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WO2008128116A1 - Traitement du syndrome de down au moyen d'antagonistes des récepteurs des benzodiazépines - Google Patents

Traitement du syndrome de down au moyen d'antagonistes des récepteurs des benzodiazépines Download PDF

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Publication number
WO2008128116A1
WO2008128116A1 PCT/US2008/060133 US2008060133W WO2008128116A1 WO 2008128116 A1 WO2008128116 A1 WO 2008128116A1 US 2008060133 W US2008060133 W US 2008060133W WO 2008128116 A1 WO2008128116 A1 WO 2008128116A1
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Prior art keywords
composition
benzodiazepine
active pharmaceutical
pharmaceutical ingredient
partial
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PCT/US2008/060133
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English (en)
Inventor
Srinivas Rao
Jeffery J. Anderson
Jay D. Kranzler
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Cypress Bioscience Inc
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Cypress Bioscience Inc
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Priority to EP08745691A priority Critical patent/EP2146576A4/fr
Priority to CA002683754A priority patent/CA2683754A1/fr
Priority to AU2008240148A priority patent/AU2008240148B2/en
Priority to JP2010503256A priority patent/JP2010523716A/ja
Publication of WO2008128116A1 publication Critical patent/WO2008128116A1/fr
Priority to US12/427,430 priority patent/US20090270373A1/en
Anticipated expiration legal-status Critical
Ceased 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • 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

Definitions

  • This application relates to methods of treating Down Syndrome and other forms of mental retardation with a composition comprising one or more benzodiazepine receptor blocker.
  • Down Syndrome (trisomy 21) is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21.
  • Down Syndrome is often, though not always, characterized by varying degrees of cognitive impairment - impairment m memory, learning capacity or both. While advances in teaching methods and a trend toward educational mainstreaming has led to an improvement m cognitive development m those who have Down Syndrome, there remain constitutive impairments that cannot be fully addressed through pedagogic methodology alone, hi particular, there is a need for improvement in the cognitive abilities of Down Syndrome patients.
  • Mental retardation is a broader classification of cognitive deficit.
  • a common criterion for diagnosing mental retardation is a score of 70 or below on one or more accepted intelligence quotient (IQ) tests.
  • IQ accepted intelligence quotient
  • Flumazenil is a tricyclic benzodiazepine (8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H- irmdazo[l,5-a]benzodiazepme-3-carboxylic acid ethyl ester) that antagonizes (as a competitive inhibitor of) benzodiazepine receptors in the central nervous system Its preparation is described in U.S. Patent No. 4,316,839. It has been administered in adults to reverse the effects of benzodiazepines in conscious sedation and general anesthesia. It has also been administered to counteract overdose of benzodiazepine agonists, such as diazepam.
  • flumazenil also known as Ro 15-1788
  • flumazenil effectively antagonizes the effects of diazepam when given orally or intravenously. Id.
  • flumazenil is often classified as a benzodiazepine receptor antagonist, although its activity is considered in some literature to be mixed (i.e. partial benzodiazepine agonist).
  • GAB A A antagonists in a murine model of Down Syndrome (Ts65Dn mice) increases memory and declarative learning.
  • F. Fernandez et al. "Pharmacotherapy for cognitive impairment in a mouse model of Down Syndrome," Nature Neuroscience, Advance Online Publication, (February 25, 2007).
  • Ts65Dn mice demonstrate learning and memory deficits, which are hypothetically due to selective decreases in the numbers of excitatory synapses in the brain rather than gross abnormalities in neuroanatomy.
  • embodiments of the present invention which provide a method of treating Down Syndrome or mental retardation, comprising administering to a patient suffering from Down Syndrome or mental retardation an effective amount of a composition comprising at least one active pharmaceutical ingredient selected from a benzodiazepine receptor antagonist, a partial benzodiazepine agonist, or both.
  • embodiments of the invention which provide a method of enhancing cognitive function in a patient suffering from mental retardation or Down Syndrome, comprising administering to the patient a cognitive function enhancing amount of an active pharmaceutical ingredient comprising a benzodiazepine receptor antagonist, a partial benzodiazepine agonist or both.
  • embodiments of the invention which provide an oral composition for the treatment of mental retardation, Down Syndrome, memory loss or impaired learning, comprising an effective amount of an active pharmaceutical ingredient comprising a benzodiazepine antagonist, a partial benzodiazepine agonist or both.
  • embodiments of the invention which provide a sublingual or buccal composition for the treatment of mental retardation, Down Syndrome, memory loss or impaired learning, comprising an effective amount of an active pharmaceutical ingredient comprising a benzodiazepine antagonist, a partial benzodiazepine agonist or both.
  • the present invention provides methods and pharmaceutical formulations for the enhancement of cognitive functioning, especially memory, learning, or both, especially in individuals suffering from Down Syndrome or mental retardation.
