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US20070071813A1 - Novel dosage formulation - Google Patents

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Publication number
US20070071813A1
US20070071813A1 US11/524,981 US52498106A US2007071813A1 US 20070071813 A1 US20070071813 A1 US 20070071813A1 US 52498106 A US52498106 A US 52498106A US 2007071813 A1 US2007071813 A1 US 2007071813A1
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United States
Prior art keywords
lower alkyl
hydrogen
hot melt
group
sulfur
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US11/524,981
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Hashim Ahmed
Susanne Page
Navnit Shah
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Individual
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Individual
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Application filed by Individual filed Critical Individual
Priority to US11/524,981 priority Critical patent/US20070071813A1/en
Publication of US20070071813A1 publication Critical patent/US20070071813A1/en
Priority to US12/954,970 priority patent/US20110070303A1/en
Priority to US13/787,870 priority patent/US8852634B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • A61K31/435—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • Some examples of how foods and drugs can interact include:
  • Food can speed up or slow down the action of a medication.
  • Drugs may alter how nutrients are used in the body.
  • NK-1 receptor antagonists of formula I have been described in commonly owned EP 1,035,115 and U.S. Pat. No. 6,297,375 wherein
  • NK1 receptor antagonists useful for the treatment of CNS disorders, such as depression, anxiety and emesis.
  • bioavailability of a drug depends on several parameters, such as on the physicochemical nature of the active compound, the dosage form, and other physiological factors.
  • Compounds of formula I are virtually insoluble in water and simulated gastric fluid, inhibiting oral bioavailability.
  • the present invention provides new galenic compositions for oral administration of pharmaceutically active compounds and a new process for preparing such galenic compositions.
  • the compositions and process employ a hot melt extrusion of the active pharmaceutical ingredient and a poloxamer.
  • the invention further provides hot melt extrudates of an active pharmaceutical ingredient and a poloxamer.
  • oral dosage forms of the invention are suitable for delivery to human patients and are designed to enable sufficient availability of the active compound at its site of action. Such formulations may overcome the disadvantage of practical insolublility in simulated intestinal fluid for these compounds.
  • the process of the invention provides, in particular, a process for preparing a pharmaceutical tablet composition, wherein the active pharmaceutical ingredient of formula I or pharmaceutically acceptable acid addition salts thereof and a water soluble poloxamer are processed by hot melt extrusion before mixing with the other ingredients.
  • the tablet composition can thereafter be coated with a composition comprising an immediate release film coating system and purified water.
  • lower alkyl denotes a straight- or branched-chain alkyl group containing from 1 to 7 carbon atoms.
  • Nonlimiting examples of lower alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, and the like.
  • alkylene group means a lower alkyl linker which is bound to a group at either end.
  • alkylene groups include methylene, ethylene, propylene, and the like.
  • lower alkoxy denotes a alkyl group as defined above, which is attached through an oxygen atom.
  • Nonlimiting examples of lower alkoxy groups include methoxy, ethoxy, propoxy, and the like.
  • cycloalkyl denotes a saturated carbocyclic group (e.g. a nonaromatic ring) containing 3 to 6 carbon atoms.
  • Nonlimiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • halogen denotes chlorine, iodine, fluorine, and bromine.
  • “Processing aids” are excipients that improve the manufacturability of the formulation by improving, for instance, flowability and by avoiding sticking.
  • colloidal silicon dioxide is a submicroscopic fumed silica with a particle size of about 15 nm. It is a light, loose, bluish-white-colored, odorless, tasteless nongritty amorphous powder.
  • Nonlimiting examples of colloid silicon dioxides useful in the invention include Aerosil 380 and Cab-O-Sil.
  • a “tablet filler/diluent” is a material that improves the bulk properties, e.g. mixing, flow, and compression, of a pharmaceutical formulation. They fill out the size of a tablet or capsule, making it practical to produce and convenient for consumer use. By increasing the bulk volume, the final product has the proper volume for patient handling.
  • Nonlimiting examples of tablet filler/diluent include starch, modified starch derivatives, cellulose, calcium salts, sugar and sugar alcohols.
  • Starch is a substance consisting of amylase and amylopectin, two polysaccharides based on a-glucose.
  • One type of starch that can be used in the invention is corn starch.
  • corn starches Nonlimiting examples of corn starches that can be used in the invention include Pure-Cote, Pure-Bind, Pure-Dent, Pure-Gel, Pure-Set, Melojel, Meritena, Paygel55, Perfectamyl D6PH, Purity 21, Purity 826, and Tablet White.
  • MCC microcrystalline cellulose
  • CMOS complementary metal-oxide-semiconductor
  • CMOS complementary metal-oxide-semiconductor
  • Vivacel a naturally occurring polymer comprised of a glucose units connected by a 1-4 ⁇ glycosidic bond.
  • MCC can be derived from a special grade of alpha cellulose.
  • Nonlimiting examples of MCC that can be used in the invention include Avicel, Vivapur, Vivacel, Emcocel.
  • mannitol One type of sugar alcohol that can be used as tablet filler/diluent is mannitol.
  • mannitol Nonlimiting examples of mannitol that can be used in the invention include Parteck M 200.
  • a “disintegrant” is a material that enhances the disintegrating properties of a pharmaceutical formulation. Typically, disintegrants expand, swell, and dissolve when wet, causing the tablet to break apart in the digestive tract, releasing the active ingredients for absorption. Different types of disintegrants such as NVP water-swellable polymers, croscarmellose and cellulose derivatives can be used in the invention.
  • a “glidant” is a material used to improve the flowability of the powder or granules or both.
  • N-vinylpyrrolidone e.g. N-vinyl-2-pyrrolidone.
  • “Pharmaceutically acceptable acid addition salts” embraces salts with inorganic or organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
  • Water-soluble poloxamers are block copolymers of ethylene oxide ,i.e. polyoxyethylene (POE), and propylene oxide, i.e. polyoxypropylene (POP), that are soluble in water and are used as wetting agents in pharmaceutical formulations.
  • POE polyoxyethylene
  • POP polyoxypropylene
  • Nonlimiting examples of poloxamers useful in the present invention include Lutrol F68 (poloxamer 188).
  • Extrusion is the process of converting a raw material into a product of uniform shape and density by forcing it through a die under controlled conditions.
  • the present invention provides a composition which comprises a hot melt extrudate that comprises an active pharmaceutical ingredient and a water-soluble poloxamer.
  • the invention provides a composition which comprises a hot melt extrudate that comprises a compound of formula I and a water soluble poloxamer, for example Lutrol F68.
