EP1928863A2 - Formes dosifiees pharmaceutiques et compositions associees - Google Patents

Formes dosifiees pharmaceutiques et compositions associees

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Publication number
EP1928863A2
EP1928863A2 EP06790193A EP06790193A EP1928863A2 EP 1928863 A2 EP1928863 A2 EP 1928863A2 EP 06790193 A EP06790193 A EP 06790193A EP 06790193 A EP06790193 A EP 06790193A EP 1928863 A2 EP1928863 A2 EP 1928863A2
Authority
EP
European Patent Office
Prior art keywords
patient
lecozotan
mean
max
dosage form
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06790193A
Other languages
German (de)
English (en)
Inventor
Krishnendu Ghosh
Arwinder S. Nagi
Xiaohong Pan
Melissa Lin
Leonid Linberg
Ping Cai
Eric N. C.. Browne
Michel Bernatchez
Mark Lankau
Sangeeta Raje
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Original Assignee
Wyeth LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wyeth LLC filed Critical Wyeth LLC
Publication of EP1928863A2 publication Critical patent/EP1928863A2/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • 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
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • This invention relates, for example, to novel formulations and methods for the delivery of 4-cy ano-N- ⁇ (2R)-2- [4-(2,3 -dihy dro-benzo [1 ,4] dioxin-5-yl)-piperazin- 1 -y 1] - propyl ⁇ -N-pyridin-2-yl-benzaniide, pharmaceutically acceptable salts thereof, structurally related compounds, and/or metabolites; as well as to use of these formulations and methods for treating disease.
  • the 5-HT 1A receptor antagonist 4-cyano-N- [(2R)-[4-(2,3- dihydrobenzo [1,4] dioxin-5-yl) piperazin-1-yl] propyl] -N-pyridin-2-yl-benzamide hydrochloride (lecozotan) has been characterized in multiple in vitro and in vivo pharmacologic assays as a drug to treat cognitive dysfunction. In vitro binding and intrinsic activity determinations demonstrated that lecozotan is a potent and selective 5-HT 1A receptor antagonist.
  • lecozotan 0.3 mg/kg sc antagonized the decrease in hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg sc) of 8 OH-DPAT and had no effects alone at doses 10-fold higher.
  • Lecozotan significantly potentiated the potassium chloride-stimulated release of glutamate and acetylcholine in the dentate gyrus of the hippocampus.
  • Chronic administration of lecozotan did not induce 5-HT 1A receptor tolerance or desensitization in a behavioral model indicative of 5-HT 1A receptor function.
  • the present invention provides, inter alia, formulations comprising 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl- benzamide, also referred to as lecozotan, pharmaceutically acceptable salts thereof, structurally related compounds, metabolites, and combinations thereof.
  • Compounds provided by the present invention include:
  • the compounds are in the form of particles.
  • the particles have a mean diameter of no more than about 20 microns.
  • the particles have a mean diameter of from about 0.75 to about 10 microns.
  • the particles have a mean diameter of from about 2 to about 8 microns.
  • compositions of the present invention comprise 4-cyano-N- ⁇ (2R) ⁇ 2-[4-(2,3- dihydro-benzo[l ,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof (e.g., 4- ⁇ (2R)-[4-(2,3-dihydro- benzo [ 1 ,4] dioxin-5-yl)-piperazin- 1 -yl] -propyl ⁇ -N-pyridin-2-yl-benzamide hydrochloride salt), structurally related compounds or metabolites thereof as described herein.
  • compositions of the present invention comprise 4-cyano-N- ⁇ (2R)-2-[4-(2,3- dihydro-benzo[l ,4]dioxin-5-yl)-piperazin- 1 -yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof and one or more structurally related compounds and/or metabolites.
  • the particles have a mean diameter of no more than about 20 microns. In another aspect, the particles have a mean diameter of from about 0.75 to about 10 microns. In another aspect, the particles have a mean diameter of from about 2 to about 8 microns.
  • the structurally related compounds and/or metabolites when provided in a composition with 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l ,4]dioxin-5-yl)-piperazin-l- yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof (e.
  • compositions of the present invention further comprise a pharmaceutically acceptable carrier.
  • compositions and dosage forms of the present invention comprising 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]- propyl ⁇ -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof are substantially free of one or more dimers of 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro- benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide.
  • “Substantially free,” as used in this context, means that the dimers will be present in the compositions in an amount of less than about 0.5% each, by weight, preferably in an amount of less than about
  • 0.3% each by weight, more preferably in an amount of less than about 0.2% each, by weight, and even more preferably in an amount of less than about 0.1% each, by weight, based on the total weight of the composition, and in the dosage forms in an amount of less than about 0.5% each, by weighty preferably in an amount of less than about 0.3% each, by weight, more preferably in an amount of less than about 0.2% each, by weight, and even more preferably in an amount of less than about 0.1% each, by weight, based on the weight of the active ingredient in the dosage form.
  • the present invention provides formulations comprising 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]- propyl ⁇ -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof that are substantially free of dimers of 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)- piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide and/or other structurally related compounds of 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l ,4]dioxin-5-yl)-piperazin-l-yl]- propyl ⁇ -N-pyridin-2-yl-benzamide.
  • Dosage forms of the present invention comprise 4-cyano-N- ⁇ (2R)-2-[4-(2,3- dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof ⁇ e.g., 4- ⁇ (2R)-2-[4-(2,3-dihydro- benzo[l,4]dioxin-5-yl)-pi ⁇ erazin-l-yl]-pro ⁇ yl ⁇ -N-pyridin-2-yl-benzamide hydrochloride salt), structurally related compounds or metabolites as described herein.
  • dosage forms of the present invention will comprise 4-cyano-N- ⁇ (2R)-2-[4- (2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]- ⁇ ropyl ⁇ -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof and one or more structurally related compounds and/or metabolites.
  • the particles have a mean diameter of no more than about 20 microns. In another aspect, the particles have a mean diameter of from 0.75 to about 10 microns.
  • the particles have a mean diameter of from about 2 to about 8 microns.
  • active ingredient refers to 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro- benzo[l ,4]dioxin-5-yl)-piperazin-l -yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof (e.g., 4- ⁇ (2R)-2-[4-(2,3-dihydro- benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide hydrochloride salt), structurally related compounds or metabolites (as shown herein) and their pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt form thereof e.g., 4- ⁇ (2R)-2-[4-(2,3-dihydro- benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N
  • compositions and/or dosage forms comprise in addition to the active ingredient (e.g., 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro- benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof) at least one rate controlling polymer and at least one organic acid.
  • the organic acid is citric acid anyhydrate, citric acid monohydrate, ascorbic acid, aspartic acid, glutamic acid, fumaric acid, malic acid or tartaric acid.
  • the organic acid is citric acid or a polyfunctional organic acid.
  • the at least one release rate controlling polymer is a methylcellulose.
  • the polymer is a hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxy ethyl cellulose or hydroxypropyl methylcellulose phthalate.
  • the hydroxypropyl methylcellulose is hypromellose 2208 or 2910 (e.g., MethocelTM K4M, MethocelTM Kl 5M, MethocelTM KIOOM, MethocelTM ElOM, MethocelTM E4M , MethocelTM KlOOLV, MethocelTM E50LV, MethocelTM E5, MethocelTM E6, or MethocelTM El 5LV.
  • MethocelTM K4M MethocelTM K4M, MethocelTM Kl 5M, MethocelTM KIOOM, MethocelTM ElOM, MethocelTM E4M , MethocelTM KlOOLV, MethocelTM E50LV, MethocelTM E5, MethocelTM E6, or MethocelTM El 5LV.
  • the organic acid is citric acid and the rate p* :T Cd/hJtrJ ⁇ Bl ⁇ in Qg " S po /lym 3e Hr"-B is 1 ny 3p1romellose 2208, (e.g., Methocel K4M premium CR and/or MethocelTM KlOOM Premium CR).
  • compositions and/or dosage forms further comprise at least one filler.
  • the filler is microcrystalline cellulose, lactose, calcium carbonate, calcium phosphate, maltodextrin, dextrose, fructose, maltose, mannitol, starch, or sucrose.
  • the microcrystalline cellulose is silicified microcrystalline cellulose and the lactose is lactose monohydrate.
  • pharmaceutical compositions and/or dosage forms further comprise at least one lubricant.
  • the lubricant is magnesium stearate, talc, stearic acid, or colloidal silicon dioxide.
  • pharmaceutical compositions and/or dosage forms of the present invention comprise, in addition to the active ingredient or ingredients, at least one rate controlling polymer, at least one organic acid, at least one filler, and at least one lubricant.
  • compositions and/or dosage forms of the present invention comprise about 2 to about 45 or 46 parts of a release rate controlling polymer and about 1 to about 5 parts of an organic acid per part of active ingredient. In some embodiments, the pharmaceutical compositions and/or dosage forms comprise about 0.4 to about 10 mg of active ingredient. In some embodiments, the pharmaceutical compositions and/or dosage forms of the present invention comprise about 50 to about 150 mg of rate controlling polymer(s), about 5 to about 50 mg of organic acid(s), about 85 to about 179 mg of filler(s) and about 1 mg of lubricant. In some embodiments, there is from about 2 to about 50 mg of organic acid(s).
  • compositions and/or dosage forms of the present invention comprise in addition to the active ingredient (e.g., 4-cyano-N- ⁇ (2R)-[4- (2,3 -dihydro-benzo [ 1 ,4]dioxin-5-yl)-piperazin- 1 -yl] -propyl ⁇ -N-pyridin-2-y 1-benzamide or a pharmaceutically acceptable salt form thereof), at least one filler and at least one lubricant.