  • the invention provides methods of treating impaired cognitive functioning with one or more active pharmaceutical ingredients selected from chemical entities selected from benzodiazepine receptor antagonists and partial benzodiazepine agonists.
  • the present invention seeks to improve cognitive functioning - e.g. memory and learning - m individuals whose cognitive functioning has been impaired by a mental disorder that affects their cognition.
  • the invention provides a method of treating Down Syndrome or mental retardation, comprising administering to a patient suffering from Down Syndrome or mental retardation an effective amount of a composition comprising at least one active pharmaceutical ingredient selected from a benzodiazepine receptor antagonist, a partial benzodiazepine agonist, or both.
  • the active pharmaceutical ingredient comprises at least one benzodiazepine receptor antagonist.
  • At least one benzodiazepine receptor antagonist is flumazenil
  • the method comprises administering to the patient about 0.05 to about 30 mg of flumazenil one to four times daily, preferably about 0.1 to about 15 mg of flumazenil one to four times daily, hi some embodiments the active pharmaceutical ingredient comprises at least one partial benzodiazepine agonist.
  • at least one partial benzodiazepine agonist is bretazenil.
  • the method comprises administering about 0.05 to about 30 mg of bretazenil one to four times daily, preferably about 0.1 to about 15 mg of bretazenil one to four times daily.
  • the composition comprising the active pharmaceutical ingredient is an oral , buccal or sublingual composition.
  • the composition comprising the active pharmaceutical ingredient is in the form of a tablet, capsule, gel capsule, caplet or liquid solution or suspension.
  • the composition comprising the active pharmaceutical ingredient is a parenteral preparation.
  • the parenteral preparation is an intravenous injection.
  • the effective amount of the composition comprising the active pharmaceutical ingredient is a sub-seizure inducing amount.
  • the effective amount of the composition is effective to produce a memory enhancing effect, a learning enhancing effect, or both.
  • the invention provides a method of enhancing cognitive function in a patient suffering from mental retardation or Down Syndrome, comprising administering to the patient a cognitive function enhancing amount of an active pharmaceutical ingredient comprising a benzodiazepine receptor antagonist, a partial benzodiazepine agonist or both.
  • the active pharmaceutical ingredient comprises at least one benzodiazepine receptor antagonist, hi some embodiments at least one benzodiazepine receptor antagonist is flumazenil.
  • the method comprises administering to the patient about 0.05 to about 30 mg of flumazenil one to four times daily, preferably about 0.1 to about 15 mg of flumazenil one to four times daily.
  • active pharmaceutical ingredient comprises at least one partial benzodiazepine agonist. In some embodiments at least one benzodiazepine agonist is bretazenil. In some embodiments the method comprises administering about 0.05 to about 30 mg of bretazenil one to four times daily, preferably about 0.1 to about 15 mg of bretazenil one to four times daily. In some embodiments at least one cognitive function that is enhanced is memory or learning. Li some embodiments the composition is an oral, buccal or sublingual composition. In some embodiments the composition comprising the active pharmaceutical ingredient is in the form of a tablet, capsule, gel capsule, caplet, liquid solution, liquid suspension or fast-dissolve tablet. In some embodiments the composition comprising the active pharmaceutical ingredient is a parenteral preparation. In some embodiments the composition comprising the active pharmaceutical ingredient is an intravenous injection. In some embodiments the effective amount of the composition as a sub-seizure inducing amount.
  • the invention provides an oral composition for the treatment of mental retardation, Down Syndrome, memory loss or impaired learning, comprising an effective amount of an active pharmaceutical ingredient comprising a benzodiazepine antagonist, a partial benzodiazepine agonist or both.
  • the active pharmaceutical ingredient comprises at least one benzodiazepine receptor antagonist.
  • at least one benzodiazepine receptor antagonist is flumazenil.
  • the composition is in unit dosage form and comprises about 0.05 to about 30 mg of flumazenil, preferably about 0.1 to about 15 mg of flumazenil per dose, hi some embodiments the active pharmaceutical ingredient consists essentially of a benzodiazepine antagonist.
  • the benzodiazepine antagonist is flumazenil.
  • the composition is in unit dosage form and comprises about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg of flumazenil per dose.
  • the active pharmaceutical ingredient comprises at least one partial benzodiazepine agonist.
  • at least one partial benzodiazepine agonist is bretazenil.
  • the composition is in unit dosage form an comprises about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg of bretazenil per dose.
  • the active pharmaceutical ingredient consists essentially of a partial benzodiazepine agonist.
  • the partial benzodiazepine agonist is bretazenil.
  • the composition is in unit dosage form an comprises about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg of bretazenil per dose.
  • the composition is in an extended release, delayed release, pulsatile or controlled release dosage form.
  • the effective amount of the active pharmaceutical ingredient is a sub-seizure inducing amount.
