Classifications

• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
  • A61K31/355—Tocopherols, e.g. vitamin E
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/67—Vitamins
  • A61K8/678—Tocopherol, i.e. vitamin E
• • 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
  • A61K9/0043—Nose
• • 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
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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

Definitions

• This application relates to the nasal administration of benzodiazepine drugs and combinations thereof
• the benzodiazepine family consists of drugs such as diazepam, lorazepam, and medazepam
• the drugs in this family have been observed as possessing sedative, tranquilizing and muscle relaxing properties They are frequently classified as an anxiolytic and skeletal muscle relaxants They are thought to be useful in preventing, treating, or ameliorating the symptoms of anxiety, insomnia, agitation, seizures (such as those caused by epilepsy), muscle S spasms and rigidity (which can be caused by tetanus), the symptoms of drug withdrawal associated with the continuous abuse of central nervous system depressants, and exposure to nerve agents [004] Benzodiazepines are thought to act by binding to the GABAA receptor of a neuron, possibly causing the receptor to change shape and making it more accessible to gama-aminobuty ⁇ c acid (GABA) 0
• GABA is an inhibitory neurotransmitter that, when bound to
• Intravenous administration perhaps provides a faster route of administration-
• intravenous administration is generally limited to trained health care professionals in tightly controlled clinical settings Additionally, sterility must be maintained Furthermore, administering any drug intravenously can be painful and is likely unpractical for patients suffering from a phobia of needles
• Suppository compositions of benzodiazepine drugs can have a rapid onset of action
• the inconvenience of suppositories is an obvious impediment to their being administered by anyone outside a very small group of the patient's intimate acquaintances and the patient's professional medical caretakers
• the pharmaceutical composition for nasal administration comprises a benzodiazepine drug, one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, in an amount from about 30% to about 95% (w/w), and one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w), preferably about 10% to about 70% (w/w) in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of the patient
• the benzodiazepine drug is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, m an amount from about 30% to about 95% (w/w), and the one or more alcohols or glycols, or any combinations thereof, m an amount from about 5% to about 70% (w/w), preferably about 10% to about 70% (w/w)
• the benzodiazepine drug is dissolved in a benzodiazepine drug, one or more natural or
• the benzodiazepine drug is selected from the group consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically-acceptable salts thereof, and any combinations thereof
• the benzodiazepine drug is diazepam, or a pharmaceutically-acceptable salt thereof
• the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or combinations thereof.
• the one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of: ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ - tocotrienol, ⁇ - tocotrienol, ⁇ - tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof.
• a synthetic tocopherol can include Vitamin E TPGS (Vitamin E polyethylene glycol succinate).
• synthetic tocopherols exclude tocopherols covalently bonded or linked (e.g. through a diacid linking group) to a glycol polymer, such as polyethylene glycol).
• a glycol polymer such as polyethylene glycol
• the compositions described herein exclude Vitamin E TPGS.
• one or more alcohols are selected from the group consisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, or any combinations thereof.
• the one or more glycols are selected from the group consisting of: ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof.
• the glycols exclude glycol polymers.
• the glycols exclude glycol polymers having an average molecular weight of greater than 200.
• the glycols exclude polyethylene glycol having an average molecular weight of greater than about 200.
• the benzodiazepine drug is present in the carrier system in a concentration from about 1 mg/mL to about 600 mg/mL. In some embodiments, the benzodiazepine drug is present in a carrier system in a concentration from about 10 mg/mL to about 250 mg/mL. In some embodiments, the benzodiazepine is present in a carrier system in a concentration from about 20 mg/mL to about SO mg/mL.
• the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 45% to about 85% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 60% to about 75% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount of about 70% (w/w). [016] In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w).
• the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 15% to about 55% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount of about 30% (w/w). [017] In some embodiments, the composition comprises at least one additional ingredient selected from the group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents
• the composition composes one or more additional excipients, such as one or more parabens, one or more povidones, and/or one or more alkyl glycosides [019]
• the mvention also discloses a method of treating a patient with a disorder that may be treatable with a benzodiazepine drug
• the patient is a human.
• the method comprises administering to one or more nasal mucosal membranes of a patient a pharmaceutical composition for nasal administration comprising a benzodiazepine drug, one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, in an amount from about 30% to about 95% (w/w), and one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70%, preferably about 10% to about 70% (w/w)
• the benzodiazepine is dissolved m the one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, in an amount from about 30% to about 95% (w/w), and the one or more alcohols or glycols, or any combinations thereof, m an amount ftom about 5% to about 70%, preferably about 10% to about 70% (w/w)
• the benzodiazepine drug is dissolved in a earner system
• the benzodiazepine drug is dissolved in a earner
• the one or more natural or synthetic tocopherols or tocotnenols are selected from the group consisting of ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ - tocotnenol, ⁇ - tocotnenol, ⁇ - tocot ⁇ enol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof
• the one or more alcohols are selected from the group consisting of ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, and any combinations thereof
• the one or more glycols are selected from the group consisting of ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof
• the alcohol or glycol is free of water (dehydrated, USP)
• the alcohol is ethanol (dehydrated, USP)
• the benzodiazepine drug is present in the cai ⁇ er system in a concentration from about 1 mg/mL to about 600 mg/mL
• the benzodiazepine drug is present in the earner system in a concentration of from about 10 mg/mL to about 250 mg/mL
• the benzodiazepine drug is present in the cai ⁇ er system in a concentration from about 1 mg/mL to about 600 mg/mL
• the benzodiazepine drug is present
• the earner system comprises one or more natural or synthetic tocopherols or tocot ⁇ enols, or any combinations thereof, in an amount from about 45% to about 85% (w/w) In some embodiments, the earner system comprises one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, in an amount from about 60% to about 75% (w/w) In some embodiments, the earner system comprises one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, in an amount of about 70% (w/w) [025] In some embodiments, the earner system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 15% to about 55% (w/w) In some embodiments, the earner system compnses one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w) In some embodiments, the carrier system comprises one or more alcohols or glycols,
• the composition is in a pha ⁇ naceutically-acceptable spray formulation, and further comprising administering the composition to one or more nasal mucosal membranes of the patient
• the therapeutically effective amount is from about 1 mg to about 20 mg of the benzodiazepine
• the pharmaceutical composition is in a pharmaceutically-acceptable spray formulation having volume from about 10 ⁇ L to 200 ⁇ L
• the administration of the composition compnses spraying at least a portion of the therapeutically effective amount of the composition into at least one nostnl
• the administration of the composition begins at any time before or after onset of symptoms of a disorder which may be treatable with the composition.
• compositions of one or more benzodiazepine drugs are provided herein. Such pharmaceutical compositions are administered nasally.
• the pharmaceutical composition for nasal administration comprises a benzodiazepine drug; one or more natural or synthetic tocopherols or tocot ⁇ enols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w) in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of the patient.
• the benzodiazepine drug is dissolved in the one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w).
• the benzodiazepine drug is dissolved m a earner system.
• at least part of the benzodiazepine drug is in a form of microparticles, nanoparticles, or combinations thereof.