  • active ingredient e.g., 4-cyano-N- ⁇ (2R)-[4- (2,3 -dihydro-benzo [ 1 ,4]dioxin-5-yl)-piperazin- 1 -yl] -propyl ⁇ -N-pyridin-2-y 1-benzamide or a pharmaceutically acceptable salt form thereof
  • the active ingredient e.g., 4-cyano-N- ⁇ (2R)-[4- (2,3 -dihydro-benzo [ 1
  • the filler is microcrystalline cellulose, lactose, calcium carbonate, calcium phosphate, maltodextrin, dextrose, fructose, maltose, mannitol, starch, sucrose or a blend thereof. In some embodiments, the filler is microcrystalline cellulose, lactose, or a blend thereof. In some embodiments, pharmaceutical compositions and/or dosage forms -T fur -t'hUer S co OmBpri /se3 at H lMeBast 1 o.3ne t lu 1 bri .cant.
  • the lubricant is magnesium stearate.
  • compositions and/or dosage forms comprise about 15 to about 300 parts of filler and about 0.1 to about 3 parts of lubricant per part of active ingredient.
  • the pharmaceutical compositions and/or dosage forms comprise about 0.1 to about 5 mg of 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro- benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof.
  • the pharmaceutical compositions and/or dosage forms comprise about 80 to about 150 mg of one or more filler(s)- and at least about 0.75 mg of one or more lubricant(s).
  • the dosage forms of the present invention are in the form of tablets.
  • the tablets are film coated.
  • compositions or dosage forms of the present invention are in the form of a dry blend.
  • the present invention provides processes of providing the compositions and dosage forms of the present invention.
  • the compositions are compressed for a time and under conditions effective to form a tablet thereof.
  • the tablets are further film coated.
  • the present invention also provides processes comprising mixing the active ingredient, at least one rate controlling polymer and at least one organic acid thereby forming a blend thereof.
  • the process further comprises compressing the blend for a time and under conditions effective to form a tablet thereof.
  • the tablets are further film coated.
  • the present invention also provides processes comprising mixing the active ingredient, at least one filler and at least lubricant thereby forming a blend thereof.
  • the process further comprises compressing the blend for a time and under j et r ⁇ « ⁇ . a j
  • the tablets are further film coated.
  • the dosage forms of the present invention are free of base.
  • the present invention provides methods and processes of administering a dosage form, compound or composition of the present invention to a mammal, e.g., to a human.
  • the dosage forms, compounds, or compositions are orally administered. In one aspect, they are orally administered once every 12 or 24 hours. In another aspect, they are orally administered once every 48 hours. In some particularly preferred embodiments, the dosage forms, compounds, or compositions are administered to treat Alzheimer's Disease.
  • the present invention provides, methods of administering to a patient an oral dosage form that comprises lecozotan and a pharmaceutically acceptable carrier.
  • the methods comprise administering to a patient an oral dosage form that comprises lecozotan and a pharmaceutically acceptable carrier and achieves a maximum plasma concentration (C max ) in a patient and a 24 hour plasma concentration (C 24 ) in a patient, wherein a mean ratio of C max /C 24 in a patient population is from about 5:1 to about 1.1:1.
  • the mean ratio of C m a ⁇ /C 24 is from about 3:1 to about 1.1 :1, from about 2.8:1 to about 1.1 :1, or from about 2.3:1 to about 1.1:1.
  • the C max and C 24 values are measured after administration of a single dose of the oral dosage form to a patient.
  • the oral dosage form comprises about 5 mg of lecozotan.
  • the mean t max in the patient population is about 3.5 hours or greater or about 5 hours or greater.
  • the mean C max in the patient population is about 100 ng/ml or lower.
  • administration of these dosage forms minimizes an adverse side effect associated with the administration of lecozotan to a patient.
  • these methods include a step of identifying a patient at risk of an adverse side effect through administration of lecozotan; and subsequently administering the oral dosage form to the patient.
  • the adverse side effect is headache, dizziness, paresthesia, abnormal vison, tinnitus, or a combination thereof.
  • the methods of administering lecozotan and a pharmaceutically acceptable carrier comprise administering to a patient an oral dosage form that comprises lecozotan and a pharmaceutically acceptable carrier and achieves a maximum plasma concentration (C max ) in a patient and a 24 hour plasma concentration (C 24 ) in a patient, wherein a mean ratio of C ma ⁇ / C 24 in a patient population is from about 2.4:1 to about 1.1:1.
  • the mean ratio of C max /C 24 is from about 2.3:1 to about 1.1:1, from about 2:1 to about 1.1 :1, from about 1.9:1 to about 1.1:1 or from about 1.5:1 to about 1.1:1.
  • the C max and C 24 values are measured at steady state in a fasting population.
  • about 10 mg of lecozotan is provided daily to the patient.
  • the mean C max in the patient population is about 350 ng/ml.
  • administration of these dosage forms minimizes an adverse side effect associated with the administration of lecozotan to a patient.
  • these methods include a step of identifying a patient at risk of an adverse side effect through administration of lecozotan; and subsequently administering the oral dosage form to the patient.
  • the adverse side effect is headache, dizziness, paresthesia, abnormal vison, tinnitus, or a combination thereof.
  • the present invention also provides methods comprising administering to a patient an oral dosage form that comprises lecozotan and a pharmaceutically acceptable carrier and achieves a mean maximum plasma concentration (C max ) in a patient population and a mean 24 hour plasma concentration (C 24 ) in a patient population, wherein a ratio of mean C max /niean C 24 is from about 5:1 to about 0.5:1.
  • the ratio of mean C ma ⁇ /mean C 24 is from about 2.8 : 1 to about 1.1:1, from about 2 : 1 to about 1.1 : 1 , or from about 1.5:1 to about 1.1:1.
  • the C max and C 24 values are measured after administration of a single dose of the oral dosage form to a patient.
  • the C max and C 24 values are measured at steady state in a fasting population.
  • the oral dosage form comprises about 5 mg of lecozotan.
  • administration of these dosage forms minimizes an adverse side effect associated with the administration of lecozotan to a patient.
  • these methods include a step of identifying a patient at risk of an adverse side effect through administration of lecozotan; and subsequently administering the oral dosage form to the patient.
  • the adverse side effect is headache, dizziness, paresthesia, abnormal vison, tinnitus, or a combination thereof.
  • the present invention also provides methods comprising administering to a patient an oral dosage form that comprises lecozotan and a pharmaceutically acceptable carrier and achieves a mean maximum plasma concentration (C max ) in a patient population and a mean 12 hour plasma concentration (C 12 ) in a patient population, wherein a ratio of mean C ma ⁇ /mean C 24 is from about 3:1 to about 0.5:1.
  • the ratio of mean C ma ⁇ /mean C 12 is from about 2:1 to about 1.1:1 or from about 1.5:1 to about 1.1:1.
  • administration of these dosage forms minimizes an adverse side effect associated with the administration of lecozotan to a patient.
  • these methods include a step of identifying a patient at risk of an adverse side effect through administration of lecozotan; and subsequently administering the oral dosage form to the patient.
  • the adverse side effect is headache, dizziness, paresthesia, abnormal vison, tinnitus, or a combination thereof.
  • the present invention provides methods for administering lecozotan to a patient comprising administering to the patient an oral dosage form that comprises lecozotan and a pharmaceutically acceptable carrier, wherein the dosage form exhibits an in vitro dissolution profile when measured in a USP type II dissolution apparatus at 50 rpm, in 900 ml of USP pH 6.8 phosphate buffer at 37 0 C and a sinker is used for each dosage form, wherein no more than 40% of lecozotan is released at about 2 hours of measurement in said apparatus; and from about 50% to about 85% of lecozotan is released at about twelve hours of measurement in said apparatus.
  • the present invention provides methods for administering lecozotan to a patient comprising administering an oral dosage form that comprises lecozotan and a pharmaceutically acceptable carrier to a patient and (i) achieves a mean C max in a patient population that is less than the mean C max obtained from administering an equivalent dose of lecozotan from an immediate release formulation to the patient population; (ii) achieves a mean t max in a patient population that is greater than the t max obtained from administering an equivalent dose of lecozotan from an immediate release formulation to the patient population; and (iii) achieves a curve of concentration of lecozotan over time, the curve having an area under the curve (AUC) in a patient population that is substantially the same as the AUC obtained from administering an equivalent dose of lecozotan from an CT im/meydi.Sate0 re£lke/ase3 dMos-BageJL f3orm + to + t,he pa +
  • ⁇ In ce ⁇ rtai.n em ,bod,i.men + ts, + t,he oral dosage form achieves a mean C max of about 100 ng/ml or less and/or a mean t max of from about 4 hours to about 8 hours and/or a mean AUC that is from about 2000 to about 2500 ng h/mL.
  • these measurements are measured after administration of a single dose of the oral dosage form, for example, a single dose of 5 mg of lecozotan.
  • the oral dosage form achieves a mean C max of less than 400 ng/mL, for example a mean C max of about 350 ng/mL, and/or a mean t max of from about 4 hours to about 8 hours and/or a mean AUC that is from about 5500 to about 6300 ng h/mL.
  • these measurements are measured at steady state in a fasting population.
  • 10 mg of lecozotan is administered daily to the patient.
  • administration of these dosage forms minimizes an adverse side effect associated with the administration of lecozotan to a patient.
  • these methods include a step of identifying a patient at risk of an adverse side effect through administration of lecozotan; and subsequently administering the oral dosage form to the patient.
  • the adverse side effect is headache, dizziness, paresthesia, abnormal vison, tinnitus, or a combination thereof.
  • FIGURE 1 presents a graph showing mean lecozotan concentration over time for three sustained release formulations and one immediate release formulation after a single dose of 5 mg of lecozotan.
  • FIGURE 2 presents a graph showing mean lecozotan plasma concentration versus time profiles in Alzheimer's patients receiving multiple oral doses of immediate release (5 mg twice daily) and sustained release (10 mg once daily) formulations.
  • FIGURE 3 presents a graph showing lecozotan plasma concentration vs time profile in Alzheimer's patients receiving single and multiple oral doses (QD) doses of 10 mg lecozotan sustained release formulation as described in part 2 of example 8.
  • the data for Day 1 shows from 0 to 24 hours.
  • the data for Day 28 shows 0 to 72 hours.