  • the effective amount of the active pharmaceutical ingredient is effective to produce a memory enhancing effect, a learning enhancing effect, or both.
  • the present invention provides a sublingual or buccal composition for the treatment of mental retardation, Down Syndrome, memory loss or impaired learning, comprising an effective amount of an active pharmaceutical ingredient comprising a benzodiazepine antagonist, a partial benzodiazepine agonist or both.
  • the active pharmaceutical ingredient comprises at least one benzodiazepine receptor antagonist.
  • at least one benzodiazepine receptor antagonist is flumazenil.
  • the composition is in unit dosage form and comprises about 0.05 to about 30 mg of flumazenil, preferably about 0.1 to about 15 mg of flumazenil per dose.
  • the active pharmaceutical ingredient consists essentially of a benzodiazepine receptor antagonist.
  • the benzodiazepine receptor antagonist is flumazenil.
  • the composition is in unit dosage form and comprises about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg of flumazenil per dose.
  • the active pharmaceutical ingredient comprises at least one partial benzodiazepine agonist, hi some embodiments at least one partial benzodiazepine agonist is bretazenil.
  • the composition is in unit dosage form an comprises about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg of bretazenil per dose.
  • the active pharmaceutical ingredient consists essentially of a partial benzodiazepine agonist.
  • the partial benzodiazepine agonist is bretazenil.
  • the composition is in unit dosage form an comprises about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg of bretazenil per dose, hi some embodiments, the buccal or sublingual composition is in the form of a fast-dissolve tablet or strip.
  • the effective amount of the active pharmaceutical ingredient is a sub-seizure inducing amount. In some embodiments the effective amount of the active pharmaceutical ingredient is effective to produce a memory enhancing effect, a learning enhancing effect, or both.
  • active pharmaceutical ingredient is intended to mean a compound or combination of compounds, at least one of such compounds is a benzodiazepine receptor antagonist or a partial benzodiazepine agonist as described in more detail herein.
  • active pharmaceutical agent is intended to mean a compound or combination of compounds, at least one of such compounds is a benzodiazepine receptor antagonist or a partial benzodiazepine agonist as described in more detail herein.
  • an active pharmaceutical ingredient requires the presence of at least one benzodiazepine receptor antagonist or at least one partial benzodiazepine agonist, but may also include one or more additional pharmaceutical compounds that does not detract from, and in some cases may enhance, the activity of the benzodiazepine receptor antagonist and/or partial benzodiazepine agonist.
  • combinations of two or more benzodiazepine receptor antagonists, two or more partial benzodiazepine agonists, or at least one benzodiazepine receptor antagonist and at least one partial benzodiazepine agonist are included within the scope of the active pharmaceutical ingredient unless otherwise limited.
  • benzodiazepine receptor antagonists act on the benzodiazepine receptors on GABA A chloride ion channels to block the effects of GABA.
  • One benzodiazepine receptor antagonist, flumazenil is used as an antidote to benzodiazepine receptor agonists, such as diazepam and midazolam, in benzodiazepine agonist overdose situations or to counteract the effects of benzodiazepin receptor agonist sedation (e.g. post-operatively).
  • the invention provides oral, buccal and sublingual dosages of benzodiazepine receptor antagonists, such as flumazenil.
  • the oral dosage of flumazenil is expected to be about one to ten, preferably about two to seven times the usual intravenous dose owing to the oral bioavailability of flumazenil, which is approximately 20% of the intravenous bioavailability.
  • the invention contemplates administering to the patient one to four doses of flumazenil per day; and those doses, for adults, are expected to be in the range of about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg of flumazenil per dose.
  • flumazenil is a preferred embodiment of the benzodiazepine receptor antagonists of the invention
  • the person skilled in the art will recognize that other benzodiazepine receptor antagonists, may be used in its place, with appropriate adjustments in dosage made for relative potency, bioavailability and pharmacokinetics.
  • Partial Benzodiazepine Agonists [0024] Several partial benzodiazepine agonists are known or under development.
  • bretazenil tert-butyl-(S)-8-bromo-l l, 12, 13, 13a-tetrahydro-9-oxo-9H-imidazo[l, 5-a]pyrrolo[2, 1- c][l, 4] benzodiazepine- 1-carboxy late (Ro 16-6028)
  • abecarnil tert-butyl-(S)-8-bromo-l l, 12, 13, 13a-tetrahydro-9-oxo-9H-imidazo[l, 5-a]pyrrolo[2, 1- c][l, 4] benzodiazepine- 1-carboxy late (Ro 16-6028)
  • abecarnil also known as partial benzodiazepine receptor agonists
  • Partial benzodiazepine agonists also known as partial benzodiazepine receptor agonists
  • the invention provides oral, buccal and sublingual dosages of partial benzodiazepine agonists, such as bretazenil.
  • the oral dosage of bretazenil is expected to be in the range of about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg of bretazenil per dose.
