation of (R)-Isometheptene Maleate
  • Acetic acid, adipic acid, aspartic acid, benzoic acid, citric acid, cyclamic acid, fumaric acid, glutaric acid, glycolic acid, hippuric acid, hydrochloric acid, maleic acid, L-malic acid, mucic acid, phosphoric acid, succinic acid, sulfuric acid, and L-tartaric acid salts of (R) ⁇ isometheptene were prepared and analyzed by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), themiogravimetric (TG) analysis, dynamic vapor sorption (DVS) analysis, raman spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy.
  • XRPD X-ray Powder Diffraction
  • DSC differential scanning calorimetry
  • TG vapor sorption
  • DVS dynamic vapor sorption
  • NMR nuclear magnetic resonance
  • the Rigaku Smart-Lab X-ray diffraction system was configured for reflection Bragg- Brentano geometry using a line source X-ray beam.
  • the X-ray source is a Cu Long Fine Focus tube that was operated, at 40 kV and 44 ma. That source provides an incident beam profile at the sample that changes from a narrow line at high angles to a broad rectangle at low angles. Beam conditioning slits are used on the line X-ray source to ensure that the maximum beam size is less than 10 mm both along the line and normal to the line.
  • the Bragg- Brentano geometry is a para- focusing geometry controlled by passive divergence and receiving slits with the sample itself acting as the focusing component for the optics.
  • the inherent resolution of Bragg-Brentano geometry is governed in part by the diffractometer radius and the width of the receiving slit used. Typically, the Rigaku Smart-Lab is operated to give peak widths of 0.1 °2 ⁇ or less.
  • the axial divergence of the X-ray beam is controlled by 5.0-degree Soiler slits in both the incident and diffracted beam paths.
  • Powder samples were prepared in a low background Si holder using light manual pressure to keep the sample surfaces flat and level with the reference surface of the sampl e holder. Each sample was analyzed from 2. to 40 °2 ⁇ using a continuous scan of 6 °2 ⁇ per minute with an effective step size of 0.02 °2f ,
  • DSC analyses were carried out using a TA Instruments 2920 instrument.
  • the instrument temperature calibration was performed using indium.
  • the DSC cell was kept under a nitrogen purge of ⁇ 50 mL per minute during each analysis.
  • Each sample was placed in a standard, crimped, aluminum pan and was heated from 20 °C to 350 C C at a rate of 10 °C per minute.
  • Thermogravimetric (TG) Analysis [ ⁇ 21 ] The TG analysis was carried out using a TA Instruments Q50 instrument. The instrument balance was calibrated using class M weights and the temperature calibration was performed using alumel. For each analysis, the nitrogen purge at the balance was -40 mL per minute, while the furnace was purged at -60 mL per minute. Each sample was placed into a pre- tared platinum pan and heated from 20 °C to 350 °C at a rate of 10 °C per minute.
  • Raman Spectroscopy [0221 J Fourier transform (FT) Raman spectra were acquired on a Nicolet model 6700 spectrometer interfaced to a Nexus Raman accessory module. This instrument is configured with a Nd:YAG laser operating at 1024 nm, a CaF 2 beam splitter, and a indium gallium arsenide detector. OMNiC 8.1 software was used for control of data acquisition and processing of the spectra. Samples were packed into a 3-inch glass NMR. tube for analysis. Nuclear Magnetic Resonance (NMR) Spectroscopy
  • E RT, oil. Put in vacuum/RT; oil.
  • E RT, oil. Put in vacuum/RT; oil .
  • mice are given an intraplantar injection of 5% formalin (25 uL) into one posterior hindpaw. This treatment induces paw licking in control animals. Mice are briefly observed at one minute intervals between 15 and 50 minutes after the injection of formalin and the number of occasions that the mice are observed licking the injected paw is recorded.
  • test substances selected from (R)-isometheptene salts or pharmaceutical compositions comprising (R)-isometheptene salts are evaluated at three doses, administered p.o. 15 minutes before the test (i.e. immediately before formalin) and compared with a vehicle control group.
  • Morphine 32 mg/kg p.o.
  • 60 minutes before the test i.e. 45 minutes before formalin
  • the experiment includes eight groups. Because of the number of animals, the experiment is divided into two sub-experiments (n :::: 5 mice/group/day).
  • Salts or compositions of the invention are tested for analgesic activity in mice using a hot plate test.
  • the method, which detects analgesic activity follows that described by Eddy and Leimbach, J. Pharmacol. Exp. Ther., 107, 385-393, (1 953 ).
  • J Mice are placed onto a hot metal plate maintained at 54 °C surrounded by a Plexiglas cylinder (height: 13 cm; diameter: 19 cm). The latency to the first foot-lick is measured
  • mice are studied per group. The test is performed partially blind .
  • the test substances selected from ( )-isometheptene salts or pharmaceutical compositions comprising (R)-isometheptene salts are evaluated at three doses (10, 30 and 100 mg/kg), administered p.o. 15 minutes before the test, and compared with a vehicle control group.
  • Morphine 32 mg/kg p.o. administered 60 mmutes before the test, is used as reference substance.
  • the experiment includes 8 groups.
  • Data with the test substance are analyzed by comparing treated groups with vehicle control using ANOVA followed by post-hoc Dunnett's tests.
  • Data with the reference substance are analyzed using unpaired Student's t tests.
  • mice are studied per group. The test is performed partial ly blind.
  • test substances selected from (R)-isometheptene salts or pharmaceutical compositions comprising (R)-isometheptene salts are evaluated at three doses (10, 30, and 100 mg), administered p.o. 1 minutes before the test, and compared with a vehicle control group.
  • J Morphine (32 mg/kg p.o.) admmister 60 mmutes before the test, is used as reference substance.
  • the experiment includes eight groups.
  • Spontaneous trigeminal al lodynia (STA) rats are a model of spontaneous headache and can be used as a model of primary headache.
  • STA rats Through a series of tactile sensor ⁇ ' tests, the periorbital, hind-paw, and jaw-pressure thresholds for STA rats are determined by applying von Frey monofilaments. These determinations are made both before and after receiving treatments with salts or compositions of interest.
  • Analgesic activity of the salts or pharmaceutical compositions described herein that is modulated through li can be evaluated by determining trigeminal von Frey thresholds in STA rats.
  • Spontaneous trigeminal allodynia (STA) rats are rats with the inherited trait of spontaneously changing trigeminal von Frey thresholds. Protocols for testing these rats are adapted from Oshinsky, MX., et al., Spontaneous Trigeminal Allodynia in Rats: A Model of Primary Headache, Headache, 2012, 52: 1336-1349. Oshinsky et al. describes these rats as a novel model of spontaneous headache that can be used as a model of primary headache.