  • " ' ' '” "FIGURE " ⁇ presents a graph showing a comparison of lecozotan mean plasma concentrations vs. time profiles in Alzheimer's patients receiving multiple oral doses of IR (5 mg) and SR (10 mg QD) formulations.
  • the present invention provides, inter alia, formulations comprising 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l ,4]dioxin-5-yl)-piperazin-l -yl]-propyl ⁇ -N-pyridin-2-yl- benzamide, pharmaceutically acceptable salts thereof, structurally related compounds, and/or metabolites.
  • formulations refers to compounds, compositions, and dosage forms, such as, for example, immediate release and sustained release dosage forms.
  • the present invention also provides processes for making the formulations and methods of administering them to a mammal.
  • Preferred formulations for use in the present invention are those that act as serotonergic agents and have 5-HT 1 A binding activity.
  • preferred compounds act as 5-HT 1A antagonists. See, for example, US-B-6,784,294, US-B-6,713,626, US-B- US-B- 6,469,007, US-B-6,586,436, US-A-5 5 710,149, and US-A-6, 127,357, and WO 97/03982, the disclosures of which are incorporated herein by reference in their entirety for all purposes.
  • compositions comprising more than one compound of the present invention can be prepared by those skilled in the art of organic synthesis employing known methods that utilize readily available reagents and starting materials, see, for example, EP-B-0512755, WO 1 97/03982, US-B-6, 127,357, US-B- 6,469,007, US-B-6,713,626, and US-B-6,784,294, and US-A-20030208075A1, the disclosures of which are incorporated herein by reference in their entirety for all purposes.
  • Such methods include alkylating l-(2,3-dihydro-l,4-benzodioxin-5-yl)piperazine hydrochloride with sulfamate 4,5-dihydro-5S-methyl-3-(2-pyridinyl)-3H[1.2.3]oxathiazole- 2,2-dioxide to give a sulfamic acid intermediate which is hydrolyzed to ⁇ (2R)-2-[4-(2,3- dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ pyridin-2-yl-amine and then treating ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-pi ⁇ erazin-l-yl]-propyl ⁇ pyridin-2-yl-amine with 4-cyanobenzoyl chloride to give 4-cyano-N- ⁇ (2R)-2
  • preparations comprising 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl- benzamide and its pharmaceutically acceptable salts are further processed and purified.
  • a preparation comprising p4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro- benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide prepared by methods disclosed herein is dissolved in organic solvent, treated with silica gel, and filtered in order to remove structurally related compounds, e.g., dimers represented by Formulas 7 and 8.
  • the remaining product can then be concentrated and re-crystallized in order to provide, e.g., 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l ,4]dioxin-5-yl)-piperazin-l -yl]- propyl ⁇ -N-pyridin-2-yl-benzamide hydrochloride salt.
  • Preferred formulations of the present invention can be used to modulate, e.g., antagonize or agonize, 5-HT 1 A receptor activity and are useful in the treatment of diseases such as CNS disorders, including, but not limited to, schizophrenia, (and other psychotic disorders such as paranoia and mano-depressive illness), Parkinson's disease and other motor disorders, anxiety (e.g., generalized anxiety disorders, panic attacks, and obsessive compulsive disorders), depression (such as by the potentiation of serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors), Alzheimer's disease, Tourette's syndrome, migraine, autism, attention deficit disorders and hyperactivity disorders.
  • diseases such as CNS disorders, including, but not limited to, schizophrenia, (and other psychotic disorders such as paranoia and mano-depressive illness), Parkinson's disease and other motor disorders, anxiety (e.g., generalized anxiety disorders, panic attacks, and obsessive compulsive disorders), depression (such as
  • Preferred formulations are useful for the treatment of sleep disorders, social phobias, pain, thermoregulatory disorders, endocrine disorders, urinary incontinence, vasospasm, stroke, eating disorders such as for example obesity, anorexia and bulimia, sexual dysfunction, and the treatment of alcohol, drug and nicotine withdrawal.
  • Preferred formulations of the present invention are also useful for the treatment of cognitive dysfunction including but not limited to cognitive dysfunction associated with mild cognitive impairment (MCI), Alzheimer's disease and other dementias including Lewy Body, vascular, and post stroke dementias.
  • Cognitive dysfunction associated with surgical procedures, traumatic brain injury or stroke can also be treated in accordance with the present '"' “toven ⁇ drF. "
  • preferreH formulations are useful for the treatment of diseases in which cognitive dysfunction is a co-morbidity such as, for example, Parkinson's disease, autism and attention deficit disorders.
  • the present invention provides formulations comprising 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5- yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide, pharmaceutically acceptable salts thereof, structurally related compounds, or metabolites in micronized and in non-micronized form.
  • a compound in micronized form is in the form of particles having a mean diameter of no more than about 20 microns.
  • compounds of the present invention can be in the form of particles having a mean diameter of greater than about 20 microns, for example in the form of particles having a mean diameter from about 20 microns to about 300 or about 500 microns.
  • the particles have a mean diameter of about 10 microns, more preferably a mean diameter from about 0.75 to about 10 microns, even more preferably from about 2 to about 8 microns. Methods of micronization or particle size reduction are known and are thus not described herein in detail.
  • the compounds of formula 1 can be prepared in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts As used herein, the term “pharmaceutically ⁇ T /I I K Ii !h / dl "+ K "L si
  • ⁇ TM atcep ⁇ able ⁇ saTts refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic salts, and organic salts.
  • Suitable non-organic salts include, for example, inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, malic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like.
  • Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most preferably is the hydrochloride salt.
  • formulations comprising 4-cyano-N- ⁇ (2R)-2-[4-(2,3- dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or pharmaceutically acceptable salts thereof will also comprise one or more structurally related compounds that can be detected and quantified using known methods.
  • structurally related compounds include, but are not limited to, those compounds represented by Formulas 2-9 and pharmaceutically acceptable salts thereof, including, for example:
  • R 1 is -CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 or -CH 2 CH 2 CH 2 CH 3 .
  • the present invention provides formulations comprising one or more compounds represented by Formulas 2, 3, 4, 5, 6, 7, 8 or 9 or a pharmaceutically acceptable salt thereof.
  • the formulations will comprise 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo [ 1 ,4]dioxin-5-yl)-piperazin- 1 -yl]- propyl ⁇ -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt thereof and one or more compounds of Formula 2, 3, 4, 5, 6, 7, 8 or 9 or a pharmaceutically acceptable salt thereof.
  • formulations of the present invention can comprise 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]- propyl ⁇ -N-pyridin ⁇ 2-yl-benzamide or a pharmaceutically acceptable salt thereof, ⁇ (2R)-2-[4- (2,3-dihy dro-benzo[ 1 ,4]dioxin-5-yl)-piperazin- 1 -yl]-propyl ⁇ -N-pyridin-2-yl-amine or a pharmaceutically acceptable salt thereof, and 4-cyano-N- ⁇ (2S)-2-[4-(2,3-dihydro- benzo[l ,4]dioxin-5-yl)-piperazin- 1 -yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt thereof.
  • the present invention provides formulations comprising 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)- piperazin-1-yl] -propyl ⁇ -N-pyridin-2-yl-benzamide hydrochloride salt, ⁇ (2R)-2-[4-(2,3- dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-amine, and 4-cyano- N- ⁇ (2S)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl- benzamide hydrochloride salt.
  • the former preferably predominates and the latter preferably are present in the composition in amount of less than about 10%, more preferably present in amount of less than about 5% and even more preferably in amounts of less than about 1% or 0.1%, for example, in amounts from between about 0.08% and about 0.27%.
  • the present invention also provides formulations comprising metabolites of 4- cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin- include, but are not limited to, 4-cyano-N- ⁇ (2R)-2-[4-(8- hydroxy-2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl- benzamide or a pharmaceutically acceptable salt thereof, 4-cyano-N- ⁇ (2R)-2-[4-(3-hydroxy- 2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt thereof,
  • the present invention provides immediate release and sustained release dosage forms comprising one or more active ingredients, e.g., 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro- benzo [1,4] dioxin-5-yl)-piperazin- 1 -y 1] -propyl ⁇ -N-pyridin-2-yl-benzamide, pharmaceutically acceptable salts thereof, structurally related compounds and metabolites thereof that have 5- HT 1 A binding activity.
  • active ingredients e.g., 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro- benzo [1,4] dioxin-5-yl)-piperazin- 1 -y 1] -propyl ⁇ -N-pyridin-2-yl-benzamide, pharmaceutically acceptable salts thereof, structurally related compounds and metabolites thereof that have 5- HT 1 A binding activity.
  • a drug "release rate” refers to the quantity of drug released from a dosage form per unit time, e.g., milligrams of drug released per hour (mg/hr). Drug release rates can be calculated, for example, under in vitro dosage form dissolution testing conditions known in the art. As used herein, a drug release rate obtained at a specified time “following administration” refers to the in vitro drug release rate obtained at the specified time following implementation of an appropriate dissolution test. Methods of performing dissolution tests or release rate assays are known in the art. The time at which a specified percentage of the drug within a dosage form has been released can be referenced as the “T x " value, where "x" is the percent of drug that has been released. A commonly used reference measurement for "evaluating ' " drug release " from oral dosage forms is the time at which 70% or 90% of drug within a dosage form has been released. This measurement is referred to as “T 70 " or "T 9 o" for the dosage form.
  • immediate release formulation refers to formulations that provide a relatively rapid and non-gradual release of active compound from the formulation; e.g., formulations that contain active compound and a rapidly dissolving carrier that does not retard the release of the active compound from the formulation.
  • immediate release formulation are either devoid of release rate controlling polymers or other species that retard the release of the active compound from the formulation, or contain such polymers or species in amounts that are sufficiently small such that the release of the active compound from the formulation is not retarded relative to an otherwise identical formulation lacking such polymers or species.
  • an immediate release formulation is the active ingredient, e.g., 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)- piperazin-1-yl] -propyl ⁇ -N-pyridin-2-yl-benzamide, pharmaceutically acceptable salt thereof, structurally related compounds, or metabolites, blended in microcrystalline cellulose, such as Avicel ® brand from FMC corporation, which results in greater than 75% dissolution of the active ingredient in less than 0.25 hours in a 0.1 N HCl solution.