  • bretazenil For adolescents and pre-adolescents, it is considered that the does will have to be reduced from 2 to 5 fold, depending upon the mass of the patient.
  • bretazenil is a preferred embodiment of the partial benzodiazepine agonists of the invention, the person skilled in the art will recognize that other partial benzodiazepine agonists may be used in its place.
  • Pharmaceutically Acceptable Salts, Stereoisomers, Polymorphs and Hydrates [0027] The person skilled in the art will recognize that various active pharmaceutical ingredients set forth herein are available in free base or salt forms, as enantiomerically pure stereoisomers and/or as polymorphs.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acid ; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, benzenesulfom ' c, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic and isethionic acids.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acid
  • organic acids such as acetic, propionic, succinic, glycolic, ste
  • the pharmaceutically acceptable salts can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington '$ Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, PA, 1985, p. 1418). hi the case of flumazenil and bretazenil, the benzodiazepine core has at least one ring amino nitrogen capable of forming a salt with an appropriate acid, such as one of the acids recited above.
  • Stereoisomers are compounds made up of the same atoms having the same bond order but having different three-dimensional arrangements of atoms which are not interchangeable. The three- dimensional structures are called configurations.
  • Two kinds of stereoisomers include enantiomers and diastereomers.
  • Enantiomers are two stereoisomers which are non-superimposable mirror images of one another. This property of enantiomers is known as chirality.
  • the terms “racemate”, “racemic mixture” or “racemic modification” refer to a mixture of equal parts of enantiomers.
  • the term “chiral center” refers to a carbon atom to which four different groups are attached.
  • Diastereomers are two stereoisomers which are not mirror images but also not superimposable. Diastereoisomers have different physical properties and can be separated from one another easily by taking advantage of these differences. [0030] Different polymorphs of the compounds may also be used. Polymorphs are, by definition, crystals of the same molecule having different physical properties as a result of the order of the molecules in the crystal lattice.
  • the polymorphic behavior of drugs can be of crucial importance in pharmacy and pharmacology.
  • the differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability).
  • Differences in stability can result from changes in chemical reactivity (e.g. differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g. tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g. tablets of one polymorph are more susceptible to breakdown at high humidity).
  • compositions can be administered orally, buccally, sublingually, intravenously, parenterally, by inhalation spray, rectally, intradermally, transdermally, pulmonary, nasally or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, or intrasteraal injection, or infusion techniques.
  • composition is administered orally, buccally or sublingually; in other preferred embodiments, the composition is administered intravenously.
  • Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1975), and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y. (1980).
  • the active pharmaceutical ingredients may be administered per se or in the form of a pharmaceutical composition wherein the active compound(s) is in admixture or mixture with one or more pharmaceutically acceptable ingredients, such as one or more carriers, excipients, disintegrants, glidants, diluents, delayed-release or controlled-release matrices or coatings.
  • pharmaceutically acceptable ingredients such as one or more carriers, excipients, disintegrants, glidants, diluents, delayed-release or controlled-release matrices or coatings.
  • Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name Eudragit ® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.
  • cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate
  • polyvinyl acetate phthalate acrylic acid polymers and copolymers
  • methacrylic resins that are commercially available under the trade name Eudragit ® (Roth Pharma, Westerstadt, Germany), ze
  • the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants.
  • Optional pharmaceutically acceptable excipients present in the drug-containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants.
  • Diluents also referred to as "fillers,” are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules.
  • Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystallme cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar.
  • Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms.
  • Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.
  • Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.
  • Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp).
  • Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.
  • Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions.
  • anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-su!fosuccinate; and alkyl sulfates such as sodium lauryl sulfate.
  • Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4- oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer* 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
  • amphoteric surfactants include sodium N-dodecyl- ⁇ -alanine, sodium N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
  • the tablets, beads, granules, or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives.
  • nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives.
  • the active pharmaceutical ingredients may be complexed with other agents as part of their being pharmaceutically formulated.
  • compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as binding agents (e.g., acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch, and ethylcellulose); fillers (e.g., corn starch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, or alginic acid); lubricants (e.g.
  • binding agents e.g., acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch, and ethylcellulose
  • fillers e.g., corn starch, gelatin, lactose, acacia,
  • disintegrators e.g. micro-crystalline cellulose, corn starch, sodium starch glycolate and alginic acid.
  • water-soluble, such formulated complex then may be formulated in an appropriate buffer, for example, phosphate buffered saline or other physiologically compatible solutions.
  • a non-ionic surfactant such as TWEENTM, or polyethylene glycol.
  • the active pharmaceutical ingredients and their physiologically acceptable solvates may be formulated for administration.
  • Liquid formulations for oral administration prepared in water or other aqueous vehicles may contain various suspending agents such as methylcellulose, alginates, tragacanth, pectin, kelgin, carrageenan, acacia, polyvinylpyrrolidone, and polyvinyl alcohol.