  • a preferred compound of formula I is the compound, 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, having the structural formula and which exhibits the above noted insolubilities, i.e. ⁇ 0.0001 mg/ml in water and aqueous buffer solutions of pH 3.0-7.0.
  • the invention provides a composition
  • a hot melt extrudate that comprises a compound of formula I, such as 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramidehydrochloride and a water-soluble poloxamer, such as Lutrol F68.
  • a preferred form of the composition is a pharmaceutical tablet, such as a coated pharmaceutical tablet, in particular a 400 mg tablet.
  • the pharmaceutical tablet composition if the invention comprises a) an active ingredient of formula I 30-60% b) a water soluble poloxamer 10-20% c) a filler 20-30% d) a disintegrant 1-10% e) processing aid and 0-5% and f) glidant 0-5%, and if desired g) immediate release film coating system 2-5% of the tablet weight h) purified water
  • An example of a representative formulation composition comprises the ingredients 2-(3,5-Bis-trifluoromethyl-phenyl)- 400.00 N-methyl-N-(6-morpholin-4-yl- 4-o-tolyl-pyridin-3-yl)- isobutyramide hydrochloride Lutrol F68 133.35 Microcrystalline Cellulose(Avicel PH102) 162.65 Parteck M 200(Mannitol) 30.00 Polyplasdone XL 16.00 Colloidal Silicon Dioxide(Aerosil 380) 16.00 Corn Starch 30.00 Magnesium Stearate 12.00 Total Weight of Kernel 800.00 An example of a representative coating composition comprises Opadry Yellow 03K 12429 25.00 Purified Water 131.25 Total Weight of Film Coated Tablet 825.00
  • the present invention also provides the hot melt extrudate employed in the composition.
  • the extrudate comprises an active pharmaceutical ingredient and a poloxamer.
  • the hot melt extrudate comprises a compound of formula I or a pharmaceutically acceptable salt thereof and a poloxamer.
  • the invention provides an extrudate of 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramidehydrochloride and a water-soluble poloxamer, such as Lutrol F68.
  • HFME hot melt extrusion
  • the invention provides a process for the manufacture of an extrudate that comprises an active pharmaceutical ingredient and a poloxamer which comprises
  • Blending of the active pharmaceutical ingredient and the poloxamer can be accomplished in any conventional manner.
  • the two ingredients can be placed in a mixer or blender, for example, a PK Bin or Bohle mixer, and mixed.
  • a portion of the active pharmaceutical ingredient for example, about 50%, can be mixed with the poloxamer, followed by addition of the remainder of the active pharmaceutical ingredient.
  • the material is preferably mixed for a period of about 30 minutes.
  • the invention provides a process for preparing an extrudate comprising 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramidehydrochloride and Lutrol F68 which comprises blending 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramidehydrochloride with Lutrol F68 to form a powder blend, extruding the powder blend from step 1) to form a hot melt extrudate, and collecting the hot melt extrudate at room temperature.
  • the invention provides a process for preparation of an extrudate which comprises
  • the powder blend contains additional ingredients, such as a tablet binder and/or wettability agent.
  • additional ingredients such as a tablet binder and/or wettability agent.
  • the hot melt extrudate can be passed through a sieving machine to obtain milled material, whereby more than one sieving step may be necessary to obtain material in the desired particle size range.
  • the present invention further provides a process for preparing a pharmaceutical tablet composition which comprises:
  • the invention provides a process for preparing a pharmaceutical tablet composition which comprises:
  • the process comprises:
  • the kernels can be coated as follows:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to a process for preparing a pharmaceutical tablet composition which comprises an active pharmaceutical ingredient of formula I
Figure US20070071813A1-20070329-C00001
 wherein the definitions are described in claim 1, or pharmaceutically acceptable acid addition salts thereof and a water soluble poloxamer in which the compound of formula I and the water soluble poloxamer are processed by hot melt extrusion, and then the hot melt extrudate is mixed with other ingredients to form a tablet, that is optionally coated with a composition comprising an immediate release film coating system and purified water. The invention also relates to such pharmaceutical compositions and hot melt extrudates.

Description

    PRIORITY TO RELATED APPLICATIONS
  • This application claims the benefit of U.S. Provisional Application No. 60/719,793, filed Sep. 23, 2005, which is hereby incorporated by reference in its entirety.
    • BACKGROUND OF THE INVENTION
  • Many substances obtained from modem drug discovery are problematic because of insufficient bioavailability. Such molecules often exhibit very low aqueous solubility and limited solubility in oils. Furthermore many substances exhibit significant food effects, i.e., when drugs and certain foods are taken at the same time they can interact in ways that diminish the effectiveness of the ingested drug or reduce the absorption of food nutrients. Additionally, vitamin and herbal supplements taken with prescribed medication can result in adverse reactions.
  • Some examples of how foods and drugs can interact include:
  • Food can speed up or slow down the action of a medication.
  • Impaired absorption of vitamins and minerals in the body.
  • Stimulation or suppression of the appetite.
  • Drugs may alter how nutrients are used in the body.
  • NK-1 receptor antagonists of formula I have been described in commonly owned EP 1,035,115 and U.S. Pat. No. 6,297,375
    Figure US20070071813A1-20070329-C00002
    wherein
      • R is lower alkyl, lower alkoxy, halogen or trifluoromethyl
      • R1 is halogen or hydrogen; and when p is 1, R1 may in addition to the above substituents be taken together with R to form —CH═CH—CH═CH—;
      • R2 and R2′ are each independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano;
        and when n is 1, R2 and R2 may in addition to the above substituents form —CH═CH—CH═CH—, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy;
      • R3 and R3′ are hydrogen, lower alkyl or taken together with the attached carbon atom form a cycloalkyl group;
      • R4 is hydrogen, —N(R5)(CH2)nOH, —N(R5)S(O)2-lower alkyl, —N(R5)S(O)2-phenyl, —N═CH—N(R5)2, —N(R5)C(O)R5,
        Figure US20070071813A1-20070329-C00003
      • R5 is hydrogen, C3-6-cycloalkyl, benzyl, or lower alkyl;
      • R6 is hydrogen, hydroxy, lower alkyl, —(CH2)nCOO—(R5), —N(R5)CO-lower alkyl, hydroxy-lower alkyl, —(CH2)nCN, —(CH2)nO(CH2)nOH, —CHO or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group, which heterocyclic ring is directly bonded or bonded via an alkylene group to the remainder of the molecule;
        Figure US20070071813A1-20070329-C00004
        is a cyclic tertiary amine which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine is directly attached to the remainder of the molecule or is attached through the linker —(CH2)nN(R5)—;
      • x is —C(O)N(R5)—, —(CH2)mO—, —(CH2)mN(R5)—, —N(R5)C(O)—, or —N(R5)(CH2)m—;
      • n, p, and q are each independently 1 to 4; and
      • m is 1 or 2;
        and pharmaceutically acceptable acid addition salts thereof.