  • active ingredient e.g., 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)- piperazin-1-yl] -propyl ⁇ -N-pyridin-2-yl-benzamide, pharmaceutically acceptable salt thereof, structurally related compounds, or metabolites, blended in microcrystalline cellulose
  • sustained release As used herein, the terms “sustained release”, “sustained release formulation,” “sustained release dosage formulation” and the like refer to formulations that contain materials that retard the release of active compound from the formulation relative to an "immediate release” formulation as described above, e.g., relative to an otherwise identical formulation lacking the release rate controlling polymer or other release-retarding materials.
  • sustained release can apply to any number of extended release forms and is considered substantially synonymous with delayed release, time release, prolonged release, time programmed release, time released, time coated release, sustained release, slow acting, long acting, delayed acting, spaced release, time spaced release, extended acting, extended action, and the like.
  • sustained release is intended to refer to sustained release formulations as described herein that release active compound at a rate that is slow, medium or fast rate relative to each other.
  • sustained release formulations can result in a release of active compound from the dosage form at a rate effective to increase the time it takes to reach maximum therapeutic concentration as compared to an immediate release formulation, for example and not limitation, by a period of 50% or more, 100% or more, 150% or more, or 200% or more as compared to an immediate release formulation; e.g., as compared to an otherwise identical formulation lacking the release rate controlling polymer or other release- retarding materials.
  • Sustained release formulations can also result in release of active compound from the dosage form at a rate effective to decrease the maximal therapeutic concentration of said compound compared to an immediate release formulation, for example and not limitation, by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, or at least 50% compared to an immediate release formulation.
  • Sustained release formulations can also result in release of active compound from the dosage form at a rate effective to increase the amount of time a pharmaceutically effective concentration of the active compound is maintained relative to an immediate release formulation, for example and not limitation, by at least 25%, at least 50%, at least 75%, at least 100%, or at least 125% the amount of time a pharmaceutically effective concentration of active compound is maintained relative to an immediate release formulation. Satisfaction of any of the preceding criteria is sufficient to make a formulation a "sustained release" formulation.
  • the present invention provides methods for sustained release of the active ingredient comprising administering to a subject the disclosed dosage forms.
  • the release rate of the active compound from the dosage forms is zero order.
  • the release rate of the active ingredient from the dosage forms is ascending.
  • release rate controlling polymer is intended to denote any polymer material suitable for pharmaceutical dosage forms that retards the release of drug substances from such dosage forms.
  • the release rate-controlling polymer will preferably inhibit the release of the drug in the stomach.
  • the release rate-controlling polymer is a hydrogel that imbibes and/or absorbs fluid thereby preventing the release of the drug in the stomach. Examples of suitable release rate controlling polymers can be found in Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA, 1990.
  • Some preferred release rate-controlling polymers suitable for use in the present invention include, without limitation, hydroxypropyl celluloses, methylcelluloses, polymethacrylates, methacrylic acid-methacrylic acid ester copolymers, cellulose acetate phthalate, ethyl celluloses, ' hydroxyethyl celluloses, hydroxymethyl celluloses, hydroxypropylethyl celluloses, polyvinyl acetate-phthalate, hydroxypropylmethylcellulose phthalate, poly(ethylene) oxides, hydroxypropyl methyl celluloses such as, for example, hypromellose 2208 and 2910 and combinations of two or more thereof.
  • Suitable release rate controlling polymers are available from commercial sources, such as Methocel K4M, MethocelTM Kl 5M, MethocelTM KlOOM 5 MethocelTM E4M, MethocelTM KlOOLV, MethocelTM E50LV, MethocelTM E5, MethocelTM E6, MethocelTM E 15LV , and SureleaseTM available from Colorcon and Eudragit , RS Eudragit RL available from Rohm GmbH & Co.
  • the formulations of the present invention will comprise high-density matrix- forming hydroxypropyl methylcellulose, low-density matrix-forming hydroxypropyl methylcellulose, or combinations thereof.
  • the sustained release formulations of the present invention comprise at least one release rate controlling polymer.
  • the range of release rate controlling polymer in the formulation is preferably from about 10% to about 75% by weight, more preferably from about 20% to about 60% by weight.
  • the amount of release rate controlling polymer in a 250 mg dosage form is from about 50 to about 150 mg.
  • the release rate controlling polymer is a cellulose ether, such as, for example, matrix-forming hydroxypropyl methylcellulose, hydroxypropyl cellulose, or hydroxyethyl cellulose, e.g., MethocelTM K4M Premium CR or MethocelTM KlOOM Premium CR.
  • sustained release dosage forms of the present invention generally comprise at least one agent to improve the release rate in the intestine, e.g., an organic acid.
  • an organic acid encompasses any acid that can be safely ingested by a mammal. While not wishing to be bound by any particular theory, the acid is believed to improve the release of the drug product in the intestine.
  • organic acids suitable for use in the present invention include, but are not limited to, tartaric acid, malic acid, fumaric acid, aspartic acid, glutamic acid, glycine h. ⁇ d_:ocm6rkiC adip ⁇ c " acio[, " succinic acid, ascorbic acid, oleic acid or citric acid.
  • Preferred organic acids are citric acid or polyfunctional organic acid.
  • the range of organic acid in the formulation is preferably from about 1% to about 30%, more preferably from about 2% to about 10% by weight.
  • the amount of organic acid in a 250 mg dosage form is from about 5 to about 50 mg, preferably from about 5 to about 25 mg. In some embodiments, the amount of organic acid is from about 2 to about 50 mg.
  • the sustained release formulations is substantially free of base.
  • a formulation, dosage form, or composition that is substantially of base refers to a formulation, dosage form, or composition that has less than about 10% base, preferably less than about 5% base, and more preferably less than about 1% or 0.1% base.
  • base refers to a chemical compound that functions as a proton acceptor.
  • the formulations of the invention can comprise any of a variety of additional materials that confer beneficial properties to the formulation.
  • additional materials include, for example, solubility modifiers such as aurfactants such as, for example, sodium lauryl sulfate, acidic compounds, antioxidants, pH modifiers, chelating agents, fillers, disintegrants, binders, lubricants, stabilizers, excipients including water soluble excipients such as sugars and water dispersing excipients such as, for example, microcrystalline cellulose, colloidal silicon dioxide, silicified microcrystalline cellulose and starch.
  • the formulation is provided at a pH of about 6 or lower, for example at a pH of from about 1 to about 6.
  • Nonlimiting examples of water-soluble excipients or water dispersing excipients include lactose, mannitol, sucrose, and the like.
  • the water-soluble excipients can be present in a range on weight percentages depending upon the particular therapeutic objective required. For use in the present invention, percentages and parts are expressed as part by weight or percentage by weight, unless otherwise noted. In general, the range of water soluble excipients can be, for example, from about 0% to about 50% or to about 99%, or from about 2% to about 25%.
  • Examples of water dispersible excipients include microcrystalline cellulose, colloidal silicone dioxide, silicified microcrystalline cellulose (ProsolvTM), starches, croscarmelose sodium and the like. , / ⁇ y s P IR' S ";:; ! ! 1 MHFP 1 " " ⁇
  • TM 'Nonlimitihg examples of stabilizers include antioxidants such as BHA, BHT, ascorbic acids, tocopherols, and the like.
  • suitable metal chelators include EDTA, citric acid and the like.
  • suitable pH modifiers include citric acid, fumaric acid, and the like.
  • Nonlimiting examples of binders include starches, PVP (polyvinylpyrrolidone), HPMC (hydroxypropyl methyl celluloses), HPC (hydroxypropyl cellulose) and the like.
  • Nonlimiting examples of flow aids include magnesium stearate and the like.
  • solubility modifiers include surfactants like sodium lauryl sulfate or polysorbate (e.g., Tween 80), and the like.
  • the sustained release formulations of the present invention comprise the active ingredient, at least one release rate controlling polymer, an organic acid, at least one filler and at least one lubricant.
  • lubricants include, but are not limited to, stearic acid, magnesium stearate, glyceryl behenate, talc, mineral oil (in PEG), colloidal silicon dioxide and the like. It is appreciated however that any lubricant known in the art can be used in the formulations described herein.
  • the range of lubricant can be, for example, from about 0.2% to about 5%, by weight. In one embodiment of the present invention, the amount of lubricant in a 250 mg dosage form is about 1 mg.
  • fillers include, but are not limited to, silicified microcrystalline cellulose, microcrystalline cellulose, cellulose acetate, cellulose diacetate, cellulose triacetate, lactose monohydrate, lactose anhydrous, calcium carbonate, calcium phosphate (e.g., dibasic anhydrous), maltodextrin, dextrose, fructose, maltose, mannitol, starch, starch (e.g., pregelatinized), sucrose, and lactose. It is appreciated, however, that any filler known in the art can be used in the formulations described herein.
  • the range of filler can be, for example, from about 25% to about 75%, or to about 99% by weight.
  • the amount of filler present in a 250 mg dosage form is from about 85 to about 179 mg.
  • the sustained release dosage forms of the present invention can comprise the active compound in any convenient percentage and part in relation to the other ingredients.
  • the formulation comprises active ingredient in percentage of from about 0.3% to about 0.3% to about 15%.
  • the formulation will comprise active ingredient in percentage of from about 1% to about 25%, preferably from about 2% to about 15%.
  • sustained release formulations will comprise from about 2 to about 46 parts of release relate controlling polymer and about 0.4 to about 10 parts of an agent to improve release rate in the intestine per part active ingredient. More preferably from about 10 to about 46 parts release rate controlling polymer and about 1 to about 5 parts of an agent to improve release rate in the intestine per part active ingredient.