• the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
• the pharmaceutical composition for nasal administration comprises a benzodiazepine drug, one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w) in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of the patient
• the benzodiazepine drug is dissolved in the one or more natural or synthetic tocopherols or tocot ⁇ enols, or any combinations thereof, m an amount from about 30% to
• the benzodiazepine drug is dissolved in a carrier system
• at least part of the benzodiazepine drug is in a form of microparticles, nanoparticles, or combinations thereof
• the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof
• the benzodiazepine drug is selected from the group consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazeml, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceuttcally-acceptable salts thereof, and any combinations thereof
• the benzodiazepine drug is diazepam, or a pharmaceutically-acceptable salt thereof
• the benzodiazepine drug composes benzodiazepine microparticles, nanoparticles,
• the one or more natural or synthetic tocopherols or tocotnenols are selected from the group consisting of o-tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ - tocotnenol, ⁇ - tocotnenol, ⁇ - tocot ⁇ enol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof
• the carrier system includes one or more synthetic tocopherols having a polymer glycol covalently bonded or linked to a tocopherol core, such as Vitamin E TPGS, which is described in United States Patent No 6,193,985, which is incorporated herein by reference in its entirety In particular, it has been found that in some particulate suspensions of benzodiazepines, wherein the benzodiazepine is not dissolved in a tocopherol phase
• the earner system specifically excludes synthetic tocopherols having a polymer glycol covalently bonded or linked to a tocopherol core, such as Vitamin E TPGS, which is described in United States Patent No 6,193,985, which is incorporated herein by reference m its entirety [037]
• one or more alcohols are selected from the group consisting of ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, or any combinations thereof
• the alcohol is ethanol (dehydrated, USP)
• the one or more glycols are selected from the group consisting of ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof
• the glycol is propylene glycol USP
• a synthetic tocopherol can include Vitamin E TPGS (Vitamin E polyethylene glycol succinate
• the compositions described herein exclude Vitamin E TPGS [038]
• the benzodiazepine drug is present in the carrier system in a concentration from about 1 mg/mL to about 600 mg/mL
• the benzodiazepine S drug is present in a earner system in a concentration from about 10 mg/mL to about 250 mg/mL
• the benzodiazepine is present in a earner system m a concentration from about 20 mg/mL to about 50 mg/mL
• the earner system comprises one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, in an amount from about 45% to about 85%
• the earner system comprises one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, in an amount from about 60% to about 75% (w/w) In some embodiments, the earner system composes one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, in an amount of about 70% (w/w) In some embodiments, a synthetic tocopherol can mclude Vitamin E TPGS (Vitamin E polyethylene glycol
• synthetic tocopherols exclude tocopherols covalently bonded or linked (e g through a diacid linking group) to a glycol polymer, such as polyethylene glycol)
• a glycol polymer such as polyethylene glycol
• the compositions descnbed herein exclude Vitamin E TPGS [040]
• the earner system comprises one or more alcohols or glycols, or any combination thereof
• the earner system compnses one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w) Ih some embodiments, the earner system compnses one or more alcohols or glycols, or any combinations thereof, in an amount of about 30% (w/w) In some embodiments, the alcohol is ethanol or contains ethanol In some preferred embodiments, the glycols exclude glycol polymers In
• the glycols exclude glycol polymers having an average molecular weight of greater than 200 In some embodiments, the glycols exclude polyethylene glycol having an average molecular weight of greater than about 200
• the earner system compnses one or more alcohols or glycols, or any combinations thereof, m an amount from about 15% to about 55% (w/w) In some embodiments, the
• 35 earner system comprises one or more alcohols or glycols, or any combinations thereof, in an amount
• the carrier system comp ⁇ ses one or more alcohols or glycols, or any combinations thereof in an amount of about 30% (w/w) [042]
• the composition comprises at least one additional ingredient selected from the group consisting of active pharmaceutical ingredients, enhancers, excipients, and agents used to adjust the pH, buffer the composition, prevent degradation, and improve appearance, odor, or taste
• the compositions comprise at least one alkyl glycoside
• the at least one alkyl glycoside is one described in United States Patent No 5,661 ,130, which is incorporated by reference herein
• the composition comprises a benzodiazepine drug that is fully dissolved ui a solvent comprising a natural or synthetic tocopherol or tocot ⁇ enol, and an alcohol or glycol
• the composition comprises a benzodiazepine drug that is fully dissolved m a solvent comprising a natural or synthetic tocopherol or tocot ⁇ enol and an alcohol or glycol, wherein the solution is at least substantially free of water (In some embodiments, "substantially free of water” indicates that the solution contains less than about 1%, less than about 05%, less than about 025% or less than about 0 1% water )
• the composition consists essentially of a benzodiazepine drug that is fully dissolved m
• the composition comp ⁇ ses a benzodiazepine drug that is fully dissolved in a solvent compnsmg a natural or synthetic tocopherol or tocot ⁇ enol, and an alcohol or glycol
• a solvent compnsmg a natural or synthetic tocopherol or tocot ⁇ enol, and an alcohol or glycol
• the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof
• the composition comp ⁇ ses a benzodiazepine drug that is fully dissolved in a solvent compnsmg a natural or synthetic tocopherol or tocot ⁇ enol, and an alcohol or glycol
• the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof
• the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
• the composition consists essentially of a benzodiazepine drug that is fully dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides
• the composition consists essentially of a benzodiazepine drug that is fully dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides
• the composition consists essentially of a benzodiazepine drug that is fully dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols,
• the benzodiazepine drug isin a microparticulate or nanoparticulate form.
• the earner system is one in which the amount of at least one benzodiazepine present in the composition exceeds its solubility in the earner system.
• a earner system in such a composition includes water
• such a liquid earner system contains water and one or more excipients
• one or more excipients are dissolved or suspended m the earner system.
• at least one such excipient stabilizes the suspension of benzodiazepine particulates m the earner system.
• the earner system may contain varying concentrations of parabens (e g methylparaben, propylparaben, etc ), and/or varying amounts of one or more surfactants, such as povidone (polyvinyl pyrrohdinone)
• benzodiazepine particulate suspensions specifically exclude one or more polymenc glycols, such as polyethylene glycol
• benzodiazepine particulate suspensions specifically exclude one or more polymenc glycols having a molecular weight greater than about 200 g/mol
• the composition comp ⁇ ses a benzodiazepine drug in a form including benzodiazepine
• the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system comprising Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, povidone and water.
• the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system comprising Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone and water.
• the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting essentially of a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, one or more surfactants and water.
• the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system consisting essentially of Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, povidone and water.
• the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting essentially of Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone and water.
• the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting of a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, one or more surfactants and water.
• the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system consisting of Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, povidone and water.
• the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting of Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone and water.
• the composition contains a benzodiazepine drug that at least partially in a particulate form suspended in a carrier system containing a natural or synthetic tocopherol or tocotrienol, one or more alcohols or glycols, and an alkyl glycoside.
• substantially all the benzodiazepine drug is in a particulate form.
• the carrier system is one in which the amount of at least one benzodiazepine present in the composition exceeds its solubility in the carrier system.
• a carrier system m such a composition includes water.
• such a liquid carrier system contains water and one or more excipients.
• one or more excipients are dissolved or suspended in the carrier system.
• at least one such excipient stabilizes the suspension of benzodiazepine particulates in
• the earner system may contain varying concentrations of parabens (e g methylparaben, propylparaben, etc ), and/or varying amounts of one or more surfactants, such as povidone (polyvinyl pyrrolidinone)
• benzodiazepine particulate suspensions specifically exclude one or more polymeric glycols, such as polyethylene glycol
• benzodiazepine particulate suspensions specifically exclude one or more polymeric glycols having a molecular weight greater than about 200 g/mol
• the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles and/or naiioparticles suspended in a earner system compnsmg a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, an alkyglycoside
• the invention also discloses a method of treating a patient with a disorder that may be treatable with a benzodiazepine drug
• the patient is a human
• the method comprises administering to one or more nasal mucosal membranes of a patient a pharmaceutical composition for nasal administration comprising a benzodiazepine drug, one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, in an amount from about 30% to about 95% (w/w), and one or more alcohols or glycols, or any combinations thereof, m an amount from about 5% to about 70% (w/w), preferably about 10% to about 70% (w/w)
• the benzodiazepine is dissolved in the one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, in an amount from about 30% to about 95% (w/w), and the one or more alcohols or
• the benzodiazepine drug is selected from the group consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepatn, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, or any pharmaceutically-acceptable salts thereof, and any combinations thereof
• the benzodiazepine drug is diazepam, or a pharmaceutically-acceptable salt thereof
• the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or combinations thereof.