  • These compounds exist in crystalline form, which is practically insoluble in water (for example <0.0001 mg/ml) and in simulated gastric fluid (for example 0.08 mg/ml) at 25° C. They are active NK1 receptor antagonists, useful for the treatment of CNS disorders, such as depression, anxiety and emesis.
    • SUMMARY OF THE INVENTION
  • The bioavailability of a drug depends on several parameters, such as on the physicochemical nature of the active compound, the dosage form, and other physiological factors. Compounds of formula I are virtually insoluble in water and simulated gastric fluid, inhibiting oral bioavailability.
  • The present invention provides new galenic compositions for oral administration of pharmaceutically active compounds and a new process for preparing such galenic compositions. In particular, the compositions and process employ a hot melt extrusion of the active pharmaceutical ingredient and a poloxamer. The invention further provides hot melt extrudates of an active pharmaceutical ingredient and a poloxamer.
  • The oral dosage forms of the invention are suitable for delivery to human patients and are designed to enable sufficient availability of the active compound at its site of action. Such formulations may overcome the disadvantage of practical insolublility in simulated intestinal fluid for these compounds.
  • The process of the invention, provides, in particular, a process for preparing a pharmaceutical tablet composition, wherein the active pharmaceutical ingredient of formula I or pharmaceutically acceptable acid addition salts thereof and a water soluble poloxamer are processed by hot melt extrusion before mixing with the other ingredients. The tablet composition can thereafter be coated with a composition comprising an immediate release film coating system and purified water.
    • DETAILED DESCRIPTION OF THE INVENTION
  • The following definitions of general terms used herein apply irrespective of whether the terms in question appear alone or in combination. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an,” and “the” include plural forms unless the context clearly dictates otherwise.
  • The term “lower alkyl” denotes a straight- or branched-chain alkyl group containing from 1 to 7 carbon atoms. Nonlimiting examples of lower alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, and the like.
  • The term “alkylene group” means a lower alkyl linker which is bound to a group at either end. Nonlimiting examples of alkylene groups include methylene, ethylene, propylene, and the like.
  • The term “lower alkoxy” denotes a alkyl group as defined above, which is attached through an oxygen atom. Nonlimiting examples of lower alkoxy groups include methoxy, ethoxy, propoxy, and the like.
  • The term “cycloalkyl” denotes a saturated carbocyclic group (e.g. a nonaromatic ring) containing 3 to 6 carbon atoms. Nonlimiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • The term “halogen” denotes chlorine, iodine, fluorine, and bromine.
  • “Processing aids” are excipients that improve the manufacturability of the formulation by improving, for instance, flowability and by avoiding sticking.
  • One type of processing aid is colloidal silicon dioxide. “Colloidal silicon dioxide” is a submicroscopic fumed silica with a particle size of about 15 nm. It is a light, loose, bluish-white-colored, odorless, tasteless nongritty amorphous powder. Nonlimiting examples of colloid silicon dioxides useful in the invention include Aerosil 380 and Cab-O-Sil.
  • A “tablet filler/diluent” is a material that improves the bulk properties, e.g. mixing, flow, and compression, of a pharmaceutical formulation. They fill out the size of a tablet or capsule, making it practical to produce and convenient for consumer use. By increasing the bulk volume, the final product has the proper volume for patient handling. Nonlimiting examples of tablet filler/diluent include starch, modified starch derivatives, cellulose, calcium salts, sugar and sugar alcohols.
  • “Starch” is a substance consisting of amylase and amylopectin, two polysaccharides based on a-glucose. One type of starch that can be used in the invention is corn starch. Nonlimiting examples of corn starches that can be used in the invention include Pure-Cote, Pure-Bind, Pure-Dent, Pure-Gel, Pure-Set, Melojel, Meritena, Paygel55, Perfectamyl D6PH, Purity 21, Purity 826, and Tablet White.
  • One type of cellulose that can be used as tablet filler/diluent is microcrystalline cellulose. “Microcrystalline cellulose” (MCC) is a naturally occurring polymer comprised of a glucose units connected by a 1-4β glycosidic bond. MCC can be derived from a special grade of alpha cellulose. Nonlimiting examples of MCC that can be used in the invention include Avicel, Vivapur, Vivacel, Emcocel.
  • One type of sugar alcohol that can be used as tablet filler/diluent is mannitol. Nonlimiting examples of mannitol that can be used in the invention include Parteck M 200.
  • A “disintegrant” is a material that enhances the disintegrating properties of a pharmaceutical formulation. Typically, disintegrants expand, swell, and dissolve when wet, causing the tablet to break apart in the digestive tract, releasing the active ingredients for absorption. Different types of disintegrants such as NVP water-swellable polymers, croscarmellose and cellulose derivatives can be used in the invention.
  • A “glidant” is a material used to improve the flowability of the powder or granules or both.
  • An “NVP water-swellable polymer” is an insoluble, swellable homo- or heteropolymer containing N-vinylpyrrolidone, e.g. N-vinyl-2-pyrrolidone.
  • “Pharmaceutically acceptable acid addition salts” embraces salts with inorganic or organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
  • “Water-soluble poloxamers” are block copolymers of ethylene oxide ,i.e. polyoxyethylene (POE), and propylene oxide, i.e. polyoxypropylene (POP), that are soluble in water and are used as wetting agents in pharmaceutical formulations. Nonlimiting examples of poloxamers useful in the present invention include Lutrol F68 (poloxamer 188).
  • “Extrusion” is the process of converting a raw material into a product of uniform shape and density by forcing it through a die under controlled conditions.
  • The present invention provides a composition which comprises a hot melt extrudate that comprises an active pharmaceutical ingredient and a water-soluble poloxamer. In particular, the invention provides a composition which comprises a hot melt extrudate that comprises a compound of formula I and a water soluble poloxamer, for example Lutrol F68.
  • A preferred compound of formula I is the compound, 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, having the structural formula
    Figure US20070071813A1-20070329-C00005
    and which exhibits the above noted insolubilities, i.e. <0.0001 mg/ml in water and aqueous buffer solutions of pH 3.0-7.0.
  • In particular, the invention provides a composition comprising a hot melt extrudate that comprises a compound of formula I, such as 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramidehydrochloride and a water-soluble poloxamer, such as Lutrol F68. A preferred form of the composition is a pharmaceutical tablet, such as a coated pharmaceutical tablet, in particular a 400 mg tablet.