  • fast sustained release formulations comprise about 10 parts of release rate controlling polymer, and about 5 parts of organic acid per part of active ingredient, e.g., 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin- 1-yl] -propyl ⁇ -N-pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
  • medium sustained release formulations comprise about 25 parts of release rate controlling polymer, and about 5 parts of organic acid per part of active ingredient, e.g., 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]- propyl ⁇ -N-pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
  • slow sustained release formulations comprise about 30 parts of release rate controlling polymer, and about 1 part of organic acid per part of active ingredient, e.g., 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l 5 4]dioxin-5-yl)-piperazin-l-yl]- propyl ⁇ -N-pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
  • sustained release formulations comprise about 18 parts of release rate controlling polymer, and about 1 part of organic acid per part of active ingredient, e.g., 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l ,4]dioxin-5-yl)-piperazin-l -yl]-propyl ⁇ -N- pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
  • sustained release formulations comprise about 46 parts of release rate controlling polymer, and about 1 part of organic acid per part of active ingredient, pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
  • sustained release formulations comprise about 5 mg of active ingredient, from about 50 to 150 mg of release rate controlling polymer, from about 5 to about 50 mg of organic acid, from about 85 to about 179 mg of filler and about 1 mg of lubricant.
  • sustained release formulations comprise about 2 mg of active ingredient, from about 50 to 150 mg of release rate controlling polymer, from about 2 to about 50 mg of organic acid > from about 85 to about 179 mg of filler and about 1 mg of lubricant.
  • exemplary sustained release formulations comprise, in a 250 mg tablet, about 5 mg of active ingredient and about 50 mg of release rate controlling polymer.
  • Such an exemplary formulation can further comprise, for example, about 169 mg of filler, about 25 mg of organic acid (or other agent to improve release rate in the intestine) and about 1 mg of lubricant.
  • exemplary sustained release formulations comprise, in a 250 mg tablet, about 5 mg of active ingredient and about 125 mg of release rate controlling polymer.
  • Such an exemplary formulation can further comprise, for example, about 94 mg of filler, about 25 mg of organic acid (or other agent to improve release rate in the intestine) and about 1 mg of lubricant.
  • exemplary sustained release formulations comprise, in a 250 mg tablet, about 5 mg of active ingredient and about 150 mg of release rate controlling polymer.
  • Such an exemplary formulation can further comprise, for example, about 89 mg of filler, about 5 mg of organic acid (or other agent to improve release rate in the intestine) and about 1 mg of lubricant.
  • exemplary sustained release formulations comprise, in a 250 mg tablet, about 5 mg of active ingredient and about 92 mg of release rate controlling T / 1 Ii f% P 6 •• • "" " El L !HB ;I 3 polymer.
  • exemplary formulation can further comprise, for example, about 150 mg of filler, about 5 mg of organic acid (or other agent to improve release rate in the intestine) and about 1 mg of lubricant.
  • exemplary sustained release formulations comprise, in a 250 mg tablet, about 2 mg of active ingredient and about 92 mg of release rate controlling polymer.
  • Such an exemplary formulation can further comprise, for example, about 150 mg of filler, about 2 mg of organic acid (or other agent to improve release rate in the intestine) and about 1 mg of lubricant.
  • sustained release formulations contemplated by the present invention can be in any form suitable for administration to a mammal and are not limited to the examples presented herein.
  • the formulations of the invention are in the form of coated pellets or spheres.
  • a formulation is a sphere containing a core of active compound in an inert matrix, coated with a release rate-controlling polymer as disclosed herein.
  • suitable release rate controlling polymers are pH dependent or independent polymers described herein, such as polymethacrylates, EudragitTM IVS, Eudragit RS/RL, cellulose acetate phthalate, ethyl celluloses, hydroxypropyl methyl celluloses, hydroxypropyl celluloses, hydroxypropyl ethyl celluloses and the like.
  • the formulations of the invention are in the form of pellets.
  • examples of such formulations include those containing pellets that contain a layer of active compound on top of an inert core, for example, a sugar sphere, and a surface coating containing one or more release rate controlling polymers.
  • the formulations are in the form of capsules, e.g., hard or soft gelatin capsules and/or powder.
  • the formulations of the invention are in the form of tablets.
  • the percentage by weight of active compound in the representative formulations of this type is from about 0.3% to about 25%, preferably from about 0.3% to about 15%.
  • the percentage by weight of active compound in the representative formulations of this type are ⁇ bb ⁇ k 4 r ⁇ lo ⁇ a1-) ⁇ ffi ⁇ 25%, " pfeJferably from about 2% to about 15%.
  • Nonlimiting examples of such tablets are co-compressed tablets , e.g., "tablet-in-tablet” and matrix tablets.
  • the co-compressed tablet can include a core and-an-outer compressed coat. Either or both of the core and the outer compressed coat can contain active compound and/or one or more release rate controlling polymers.
  • the dosage form is a co-compressed tablet wherein both the core and the outer compressed coat contain active compound, and at least one release rate-controlling polymer, one of which is preferably a hydroxypropyl methyl cellulose.
  • Preferred matrix forming polymers include a hydroxypropyt methylcellulose selected from MethocelTM K4M, MethocelTM Kl 5M, MethocelTM KIOOM, MethocelTM ElOM, MethocelTM ElOM, MethocelTM E4M, Methocel K4M, MethocelTM KlOOLV, MethocelTM E50LV, MethocelTM E5, MethocelTM E6, MethocelTM El 5LV or a combination of two or more thereof.
  • the tablet is a matrix tablet.
  • the matrix forming composition can contain waxes, gums, polyethylene oxides, carbapols, hydroxypropyl methylcelluloses, hydroxypropyl celluloses, hydroxyethyl celluloses, polymethacrylates or other release rate controlling polymers as described herein, hi some embodiments, such matrix tablets are prepared by blending the active compound and the matrix-forming polymer together, and compressing the blend.
  • the tablet is a matrix tablet that includes a wax matrix.
  • a wax matrix such as carnauba wax, cetostearyl alcohol or fatty acids, or combinations thereof, and adding active compound along with a filler, such as microcrystalline cellulose as well as other excipients, fillers, lubricants and the like, and allowing the mixture to cool.
  • the formulations prepared can be optionally coated with or contain one or more water-soluble or release rate controlling control release polymers.
  • the wax can be present in the formulation in a total amount by weight of, for example, from about 10% to about 60%, preferably from about 20% to about 40%.
  • suitable waxes is amenable to the present invention.
  • the matrix tablet also can contain one or more release rate-controlling polymers as described herein.
  • the matrix tablet is a tablet that includes a polyethylene oxide matrix, for example and not limitation, polyethylene oxide resins such as SENTRY POLYOXTM (Union Carbide Corporation) or equivalents. Suitable POLYOX's include POLYOXTM WSRN-10, N-60 K, WSR-1105N, or WSR 303.
  • the POLYOXTM can have a molecular weight in the range of, for example, 100,000 to 7,000,000, or 900,000 to 5,000,000.
  • the polyethylene oxide can be present in the formulation in a total amount by weight of, for example, from about 5% or about 10% to about 40%, or about 75% preferably from about 5% to about 40% or from about 10% to about 20% of the formulation.
  • the matrix tablet also can contain one or more release rate-controlling polymers as described herein.
  • the matrix tablet is a tablet that includes one or more release rate controlling polymers as described herein as the matrix forming polymer, hi some embodiments, such tablets include one or more matrix forming hydroxypropyl methyl celluloses as described herein as the matrix forming polymer.
  • a high viscosity hydroxypropyl methylcellulose such as Methocel K4M at an amount by weight of, for example, from about 15% to about 70%, preferably from about 18% to about 50%.
  • Other high viscosity polymers can also be used such as, for example, MetihocelTM Kl 5M, MethocelTM KlOOM, or MethocelTM E4M and the like.
  • a low viscosity hydroxypropyl methylcellulose can be used, such as Methocel E5OLV, Methocel E5, Methocel M E6, or MethocelTM El 5LV or combinations thereof and the like.
  • both a high viscosity and a low viscosity hydroxypropyl methylcellulose can be used in the matrix.
  • the low density hydroxypropyl methylcelluloses is present in a range of from about 15% to about 70%, preferably from about 25% to about 50%
  • the high density hydroxypropyl methylcellulose is present in an amount by weight of from about 20% to about 50%.
  • the active compound or ingredient can be contained within any layer of a dosage form of the invention, and sustained release of the active compound can be achieved by the use of a release rate controlling polymer either contained within the layer containing the active compound, or in any layer encompassing the layer containing the active compound, for example an enteric coating.
  • a release rate controlling polymer either contained within the layer containing the active compound, or in any layer encompassing the layer containing the active compound, for example an enteric coating.
  • Such an enteric coating can also be applied to pellets, beads or spheroids containing active compound, or the active compound can be contained within the enteric coating itself.
  • the active compound is present in an amount by weight of from about 0.02% to about 16%, preferably from about 0.02% to about 4%.
  • Tablets of the invention can be coated with water-soluble film coat(s), coloring agents, or coated with pH dependent or pH independent polymers to further control the rate of release of active compound.
  • the tablets are coated with a subcoat, an enteric coating or an overcoating, or any combination thereof.
  • the tablets of the formulations of the invention are coated with film.
  • the present inventions provides methods and/or processes for preparing sustained- release formulations comprising 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)- piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide, pharmaceutically acceptable salts thereof, structurally related compounds, and/or metabolites.
  • a composition comprising the active ingredient with at least one rate controlling polymer and at least one organic acid is compressed for a time and under conditions effective for forming a tablet thereof.
  • the tablet is further coated, e.g., with film.
  • the active ingredient is mixed with at least one release rate controlling polymer and a least one organic acid thereby forming a blend.
  • the blend can be further compressed for a time and under conditions to form a tablet.
  • the tablet is further coated, e.g., with film.
  • the blend is a dry blend.
  • the formulations are prepared by roller compaction.
  • tablets can be prepared by granulation followed by milling.
  • the active ingredient, filler (e.g., microcrystalline cellulose) and polymer (e.g., hydroxypropylmethylcellulose) are granulated and then milled. The milled granules are then mixed with additional excipients, such as, for example, citric acid and magnesium stearate.
  • the active compound can be formulated in such a way that the drug achieves a single maximal concentration or can be formulated so that the drug is pulsed in two or more peaks.