• the one or more natural or synthetic tocopherols or tocotnenols are selected from the group consisting of ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ - tocotnenol, ⁇ - tocotnenol, ⁇ - tocot ⁇ enol, ⁇ - tocotaenol, tocophersolan, any isomers thereof, any esters thereof, any analogs or de ⁇ vatives thereof, and any combinations thereof
• a synthetic tocopherol may include a tocopherol that has been modified to include a hydrophihc group, such as a polyethylene glycol group, which may be directly covalently bonded to the tocopherol or may be linked to the tocopherol through a covalent linking group, such as a diacid
• An exemplary synthetic tocopherol of this type is Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS), although the person skilled
• the one or more glycols are selected from the group consisting of ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof
• one or more glycols specifically excludes polymeric glycols, such as polyethylene glycol
• one or more glycols 5 specifically excludes a polymeric glycol having a molecular weight of greater than about 200 g/mol [052]
• the benzodiazepine drug is present m the earner system m a concentration from about 1 mg/mL to about 600 mg/mL
• the benzodiazepine drug is present in the earner system in a concentration of from about 10 mg/mL to about 250 mg/mL
• the benzodiazepine drug is present in the earner system in a concentration of
• the carrier system comprises one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, m an amount from about 45% to about 85% (w/w)
• the earner system compnses one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, m an amount from about 60% to about 75%
• the earner system compnses one or more natural or synthetic tocopherols or tocotnenols, or any combinations thereof, in an amount of about 70% (w/w)
• the compositions may include a tocopherol, especially a synthetic tocopherol having a hydrophilic group covalently linked to a tocopherol In other embodiments, especially where a solution of
• the tocopherol is substantially or completely free of Vitamin E TPGS
• the earner system compnses one or more alcohols or glycols, or any combinations thereof m an amount from about 10% to about 55% (w/w) In some embodiments, the earner system compnses one or more alcohols or glycols, or any combinations thereof, in an amount
• the earner system compnses one or more alcohols or glycols, or any combinations thereof, in an amount from about 30% (w/w) In some embodiments the amount of one or more alcohols or glycols in the earner system is about 10% to about 55%, about 10% to about 40%, about 10% to about 35%, about 12% to about 55%, about 12% to about 40%, about 12% to about 35%, about 15% to about 55%, about 15% to about 40%, about
• the composition comprises at least one additional ingredient selected from the group consisting of active pharmaceutical ingredients, enhancers, excipients, and agents
• a composition compnses at least one penetration enhancer in addition to a benzodiazepine drug, a natural or synthetic tocopherol or tocotnenol, and an alcohol or glycol
• the penetration enhancer is an alkyl glycoside
• the alkyl glycoside refers to any sugar joined to any hydrophobic alkyl, as desc ⁇ bed in United States patent number 5,661,130, which is incorporated herein by reference in its entirety
• the hydrophobic alkyl can be any suitable length, for example about 9 to about 24 carbons in length, especially about 10 to about 14 carbons in length
• the hydrophobic alkyl can be branched and/or partially or wholly unsaturated
• the alkyl may be joined to the saccharide core for example through a carbonyl group, whereby an ester group may be formed
• a suitable alkyl glycoside will have the characteristics of being nontoxic, nomonic, and capable of increasing the absorption
• Exemplary saccharides that may be covalently joined to an alkyl according to the present invention include glucose, maltose, maltotriose, maltotetrose, sucrose and trehalose
• Exemplary alkyl glycosides that may be employed include octyl-, nonyl-, decyl-, undecyl-, dodecyl, tndecyl, tetradecyl, pentadecyl, octadecyl ⁇ - or ⁇ -D-maltoside, -glucoside or sucroside
• the preferred glycosides include maltose, sucrose or glucose linked by glycosidic linkage to an alkyl chain of 9, 10, 12, 14, 16, 18 or 20 carbon atoms Where present, the amount of alkyl glycoside in the composition is sufficient to enhance the absorption of a benzodiazepine drug administered by the intranasal route hi some embodiments, the amount of alkyl glycoside in the composition is selected so
• the amount of alkyl glycoside in the composition isin a range of about 0 01 % (w/v) to about 1 % (w/v) In some embodiments, the amount of alkyl glycoside in the composition is in a range of about 0 05 % (w/v) to about 05% (w/v), or about 0 125 % (w/v) to about 05% (w/v)
• the composition is in a pharmaceutically-acceptable spray formulation, and further comprising administering the composition to one or more nasal mucosal membranes of the patient
• the therapeutically effective amount is from about 1 mg to about 20 mg of the benzodiazepine
• the pharmaceutical composition is in a pharmaceutically-acceptable spray formulation having volume from about 10 ⁇ L to 200 ⁇ L
• the administration of the composition compnses spraying at least a portion of the therapeutically effective amount of the composition into at least one nostril
• the administration of the composition compnses spraying at least a portion of the therapeutically effective amount of the composition into each nostnl
• the administration of the composition compnses spraying a first quantity of the composition into the first nostnl, spraying a second quantity of the composition mto a second nostnl, and optionally after a pre- selected time delay, spraying a third quantity of the composition into the first nostn
• -15- WSGRDocketNo 35401 716601 embodiments further comprise, optionally after a pre-selected time delay, administering at least a fourth quantity of the composition to the second nostril
• the administration of the composition begins at any time before or after onset of symptoms of a disorder which may be treatable with the composition.
• therapeutically effective amount includes an amount sufficient to provide a specific therapeutic response for which the drug is administered to a patient in need of particular treatment
• therapeutically effective amount of drug will depend upon the patient, the indication and the particular drug administered
• the modifier "about” is intended to have its regularly recognized meaning of approximately In some embodiments, the term may be more precisely interpreted as meaning within a particular percentage of the modified value, e g "about” may m some embodiments mean ⁇ 20%, ⁇ 10%, ⁇ 5%, ⁇ 2%, or ⁇ 1% or less
• the phrase “analogs or derivatives” includes molecules that differ from one another molecule due to one or more atoms or functional groups having been replaced with a different atom or functional group This may result m molecules with similar chemical formulas but different chemical and/or biological properties
• the term, "isomer” mcludes molecules with identical chemical formulas, but between which the arrangement of the molecules may vary These varying arrangements may result in molecules with identical chemical formulas but different chemical properties
• propanol has the chemical formula C 3 H 7 OH It may be found as propan-1 -ol, wherein the -OH
• seizure mcludes commonly recognized types of seizures, mcludmg absence seizures, myoclonic seizures, clonic seizures, tome seizures, tomc-clomc seizures, and atonic seizures Often seizures, particularly severe tome or tomc-clomc seizures, will be presaged by one or more aura that will be familiar to the patient or those familiar with the patient Each patient will generally experience a different type of aura, which is unique to the patient, however auras may be classified as audible, visual, olfactory or tactile sensations that usually, or at least often, precedes a patient's experiencing a seizure (Not all patients who suffer seizures experience aura, however aura
• prevention refers to a forestalling, including temporary forestalling, of the onset of a disorder In the case of seizures, this can occur either with or without the benefit of a warning aura
• treatment refers to a reduction in the intensity and/or duration of a disorder, or similar effects The term also encompasses the side-effects of such a “treatment " [067] As used herein, unless otherwise qualified, "a” and “an” can mean one or more [068] As used herein, the term “composing” m all its variants, is a transitional phrase used in a claim to indicate that the invention includes or contains, but is not limited to, the specifically recited claim elements
• benzodiazepine drug includes any therapeutically effective benzodiazepine compound, or pharmaceutically acceptable salt, or combinations thereof
• benzodiazepine comprises a member of the group consisting of alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts and combinations thereof
• additional benzodiazepine compounds that have heretofore been considered to have marginal or little therapeutic benefit, either because of low bioavailability, poor pharmacokinetic properties or poor pharmacodynamic properties, may find use through the present invention, which can provide for improved bioavailability of benzodiazepine drags, delivery of higher concentrations of benzodiazepine drags via the nasal route, faster attainment of therapeutic levels of benzodiazepine in the blood plasma,
• -17- WSGR Docket No 35401 716601 drags to be administered to one or more mucosal membranes, including to nasal mucosal membranes. This can allow one to administer the drug without hospitalization or unnecessary discomfort. Additionally, in some embodiments of the present invention, such as nasal administration, the digestive system largely may be bypassed. This latter improvement can yield improved bioavailability, faster attainment of therapeutic levels of benzodiazepine in the blood plasma, avoidance of the liver portal vein, and/or concomitant avoidance of first pass effects. (074] Nasal administration of the composition can result in faster presentation of the one or more benzodiazepine drugs to the brain due to the close proximity of the membranes and the brain.