  • the liquid formulations may also include solutions, emulsions, syrups and elixirs containing, together with the active compound(s), wetting agents, sweeteners, and coloring and flavoring agents.
  • Various liquid and powder formulations can he prepared by conventional methods for inhalation by the patient.
  • Delayed release and extended release compositions can be prepared.
  • the delayed release/extended release pharmaceutical compositions can be obtained by complexing drug with a pharmaceutically acceptable ion-exchange resin and coating such complexes.
  • the formulations are coated with a substance that will act as a barrier to control the diffusion of the drug from its core complex into the gastrointestinal fluids.
  • the formulation is coated with a film of a polymer which is insoluble in the acid environment of the stomach, and soluble in the basic environment of lower GI tract in order to obtain a final dosage form that releases less than 10% of the drug dose within the stomach.
  • combinations of immediate release compositions and delayed release/extended release compositions may be formulated together.
  • an active pharmaceutical ingredient of the invention may be administered as a pulsatile formulation.
  • a formulation can be administered as a capsule, tablet or aqueous suspension.
  • a capsule, tablet or aqueous suspension may be formulated containing two or more populations of active pharmaceutical ingredient particle - one containing active pharmaceutical ingredient in an immediate release form (e.g. uncoated or coated with an immediate release coating) and another population in which the active pharmaceutical ingredient is coated with a delayed release coating and/or an enteric coating.
  • a pulsatile release of active pharmaceutical ingredient results in a longer-lasting formulation, which may be administered on a twice-a-day (b.i.d.) or once-a-day (q.d.) basis.
  • the two populations of particles maybe encased within an immediate release or delayed release capsule.
  • the two populations of particles may be compressed, optionally in admixture with an appropriate binder and/or disintegrants, to form a tablet core, which is then coated with an immediate release coating, an enteric coating or both. The tablet then may be coated with a coating that enhances the swallowability of the dosage.
  • the first population of particles may be uncoated (and indeed wholly or partially dissolved in the aqueous medium) or may be coated with an immediate release coating, an enteric coating or both.
  • the second population of particles is coated with a delayed release coating and optionally an immediate release coating and/or an enteric coating.
  • Enteric coatings are generally applied where the active pharmaceutical ingredient is sensitive to low pH conditions and thus would be expected to be unstable in the stomach. They may also be applied to the delayed release population of particles in order to add an additional delay to the release of the active pharmaceutical ingredient within the delayed release particles.
  • the active pharmaceutical ingredient will be administered as an oral liquid solution or suspension, or as a buccal or sublingual liquid, tablet or gel strip.
  • buccal and sublingual formulations should be of the fast- dissolvmg type in order to enhance the ease and convenience of use.
  • the present invention provides methods of treating cognitive dysfunction, especially the treatment of impaired learning and/or memory associated with Down Syndrome (also referred to as Down's Syndrome or trisomy 21) and/or mental retardation
  • Down Syndrome is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21.
  • Down Syndrome is often, though not always, characte ⁇ zed by varying degrees of cognitive impairment - e.g. impairment in memory, learning capacity or both.
  • Mental retardation is a broader classification of cognitive deficit.
  • a common criterion for diagnosing mental retardation is a score of 70 or below on one or more accepted intelligence quotient (IQ) tests.
  • IQ accepted intelligence quotient
  • Benzodiazepine receptor antagonists such as flumazeml inhibit the binding of compounds that bind to the benzodiazepine receptor on GABA A chloride ion channels.
  • the GABA A receptor is a multimenc transmembrane receptor consisting of five subumts arranged around a central ion channel.
  • the GABA A receptors are located within neuronal membranes at a synapse.
  • the hgand GABA ( ⁇ - aminobuty ⁇ c acid) is the endogenous compound that causes this receptor to open.
  • Benzodiazepine receptors are alloste ⁇ c hgand binding sites on the GABA A receptor, and are thus separate from the GABA hgand binding sites.
  • Benzodiazepine agonists such as diazepam, lorazepam and midazolam, bind to benzodiazepine receptors and increase the activity of the chlo ⁇ de channel, thereby enhancing the neuronal activity inhibitory effect of GABA binding to GAB A A receptors.
  • the physiologic effect of benzodiazepine agonists is generally sedative and amnesic
  • benzodiazepine receptor antagonists such as flumazeml, bind to the benzodiazepine receptor and block the effect of benzodiazepine agonists.
  • flumazenil has been used as an antidote to benzodiazepine agonist overdose or to reverse the sedative effects of benzodiazepine agonist sedatives after surgery.
  • GABA A antagonists such as picrotoxin rescue cognition in the Ts65Dn murine model of Down Syndrome (See Fernandez, supra)
  • benzodiazepine receptor antagonists also counteract the effects of GABA binding- i.e. that they have positive effects on enhancing the activity of neurons involved in cognition.