  • Oral delivery can be via way of liquid or solid dosage form.
  • Liquid dosage forms include syrups, suspensions, emulsions, elixirs, and the like.
  • the liquid carrier can include an organic or aqueous base and can be further modified with suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colorants, viscosity regulators, stabilizers or osmoregulators, or combinations thereof.
  • the aqueous carrier can also contain, for example, polymeric substances or oils.
  • the present invention also provides immediate release dosage forms.
  • Immediate release dosage forms of the present invention can comprise the active ingredient, for example, 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro ⁇ benzo[l ,4]dioxin-5-yl)-piperazin-l -yl]- propyl ⁇ -N-pyridin-2-yl-benzamide, pharmaceutically acceptable salts thereof, structurally related compounds, or metabolites.
  • the active ingredient is micronized.
  • the immediate release formulations are substantially free of base.
  • the immediate release formulation comprises the active ingredient, at least one filler and at least one lubricant.
  • the formulations of the invention additionally can include any of a variety of materials that confer beneficial properties to the formulation.
  • materials include, for example, solubility modifiers such as surfactants such as, for example, sodium lauryl sulfate, acidic compounds, fillers, lubricants, antioxidants, pH modifiers, chelating agents, disintegrants, binders, stabilizers, excipients including water soluble excipients such as sugars, and water dispersing excipients such as microcrystalline cellulose, colloidal silicone dioxide, silicified microcrystalline cellulose and starch.
  • solubility modifiers such as surfactants such as, for example, sodium lauryl sulfate, acidic compounds, fillers, lubricants, antioxidants, pH modifiers, chelating agents, disintegrants, binders, stabilizers
  • excipients including water soluble excipients such as sugars, and water dispers
  • the range of lubricant is typically from about, for example, 0.2% to about 5% by weight. In one embodiment of the present invention, the amount of lubricant in a 150 mg dosage form is from about 0.5 to about 1 mg.
  • the range of filler can be, for example, from about 70% to about 99%, of the present invention, the amount of filler in a 150 mg dosage form is from about 80 to about 149 mg.
  • the immediate release dosage forms of the present invention can contain the active compound in any convenient percentage and part in relation to the other ingredients.
  • the formulation comprises active ingredient in percentage of from about 0.05% to about 10%.
  • immediate release formulations comprise about 297 parts of filler, and about 1.5 parts of lubricant per part of active ingredient, e.g., 4-cyano- N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l 3 4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl- benzamide or pharmaceutically acceptable salt thereof.
  • immediate release formulations comprise about 29 parts of filler, and about 0.15 parts of lubricant per part of active ingredient, e.g., 4-cyano-N- ⁇ (2R)-2- [4-(2,3-dihydro-benzo[l ,4]dioxin-5-yl)-piperazin-l -yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
  • active ingredient e.g., 4-cyano-N- ⁇ (2R)-2- [4-(2,3-dihydro-benzo[l ,4]dioxin-5-yl)-piperazin-l -yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
  • immediate release formulations comprise about 148 parts of filler, and about 0.75 parts of lubricant per part of active ingredient, e.g., 4-cyano-N- ⁇ (2R)-2- [4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
  • active ingredient e.g., 4-cyano-N- ⁇ (2R)-2- [4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
  • immediate release formulations comprise about 58 parts of filler, and about 0.3 parts of lubricant per part of active ingredient, e.g., 4-cyano-N- ⁇ (2R)-2- [4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
  • active ingredient e.g., 4-cyano-N- ⁇ (2R)-2- [4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
  • the immediate release formulations contemplated by the present invention can be in any form suitable for administration to a mammal and are not limited to the examples presented herein.
  • [DIw]' ⁇ v ""Tne ⁇ p ⁇ esent invention provides methods and/or processes for preparing immediate release formulations comprising 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxm-5-yl)- piperazin-1-yl] -propyl ⁇ -N-pyridin-2-yl-benzamide, pharmaceutically acceptable salts thereof, and/or metabolites thereof.
  • a composition comprising the active ingredient with at least one filler and at least one lubricant is compressed for a time and under conditions effective to form a tablet thereof.
  • the tablet is further coated, e.g., with film.
  • the active ingredient is mixed with at least filler and a least one lubricant thereby forming a blend.
  • the blend can be further compressed for a time and under conditions to form a tablet.
  • the tablet is further coated, e.g., with film.
  • the formulations are prepared by roller compaction.
  • the immediate release dosage forms like the sustained release dosage forms can be, for example, in the form of coated pellets, spheres, capsules, powder, or tablets.
  • sustained release and immediate release dosage forms including oral and non-oral sustained release dosage formulations. Accordingly, the present invention includes each of the numerous technologies that exist for immediate release non-oral dosage formulations. Delivery of active compound in accordance with the present invention can be via mucosal, vaginal, rectal, ocular, transdermal, intrauterine, routes and the like.
  • the present invention therefore provides, inter alia, dosage forms for 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl- benzamide, pharmaceutically acceptable salts thereof, structurally related compounds, and/or metabolites, methods for immediate delivery of 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro- benzo[ 1 ,4] dioxin-5 -yl)-piperazin- 1 -yl] -propyl ⁇ -N-pyridin-2-yl-benzamide, pharmaceutically acceptable salts thereof, structurally related compounds, and/or metabolites, and methods for sustained delivery of 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-
  • the dosage forms described herein facilitate the immediate or sustained release of active compounds in a mammal through many routes, including oral administration.
  • the dosage forms include the compound 4-cyano-N- ⁇ (2R)-2-[4-(2,3- dihydro-benzo[l,4]diox ⁇ i-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide, preferably the hydrochloride salt thereof, commonly referred to as lecozotan.
  • oral sustained release dosage forms comprising the drug lecozotan and a pharmaceutically acceptable carrier are provided.
  • sustained release dosage forms comprising lecozotan possess improved pharmacokinetic profiles as compared to immediate release dosage forms.
  • oral dosage forms comprising lecozotan When administered to a patient population, oral dosage forms comprising lecozotan achieve a mean maximum (e.g., peak) plasma concentration (C ma ⁇ ) of lecozotan in the patient population and a mean minimum plasma concentration (C m i n ) of lecozotan in the patient population.
  • Preferred sustained release dosage forms of the present invention will minimize the variance between the C max and C m j n plasma levels in the patient population.
  • preferred sustained release dosage forms of the present invention will minimize the variance between the maximum and trough plasma levels in the patient population.
  • peak or maximum concentration (C max ) of an active ingredient, such as lecozotan, in blood plasma, area under concentration vs. time curve (AUC) of an active ingredient, such as lecozotan, in blood plasma, and time to maximal plasma concentration (W K ) of an active ingredient, such as lecozotan, in blood plasma are pharmacokinetic parameters known to one skilled in the art. (Applied Biopharmaceutics and Pharmacokinetics, Chapter 7; Scargle and Yu, 4th edition, 1999). Unless otherwise indicated, the pharmacokinetic parameters are measured at steady state in a fasting population.
  • the concentration vs. time curve measures the concentration of active ingredient in blood serum of a subject verses time after oral administration of a dosage form.
  • C max is the maximum concentration of active ingredient in the blood serum of a subject after administration of the dosage form to the subject.
  • t ma ⁇ is the time to reach maximum T '"If B c ii O fi / ' ";;; l ! MHP It ";;; i ; cb ⁇ ce ⁇ ffafi ⁇ n “of active " ingredient in the blood serum of a subject following administration of the dosage form to a subject.
  • the plasma drug concentration at any time following drug administration is referenced as C t i me , as in Cgh or C 24I i.. "Ctr 0U gh” refers to the plasma drug concentration at the end of the dosing interval.
  • the "plasma drug concentration” or “plasma concentration” is, generally expressed as mass per unit volume, typically nanograms per milliliter.
  • the area under concentration vs. time curve (AUC) of active ingredient, e.g., lecozotan, in blood plasma is calculated according to the linear up / log down trapezoidal rule.
  • the "delivery rate” or “rate of absorption” is estimated by comparison of the time (t max ) to reach the maximum concentration (C max ). Both C max and t max are analyzed using non-parametric methods. Comparisons of the pharmacokinetics of immediate and sustained release formulations are performed by analysis of variance (ANOVA). P ⁇ 0.05 is considered significant. Results are given as mean values +/- SEM. Equivalence of a pharmacokinetic parameter generally refers to the 90 % confidence interval of the ratio of the central values of the pharmacokinetic parameter of the test formulation to the reference formulation being contained within about 0.8 to about 1.25.
  • the sustained release formulations will achieve a C max in a patient and a C 24 in a patient wherein the mean ratio of C max /C 24 in a patient population is from about 5:1 to about 1.1:1.
  • the mean ratio of C max /C 24 in a patient population is from about 3:1 to about 1.1:1, from about 2.8:1 to about 1.1:1, from about 2.5 to about 1.1:1, from about 2.3:1 to about 1.1:1 or even from about 2:1 to about 1.1:1 or from about 1.5:1 to about 1.1:1.
  • the mean ratio of C max /C2 4 in a patient population is about 5.
  • the mean ratio of C max /C2 4 in a patient population is about 3, about 2.8, about 2.5 or even about 2.3, about 2, or about 1.5.
  • these C max and C 24 of a single dose of the drug to a patient In some embodiments, a 5 mg single dose of the drug is administered. In other embodiments, these C max and C 24 values are measured at steady state in a fasting population.
  • the sustained release formulations will achieve a C max in a patient and a C 24 in a patient wherein the mean ratio of C max /C 24 in a patient population is from about 2.4:1 to about 1.1:1, from about 2.3:1 to about 1.1 :1, from about 2:1 to about 1.1:1, from about 1.9 to about 1.1:1, from about 1.5:1 to about 1.1:1 or from about 1.25:1 to about 1.1:1.
  • the mean ratio of C ma ⁇ /C 24 in a patient population is about 2.3.
  • the mean ratio of C ma ⁇ /C 24 in a patient population is about 2, about 1.9, about 1.5 or even about 1.25.