• a seizing patient for example, suffers from rigid muscles and uncontrollable movement. This can make oral and/or intravenous administration difficult or inconvenient. However, the nasal passageways remain open and easily accessible, and therefore is a useful route of administration for of the present invention.
• the pharmaceutical composition is used to treat a patient suffering from a disorder that is amenable to treatment or prevention with an effective amount of the one or more benzodiazepine drugs.
• disorders can include: insomnia, anxiety, seizures, muscle spasms and rigidity, and the symptoms of drug withdrawal.
• the one or more benzodiazepine drugs are used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
• Alprazolam (8-chloro-6-phenyl-l -methyl-4H-l ,2,4 ⁇ triazolo[4,3-a][l ,4]benzodiazepine).
• Alprazolam is a benzodiazepine drug having sedative, tranquilizing and muscle relaxing properties. It is classified as an anxiolytic. Alprazolam has also been shown to be useful in the treatment of panic disorder.
• the dosage of alprazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.5 to about 4, preferably about 1 to about 2 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6
• Alprazolam may be manufactured using the process disclosed m Umted States patent 3,987,052, which is incorporated herein by reference in its entirety
• alprazolam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects
• alprazolam is used alone or m combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure
• Alprazolam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure Even where protection against seizure is not absolute, administration of alprazolam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure In some embodiments, administration of alprazolam may prevent occurrence of seizure In some embodiments, especially where the patient is prone to experiencing serial seizures or status epilepticus, administration of alprazolam may aid m interrupting the seizure cycle and may thus prevent the re-occurrence of seizure Ih addition to the benzodiazepines (such as diazepam), other anti-convul
• the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura.
• intra- aural administration of benzodiazepine drug for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure.
• prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
• Diazepam is a benzodiazepine drug having sedative, tranquilizing and muscle relaxing properties. It is classified as an anxiolytic and skeletal muscle relaxant. It possesses anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant and amnesic properties.
• the dosage of diazepam may vary by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 20, preferably about 2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Diazepam may be manufactured using the process disclosed in one of United States patents 3,371,085; 3,109,843; 3,136,815 or 3,102,116, each of which is incorporated herein by reference in its entirety.
• diazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
• diazepam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
• Diazepam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure.
• administration of diazepam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of diazepam may prevent occurrence of seizure. In some embodiments, especially where the patient is prone to experiencing serial seizures or status epilepticus, administration of diazepam may aid in interrupting
• Diazepam may also be administered by another person (eg an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure
• another person eg an acquaintance or associate, a family member or a health care professional
• one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally
• beneficial therapeutic effects that may be imparted by acute dosmg of benzodiazepine anticonvulsants, such as nasal dosing are reduction m the seventy of the seizure (e g general relaxation of the muscles, reduction m seizure-induced anxiety experienced by the patient and a general impartation of a feehng of well-being to the patient), reduction in the duration of the seizure, reduction in the probability that the patient will experience a repeat seizure, an increase in the interval between the current seizure and the next seizure
• the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura
• such lntra- aural administration of benzodiazepine drug for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure
• prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura
• Flurazepam is a benzodiazepine drag having sedative (especially soporific and hypnotic), anxiolytic, anticonvulsant and muscle relaxing properties. It is classified as an sedative, hypnotic. Flurazepam has been shown to be useful in the treatment of insomnia.
• the dosage of flurazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 5 to 40, preferably about 20 to about 35 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
• Flurazepam may be manufactured using the process disclosed in United States patent 3,567,710 or 3,299,053, each of which is incorporated herein by reference in its entirety. [091] Ih some embodiments, flurazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
• flurazepam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
• Flurazepam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of flurazepam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of flurazepam may prevent occurrence of seizure.
• flurazepam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure.
• other anti-convulsant drugs may be combined with flurazepam to provide a synergistic anticonvulsant effect.
• Flurazepam may also be administered by another person (e g an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure
• another person e g an acquaintance or associate, a family member or a health care professional
• Flurazepam may also be administered by another person (e g an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure
• another person e g an acquaintance or associate, a family member or a health care professional
• Flurazepam may also be administered by another person (e g an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure
• the beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing are reduction m the seventy of the seizure (e g general relaxation of the muscles, reduction in seizu
• the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura
• intra- aural administration of benzodiazepine drug for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure
• prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura
• Lorazepam is a benzodiazepine drug having sedative, tranquilizing, anticonvulsant, amnesic and muscle relaxing properties It is classified as an anxiolytic Lorazepam has also been shown to be useful in the treatment of nausea
• Lorazepam may be manufactured using the process disclosed in Umted States patent 3,296,249, which is incorporated herein by reference in its entirety [097]
• lorazepam is used alone or m combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations
• lorazepam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure Lorazepam may be administered by the patient or other person (such as a healthcare professional) while the patient is m a non-seizing state to protect against seizure Even where protection against seizure is not absolute, administration of lorazepam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure In some embodiments, administration of lorazepam may prevent occurrence of seizure In some embodiments, especially where the patient is prone to experiencing serial seizures or status epilepticus, administration of lorazepam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure In addition to the benzodiazepines (such as diazepines (such as diazep
• Lorazepam may also be administered by another person (e g an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure
• another person e g an acquaintance or associate, a family member or a health care professional
• the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally
• beneficial therapeutic effects lhat may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing, are reduction in the seventy of the seizure (e g general relaxation of the muscles, reduction in seizure-induced anxiety experienced by the patient and a general impartation of a feelmg of well-being to the patient), reduction in the duration of the seizure, reduction in the probability that the patient will expenence a repeat seizure, an increase in the interval between the current seizure and the next seizure
• the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura
• benzodiazepine drug for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure
• prevention of seizure refers to a temporary forestalling
• Medazepam is a benzodiazepine drug having sedative, tranquilizing, anticonvulsant, amnesic and muscle relaxing properties It is classified as an anxiolytic Medazepam has also been shown to be useful m the treatment of nausea
• the dosage of medazepam vanes by indication it is expected that a therapeutic dose will be in the range of about 0 1 to about 10, preferably about 02 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day Medazepam may be manufactured using the process disclosed in United States patent 3,243,427, which is incorporated herein by reference in its entirety
• medazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects
• Ih some embodiments, medazepam is used alone or in combination with other
• administering may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure
• administration of medazepam may prevent occurrence of seizure
• administration of medazepam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure
• other anticonvulsant drugs may be combined with medazepam to provide a synergistic anticonvulsant effect
• Medazepam may also be administered by another person (e g an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure
• Mexazolam is a benzodiazepine drug having sedative, tranquilizing, anticonvulsant, amnesic and muscle relaxing properties. It is classified as an anxiolytic. Mexazolam has also been shown to be useful in the treatment of nausea. The dosage of mexazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Mexazolam may be manufactured using the process disclosed in United States patent 3,722,371, which is incorporated herein by reference in its entirety.
• mexazolam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
• mexazolam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
• Mexazolam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure.
• administration of mexazolam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure.
• administration of mexazolam may prevent occurrence of seizure.
• administration of mexazolam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure.