  • The pharmaceutical tablet composition if the invention comprises
    a) an active ingredient of formula I 30-60%
    b) a water soluble poloxamer 10-20%
    c) a filler 20-30%
    d) a disintegrant  1-10%
    e) processing aid and  0-5% and
    f) glidant  0-5%, and if desired
    g) immediate release film coating system  2-5% of the tablet weight
    h) purified water
  • mg/Tablet
    An example of a representative formulation composition
    comprises the ingredients
    2-(3,5-Bis-trifluoromethyl-phenyl)- 400.00
    N-methyl-N-(6-morpholin-4-yl-
    4-o-tolyl-pyridin-3-yl)-
    isobutyramide hydrochloride
    Lutrol F68 133.35
    Microcrystalline Cellulose(Avicel PH102) 162.65
    Parteck M 200(Mannitol) 30.00
    Polyplasdone XL 16.00
    Colloidal Silicon Dioxide(Aerosil 380) 16.00
    Corn Starch 30.00
    Magnesium Stearate 12.00
    Total Weight of Kernel 800.00
    An example of a representative coating composition comprises
    Opadry Yellow 03K 12429 25.00
    Purified Water 131.25
    Total Weight of Film Coated Tablet 825.00
  • The present invention also provides the hot melt extrudate employed in the composition. The extrudate comprises an active pharmaceutical ingredient and a poloxamer. In particular, the hot melt extrudate comprises a compound of formula I or a pharmaceutically acceptable salt thereof and a poloxamer. More particularly, the invention provides an extrudate of 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramidehydrochloride and a water-soluble poloxamer, such as Lutrol F68.
  • The hot melt extrusion (HFME) approach wherein the active pharmaceutical ingredient and a water soluble poloxamer, such as poloxamer 188 (Lutrol F68), a tablet binder and wetability agent are the only components which are processed through the extruder led to a microcrystalline solid dispersion having low particle size, acceptable particle dispersability, and dissolution characteristics that when the extrudate was combined with other excipients produced a tablet having the desired drug dissolution characteristics.
  • Manufacturing Process:
  • The invention provides a process for the manufacture of an extrudate that comprises an active pharmaceutical ingredient and a poloxamer which comprises
    • 1) blending the active pharmaceutical ingredient with a water soluble poloxamer to form a powder blend,
    • 2) extruding the powder blend from step 1) to form a hot melt extrudate, and
    • 3) collecting the hot melt extrudate at room temperature.
  • Blending of the active pharmaceutical ingredient and the poloxamer can be accomplished in any conventional manner. For example, the two ingredients can be placed in a mixer or blender, for example, a PK Bin or Bohle mixer, and mixed. Alternatively, a portion of the active pharmaceutical ingredient, for example, about 50%, can be mixed with the poloxamer, followed by addition of the remainder of the active pharmaceutical ingredient. The material is preferably mixed for a period of about 30 minutes.
  • In one embodiment, the invention provides a process for preparing an extrudate comprising 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramidehydrochloride and Lutrol F68 which comprises blending 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramidehydrochloride with Lutrol F68 to form a powder blend, extruding the powder blend from step 1) to form a hot melt extrudate, and collecting the hot melt extrudate at room temperature.
  • In another embodiment, the invention provides a process for preparation of an extrudate which comprises
    • 1) placing about 50% of the active pharmaceutical ingredient/drug substance in a blender, e.g. PK, Bin or Bohle mixer,
    • 2) adding the water soluble poloxamer, followed by the remainder of the drug substance,
    • 3) mixing the material from step 2) for about 30 minutes to form a powder blend,
    • 4) transferring the powder blend from step 3) into a hot melt extruder (e.g. Leistritz) using a hopper-feeder (e.g. K-Tron Soder),
    • 5) extruding the powder blend through the hot melt extruder, and
    • 6) collecting the hot melt extrudate at room temperature.
  • Optionally, the powder blend contains additional ingredients, such as a tablet binder and/or wettability agent. Optionally, the hot melt extrudate can be passed through a sieving machine to obtain milled material, whereby more than one sieving step may be necessary to obtain material in the desired particle size range.
  • The present invention further provides a process for preparing a pharmaceutical tablet composition which comprises:
    • 1) blending the active pharmaceutical ingredient with a water soluble poloxamer to form a powder blend,
    • 2) extruding the powder blend from step 1) to form a hot melt extrudate,
    • 3) passing the hot melt extrudate through a sieving machine to obtain milled material, whereby more than one sieving step may be necessary to obtain material in the desired particle size range,
    • 4) blending the milled extrudate from step 3) with a filler(s) and a disintegrant,
    • 5) blending the mixture from step 4) with a processing aid and a glidant, and
    • 6) compressing the final blend prepared in step 5) into tablets.
  • In one embodiment, the invention provides a process for preparing a pharmaceutical tablet composition which comprises:
    • 1) blending 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramidehydrochloride with Lutrol F68 to form a powder blend,
    • 2) extruding the powder blend from step 1) to form a hot melt extrudate,
    • 3) passing the hot melt extrudate through a sieving machine to obtain milled material, whereby more than one sieving step may be necessary to obtain material in the desired particle size range,
    • 4) blending the milled extrudate from step 3) with a filler(s) and a disintegrant,
    • 5) blending the mixture from step 4) with a processing aid and a glidant, and
    • 6) compressing the final blend prepared in step 5) into tablets.
  • In another embodiment, the process comprises:
    • 1) placing about 50% of the active pharmaceutical ingredient/drug substance in a blender, e.g. PK, Bin or Bohle mixer,
    • 2) adding the water soluble poloxamer, followed by the remainder of the drug substance,
    • 3) mixing the material from step 2) for about 30 minutes to form a powder blend,
    • 4) transferring the powder blend from step 3) into a hot melt extruder (e.g. Leistritz) using a hopper-feeder (e.g. K-Tron Soder)
    • 5) extruding the powder blend through the hot melt extruder,
    • 6) collecting the hot melt extrudate at room temperature,
    • 7) passing the hot melt extrudate through a sieving machine, e.g. FitzMill, on a first pass set using slow speed knives forward through a #3 screen and then a second pass at medium speed knives forward through a #2 screen,
    • 8) placing about 50 % of the milled material in a PK blender or equivalent along with a filler (e.g. Avicel PH 102 or Parteck M 200, after passing through a #40 mesh screen), Corn Starch, a disintegrant (e.g. Polyplasdone XL), and other excipients (e.g. Aerosil, 380 after passing through a # 12 mesh screen),
    • 9) adding the remaining milled material and mixing for about 30 minutes to produce a powder mixture,
    • 10) removing about 50% of the powder mixture,
    • 11) adding a glidant (e.g. Magnesiun Stereate, after passing through a #40 mesh screen) to the remaining material in the blender, followed by readding the balance of the powder mixture and mixing for about 5 minutes, and
    • 12) compressing the final blend into to tablets using, for instance, a 0.738″×0.344″ oval shaped punches.