  • these C max and C 24 values are measured at steady state in a fasting population, e.g., after 28 daily doses of the drug to a patient.
  • the drug is administered at a daily dose of 10 mg.
  • these C max and C 24 values are measured after administration of a single dose of the drug to a patient.
  • the variation between C max and C 12 or C 24 in a patient population can be characterized as a percent variation.
  • the mean ratio of C max /C 24 or C max /C 12 in a patient population that has been administered lecozotan will vary no more than about 250%.
  • the mean ratio of C ma ⁇ /C 24 or C raax /C 12 in a patient population will vary no more than about 100%, about 50%, about 30%, or even about 25%.
  • the C max and C 12 or C 24 are measured at steady state.
  • the C max and C m j n are measured after administration of a single dose of the drug to a patient.
  • the sustained release formulations will achieve a mean C max in a patient population and a mean C 24 in a patient population wherein the ratio of mean C ma ⁇ /mean C 24 is from about 5:1 to about 1.1:1.
  • the ratio of mean C m a ⁇ /mean C 24 is from about 2.8:1 to about 1.1:1, from about 2:4 to about 1.1 :1, from about 2.3 to about 1.1:1, from about 2:1 to about 1.1:1, from about 1.5:1 to about 1.1:1 or even from about 1.25:1 to about 1.1:1.
  • the ratio of mean C max /mean C 24 is about 5, about 2.8, about 2.4, about 2.3, about 2, about 1.5, or even about 1.25.
  • these C max and C 24 values are measured after a ⁇ mims'tratio ⁇ l ⁇ fa single dose of the drag to a patient.
  • a 5 mg single dose of the drug is administered.
  • these C max and C 24 values are measured at steady state in a fasting population, e.g., after 28 daily doses of the drug to a patient.
  • the sustained release formulations will achieve a mean C ma ⁇ in a patient population and a mean C 12 in a patient population wherein the ratio of mean C max /mean C 12 is from about 3:1 to about 1.1:1.
  • the ratio of mean C max /mean C 12 is from about 2.3:1 to about 1.1:1, from about 2:1 to about 1.1:1, from about 1.9 to about 1.1:1, from about 1.5:1 to about 1.1:1 or from about 1.25:1 to about 1.1:1.
  • the ratio of mean C ma ⁇ /mean C 12 is about 2.3.
  • the ratio of mean C max /mean C 12 is about 2, about 1.9, about 1.75 or even about 1.5, about 1.4, about 1.3, about 1.25, about 1.2, or about 1.1.
  • the C max and C 12 are measured at steady state.
  • the C max and C 12 are measured after administration of a single dose of the drag to a patient.
  • the drag is administered at a dosage of 5 mg.
  • Certain preferred sustained release formulations maintain therapeutic levels of lecozotan over a 24 hour dosing period, thus providing for once daily dosing.
  • Preferred sustained release formulations also reduce the incidence or severity of side effects associated with lecozotan therapy.
  • the adverse side effects include headache, dizziness, paresthesia, abnormal vision, tinnitus, or a combination thereof.
  • a decreased incidence of side effects refers to a reduced incidence of side effects in a patient population, and not to a total absence of side effects, when measured in a comparable population consuming an immediate release formulation of lecozotan.
  • the sustained release formulations that have an improved pharmacokinetic profile have a dissolution profile wherein no more than about 40% of lecozotan is released at about 2 hours of measurement, and from about 50 to 85% of lecozotan is released at about 12 hours of measurement.
  • " 'Vhe'Cl&soiutio'n of th ' e sustained release tablets or oral dosage forms is determined as directed in the USP, using Apparatus II (paddles), at 50 rpm, in 900 milliliters of USP pH 6.8 phosphate buffer at 37 0 C. A sinker is used for each tablet or dosage form. A filtered sample of the dissolution medium is taken at the time(s) specified.
  • the amount of active ingredient dissolved is determined by chromatographing the sample, along with a standard of known concentration, on a reverse-phase high performance liquid chromatography column.
  • concentration of active ingredient in each sample is determined by comparing the peak responses of the sample chromatogram with the peak responses of the standard chromatograms obtained concomitantly.
  • sustained release formulations preferably reduce peak plasma levels of lecozotan without have a substantial impact on either C m j n (e.g., trough) levels of lecozotan or the extent of lecozotan absorption in the patient.
  • sustained release formulations achieve certain pharmacokinetic parameters when compared to an immediate release dosage form.
  • an immediate release formulation is lecozotan, blended in microcrystalline cellulose, such as Avicel ® brand from FMC Corporation, lactose monohydrate and magnesium stearate that results in greater than 75% dissolution of the active ingredient in less than 0.25 hours in a 0.1 N HCl solution.
  • Certain sustained release formulations of the present invention preferably achieve a mean C max in a patient population that is lower than the mean C max achieved in a patient population administered an immediate release dosage form.
  • mean peak plasma levels are reduced by at least about 10%, more preferably at least about 20%.
  • mean peak plasma levels are reduced by at least about 30% or more.
  • mean peak plasma levels are reduced by greater than 50%.
  • a single dose of a 5 mg oral dosage formulation achieves a mean C max in a patient population that is about 100 ng/ml or lower.
  • multiple daily doses of 10 mg of lecozotan achieve a mean C max in a patient population that is about 350 ng/ml.
  • the C max is measured at steady state.
  • the C max is measured after administration of a single dose of the drug to a patient.
  • Certain sustained release formulations of the present invention preferably achieve a. mean t max in a patient population that is greater than the mean t max achieved in a patient release dosage form.
  • t max is doubled, tripled, or even quadrupled.
  • the mean t max achieved in a patient population administered a sustained release dosage form of lecozotan is from about 4 to about 8 hours.
  • Sustained release formulations of the present invention preferably achieve a mean C trou g h in a patient population that is substantially equivalent to the Chough achieved in a patient population administered an immediate release dosage form. Maintaining comparable trough levels to those obtained with immediate release dosage forms maintains the therapeutic efficacy of the active ingredient.
  • a mean Ctr o ug h of at least 80% should be achieved with the preferred sustained release formulations of the present invention over a 24- hour interval when compared to immediate release dosage form over a 12-hour interval.
  • the mean C trou g h is at least about 90% or at least about 95% when compared to immediate release dosage form.
  • the total amount of lecozotan absorbed from the sustained release dosage form is, substantially equivalent to the total amount of lecozotan absorbed from an immediate release formulation over a 24 hour dosing interval.
  • the sustained release dosage forms achieve a mean AUC in a patient population that is substantially equivalent to the mean AUC achieved in a patient population administered an immediate release dosage form.
  • a mean AUC of at least about 80% should be achieved with the preferred sustained release formulations of the present invention when compared to immediate release dosage form over a 24 hour interval.
  • the mean AUC is at least about 90% or at least 95% when compared to immediate release dosage form over a 24-hour interval.
  • the AUC should be no more than about 125% of the AUC of an immediate release formulation.
  • the present invention provides methods comprising administering the sustained release dosage forms to a patient.
  • the sustained release dosage forms are administered to treat Alzheimer's disease in a patient.
  • the methods of administering sustained release dosage forms also include a step of identifying a patient at risk at adverse side effects through administration of lecozotan.
  • accepted screening methods can be employed to determine the status of Alzheimer's disease in a subject.
  • a routine medical history can be taken to determine whether the patient already suffers from or is prone to suffer from one or more of the side effects associated with administration of immediate release dosage forms of lecozotan.
  • a patient that already suffers from one or more of these side effects or is prone to suffer from one or more of these side effects can be classified as a patient at risk of adverse effects through administration of lecozotan.
  • an electrocardiogram can be performed to determine if the patient has any cardiac abnormalities, e.g., slow heart rate, that may indicate that he or she will be better treated with a formulation that has a reduced jS max .
  • Preferred sustained release formulations of the present invention achieve certain mean pharmacokinetic parameters in a patient population.
  • the patient population is selected in accordance with standard procedures for performing randomized studies.
  • the patient population comprises at least 12 people selected without prior knowledge of the manner in which drugs of this class would be metabolized in them.
  • Example 1 Identification of metabolites of 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro- benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yI-benzamide
  • the structures of the metabolites were determined based on NMR and mass spectra data. For NMR, all samples were dissolved in CD 3 CN. For sample Mi l, about 10% D 2 O was added to increase solubility. Proton and COSY data were acquired on all samples. For the samples containing Mi l and M12, HSQC and HMBC data were also acquired to determine the structures.
  • Ml 2 and Ml 3 metabolites were formed through hydroxylation at the dihydrobenzo-[l, 4]dioxin-piperazine moiety.
  • the NMR studies were conducted to determine the locations of the hydroxylation in these metabolites and to confirm the structure ofM8.
  • M12 ID proton spectrum of Ml 2 was more complicated than expected for the metabolite. ' A careful analysis of the spectrum however, suggested the sample contained isomers. Comparison of the proton spectrum of the Ml 2 metabolite with that of the parent compound indicated that the aromatic moieties and the piperazine moiety are intact in Ml 2. The protons of the 1,4-dioxin ring however, are quite different. Three methine signals are observed at 5.5, 5.15 sand 5.1 ppm. These methine protons integrated into one equivalent proton for the sample. The HSQC data showed that the carbon shifts of these methine groups are between 80 to 88 ppm, suggesting the hydroxylation on one of the dioxin methylenes.
  • M13 Comparison of the proton spectrum of M13 with that of M12 suggests M12 and Ml 3 are very similar. All aromatic protons observed in the parent compound were observed in Ml 3 suggesting that the aromatic moieties are intact in the metabolite. It appeared ' that " ⁇ h Ml3, TM' tKe " Kydroxylation also occurred on the dioxin ring. Similar to M12, M13 contained isomers as indicated by four methine protons observed at 5.5, 5.19, 5.10 and 4.86 ppm. It was noted that over time the intensity of these four methine signals changed, suggesting the ratio of the isomers have changed. Similar changes were observed in Ml 2.
  • Ml 2 and Ml 3 might not represent the original components.