• other anticonvulsant drugs may be combined with mexazolam to provide a synergistic anticonvulsant effect.
• Mexazolam may also be administered by another person (e.g.
• one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally.
• beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing are: reduction in the severity of the seizure (e.g. general relaxation of the muscles, reduction in seizure-induced anxiety experienced by the patient and a
• the mexazolam formulations of the invention, and in particular nasal formulations provide fast onset of therapeutic benefit - in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about S minutes
• the mexazolam formulations of the invention, and in particular nasal formulations also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration [0112] Often seizures, particularly severe tonic or tonic-clomc seizures, will be presaged by one or more aura events that will be familiar to the patient or those familiar with the patient These auras are practically stu generis for each patient, but may be classified as audible, visual, olfactory
• Midazolam is a tricyclic benzodiazepine having anxiolytic, amnesic, hypnotic, anticonvulsant, skeletal muscle relaxant and sedative properties
• Midazolam is considered soluble in water at a pH lower than about 4, but is relatively insoluble in most aqueous solutions at neutral pH (e g about 6 to 8)
• aqueous nasal preparations of midazolam to have a pH above about 5 5, preferably above about 60, or above about 6 5 Ih some preferred embodiments, the pH is between about 6 and 9, between about 6 and 8 It is considered that preparations of midazolam are particularly suitable for nasal administration as the lipid-soluble (at approximately
• midazolam is rapidly absorbed across nasal mucosa, leading to efficient uptake of midazolam. It is further considered that midazolam may be formulated in a non-aqueous delivery vehicle, such as is known in the aerosol administration art, such as hydrofluorocarbon propellents, hydrocarbon propellents, etc [0115]
• the dosage of midazolam vanes by indication it is expected that a therapeutic dose will be m the range of about 0 1 to about 20, preferably about 0 2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day
• Midazolam may be manufactured using the process disclosed in one of United States patents 4,280,9 5 7 or 5,831,089, each of which is incorporated herein by reference m its entirety [0116]
• midazolam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvul
• midazolam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure
• Midazolam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-serang state to protect against seizure Even where protection against seizure is not absolute, administration of midazolam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure In some embodiments, administration of midazolam may prevent occurrence of seizure In some embodiments, especially where the patient is prone to experiencing serial seizures or status epilepticus, administration of midazolam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure In addition to the benzodiazepines (such as diazepam), other anb-convtils
• the midazolam formulations of the invention also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration [0119] Often seizures, particularly severe tonic or tonic-cloiuc seizures, will be presaged by one or more aura events that will be familiar to the patient or those familiar with the patient These auras are practically sui generis for each patient, but may be classified as audible, visual, olfactory or tactile sensations that usually, or typically, precedes a patient's experiencing a seizure
• the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura
• such lntra- aural administration of benzodiazepine drug for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure
• Temazepam is a benzodiazepine drug having sedative, tranquilizmg, anticonvulsant, amnesic and muscle relaxing properties It is classified as an anxiolytic Temazepam has also been shown to be useful in the treatment of nausea
• the dosage of temazepam vanes by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 50, preferably about 5 to about 30 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day
• Temazepam may be manufactured using the process disclosed in United States patent 3,340,253 or 3,374,225, each of which is incorporated herein by reference in its entirety
• temazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects
• temazepam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of
• Temazepam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure
• administration of temazepam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure
• administration of temazepam may prevent occurrence of seizure
• administration of temazepam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure
• other anticonvulsant drugs may be combined with temazepam to provide a synergistic anticonvulsant effect
• Temazepam may also be administered by another person (eg an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure
• another person eg an acquaintance or associate, a family member or a health care professional
• one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally
• beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing are reduction in the seventy of the seizure (e g general relaxation of the muscles, reduction m seizure-induced anxiety experienced by the patient and a general impartation of a feeling of well-being to the patient), reduction in the duration of the seizure, reduction m the probability that the patient will experience a repeat seizure, an increase in the interval between the current seizure and the next seizure
• the temazepam formulations of the invention and in particular
• the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura
• such lntra- aural administration of benzodiazepine drug for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure
• prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura
• Benzodiazepines have the generally basic structure of formula I
• R t is an optionally substituted alkyl or forms a ring with R 4
• R 2 is a halogen (e g Cl, Br)
• R 3 is optionally substituted aryl (e g 2-Chloro or 2- Fluorophenyl)
• R 5 is H or OH
• R 4 and Ri form an optionally substituted heterocyclic ring with the diazepam ring atoms to which they are respectively attached
• R 3 ' and R 6 together form a double bond or may be combined to form an optionally substituted heterocyclic ring along with the diazepam ring atoms to which they are respectively attached
• Such basic compounds may form acid addition salts with pharmaceutically acceptable acids, such as pharmaceutically acceptable mineral acids and pharmaceutically acceptable organic acids [0127]
• Pharmaceutically acceptable mineral acids include HCl, H 2 SO 4 , H 2 SO 3
• the invention provides nasal compositions composing one or more acidic pharmaceutically active ingredients It is considered well within the ordinary skill in the art to determine which of the compounds set for the above are acidic Such compounds may be prepared as base addition salts, e g by the addition of one or more mineral bases (e g NaOH, KOH, NaHCO 3 , Na 2 CO 3 , NH 3 ) or organic bases It is considered within the skill in the art to choose a pharmaceutically acceptable base [0129]
• Known benzodiazepine compounds have anxiolytic, anticonvulsant, sedative and/or skeletal muscle relaxant effect
• anticonvulsant includes treatment of seizures, protection against seizure, reduction or amelioration of the intensity of seizure, reduction or amelioration of the frequency of seizure, and/or prevention of the occurrence or re-occurrence of seizure
• treatment of seizure includes cessation of an ongoing seizure, reduction m the severity of an ongoing seizure, reduction in the
• Vitamin E is a class of fat soluble methylated phenols There are at least eight naturally- occurring compounds that comprise this class ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocot ⁇ enol, ⁇ - tocotnenol, ⁇ - tocot ⁇ enol, and ⁇ - tocotnenol, all of which may be used m the compositions and methods of the present invention There are multiple isomers of each of these compounds, all of which may be used in the compositions and methods of the present invention There are also multiple esters of each of these compounds, including tocophersolan, all of which may be used in the compositions and methods of the present invention. As used herein, Vitamin E refers to any of the natural or synthetic tocopherols, tocotnenols, any isomers thereof, any esters thereof, any analogs or derivatives thereof, or any combinations thereof
• Vitamin E is antioxidants There is also evidence that they can prevent, delay the onset of, or ameliorate the symptoms of heart disease, cancer, cataracts, macular degeneration, glaucoma, Alzheimer's, and Parkinson's disease
• Vitamin E can provide an effective earner for benzodiazepine drugs
• benzodiazepines are soluble, or partially soluble, in Vitamin E
• Vitamin E may be present as microparticles, nanoparticles, or any combination thereof
• use of Vitamin E can have the added benefit of either avoiding irritation of sensitive mucosal membranes and/or soothing irritated mucosal membranes
• Vitamin E is generally classified as hydrophobic, and when used as a earner may be limited to formulations as an emulsion
• emulsions can have several drawbacks For instance, they may be difficult to create and can be highly unstable Additionally, they can leave an oily film on the surface of the skin
• some embodiments of the present invention compose solutions of one or more benzodiazepine drugs in Vitamin E and one or more
• Lower alkyl alcohols are those with six or fewer carbon atoms Thus, any of ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, or any combinations thereof can be used [0135] Lower alkyl glycols are those with six or fewer carbon atoms Thus, any of ethylene glycol,
• a composition comprises at least one penetration enhancer in addition
• the penetration enhancer is at least one alkyl glycoside
• the alkyl glycoside refers to any sugar joined to any hydrophobic alkyl, as described in United States patent number 5,661,130, which is incorporated herein by reference in its entirety
• the hydrophobic alkyl can be any suitable length, for example about 9 to about 24 carbons in length, especially about
• the hydrophobic alkyl can be branched and/or partially or wholly unsaturated
• the alkyl may be joined to the saccharide core for example through a carbonyl group, whereby an ester group may be formed
• a suitable alkyl glycoside will have the characteristics of being nontoxic, nomonic, and capable of increasing the absorption of a benzodiazepine drug when it is administered intranasally as described herein
• alkyl glycosides that may be employed include octyl-, nonyl-,
• the preferred glycosides include maltose, sucrose or glucose linked by glycosidic linkage to an alkyl chain of 9, 10, 12, 14, 16, 18 or 20 carbon atoms
• alkylsacchande is dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and/or combinations of two or more thereof
• Alkyl glycosides that are particularly considered useful in embodiments of the invention include those marketed under the name Intravail ® by Aegis Therapeutics, LLC, San Diego,
• agents that modify the membrane fluidity and permeability are appropriate such as enamines (e.g. phenylalanine enamine of ethylacetoacetate), malonates (e.g. diethyleneoxymethylene nralonate), salicylates, bile salts and analogues and fusidates. Suitable concentrations are up to 20% w/v.