  • an effective amount of benzodiazepine antagonist would provide cognition enhancing effects, especially to those patients who are genetically disposed to an imbalance in GABA A receptor activity.
  • an effective amount of a benzodiazepine antagonist would provide cognition enhancing effects in patients suffering from cognitive impairment caused by Down Syndrome or mental retardation.
  • benzodiazepine receptor antagonists are considered to have a lower seizure- inducing potential than GABA A receptor antagonists, such as picrotoxin, it is considered that an effective amount of a benzodiazepine receptor antagonist will also be less than a seizure inducing amount of the benzodiazepine receptor antagonist.
  • Partial benzodiazepine agonists such as bretazenil, bind to the benzodiazepine receptor and provide both agonistic and antagonistic effects.
  • bretazenil has been suggested as an alternative to benzodiazepine antagonists such as diazepam.
  • GABA A antagonists such as picrotoxin rescue cognition in the Ts65Dn murine model of Down Syndrome
  • partial benzodiazepine agonists which in part counteract the effects of GABA binding, would also demonstrate positive effects on enhancing the activity of neurons involved in cognition.
  • an effective amount of a partial benzodiazepine agonist would provide cognition enhancing effects, especially to those patients who are genetically disposed to an imbalance in GAB A A receptor activity.
  • an effective amount of a partial benzodiazepine agonist would provide cognition enhancing effects in patients suffering from cognitive impairment caused by Down Syndrome or mental retardation.
  • partial benzodiazepine agonists are considered to have a lower seizure-inducing potential than GABA A receptor antagonists, such as picrotoxin, it is considered that an effective amount of a partial benzodiazepine agonist will also be less than a seizure inducing amount of the partial benzodiazepine agonist.
  • the cognitive impairment associated with Down Syndrome and mental retardation may be the result of an imbalance in GABA A functioning, it is considered that a combination of two or more benzodiazepine receptor antagonists, two or more partial benzodiazepine agonists or of at least one benzodiazepine receptor antagonist and at least one partial benzodiazepine agonist may provide an optimal balance of GABA A antagonism and thus optimized improvement in memory, learning or both along.
  • the present invention provides a method of treating a patient suffering from cognitive impairment, such as a Down Syndrome patient or a patient suffering from mental retardation, comprising administering to the patient an effective amount of an active pharmaceutical ingredient according to the invention.
  • active pharmaceutical ingredient is described in more detail above.
  • an “effective amount” of the active pharmaceutical ingredient is an amount of the active pharmaceutical ingredient that provides temporary relief of one or more impairments of cognition.
  • an effective amount of an active pharmaceutical ingredient is expected to provide relief of impaired memory, impaired learning capacity or both.
  • the relief provided is considered temporary, the person skilled in the art will recognize that even a temporary improvement in learning capacity can have a long term beneficial effect on long-term learning, as learning tends to be cumulative over time.
  • the use of the qualifier "temporary" is not intended to exclude potential long-term improvements in cumulative learning.
  • the invention provides a method of treating cognitive impairment in a patient, comprising administering an effective amount of an active pharmaceutical ingredient comprising at least one benzodiazepine receptor antagonist, at least one partial benzodiazepine agonist, or both.
  • the amount of active pharmaceutical ingredient administered to the patient, while being effective to enhance cognition is a sub-seizure inducing amount.
  • the amount of active pharmaceutical ingredient administered to the patient is sufficient to enhance memory, learning or both, but is not sufficient to induce seizure.
  • the effective amount of flumazenil will be about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg per dose, administered orally, buccally or sublingually 1 to 4 times per day. In some preferred embodiments, the effective amount of bretazenil will be about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg per dose, administered orally, buccally or sublingually 1 to 4 times per day.
  • Example 1 The Effect of Flumazenil on Ts65Dn Mice
  • Ts65Dn mice The effect of a benzodiazepine receptor antagonist, flumazenil, on a murine model of Down Syndrome is investigated using Ts65Dn mice.
  • the validity of the Ts65Dn mouse as a model of the cognitive impairments associated with Down Syndrome is established by Fernandez et al., supra.
  • a 4-week longitudinal crossover study is carried out following the method outlined by Fernandez et al., supra. Wild-type and Ts65Dn mice (3-4 months of age) are randomly assigned to groups receiving daily i.p. injections of saline or flumazenil (1.0 mg/kg), and are submitted to four weekly repetitions of object recognition testing, in which the animals are serially presented with four different object sets.
  • wild-type and Ts65Dn mice that have been receiving saline are randomly segregated into groups that either continue to receive daily saline injections or begin to receive daily injections of flumazenil.
  • wild-type and Ts65Dn mice that have been chronically administered flumazenil in the first 2 weeks of testing are switched onto a saline regimen.
  • bilobalide i.p. 5.0 mg/kg
  • Bilobalide is a picrotoxin-like compound that may safely be administered for the whole 4-week experiment.