  • M8 Proton and COSY spectra of M8 were acquired for this sample. The data are consistent with the proposed structure for M8 based on MS/MS analysis performed by DSM. The pyridine moiety, the piperazine moiety and the cyano-propyl benzamide moieties are all intact. Compared with the parent compound, the only group missing is the 2,3-dihydro- benzo[ 1,4] dioxin moiety.
  • Example 2 Identification of compounds structurally related to 4-cyano-N- ⁇ (2R)-2-[4- (2,3-dihydro-benzo [1 ,4] dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide
  • Structurally related compounds represented by Formulas 2-9 were identified.
  • the structurally related compounds were isolated from a preparation comprising 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl- benzamide by preparative chromatography in the amounts of about 1 mg with the purity of about'"yO%r "Tne ' "struclures were established by nuclear magnetic resonance spectroscopy, electrospray ionization mass spectrometry and determination of the number of exchangeable protons.
  • a preparation comprising 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5- yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide hydrochloride salt was further processed as follows.
  • the starting material was converted to base by treatment with aqueous sodium hydroxide and ethyl acetate.
  • the resulting ethyl acetate solution was dried azeotropically, diluted with heptane to give a 3:1 ethyl acetate heptane mixture and treated with silica gel.
  • the resulting mixture was filtered and concentrated repeatedly to remove heptane.
  • the base was treated in ethyl acetate solution with 1.0 equivalent of hydrogen chloride in ethyl acetate.
  • the product was dissolved in hot denatured ethanol.
  • the mixture was filtered and concentrated.
  • the product was crystallized by cooling and isolated by filtration.
  • the final wet cake was dried. This process reduced the levels of dimeric impurities of 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l ,4]dioxin-5-yl)-piperazin-l -yl]- propyl ⁇ -N-pyridin-2-yl-benzamide.
  • Example 3 Representative sustained release formulations of the present invention.
  • a The amount of active ingredient may need to be adjusted according to its release potency.
  • Example 5 Representative immediate release formulations of the present invention.
  • the active ingredient is 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-pro ⁇ yl ⁇ -N- pyridin-2-yl-benzamide hydrochloride a:
  • the active moiety portion (free base) is theoretically 93% of 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro- benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide hydrochloride drug substance. Actual amounts added are based on the potency of the hydrochloride drug substance.
  • Inputs listed in the table above are based on the weight of the active ingredient, b: If the hydrochloride drug substance is not at 100% potency, adjustment to the drug substance input must be made with corresponding adjustment to the lactose monohydrate input, c: - Includes an excess quantity. Theoretical quantity is 0.075 Kg. 1.0 mg Tablets,
  • the active ingredient is 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N- pyridin-2-yl-,benzamide hydrochloride a:
  • the active moiety portion (free base) is theoretically 93% of 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro- benzo[l ,4]dioxin-5-yl)-piperazin- 1 -yl]- ⁇ ro ⁇ yl ⁇ -N-pyridin-2-yl-benzamide hydrochloride drug substance. Actual amounts added are based on the potency of the hydrochloride drug substance.
  • Inputs listed in the table above are based on the weight of the active ingredient, b: If the hydrochloride drug substance is not at 100% potency, adjustment to the drug substance input must be made with corresponding adjustment to the lactose monohydrate input, c: Includes an excess quantity. Theoretical quantity is 0.075 kg
  • the active ingredient is 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N- pyridin-2-yl-benzamide hydrochloride a:
  • the active moiety portion (free base) is theoretically 93% of 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro- benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl ⁇ -N-pyridin-2-yl-benzamide hydrochloride drug substance. Actual amounts added are based on the potency of the hydrochloride drug substance.
  • Inputs listed in the table above are based on the weight of the active ingredient, b: If the hydrochloride drug substance is not at 100% potency, adjustment to the drug substance input must be made with corresponding adjustment to the lactose monohydrate input, c: Includes an excess quantity. Theoretical quantity is 0.075 kg
  • the active ingredient is 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-pi ⁇ erazin-l-yl]-propyl ⁇ -N- pyridin-2-yl-benzamide hydrochloride a:
  • the active moiety portion (free base) is theoretically 93% of 4-cyano-N- ⁇ (2R)-2-[4-(2,3-dihydro- benzo[l,4]dioxin-5-yl)-piperazin-l-yl]- ⁇ ropyl ⁇ -N-pyridin-2-yl-benzamide hydrochloride drug substance.
  • Example 6 Representative manufacturing directions for representative immediate release tablets
  • step 4 Transfer the pre-blend from step 3 into a suitably sized tumbler mixer bowl. Pass the remaining lactose monohydrate through a 500 ⁇ m screen into the mixing bowl. Mix.
  • step 7 Compress the blend from step 6 using a suitable compression machine fitted with appropriate tooling, to produce tablets with the required weight and hardness.
  • Example 7 Single dose study between three sustained release formulations and an immediate release formulation of lecozotan
  • This study was a single-dose, randomized, 4-period, crossover, bioequivalence study between three modified release formulations and an immediate release formulation of lecozotan in healthy subjects. Doses were administered orally after an overnight fast of at least 10 hours. Formulations used in this study were 5 mg of an immediate release (IR), 5 mg of a modified fast-release formulation (MR (fast)), 5 mg of a modified medium-release formulation (MR (medium)), and 5 mg of a modified slow-release formulation (MR (slow)). These formulations are provided in Example 3. Blood samples for lecozotan analysis were obtained within 2 hours of test article administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours after test article administration.
  • Plasma concentration data and PK parameters of lecozotan were compared between the four formulations using an analysis of variance for a four-period crossover study. Additionally, the geometric mean (log-transformed) relative bioavailability of the maximum observed concentration (C raax ) of lecozotan, area under the concentration-time curve (AUC) and AUC up to the time of the last quantifiable concentration (AUC T ) and their 90% confidence limits were estimated to determine the magnitude of difference in these parameters between the 4 formulations.
  • the lecozotan immediate release tablet was used as the reference treatment.
  • the 90% confidence limits for parameter estimates were constructed on the log scale using uie 2 1 -sided tests procedure. The 4 treatments (formulations) were judged to be bioequivalent if the 90% confidence limits fell within the interval (0.80, 1.25).
  • Figure 1 provides mean concentrations of lecozotan versus time for the four formulations.
  • the mean C ma ⁇ for the IR formulation is 278.5 ng/niL.
  • the mean values for the modified release formulations are below 100 ng/mL.
  • the MR (fast) and MR (medium) formulations have C ma ⁇ values of 99.7 and 95.1 ng/mL, respectively.
  • the MR (slow) formulation has a C max value of 58.4 ng/mL.
  • the T max for the IR formulation occurs at 0.88 hours.
  • T max values for the MR (fast), MR (medium) and MR (slow) occur at 5.63, 8.83 and 7.90 hours, respectively.
  • AUC values for the IR, MR (fast) and MR (medium) formulations range from 2058.8 to 2246.8 ng h/mL.
  • the AUC value for the MR (slow) formulation is 1565.0 ng h/mL.
  • the mean AUC ratio of MR to the IR formulations is above 100% for the MR (fast) and MR (medium).
  • the mean ratio of AUC for MR (slow) to IR is 79.3%.
  • C max /C24 h ratio The mean ratio of C max lecozotan concentrations at 24 hours (C max /C24 h ratio) ranges from 23 for the IR formulation to values of 2.8, 2.3 and 3.5 for the MR (fast), MR (medium), MR (slow) formulations, respectively.
  • Example 8 Multiple dose study between three sustained release formulations and an immediate release formulation of lecozotan
  • IR FORMULATION [Ol45p ⁇ ix subjects receivecl lecozotan and 2 received placebo in the 0.5, 1 and 2.5 mg dose groups (cohorts 1- 3) whereas 12 subjects received lecozotan and 4 received placebo in the 5 mg dose group (cohort 4). Blood samples for lecozotan analysis were obtained on days 1 and 28 within 2 hours of test article administration and at 0.5, 1, 1.5, 2, 4, 8, 24 (day 1 only) and 28 (day 28 only) hours after test article administration.
  • SR formulation After both single and multiple dose administration of the SR formulation, a plateau-like concentration vs. time profile was seen for all subjects up to a period of 24 hours, with peak/trough fluctuation (i.e. C ma ⁇ /C m j n ) — 1.9 at steady-state.
  • Lecozotan concentrations were seen to start declining after 24 hours.
  • mean t max for lecozotan with the IR formulation was seen to range from 1 — 1.5 hours after both single and multiple dose administration.
  • lecozotan mean t max values with the SR formulation after single and multiple dosing were 8 and 4 hrs, respectively.
  • Mean lecozotan steady-state C max r was 45 ⁇ n
  • Mean C max /C min ratio at steady-state for 10 mg QD SR formulation was 1.91.
  • Mean C max /C m in ratio at steady- state for 5 mg ql2h of IR was 2.4.
  • Mean t max with the 5 mg ql2h IR regimen was 0.8 while mean t max with 10 mg QD SR formulation was 4.2.

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Abstract

L'invention concerne, par exemple de nouvelles formulations et de nouvelles méthodes pour distribuer du 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l -yl]-propyl}-N- pyridin-2-yl-benzamide, des sels pharmaceutiquement acceptables de celui-ci, des composés structurellement associés à celui-ci et/ou des métabolites structurellement associés à celui-ci. L'invention concerne également l'utilisation de ces formulations et de ces méthodes pour traiter des maladies.
EP06790193A 2005-09-09 2006-09-06 Formes dosifiees pharmaceutiques et compositions associees Withdrawn EP1928863A2 (fr)

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MX2008000250A (es) 2005-07-06 2008-03-19 Sepracor Inc Combinaciones de eszopiclona y trans-4-(3,4-diclorofenil)-1,2,3,4- tetrahidro-n-metil-1-naftalenamina o trans 4-(3,4-diclorofenil)-1, 2,3,4-tetrahidro-1-naftalenamina y metodos de tratamiento de menopausia y trastornos del estado de animo, ansiedad y
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