• the invention provides a pharmaceutical composition for nasal administration comprising: a benzodiazepine drug, one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); one or more alkyl glycosides; and one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w), in a pha ⁇ naceutically-acceptable formulation for administration to one or more nasal mucosal membranes of a patient.
• the alkyl glycoside is an Intravail ⁇ brand alkyl glycoside.
• the alkyl glycoside is dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and/or a combination of two or more thereof.
• the alkyl glycoside is dodecyl maltoside.
• the alkyl glycoside is tetradecyl maltoside.
• the alkyl glycoside is sucrose dodecanoate.
• the alkyl glycoside is sucrose monostearate.
• the alkyl glycoside is sucrose distearate.
• the alkyl glycoside is a combination of two or more of dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, or sucrose distearate.
• the invention provides a pharmaceutical composition for nasal administration comprising: a benzodiazepine drug, which benzodiazepine drug comprises microparticles, nanoparticles or both, one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); one or more alkyl glycosides; and one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w), in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of a patient.
• the alkyl glycoside is an Intravail 1 brand alkyl glycoside.
• the alkyl glycoside is dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and/or a combination of two or more thereof.
• the alkyl glycoside is dodecyl maltoside.
• the alkyl glycoside is tetradecyl maltoside.
• the alkyl glycoside is sucrose dodecanoate.
• the alkyl glycoside is sucrose monostearate.
• the alkyl glycoside is sucrose distearate.
• the alkyl glycoside is a combination of two or more of dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, or sucrose distearate.
• Mucosal membrane preparations are generally administered in metered sprays having volumes of less than 250 ⁇ L, preferably less than 150 ⁇ L, and ideally from 25 to 100 ⁇ L. Although not prohibited in this invention, administration of volumes larger than about 300 ⁇ L per dose usually exceeds the absorption capacity of the membranes. This results m a large portion of the pharmaceutically-active ingredient being lost.
• the dosage volume of preparations in particular nasal preparations, preferably ranges from
• Alprazolam The dosage of alprazolam vanes by indication, however it is expected that a therapeutic dose will be m the range of about 0.5 to about 4, preferably about 1 to about 2 mg per dose, from 1 to 8, preferably from 2 to 8, and m some preferred embodiments about 4 to about 6 times per day.
• Alprazolam may be manufactured using the process disclosed in Umted States patent 3,987,052, which is incorporated herein by reference in its entirety. [0145] As a nasal formulation, alprazolam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, alprazolam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays
• the dosage of diazepam may vary by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 20, preferably about 2 to about 10 mg per dose, from 1 to
• Diazepam may be manufactured using the process disclosed in one of Umted States patents
• diazepam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, diazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays
• the dosage of flurazepam vanes by indication is expected that a therapeutic dose will be m the range of about 5 to 40, preferably about 20 to about 35 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
• Flurazepam may be manufactured using the process disclosed in Umted States patent 3,567,710 or
• flurazepam may be administered in 25 to 250 ⁇ L metered sprays In some preferred embodiments, flurazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays.
• the dosage of Lorazepam vanes by indication may be in the range of about 0 1 to about 10, preferably about 02 to about 1 mgperdose, from l to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 tunes per day Lorazepam may be manufactured using the process disclosed in Umted States patent 3,296,249, which is incorporated herein by reference in its entirety
• lorazepam may be administered in 25 to 250 ⁇ L metered sprays In some preferred embodiments, lorazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays Medazepam
• medazepam vanes by indication, however it is expected that a therapeutic dose will be in the range of about 0 1 to about 10, preferably about 02 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 tunes per day Medazepam may be manufactured using the process disclosed in Umted States patent 3,243,427, which is incorporated herein by reference m its entirety
• medazepam may be administered in 25 to 250 ⁇ L metered sprays In some preferred embodiments, medazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays Mexazolam [0154]
• the dosage of mexazolam vanes by indication however it is expected that a therapeutic dose will be Ui the range of about 0 1 to about 10, preferably about 02 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 tunes per day Mexazolam may be manufactured using the process disclosed in United States patent 3,722,371 , which is incorporated herein by reference in its entirety [0155]
• mexazolam may be administered in 25 to 250 ⁇ L metered sprays In some preferred embodiments, mexazolam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays Midazolam [0156] The dosage of midazolam
• the dosage of temazepam vanes by indication is expected that a therapeutic dose will be in the range of about 1 to about 50, preferably about 5 to about 30 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day 5 Temazepam may be manufactured using the process disclosed in United States patent 3,340,253 or 3,374,225, each of which is incorporated herein by reference in its entirety
• temazepam may be administered in 25 to 250 ⁇ L metered sprays In some preferred embodiments, temazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays
• compositions comprising one or more
• compositions disclose a composition composing one or more benzodiazepine drugs or pharmaceutically-acceptable salts thereof in a concentration of about 10 mg/mL up to about 250 mg/mL Further, some embodiments disclose a composition comprising one or more benzodiazepine drugs or pharmaceutically-acceptable salts thereof in a concentration of about 20 mg/mL up to about
• Some embodiments disclose a earner system that is about 50% to about 90% (w/w) Vitamin E and about 10% to about 50% (w/w) lower alcohol or lower alkyl glycol, or any combinations thereof Some embodiments disclose a earner system that is about 65% to about 75% (w/w) Vitamin E and about 25% to about 35% (w/w) lower alkyl alcohol or lower alkyl glycol, or any combinations
• Some embodiments of the invention provide a method of admimstenng the benzodiazepine drag composition to a patient The preferred embodiment compnses use of diazepam. Some embodiments of the method disclose a dosage level of diazepam of about 1 0 mg to about 200 mg
• dosage levels disclose a dosage level of about 20 mg to about 15 0 mg until the desired result is achieved Some embodiments disclose a dosage level of about 5 0 mg to about 100 mg until the desired result is achieved
• the dosage volume ranges from about 10 ⁇ L to about 200 ⁇ L In some embodiments, the dosage volume ranges from about 20 ⁇ L to about 180 ⁇ L
• some embodiments disclose a dosage volume of about 50 ⁇ L to about 140 ⁇ L Formulation Process
• the composition for nasal administration is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
• the composition is made by slowly warming or heating the Vitamin E until it is liquefied.
• the one or more benzodiazepine drugs are added.
• the mixture is stirred and heated until the one or more benzodiazepine drugs dissolve or are substantially dissolved.
• the one or more alcohols or glycols, or any combinations thereof are added to the composition. This composition is stirred until a less viscous composition is achieved.
• the aforementioned formulations are preferably sterile with a bacteria count of 10 below the allowable level on a per mL basis. Additionally, pathogens are preferably absent.