  • The kernels (tablets) can be coated as follows:
    • 1) dispersing a complete film coating system, e.g. the Opadry Yellow, in purified water in a stainless steel container by mixing for 45 minutes until completely dispersed to form a coating suspension,
    • 2) placing the kernels into a perforated coating pan and heating with inlet air of 45°±5° C. with intermittent jogging until the exhaust air reaches 40°±5° C.,
    • 3) increasing the inlet temperature to 60°±5° C. and coating the kernels with the coating suspension, stirring continuously, and using an air spray system to apply a certain amount of the film coat (approx. 2 to 5% of the tablet weight) on a dry basis per tablet,
    • 4) drying the coated tablets by jogging until the moisture content is less than 2%, and
    • 5) cooling the tablets to room temperature and storing in a tight double polyethylene-lined container.

Claims (24)

1. A process for preparing a pharmaceutical composition comprising
1) blending an active pharmaceutical ingredient and a water soluble poloxamer to form a powder blend;
2) extruding the powder blend form step 1) to form a hot melt extrudate;
3) passing the hot melt extrudate through a sieving machine to obtain milled material, whereby more than one sieving step may be necessary to obtain material in the desired particle size range;
4) blending the milled extrudate from step 3) with a filler(s) and a disintegrant;
5) blending the mixture from step 4) with a processing aid and a glidant; and
6) compressing the final blend prepared in step 5) into tablets.
2. The process of claim 1, wherein the active pharmaceutical ingredient is a compound of formula I
Figure US20070071813A1-20070329-C00006
wherein
R is lower alkyl, lower alkoxy, halogen or trifluoromethyl
R1 is halogen or hydrogen; and when p is 1, R1 may in addition to the above substituents be taken together with R to form —CH═CH—CH═CH—;
R2 and R2′ are each independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano;
and when n is 1, R2 and R2′ may in addition to the above substituents form —CH═CH—CH═CH—, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy;
R3 and R3′ are hydrogen, lower alkyl or taken together with the attached carbon atom form a cycloalkyl group;
R4 is hydrogen, —N(R5)(CH2)nOH, —N(R5)S(O)2-lower alkyl, —N(R5)S(O)2-phenyl, —N═CH—N(R5)2, —N(5)C(O)R5,
Figure US20070071813A1-20070329-C00007
R5 is hydrogen, C3-6-cycloalkyl, benzyl, or lower alkyl;
R6 is hydrogen, hydroxy, lower alkyl, —(CH2)nCOO—(R5), —N(R5)CO-lower alkyl, hydroxy-lower alkyl, —(CH2)nCN, —(CH2)nO(CH2)nOH, —CHO or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group, which heterocyclic ring is directly bonded or bonded via an alkylene group to the remainder of the molecule;
Figure US20070071813A1-20070329-C00008
is a cyclic tertiary amine which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine is directly attached to the remainder of the molecule or is attached through the linker —CH2)nN(R5)—;
x is —C(O)N(R5)—, —(CH2)mO—, —(CH2)mN(R5)—, —N(R5)C(O)—, or —N(R5)(CH2)m—;
n, p, and q are each independently 1 to 4; and
m is 1 or 2;
or pharmaceutically acceptable acid addition salts thereof.
3. The process of claim 2, wherein the water soluble poloxamer is poloxamer 188.
4. The process of claim 2, wherein the compound of formula I is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramidehydrochloride.
5. The process of claim 4, wherein the water soluble poloxamer is poloxamer 188.
6. The process of claim 1, which comprises
1) placing about 50% of the active pharmaceutical ingredient/drug substance is placed in a blender, e.g. PK, Bin or Bohle mixer,
2) adding the water soluble poloxamer, followed by the remainder of the drug substance,
3) mixing the material from step 2) for about 30 minutes to form a powder blend,
4) transferring the powder blend from step 3) into a hot melt extruder (e.g. Leistritz) using a hopper-feeder (e.g. K-Tron Soder)
5) extruding the powder blend through the hot melt extruder,
6) collecting the hot melt extrudate at room temperature,
7) passing the hot melt extrudate through a sieving machine, e.g. FitzMill, on a first pass set using slow speed knives forward through a #3 screen and then a second pass at medium speed knives forward through a #2 screen,
8) placing about 50% of the milled material in a PK blender or equivalent along with a filler (e.g. Avicel PH 102 or Parteck M 200, after passing through a #40 mesh screen), Corn Starch, a disintegrant (e.g. Polyplasdone XL), and other excipients (e.g. Aerosil, 380 after passing through a # 12 mesh screen),
9) adding the remaining milled material and mixing for about 30 minutes,
10) removing about 50% of the powder mixture,
11) adding a glidant (e.g. Magnesiun Stereate, after passing through a #40 mesh screen) to the remaining material in the blender, followed by readding the balance of the powder mixture and mixing for about 5 minutes, and
12) compressing the final blend into to tablets using, for instance, a 0.738″∴0.344″ oval shaped punches.
7. A process for preparing a pharmaceutical tablet composition comprising an active pharmaceutical ingredient of formula I
Figure US20070071813A1-20070329-C00009
wherein
R is lower alkyl, lower alkoxy, halogen or trifluoromethyl
R1 is halogen or hydrogen; and when p is 1, R1 may in addition to the above substituents be taken together with R to form —CH═CH—CH═CH—;
R2 and R2′ are each independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano;
and when n is 1, R2 and R2′ may in addition to the above substituents form —CH═CH—CH═CH—, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy;
R3 and R3′ are hydrogen, lower alkyl or taken together with the attached carbon atom form a cycloalkyl group;
R4 is hydrogen, —N(R5)(CH2)nOH, —N(R5)S(O)2-lower alkyl, —N(R5)S(O)2-phenyl, —N═CH—N(R5)2, —N(R5)C(O)R5,
Figure US20070071813A1-20070329-C00010
R5 is hydrogen, C3-6-cycloalkyl, benzyl, or lower alkyl;
R6 is hydrogen, hydroxy, lower alkyl, —(CH2)nCOO—(R5), —N(R5)CO-lower alkyl, hydroxy-lower alkyl, —(CH2)nCN, —(CH2)nO(CH2)nOH, —CHO or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group, which heterocyclic ring is directly bonded or bonded via an alkylene group to the remainder of the molecule;
Figure US20070071813A1-20070329-C00011
is a cyclic tertiary amine which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine is directly attached to the remainder of the molecule or is attached through the linker —(CH2)nN(R5)—;
X is —C(O)N(R5)—, —(CH2)mO—, —(CH2)mN(R5)—, —N(R5)C(O)—, or —N(R5)(CH2)m—;
n, p, and q are each independently 1 to 4; and
m is 1 or 2;
or pharmaceutically acceptable acid addition salts thereof
and a water soluble poloxamer which comprises processing the compound of formula I and the water soluble poloxamer by hot melt extrusion and then mixing the hot melt extrudate with other ingredients to form a tablet, that is optionally coated with a composition comprising an immediate release film coating system and purified water.