  • Ts65Dn mice treated with flumazenil during the first or second 2 week period have normalized object recognition performance as do those treated with bilobalide throughout the study.
  • Flumazenil may also be tested for its effects on declarative memory in the novel object recognition test and in a modified spontaneous alternation task.
  • Wild-type and Ts65Dn mice may be administered flumazenil (3 mg/kg in milk via voluntary oral feeding or 1 mg/kg i.p.).
  • the wild-type and Ts65Dn mice are administered from 5 to 30 doses of milk or milk-flumazenil (or saline or flumazenil solution i.p.).
  • the mice are then subjected to two repetitions of novel object recognition testing or three daily T-maze sessions at the tail end of the treatment regimen.
  • flumazenil-treated Ts65Dn mice will show long-term improvement in novel object recognition testing (up to at least 2 months after treatment) when treated with flumazenil for at least about 15 days.
  • LTP long- term potentiation
  • Example 2 The Effect of Bretazenil on Ts65Dn Mice
  • the effect of a benzodiazepine receptor antagonist, bretazenil, on a murine model of Down Syndrome is investigated using Ts65Dn mice.
  • the validity of the Ts65Dn mouse as a model of the cognitive impairments associated with Down Syndrome is established by Fernandez et al., supra.
  • a 4-week longitudinal crossover study is carried out following the method outlined by Fernandez et al., supra. Wild-type and Ts65Dn mice (3-4 months of age) are randomly assigned to groups receiving daily i.p.
  • Ts65Dn and wild-type mice are tested for novel object recognition.
  • Ts65Dn mice treated with bretazenil during the first or second 2 week period have normalized object recognition performance as do those treated with bilobalide throughout the study.
  • Bretazenil may also be tested for its effects on declarative memory in the novel object recognition test and in a modified spontaneous alternation task.
  • Wild-type and Ts65Dn mice may be administered bretazenil (3 mg/kg in milk via voluntary oral feeding or 1 mg/kg i.p.).
  • the wild-type and Ts65Dn mice are administered from 5 to 30 doses of milk or milk-flumazenil (or saline or fluniazenil solution i.p.).
  • the mice are then subjected to two repetitions of novel object recognition testing or three daily T-maze sessions at the tail end of the treatment regimen.
  • LTP long- term potentiation
  • the foregoing experiment may be repeated with one or more other benzodiazepine receptor antagonists and/or partial benzodiazepine agonists.
  • Example 3 Effect of Flumazenil and Bretazenil on Cognition in Down Syndrome Patients
  • the drugs administered are flumazenil (5 and 20 mg), bretazenil (5 and 20 mg) or placebo.
  • Subjects are randomly assigned to treatments according to a Williams Square design (Higgitt, supra (citing Williams, "Experimental designs balanced for the estimation of residual effects of treatments, Aust. J. Sci. Res. 2: 149-168 (1949))). Each subject receives a different sequence of four treatments balanced for carry-over effects and separated by at least 1 week of wash-out period.
  • ⁇ At each treatment session, subjects are tested before treatment and at time points 30, 60, 90, 120, 150 and 180 min. after drug administration on a set of psychophysiological measures. At pretest, 60, 120 and 180 min., paper and pencil performance measures and subjective ratings are administered.
  • Psychophysiological indices to be measured include: EEG, skin conductance, finger tremor, critical flicker fusion threshold, blood pressure and pulse rate, key tapping rate, and reaction time.
  • Paper and pencil performance measures include: A cancellation task, digit symbol substitution and a symbol copying test. Self ratings include mood ratings, and a bodily symptom scale.
  • EEG and evoked responses These are recorded during the same EEG recording procedure. Recordings are made from bipolar electrodes attached to the temporal and vertex sites (C 3 . and T3 in the 10-20 system). After amplification, the EEG is fed into four parallel band-pass filters with respective upper and lower frequencies set as follows: “delta” (2.4-4.0 Hz), “theta” (4.0-7.5 Hz), “alpha” (7.5-13.5 Hz) and "beta” (13.5-26.0 Hz).
  • Each filter output is sampled 32 times for 5-s periods while the subject is instructed to respond to a series of clicks presented at intervals varying from 8 to 12 s.
  • the output is rectified and averaged to yield the mean rectified voltage in each of the four wavebands.
  • the four values are summed and each is expressed as a percentage of the total.
  • the averaged evoked responses are obtained from the 500 ms epoch of the EEG following each of the 32 click stimuli.
  • the averaged response is displayed on an oscilloscope screen and the four peaks (Pl, the first positive wave in the 30-60 ms latency range, Nl, the first negative wave with a latency of 100-160 ms and N2, the second negative wave with a latency of 130-200 mg) are identified semi-automatically.