• the benzodiazepine drug is formulated as a mier ⁇ particulate and/or nanoparticulate suspension of the benzodiazepine. Preparation of microparticulate and nanoparticulate benzodiazepine may be accomplished by methods such as milling, etc. Such methods are known to those skilled in the art.
• the benzodiazepine drug is formulated as a solution. It is considered an aspect of the invention that employment of microparticulate and/or nanoparticulate benzodiazepine drug during the process of preparing the formulation, can improve the overall solubility of the benzodiazepine drug in the solvent system.
• compositions and methods of using the compositions comprise an additional ingredient in the composition selected from active ingredients.
• active ingredients include insulin, calcitonins (for example porcine, human, salmon, chicken, or eel) and synthetic modifications thereof, enkephalins, LHRH and analogues (Nafarelin, Buserelin, Zolidex), GHRH (growth hormone releasing hormone), nifedipin, THF (thymic humoral factor), CGRP (calcitonin gene related peptide), atrial natriuretic peptide, antibiotics, metoclopramide, ergotamine, Pizotizin, nasal vaccines (particularly HIV vaccines, measles, rhinovirus Type 13 and respiratory syncitial virus), pentamidine, CCK (Cholecystikinine), DDVAP, Interferons, growth hormone (solatotropir polypeptides or their derivatives (preferably with a molecular
• compositions and methods of using the compositions comprise an additional ingredient in the composition selected from other anticonvulsants
• active ingredients include paraldehyde, aromatic allylic alcohols (such as stinpentol), barbiturates (e g phenobarbitol, primidone, methylphenobarbital, metharbital and S barbexaclone), bromides (such as potassium bromide), carbamates (such as felbamate), carboxamides (such as carbamazepine and oxcarbazepine), fatty acids (such as valproic acid, sodium valproate, and divalproex sodium, vigabatnn, progabide, hagabine), fructose, topiramate, Gaba analogs (e g gabapentm and pregabalin), hydantoins (e g
• -41 WSGR Docka No 35401 716601 minor amounts of ingredients such as stabilizers, coloring agents, pH adjusters, buffering agents, preservatives such as agents which may prevent degradation, wetting agents, and flavoring agents may also be present
• coloring agents include ⁇ -carotene, Red No 2 and Blue No 1
• preservatives include stearic acid, ascorbyl stearate and ascorbic acid
• cor ⁇ gents include menthol and citrus perfume
• the drug delivery system of the invention may advantageously comprise an absorption enhancer
• an absorption enhancer means any material which acts to increase absorption across the mucosa and/or increases bioavailability
• such materials include mucolytic agents, degradative enzyme inhibitors and compounds which increase permeability of the mucosal cell membranes Whether a given compound is an "enhancer" can be determined by comparing two formulations composing a non-associated, small polar molecule as the drug, with or without the enhancer, in an in vivo or good model test and determining whether the uptake of the drug is enhanced to a clinically significant degree
• the enhancer should not produce any problems in terms of chronic toxicity because m vivo the enhancer should be non-imtant and/or rapidly metabolized to a normal cell constituent that does not have any significant irritant effect
• preferred enhancing materials lysophosphohpid ⁇ for example lysophosphatidylcholine obtainable from egg or soy lecithin
• lysophosphatidylcholines that have different acyl groups as well as lyso compounds produced from phosphahdylethanolamines and phosphatide acid which have similar membrane modifying properties
• Acyl carnitines e g pahmtoyl-dl-ca ⁇ utine-chlo ⁇ de
• a suitable concentration is from 002 to 20% w/v
• enhancing agents that are appropriate include chelating agents (EGTA, EDTA, alginates), surface active agents (especially non-ionic materials), acyl glycerols, fatty acids and salts, tyloxapol and biological detergents listed m the SIGMA Catalog, 1988, page 316-321 (which is incorporated herein by reference)
• agents that modify the membrane fluidity and permeability are appropriate such as enamines (e g phenylalanine enamine of ethylacetoacetate), malonates (e g diethyleneoxymethylene malonate), salicylates, bile salts and analogues and fusidates Suitable concentrations are up to 20% w/v
• the invention takes advantage of delivery of a drug incorporated into or onto a bioadhesive microsphere with an added pharmaceutical adjuvant applies to systems that contain active drug and mucolytic agent, peptidase inhibitors or non-drug polypeptid
• the administration of the composition comprises administering at least a portion of the therapeutically effective amount of Hie composition onto at least one mucosal membrane. In some embodiments, the administration of the composition comprises spraying at least a portion of the therapeutically effective amount of the composition into at least one nostril. In some embodiments, the administration of the composition comprises spraying at least a portion of the therapeutically effective amount of the composition into each nostril. In some embodiments, the administration of the composition comprises spraying a first quantity of the composition into the first nostril, spraying a second quantity of the composition into a second nostril, and optionally after a preselected time delay, spraying a third quantity of the composition into the first nostril. Some embodiments further comprise, optionally after a pre-selected time delay, administering at least a fourth quantity of the composition to the second nostril. Alprazolam
• alprazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.5 to about 4, preferably about 1 to about 2 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
• Alprazolam may be manufactured using the process disclosed in United States patent 3,987,052, which is incorporated herein by reference in its entirety.
• alprazolam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, alprazolam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient.
• the dosage of diazepam may vary by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 20, preferably about 2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day Diazepam may be manufactured using the process disclosed in one of Umted States patents 3,371,085, 3,109,843, 3,136,815 or 3,102,116, each of which is incorporated herein by reference in its entirety
• diazepam may be administered in 25 to 250 ⁇ L metered sprays In some preferred embodiments, diazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril In some optional embodiments, a third metered spray is applied to the first nostril In some embodiments, a fourth metered spray is applied to the second nost ⁇ l In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient In some embodiments, there is a time increment of from several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applications of benzodiazepine drug to the same nost ⁇ l This allows time for the drug to cross the nasal mucosa and enter the blood stream.
• a therapeutic dose will be in the range of about 5 to 40, preferably about 20 to about 35 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day
• Flurazepam may be manufactured using the process disclosed in United States patent 3,567,710 or 3,299,053, each of which is incorporated herein by reference m its entirety
• flurazepam may be administered in 25 to 250 ⁇ L metered sprays In some preferred embodiments, flurazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nost ⁇ l In some optional embodiments, a third metered spray is applied to the first nost ⁇ l In some embodiments, a fourth metered spray is applied to the second nostril In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient In some embodiments, there is a time increment of from several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applications of benzodiazepine drug to the same nost ⁇ l This allows tune for the drug to cross the nasal mucosa and enter the blood stream Multiple applications of metered sprays to each nost ⁇ l, optionally separated by a tune
• lorazepam may be administered in 25 to 250 ⁇ L metered sprays
• lorazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L
• metered sprays a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril
• a third metered spray is applied to the first nostril
• a fourth metered spray is applied to the second nostril
• a therapeutic dose will be in the range of about 0 1 to about 10, preferably about 02 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day
• Medazepam may be manufactured using the process disclosed m Umted States patent 3,243,427, which is incorporated herein by reference m its entirety
• medazepam may be administered in 25 to 250 ⁇ L metered sprays In some preferred embodiments, medazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril In some optional embodiments, a third metered spray is applied to the first nostnl In some embodiments, a fourth metered spray is applied to the second nostnl In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient In some embodiments, there is a time increment of from several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applications of benzodiazepine drug to the same nostnl This
• mexazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0 1 to about 10, preferably about 02 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day Mexazolam may be manufactured usmg the process disclosed in United States patent 3,722,371, which is incorporated herein by reference in its entirety
• mexazolam may be administered in 25 to 250 ⁇ L metered sprays In some preferred embodiments, mexazolam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays In some embodiments, a first metered spray is applied to a first nostnl and if necessary a second metered spray is applied to a second nostnl In some optional embodiments, a third metered spray is applied to the first nostril In some embodiments, a fourth metered spray is applied to the second nostnl In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient In some embodiments, there is a tune increment of from several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applications of benzodiazepine drug to the same nostril This allows time for the drug to cross the nasal mucosa and enter the blood stream Multiple applications of metered sprays to each nostnl, optionally separated by a tune
• a therapeutic dose will be in the range of about 1 to about 50, preferably about 5 to about 30 mg per dose, from 1 to 8, preferably from 2 to 8, and m some preferred embodiments about 4 to about 6 tunes per day
• Temazepam may be manufactured using the process disclosed in United States patent 3,340,253 or 3,374,225, each of which is incorporated herein by reference m its entirety
• temazepam may be administered in 25 to 250 ⁇ L metered sprays In some preferred embodiments, temazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nost ⁇ l In some optional embodiments, a third metered spray is applied to the first nost ⁇ l In some embodiments, a fourth metered spray is applied to the second nost ⁇ l In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient In some embodiments, there is a tune increment of from several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applications of benzodiazepine drug to the same nost ⁇ l This allows time for the drug to cross the nasal mucosa and enter the blood stream Multiple applications of metered sprays to each nostril, optionally separated by a tune interval,
• a pharmaceutical composition comprising diazepam is prepared. It is formulated as a solution to be delivered via a nasal delivery device. The composition is used to treat or prevent seizures associated with epilepsy in adults. Treatment is administered either before or after a seizure has begun. If the patient is seizing, it is administered as 1 puff from any nasal delivery device (1 puff at 5.0 mg/puff (5.0 mg/0.1 mL and 0.1 mL/puf ⁇ )) every 5 minutes until cessation of the seizure.