8. A pharmaceutical composition comprising the following components
a) an active pharmaceutical ingredient 30-60% b) a water soluble poloxamer 10-20% c) a filler 20-30% d) a disintegrant  1-10% e) processing aid and  0-5% and f) glidant  0-5%, and if desired g) immediate release film coating system  2-5% of the tablet weight h) purified water.
9. The pharmaceutical composition of claim 8, wherein the active pharmaceutical ingredient comprises a compound of formula I
Figure US20070071813A1-20070329-C00012
wherein
R is lower alkyl, lower alkoxy, halogen or trifluoromethyl
R1 is halogen or hydrogen; and when p is 1, R1 may in addition to the above substituents be taken together with R to form —CH═CH—CH═CH—;
R2 and R2′ are each independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano;
and when n is 1, R2 and R2′ may in addition to the above substituents form —CH═CH—CH═CH—, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy;
R3 and R3′ are hydrogen, lower alkyl or taken together with the attached carbon atom form a cycloalkyl group;
R4 is hydrogen, —N(R5)(CH2)nOH, —N(R5)S(O)2-lower alkyl, —N(R5)S(O)2-phenyl, —N═CH—N(R5)2, —N(R5)C(O)R5,
Figure US20070071813A1-20070329-C00013
R5 is hydrogen, C3-6-cycloalkyl, benzyl, or lower alkyl;
R6 is hydrogen, hydroxy, lower alkyl, —(CH2)nCOO—(R5), —N(R5)CO-lower alkyl, hydroxy-lower alkyl, —(CH2)nCN, —(CH2)nO(CH2)nOH, —CHO or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group, which heterocyclic ring is directly bonded or bonded via an alkylene group to the remainder of the molecule;
Figure US20070071813A1-20070329-C00014
is a cyclic tertiary amine which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine is directly attached to the remainder of the molecule or is attached through the linker —(CH2)nN(R5)—;
X is —C(O)N(R5)—, —(CH2)mO—, —(CH2)mN(R5)—, —N(R5)C(O)—, or —N(R5)(CH2)m—;
n, p, and q are each independently 1 to 4; and
m is 1 or 2;
or pharmaceutically acceptable acid addition salts thereof.
10. A pharmaceutical composition of claim 9, wherein the compound of formula I is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide.
11. A pharmaceutical composition of claim 8, in the form of a tablet.
12. A pharmaceutical composition of claim 11, wherein the tablet contains 400 mg of an active pharmaceutical ingredient.
13. A pharmaceutical composition of claim 8, wherein the water soluble poloxamer is poloxamer 188.
14. A pharmaceutical composition of claim 8, wherein the filler is a mixture of corn starch, microcrystalline cellulose and sugar alcohol.
15. A pharmaceutical composition of claim 14, wherein the filler is selected from the group consisting of pure-Cote, Pure-Bind, Pure-Dent, Pure Gel, Pure-Set, Melojel, Meritena, Paygel55, perfectamylD6PH, Purity 21, Purity 826, Tablet White, Avicel, Vivapur, Vivacel, Emcocel, and Parteck M 200.
16. A pharmaceutical composition of claim 8, wherein the processing aid is colloidal silicon dioxide.
17. A pharmaceutical composition of claim 16, wherein the processing aid is Aerosil 380 or Cab-O-Sil.
18. A pharmaceutical composition of claim 8, wherein the disintegrant is polyplasdone XL.
19. A pharmaceutical composition of claim 8, wherein the glidant is magnesium stearate.
20. A pharmaceutical tablet composition according to claim 11, comprising
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6- 400.00 mg morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide hydrochloride Lutrol F68 133.35 mg Microcrystalline Cellulose(Avicel PH102) 162.65 mg Parteck M 200(Mannitol) 30.00 mg Polyplasdone XL 16.00 mg Colloidal Silicon Dioxide(Aerosil 380) 16.00 mg Corn Starch 30.00 mg Magnesium Stearate 12.00 mg Opadry Yellow 03K 12429 25.00 mg and Purified Water 131.25 ml.
21. A hot melt extrudate comprising an active pharmaceutical ingredient and a water-soluble poloxamer.
22. The hot melt extrudate of claim 21, wherein the active pharmaceutical ingredient is a compound of formula I
Figure US20070071813A1-20070329-C00015
wherein
R is lower alkyl, lower alkoxy, halogen or trifluoromethyl
R1 is halogen or hydrogen; and when p is 1, R1 may in addition to the above substituents be taken together with R to form —CH═CH—CH═CH—;
R2 and R2′ are each independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano;
and when n is 1, R2 and R2′ may in addition to the above substituents form —CH═CH—CH═CH—, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy;
R3 and R3′ are hydrogen, lower alkyl or taken together with the attached carbon atom form a cycloalkyl group;
R4 is hydrogen, —N(R5)(CH2)nOH, —N(R5)S(O)2-lower alkyl, —N(R5)S(O)2-phenyl, —N═CH—N(R5)2, —N(R5)C(O)R5,
Figure US20070071813A1-20070329-C00016
R5 is hydrogen, C3-6-cycloalkyl, benzyl, or lower alkyl;
R6 is hydrogen, hydroxy, lower alkyl, —(CH2)nCOO—(R5), —N(R5)CO-lower alkyl, hydroxy-lower alkyl, —(CH2)nCN, —(CH2)nO(CH2)nOH, —CHO or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group, which heterocyclic ring is directly bonded or bonded via an alkylene group to the remainder of the molecule;
Figure US20070071813A1-20070329-C00017
is a cyclic tertiary amine which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine is directly attached to the remainder of the molecule or is attached through the linker —(CH2)nN(R5)—;
X is —C(O)N(R5)—, —(CH2)mO—, —(CH2)mN(R5)—, —N(R5)C(O)—, or —N(R5)(CH2)m—;
n, p, and q are each independently 1 to 4; and
m is 1 or 2;
or pharmaceutically acceptable acid addition salts thereof.