  • test substances selected from (R)-isometheptene salts or pharmaceutical compositions comprising (R.)-isometheptene salts on days when their thresholds in spontaneous allodynia rats are 4 g or belo w for STA rats. Testing days for each of the salts are separated by at least one week. Tactile sensory thresholds are recorded prior to and following injections at 0.5 hours, 1 .5 hours, 2,5 hours, 3.5 hours, and 24 hours. Tactile sensor ⁇ ' testing
  • Rats are trained and acclimated to a plastic tube restraint and entered uncoaxed. This restrainer allows the rats to undergo sensory testing.
  • Periorbital, hind-paw, and jaw-pressure thresholds are determined by applying von Frey monofilaments (Stoelting Co., Wood Dale, IL, USA). Each monofilament is identified by manufacturer-assigned force values (26, 15, 10, 8, 6, 4, 2, 1.4, 1, 0.6, 0.4, 0.07 g). For trigeminal testing, the fi laments are tested on both the left and right sides of the face, over the rostral portion of the eye for periorbital testing, and on the skin over the masseter muscle for jaw testing. The vibrissae are not touched during testing.
  • the filaments are applied to the mid-plantar region of the left and right hind paws, avoiding the less sensitive foot pads.
  • the maximum value tested is 26 g; the rats that do not respond to this stimulus are assigned this value.
  • Left and right threshold data are recorded separately.
  • the von Frey stimuli are presented in sequential order, either ascending or descending, as necessary, to determine the threshold of response. After a positive response, a weaker stimulus is presented, and after a negative response, a stronger stimulus is presented.
  • Results are presented either as the threshold in grams ⁇ standard error of the mean (SEM), or as a percent change from baseline on the side that has the lowest value.
  • the threshold is defined as a positive response to 2 of 3, or in some cases 3 of 5 trials of a single von Frey monofilament .
  • the value of the von Frey filament that elicited head withdrawal in 2 of 3 repetitions of the stimulus is designated as that day's threshold.
  • Several behaviors are considered a positive head-withdrawal response, including when the rat vigorously stroked its face with the ipsilaterai forepaw and quickly recoiled its head away from the stimulus or vocalized.
  • rats that do not respond to the 10-g stimulus are assigned 10 g as their threshold.
  • [0254 J Stability of the salts described herein can be assessed using pharmacokinetic studies in animals such as dogs, rats, and humans. Animals are treated with varying doses of the salts described herein and after specified time periods, plasma samples are drawn and then analyzed for the presence of (R)- or (S)-isometheptene. Not wishing to be bound by theory, in some embodiments, such pharmacokinetic studies can be used to identify slow, normal, and fast metabolizers of the salts of the invention.
  • the vehicle is saline 0.9% NaCl for injection, USP, and for PO, the vehicle is deionized tap water.
  • the test salts are mixed with vehicle to achieve the desired concentrations.
  • the animals used are beagles (dogs) from the MP] Research Colony.
  • the dogs are at least five months of age and the males weigh 5.5 to 12.0 kg and the females weigh 5.0 to 10.0 kg at arrival, as measured within three days of arrival.
  • the stud)' uses four males and four females.
  • the dogs are acclimated for at least one week prior to testing and are acclimated to a sling restraint for at least three times for a period of at least 20 minutes each time.
  • Prior to dose initiation animals are acclimated to the oral gavage dosing procedure at least three times.
  • a fixed dose volume of 10 mL/animal of tap water is administered on each occasion. Study design
  • Salts are administered via oral gavage or intravenous injection.
  • the test salt is administered once intravenously on Day 1. After a 7-day washout period the test salt is administered once via oral gavage.
  • PO oral gavage
  • the test salt is withdrawn from stirred formulations and dosed via oral gavage. Individual doses are based on the most recent body weights. After each dose, and prior to removal of the gavage tube, the tube is flushed with 5 to 10 mL of tap water.
  • test salt is administered via the cephalic or other suitable vein. Individual doses are based on the most recent body weights. The dose is administered by bolus injection, unless otherwise indicated. If a catheter is used for dosing, the catheter is flushed with approximately 1 mL of sterile 0.9% Sodium Chloride for Injection, USP following dosing. The intravenous route is used for pharmacodynamic studies in nonclinical species and for calculation of absolute bioavailability. Sample collection and analysis
  • [ ⁇ 261] 0.5 mL samples are collected from the jugular or other suitable vein.
  • the anticoagulant used is K 2 EDTA. Samples are centrifuged and the plasma stored frozen (-60 to -90 °C). The plasma is analyzed for the test salts.
  • the vehicle is saline 0.9% NaCl for Injection, IJSP, and for PO, the vehicle is deionized tap water.
  • the test salts are mixed with vehicle to achieve the desired concentrations.
  • the animals used are CD* rats [Crl;CD*(SD)] from Charles River Laboratories.
  • the rats are six weeks of age at arrival and the males weigh 130 to 210 g and the females weigh 100 to 170 g at arrival, as measured within three days of arrival.
  • the study uses 20 males and 20 females.
  • the rats are acclimated for at least one week prior to testing. During this acclimation period, ail animals are observed daily for any clinical signs of disease, and all animals are given a detailed clinical examination prior to selection for study.
  • Salts are administered via oral gavage or intravenous injection.
  • the test salt is administered once on Day 1.
  • PO oral gavage
  • IV intravenous
  • the test salt is administered via the tai l vein. Individual doses are based on the most recent body weights. The dose is administered by bolus injection, unless otherwise indicated.
  • the intravenous route is used for pharmacodynamic studies in nonclinical species and for calculation of absolute bioavailability.
  • the study is a single-center, randomized, double-blind, placebo-controlled, single ascending dose, safety and tolerability study of test salt capsules in healthy volunteers.
  • Four successive cohorts are planned with doses of test salt capsules, 35 mg, 70 mg, 140 mg, and 280 nig, respectively.
  • Each cohort consists of 15 subjects, and subjects are randomly assigned in a 3: 1 : 1 ratio to one of the (R)-isometheptene salts, raceniic isometheptene, or placebo capsules:

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Abstract

L'invention concerne la préparation et la caractérisation de nouveaux sels de (R)-isometheptène et de formes cristallines de ceux-ci; de plus, l'invention concerne l'utilisation de ces nouveaux sels, seuls ou en combinaison avec d'autres sels thérapeutiques pour le traitement de divers états, tels que l'hypertension ou une céphalée, ou bien comme sédatif.
PCT/US2015/034292 2014-06-04 2015-06-04 Nouvelles compositions de (r)-isometheptène et utilisations WO2015188005A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002094238A1 (fr) * 2001-05-24 2002-11-28 Alexza Molecular Delivery Corporation Apport de composes anti-migraine par voie d'inhalation
WO2014113734A2 (fr) * 2013-01-18 2014-07-24 Tonix Pharmaceuticals Inc. Isomère de l'isométheptène

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002094238A1 (fr) * 2001-05-24 2002-11-28 Alexza Molecular Delivery Corporation Apport de composes anti-migraine par voie d'inhalation
WO2014113734A2 (fr) * 2013-01-18 2014-07-24 Tonix Pharmaceuticals Inc. Isomère de l'isométheptène

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
NINAN, T. M.: "Miscellaneous Drugs in Acute Migraine Therapy", MONOGRAPHS IN CLINICAL NEUROSCIENCE, (DRUG TREATMENT OF MIGRAINE AND OTHER HEADACHES), FRONTIERS OF NEUROLOGY AND NEUROSCIENCE, vol. 17, 2000, pages 237 - 242 *
TAYLOR, W.G. ET AL.: "Studies on Isometheptene Metabolism. Identification and Stereochemistry of a Major Metabolite Isolated from Rat Urine", DRUG METABOLISM AND DISPOSITION, vol. 5, no. 6, 1977, pages 564 - 571, XP008175790 *
VIDRIO, H. ET AL.: "Antihypertensive Effects of Sympathomimetic Amines", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 187, no. 2, 1973, pages 308 - 314, XP055242172 *
WILLEMS, E.W. ET AL.: "Pharmacological Profile of the Mechanisms Involved in the External Carotid Vascular Effects of the Antimigraine Agent Isometheptene in Anaesthetised Dogs", NAUNYN-SCHMIEDEBERG'S ARCH PHARMACOL, vol. 364, no. 1, 2001, pages 27 - 32, XP055180750, ISSN: 0028-1298 *

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