• a pharmaceutical composition comprising diazepam is prepared. It is formulated as a solution to be delivered via a nasal delivery device.
• the composition is used to treat or prevent seizures associated with epilepsy in children. Treatment is administered either before or after a seizure has begun. If the patient is seizing, it is administered as 1 puff from any nasal delivery device (1 puff at 2.0 mg/puff (2.0 mg/0.1 mL and 0.1 mL/puff)). If the seizure fails to stop another dose may be administered after 5 minutes. However, it can be given as 1 puff per nostril in each nostril (2 puffs at 1.0 mg/puff (2.0 mg/0.1 mL and 0.05 mL/puff)). If the seizure fails to stop another dose may be administered after 5 minutes.
• the composition according to this example is set forth in the following table.
• benzodiazepine solutions may be formulated by combining one or more natural or synthetic tocopherols or tocotrienols and one or more lower alcohols or glycols and mixing until a homogeneous mixture is formed, adding the benzodiazepine drug to the homogeneous mixture, heating and mixing the ingredients until the benzodiazepine is fully dissolved in the homogeneous
• Vitamin E USP and dehydrated ethanol USP were combined in the amounts set forth in the following table and mixed to form a homogeneous mixture.
• Diazepam in the amounts set forth in the following table was then added to the homogeneous mixture.
• the ingredients were heated to 40-45 0 C with mixing until the diazepam was fully dissolved, thereby forming a solution.
• the solution was cooled to 20-25 0 C, whereupon the solution was brought to its final target weight with dehydrated ethanol USP and the solution was mixed thoroughly to assure homogeneity.
• the solution was then sampled for in-process testing and packaged in 3 mL amber glass vials.
• Table 3-1 Diazepam Solutions - 70 mp/mT .
• Component Solution 00 65% Vitamin E
• Solution 02 80% Vitamin E
• benzodiazepine solutions are made in a similar manner, by varying the amount of diazepam and the relative amounts of Vitamin E and ethanol.
• Other benzodiazepine solutions are made by substituting one or more benzodiazepines for diazepam.
• Other ingredients such as alkyl glycoside, can be added at a suitable step in the process (e.g. before or concurrently with the addition of benzodiazepine).
• Example 4 Formulation of Diazepam Suspensions [0200] In general, benzodiazepine suspensions are formulated by micronizing benzodiazepine and combining the benzodiazepine with a carrier.
• the carrier is prepared by combining one or more lower alcohols or glycols with water, adding a natural or synthetic tocopherol or tocotrienol, heating the mixture until the tocopherol or tocotrienol is dissolved, adding one or more parabens and mixing until the parabens are dissolved and cooling the carrier.
• additional excipients such as surfactants, can optionally be added and dissolved in the carrier.
• the suspension is then brought up to its final mass or volume with water.
• Two different diazepam suspensions were formulated by the foregoing general process. Two different diazepam particle sizes were prepared - A: a small particle size by prepared by high pressure micronization, and B: a large particle size prepared by low pressure micronization.
• the carrier was prepared by combining propylene glycol USP and purified water USP, then adding
• Vitamin E Polyethylene Glycols Succinate NF then mixing and heating the combined ingredients to
• Additional suspensions of diazepam at varying concentrations are made in a similar manner, by varying the amount of diazepam and optionally other excipients.
• Other benzodiazepine suspensions are made by substituting one or more benzodiazepines for diazepam.
• Other ingredients such as alkyl glycoside, can be added at a suitable step in the process.
• an alkylglycoside may be added to the carrier during compounding of the carrier, or may be added to the suspension mixture concurrently with or after addition of the povidone.
• Solutions 00 and 02 (Example 3) and Suspensions 01 and 03 (Example 4) were set up on stability at 25 0 C / 60% RH, 3O 0 C / 65% RH and 40 0 C / 75% RH.
• One batch each of four different formulations, packaged in 3-ml vials with screw-top closures, along with corresponding actuators, were set up at three storage conditions. They are listed in Table 1 with their corresponding Particle Sciences initial sample control numbers.
• UV and on-UV RT pass N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
• AU of the solutions and suspensions described in Examples 3 and 4 are formulated as described in Examples 3 and 4, with the addition of a suitable amount of an alkyl glycoside, as described herein, such as dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and/or combinations of two or more thereof, or marketed as Intravail ® by Aegis Therapeutics, San Diego, CA
• the solutions and suspensions with added alkyl glycoside may then be put up on stability as described in Example 5, mutatis mutandis
• Example 3 The solutions and suspensions of Examples 3, 4 and 6 are evaluated for pharmacokinetics m a suitable animal model, such as in mice, rats, rabbits or dogs
• a suitable animal model such as in mice, rats, rabbits or dogs
• each animal e g rabbit
• the amount of intravenously dosed benzodiazepine drug is selected to be less, e g roughly half, of what is considered an effective dose administered nasally
• the intravenous dose of diazepam administered to rabbits is about 005 to about 02 mg/kg, e g about 0 1 mg/kg
• Plasma blood levels of the drug are assayed for each of the blood samples After at least a one day washout penod, each animal is administered, lntranasally, an amount of a solution or suspension as descnbed m Examples 3, 4 and 6 Blood is collected immediately before administration and at substantially the same specific time points as
• Pharmacokinetic curves blood plasma concentration of drug versus tune are constructed for the intravenous route of administration and for each of the solutions and suspensions administered by the intranasal administration route [0211] Toxicity is assessed by known means In particular, histological samples are collected from the nasal mucosal tissues of the test animals Other toxo logical methods are optionally employed as well
• the solutions and suspensions of Examples 3, 4 and 6 are evaluated for their ability to deliver drug across the blood brain barrier in a suitable animal model, such as in mice, rats, rabbits or dogs Each animal is administered, lntranasally, an amount of a solution or suspension as descnbed in Examples 3, 4 and 6, with the solution or suspension optionally containing an imaging agent, such as a dye, that may be used as a proxy for determining the ability of the drug to cross the blood brain barrier
• an imaging agent such as a dye
• an IV dose of diazepam administered to humans may be in the range of 1 to 15 mg, e g about 75 mg
• Plasma blood levels of the drug are assayed for each of the blood samples After at least a one day washout penod, each subject is administered, lntranasally, an amount of a solution or suspension as descnbed

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