23. The hot melt extrudate of claim 22, wherein the compound of formula I is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3 -yl)-isobutyramide.
24. The hot melt extrudate of claim 23, wherein the water soluble poloxamer is poloxamer 188.
US11/524,981 2005-09-23 2006-09-21 Novel dosage formulation Abandoned US20070071813A1 (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100159003A1 (en) * 2007-06-12 2010-06-24 Ratiopharm Gmbh Process for the preparation of a medicament comprising vardenafil hydrochloride trihydrate
US20110028456A1 (en) * 2008-01-11 2011-02-03 Cipla Limited Solid Pharmaceutical Dosage Form
US20120114751A1 (en) * 2010-11-09 2012-05-10 Andreas Leiminer Pharmaceutical composition for treating hcv infections
CN104586770A (en) * 2014-12-30 2015-05-06 山东博迈康药物研究有限公司 Hot-melt extrusion preparation of pazopanib hydrochloride and preparation method of hot-melt extrusion preparation
WO2015068744A1 (en) 2013-11-08 2015-05-14 キッセイ薬品工業株式会社 Carboxymethyl piperidine derivative
KR20170002474A (en) 2014-05-07 2017-01-06 깃세이 야쿠힌 고교 가부시키가이샤 Cyclohexyl-pyridine derivative
US10647705B2 (en) 2017-11-14 2020-05-12 Merck Sharp & Dohme Corp. Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
US11771655B2 (en) * 2014-09-08 2023-10-03 University Of Central Lancashire Solid dosage form production
US12539290B2 (en) 2018-08-17 2026-02-03 Eidos Therapeutics, Inc. Formulations of AG10

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US7671221B2 (en) 2005-12-28 2010-03-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
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PL2806859T3 (en) 2012-01-25 2019-11-29 Vertex Pharma Formulations of 3- (6- (1- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -3-methylpyridin-2-yl) benzoic acid
JP5917964B2 (en) * 2012-03-19 2016-05-18 富士ゼロックス株式会社 Tablet, tablet manufacturing method, tablet management device, tablet verification device, and program
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CN108159008B (en) * 2018-02-27 2021-03-23 河北化工医药职业技术学院 Preparation method of valsartan chewable tablet

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4764361A (en) * 1986-03-25 1988-08-16 Imperial Chemical Industries Plc Pharmaceutical compositions
US5387595A (en) * 1992-08-26 1995-02-07 Merck & Co., Inc. Alicyclic compounds as tachykinin receptor antagonists
US5506248A (en) * 1993-08-02 1996-04-09 Bristol-Myers Squibb Company Pharmaceutical compositions having good dissolution properties
US5554633A (en) * 1992-07-31 1996-09-10 Merck, Sharp & Dohme, Ltd. Substituted amines as tachykinin receptor antagonists
US5612337A (en) * 1993-12-29 1997-03-18 Merck Sharp & Dohme Limited Substituted morpholine derivatives and their use as therapeutic agents
US5719147A (en) * 1992-06-29 1998-02-17 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists
US5972938A (en) * 1997-12-01 1999-10-26 Merck & Co., Inc. Method for treating or preventing psychoimmunological disorders
US6294537B1 (en) * 1995-03-17 2001-09-25 Sanofi-Synthelabo Compounds which are specific antagonists of the human NK3 receptor and their use as medicinal products and diagnostic tools
US6297375B1 (en) * 1999-02-24 2001-10-02 Hoffmann-La Roche Inc. 4-phenyl-pyridine derivatives
US6303790B1 (en) * 1999-11-29 2001-10-16 Hoffman-La Roche Inc. Process for the preparation of pyridine derivatives
US6706281B2 (en) * 1994-11-04 2004-03-16 Euro-Celtique, S.A. Melt-extrusion multiparticulates

Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1557420A (en) 1977-03-10 1979-12-12 Soc D Etudes Prod Chimique Preparation of isobutyramide derivatives
DE3366369D1 (en) 1982-03-17 1986-10-30 Smith Kline French Lab Pyridine derivatives
JPS60184008A (en) * 1984-03-02 1985-09-19 Eisai Co Ltd Composition containing theophylline or aminophylline
US4745123A (en) 1986-02-18 1988-05-17 Warner-Lambert Company Substituted tetrahydro-3-pyridine-carboxylic acid, ester, and amide cholinergic agents
GB8607312D0 (en) 1986-03-25 1986-04-30 Ici Plc Therapeutic agents
CA1339423C (en) 1988-09-14 1997-09-02 Yuji Ono Pyridine compounds and pharmaceutical use thereof
US4994456A (en) 1989-03-01 1991-02-19 Nisshin Flour Milling Co., Ltd. Pyridinecarboxylic acid amide derivatives and pharmaceutical compositions comprising same
US4973597A (en) 1989-06-30 1990-11-27 Eli Lilly And Company Anticonvulsant agents
HU207047B (en) 1989-11-07 1993-03-01 Richter Gedeon Vegyeszet Process for producing new pyridine derivatives and pharmaceutical copositions comprising same
US5364943A (en) 1991-11-27 1994-11-15 Pfizer Inc. Preparation of substituted piperidines
GB9021056D0 (en) 1990-09-27 1990-11-07 Pfizer Ltd Antiarrhythmic agents
GB9214120D0 (en) 1991-07-25 1992-08-12 Ici Plc Therapeutic amides
US5281420A (en) * 1992-05-19 1994-01-25 The Procter & Gamble Company Solid dispersion compositions of tebufelone
GB9305672D0 (en) 1993-03-19 1993-05-05 Wyeth John & Brother Ltd Amide derivatives
AU6807994A (en) 1993-05-28 1994-12-20 Taisho Pharmaceutical Co., Ltd. Medicinal use of pyridine derivative
NZ264063A (en) 1993-08-13 1995-11-27 Nihon Nohyaku Co Ltd N-(2-phenylpyrid-3-yl)- and n-(4-phenylpyrimidin-5-yl)-n'-phenylurea derivatives and pharmaceutical compositions
IL111960A (en) 1993-12-17 1999-12-22 Merck & Co Inc Morpholines and thiomorpholines their preparation and pharmaceutical compositions containing them
IL112778A0 (en) 1994-03-04 1995-05-26 Merck & Co Inc Substituted heterocycles, their preparation and pharmaceutical compositions containing them