  • the latency at each peak and peak-to-peak amplitudes are computed and recorded automatically. Reductions in amplitude and increases in latency are indicators of reduced responsiveness to stimuli and are frequently correlated with subjective decreases in alertness. Conversely, increases in amplitude and/or reductions in latency are objective indicators of increased responsiveness to stimuli.
  • Skin conductance, blood pressure and pulse rate can be measured by the method of Higgitt et al., supra. See especially page 396, which is incorporated herein by reference in its entirety.
  • Finger tremor is measured using an accelerometer as discussed by Higgitt et al., supra. An accelerometer is taped to the dorsal surface of the middle finger of the left hand just proximal to the nail bed. The hand is held out with wrist extended and lower arm supported by the arm of the chair. The signal is amplified and 16 5-s samples are frequency analyzed on line using fast Fourier transformation.
  • Critical flicker fusion threshold is measured using a red LED at the end of a 20 cm black tube according to the method of Higgitt et al, supra. Each subject view the stimulus using his or her dominant eye. The duration of the on-off cycle is changed in 0.5 Hz steps each second. Six alternating ascending and descending trials are administered commencing at 20 and 50 Hz, respectively. The mean of the six limit values is used as the estimate of the threshold. [0078] Key tapping rate is measured per the method of Higgitt et al., supra. The subject is instructed to tap a one inch diameter key as fast as possible for 60 s. The mean inter-tap interval is calculated as a measure of motor speed.
  • Auditory reaction time is measured to 32 clicks of moderate intensity per Higgitt et al., supra. The mean reciprocal value is calculated.
  • Paper-and-pencil performance measures including a cancellation task, a digit symbol substitution test and a symbol copying test are performed essentially as described by Higgitt et al., supra.
  • the cancellation task subjects are instructed to cross out all the 4's in a block of numbers containing 40 target items. Time to complete the task and number of errors are recorded.
  • the digit symbol substitution test (DSST) is a sub-test of the Wechsler Adult Intelligence Scale (WAIS), which assesses coding skills and involves the substitution of symbols for numbers. The task is presented as in the WAIS manual and the measure is the number of correct codings in a 90-s period.
  • the symbol copying test measures the motor component of the DSST as the subject is instructed to copy the same symbols as are used in the DSST.
  • the score is the number of items correctly copied in a 90-s period. Sixteen equivalent forms of the above three tests are used, one for each time of testing, to minimize practice effects.
  • Additional tests of cognitive function, such as memory and learning ability, may also be used.
  • Self ratings of patient mood and bodily symptoms are performed essentially per Higgitt et al., supra.

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Abstract

L'invention concerne des compositions pharmaceutiques et des méthodes pour traiter le syndrome de Down et/ou un retard mental. Ces compositions pharmaceutiques comprennent un ou plusieurs antagonistes des récepteurs des benzodiazépines, tels que le flumazénil.
PCT/US2008/060133 2007-04-11 2008-04-11 Traitement du syndrome de down au moyen d'antagonistes des récepteurs des benzodiazépines Ceased WO2008128116A1 (fr)

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EP08745691A EP2146576A4 (fr) 2007-04-11 2008-04-11 Traitement du syndrome de down au moyen d'antagonistes des récepteurs des benzodiazépines
CA002683754A CA2683754A1 (fr) 2007-04-11 2008-04-11 Traitement du syndrome de down au moyen d'antagonistes des recepteurs des benzodiazepines
AU2008240148A AU2008240148B2 (en) 2007-04-11 2008-04-11 Treatment of down syndrome with benzodiazepine receptor antagonists
JP2010503256A JP2010523716A (ja) 2007-04-11 2008-04-11 ベンゾジアゼピン受容体拮抗薬を用いるダウン症候群の治療
US12/427,430 US20090270373A1 (en) 2008-04-11 2009-04-21 Treatment of down syndrom with benzodiazepine receptor antagonists

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US9585893B2 (en) 2011-02-23 2017-03-07 Coeruleus Ltd. Flumazenil complexes, compositions comprising same and uses thereof

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US20220354807A1 (en) * 2019-09-30 2022-11-10 Xiamen University Use of valeric acid derivative in treatment of down's syndrome

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US20070078083A1 (en) * 2005-09-07 2007-04-05 Braincells, Inc. MODULATION OF NEUORGENESIS BY HDac INHIBITION

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US20050038043A1 (en) * 2003-07-25 2005-02-17 Neurogen Corporation, A Corporation Of The State Of Delaware Imidazo-pyrimidines and triazolo-pyrimidines: benzodiazepine receptor ligands
US20070078083A1 (en) * 2005-09-07 2007-04-05 Braincells, Inc. MODULATION OF NEUORGENESIS BY HDac INHIBITION

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
US9585893B2 (en) 2011-02-23 2017-03-07 Coeruleus Ltd. Flumazenil complexes, compositions comprising same and uses thereof

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JP2010523716A (ja) 2010-07-15
CA2683754A1 (fr) 2008-10-23

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