CA2187531A1 (en) 1994-06-06 1995-12-14 David Christopher Horwell Tachykinin (nk1) receptor antagonists
WO1996000213A1 (en) 1994-06-24 1996-01-04 Taisho Pharmaceutical Co., Ltd. Pyridine derivative
NO309272B1 (en) 1995-03-24 2001-01-08 Takeda Chemical Industries Ltd Cyclic compounds, preparations containing the compounds and intermediates for the preparation of the compounds
EA002270B1 (en) 1996-03-29 2002-02-28 Пфайзер Инк. 6-phenylpyridyl-2-amine derivatives
US5834472A (en) * 1996-05-24 1998-11-10 Schering Corporation Antifungal composition with enhanced bioavailability
WO1998021185A1 (en) 1996-11-08 1998-05-22 Sankyo Company, Limited Arylureas or arylmethylcarbamoyl derivatives
CO4920215A1 (en) * 1997-02-14 2000-05-29 Novartis Ag OXACARBAZEPINE TABLETS COATED WITH A FILM AND METHOD FOR THE PRODUCTION OF THESE FORMULATIONS
JPH11189546A (en) 1997-12-25 1999-07-13 Saitama Daiichi Seiyaku Kk Percutaneous absorption promoter
JPH11189548A (en) * 1997-12-25 1999-07-13 Toshio Sato Amorphous pharmaceutical composition and its production
BR0008489A (en) 1999-02-24 2002-02-05 Hoffmann La Roche Phenyl- and pyridinyl derivatives
ATE253561T1 (en) 1999-11-29 2003-11-15 Hoffmann La Roche 2-(3,5-BIS-TRIFLUOROMETHYL-PHENYL)-N-METHYL-N-( - MORPHOLINE-4-YL-4-O-TOLYL-PYRIDINE-3-YL)- ISOBUTYRAMIDE
EP1390063B1 (en) * 2001-05-03 2004-11-17 F. Hoffmann-La Roche Ag Pharmaceutical dosage form of amorphous nelfinavir mesylate
KR100810320B1 (en) 2005-06-16 2008-03-04 삼성전자주식회사 Method that digital broadcasting player makes call using telephone number provided during broadcasting and its digital broadcasting system

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4764361A (en) * 1986-03-25 1988-08-16 Imperial Chemical Industries Plc Pharmaceutical compositions
US5719147A (en) * 1992-06-29 1998-02-17 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists
US5554633A (en) * 1992-07-31 1996-09-10 Merck, Sharp & Dohme, Ltd. Substituted amines as tachykinin receptor antagonists
US5387595A (en) * 1992-08-26 1995-02-07 Merck & Co., Inc. Alicyclic compounds as tachykinin receptor antagonists
US5506248A (en) * 1993-08-02 1996-04-09 Bristol-Myers Squibb Company Pharmaceutical compositions having good dissolution properties
US5612337A (en) * 1993-12-29 1997-03-18 Merck Sharp & Dohme Limited Substituted morpholine derivatives and their use as therapeutic agents
US6706281B2 (en) * 1994-11-04 2004-03-16 Euro-Celtique, S.A. Melt-extrusion multiparticulates
US6294537B1 (en) * 1995-03-17 2001-09-25 Sanofi-Synthelabo Compounds which are specific antagonists of the human NK3 receptor and their use as medicinal products and diagnostic tools
US5972938A (en) * 1997-12-01 1999-10-26 Merck & Co., Inc. Method for treating or preventing psychoimmunological disorders
US6297375B1 (en) * 1999-02-24 2001-10-02 Hoffmann-La Roche Inc. 4-phenyl-pyridine derivatives
US6479483B2 (en) * 1999-02-24 2002-11-12 Hoffmann-La Roche Inc. 4-phenyl-pyridine derivatives
US6303790B1 (en) * 1999-11-29 2001-10-16 Hoffman-La Roche Inc. Process for the preparation of pyridine derivatives

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8772292B2 (en) * 2007-06-12 2014-07-08 Ratiopharm Gmbh Process for the preparation of a medicament comprising vardenafil hydrochloride trihydrate
US20100159003A1 (en) * 2007-06-12 2010-06-24 Ratiopharm Gmbh Process for the preparation of a medicament comprising vardenafil hydrochloride trihydrate
US20110028456A1 (en) * 2008-01-11 2011-02-03 Cipla Limited Solid Pharmaceutical Dosage Form
CN103200934B (en) * 2010-11-09 2016-02-03 弗·哈夫曼-拉罗切有限公司 Pharmaceutical composition for treating HCV infection
US20120114751A1 (en) * 2010-11-09 2012-05-10 Andreas Leiminer Pharmaceutical composition for treating hcv infections
CN103200934A (en) * 2010-11-09 2013-07-10 弗·哈夫曼-拉罗切有限公司 Pharmaceutical composition for treating HCV infection
US20130331314A1 (en) * 2010-11-09 2013-12-12 Hoffmann-La Roche Inc. Pharmaceutical composition for treating hcv infections
AU2011328307B2 (en) * 2010-11-09 2016-04-21 F. Hoffmann-La Roche Ag Pharmaceutical composition for treating HCV infections
KR20160078997A (en) 2013-11-08 2016-07-05 깃세이 야쿠힌 고교 가부시키가이샤 Carboxymethyl piperidine derivative
WO2015068744A1 (en) 2013-11-08 2015-05-14 キッセイ薬品工業株式会社 Carboxymethyl piperidine derivative
US10100030B2 (en) 2013-11-08 2018-10-16 Kissei Pharmaceutical Co., Ltd. Carboxymethyl piperidine derivative
KR20170002474A (en) 2014-05-07 2017-01-06 깃세이 야쿠힌 고교 가부시키가이샤 Cyclohexyl-pyridine derivative
US9708266B2 (en) 2014-05-07 2017-07-18 Kissei Pharmaceutical Co., Ltd. Cyclohexyl pyridine derivative
US10011568B2 (en) 2014-05-07 2018-07-03 Kissei Pharmaceutical Co., Ltd. Cyclohexyl pyridine derivative
US11771655B2 (en) * 2014-09-08 2023-10-03 University Of Central Lancashire Solid dosage form production
US20240148657A1 (en) * 2014-09-08 2024-05-09 University Of Central Lancashire Solid dosage form production
US12447129B2 (en) 2014-09-08 2025-10-21 University of Lancashire Solid dosage form production
CN104586770A (en) * 2014-12-30 2015-05-06 山东博迈康药物研究有限公司 Hot-melt extrusion preparation of pazopanib hydrochloride and preparation method of hot-melt extrusion preparation
US10647705B2 (en) 2017-11-14 2020-05-12 Merck Sharp & Dohme Corp. Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
US10995085B2 (en) 2017-11-14 2021-05-04 Merck Sharp & Dohme Corp. Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
US12539290B2 (en) 2018-08-17 2026-02-03 Eidos Therapeutics, Inc. Formulations of AG10

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