[go: up one dir, main page]

US20160346216A1 - Composition and method for aiding sleep - Google Patents

Composition and method for aiding sleep Download PDF

Info

Publication number
US20160346216A1
US20160346216A1 US15/234,620 US201615234620A US2016346216A1 US 20160346216 A1 US20160346216 A1 US 20160346216A1 US 201615234620 A US201615234620 A US 201615234620A US 2016346216 A1 US2016346216 A1 US 2016346216A1
Authority
US
United States
Prior art keywords
formulation
release
stage
compounds
hours
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US15/234,620
Inventor
Lan Bo Chen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sequential Medicine Ltd
Original Assignee
Sequential Medicine Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sequential Medicine Ltd filed Critical Sequential Medicine Ltd
Priority to US15/234,620 priority Critical patent/US20160346216A1/en
Publication of US20160346216A1 publication Critical patent/US20160346216A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat

Definitions

  • the formulation includes one or more compounds for aiding sleep, wherein the formulation is formulated for releasing each compound at a specific time and a specific dose in a subject after the formulation is administered to the subject.
  • the formulation is formulated for two to twelve stages of release, wherein each stage initiates release of a compound or a combination of compounds in a subject at a specific time point after administration of the formulation to the subject.
  • the time interval between the initiation of each stage of release can be 0.5 to 23 hours.
  • the first stage can be for immediate release of a compound or combination of compounds.
  • the compound or compounds can be selected from the group consisting of barbiturates (e.g., amobarbital (Amytal), pentobarbital (Nembutal), secobarbital (Seconal), and phenobarbital (Luminal); benzodiazepines (e.g., clonazepam (Klonopin N.America; Rivotril Europe, Asia), diazepam (Valium), estazolam (Prosom), flunitrazepam (Rohypnol), lorazepam (Ativan), midazolam (Versed), nitrazepam (Mogadon), oxazepam (Serax), triazolam (Halcion), temazepam (Restoril, Normison, Planum, Tenox, and Temaze), chlordiazepoxide (Librium), and alprazolam (Xanax)); non-benzodiazepine “Z-drugs” sedatives
  • the formulation is a tablet or capsule for oral administration.
  • the tablet or capsule can contain a plurality of particles, each particle including a drug core and a polymeric composition encapsulating the core, wherein the drug core contains the one or more compounds for aiding sleep.
  • the method includes administering the above-described formulation to a subject in need thereof.
  • disturbed sleep refers to a condition characterized by waking up feeling unrestored, waking up in the middle of the night, difficulty returning to sleep after waking, difficulty falling asleep, and/or waking too early. Stress, a health condition, pain, a medication, jet lag, and noise are some factors that can lead to disturbed sleep. Disturbed sleep can be acute (i.e., short-termed) or chronic in duration.
  • An individual with insomnia experiences frequent and long-term disturbed sleep with daytime impairment or distress despite having adequate opportunity and circumstance for sleep.
  • Disturbed sleep can have various negative consequences such as fatigue, lack of energy, initiative reduction, daytime sleepiness, tension headache, gastrointestinal symptoms, irritability, anxiety, mood disturbance, reduced motivation, and impairment in cognitive functions (attention, concentration, and memory).
  • Whether a subject has disturbed sleep or insomnia can be determined by a skilled practitioner in the art.
  • a controlled-release formulation containing one or more compounds or compositions for aiding sleep (e.g., sedative or hypnotic agents).
  • Such compounds or compositions for aiding sleep include, but are not limited to, barbiturates (e.g., amobarbital (Amytal), pentobarbital (Nembutal), secobarbital (Seconal), and phenobarbital (Luminal); benzodiazepines (e.g., clonazepam (Klonopin N.America; Rivotril Europe, Asia), diazepam (Valium), estazolam (Prosom), flunitrazepam (Rohypnol), lorazepam (Ativan), midazolam (Versed), nitrazepam (Mogadon), oxazepam (Serax), triazolam (Halcion), temazepam (Restoril, Normison, Planum, Tenox, and Te
  • the controlled-release formulation is formulated to release one compound/composition or one combination of compounds/compositions for aiding sleep.
  • the formulation releases the compound/composition or combination of compounds/compositions at multiple stages (e.g., 2 to 12 stages). Each stage initiates release of the compound/composition or combination of compounds/compositions at a specific time after administration of the formulation.
  • the formulation can release a first dose of a compound immediately, release a second dose of the same compound 1 hour after release of the first dose, and then release a third dose of the compound 2 hours after release of the second dose.
  • the controlled-release formulation releases two or more compounds/compositions or combinations of compounds/compositions for aiding sleep.
  • the formulation releases the compounds or compositions at multiple stages (e.g., 2 to 12 stages). Each stage initiates release of a specific compound/composition or combination of compounds/compositions at a specific time after administration of the formulation to a subject.
  • the formulation can release immediately a first compound, release a second compound 30 minutes after the release of the first compound, and then release a third compound and a fourth compound together 3.5 hours after the release of the second compound.
  • the formulation can release a first compound at time 0, 2 hours, 4 hours, and 6 hours, and a second compound at time 1 hour, 3 hours, 5 hours, and 7 hours.
  • the time interval between the initiation of each stage of release can be 30 minutes to 23 hours (e.g., 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12.5 hours, 13 hours, 15 hours, 20 hours, 22 hours, and 23 hours).
  • Each stage can release a dose of a compound in the range of 0.01 mg to 100 mg (e.g., 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and 100 mg).
  • 0.01 mg to 100 mg e.g., 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and 100 mg.
  • the first stage of release can be an immediate release, in which release of one or more active agents is initiated shortly (e.g., within 30 minutes) after administration of the formulation.
  • the first stage of release can also be a delayed released.
  • the above-described controlled-release formulation can be a tablet (e.g., a pill) or a capsule (e.g., a hard-shelled capsule or a softgel) for oral administration.
  • Other formulations such as implants and patches can also be used.
  • controlled-release formulations can be designed based on particular physical mechanisms, e.g., dissolution, diffusion, osmosis, and ion exchange.
  • a drug is surrounded by or distributed in a polymeric composition (e.g., a polymeric membrane or a polymeric matrix).
  • the drug is released when the polymeric composition dissolves.
  • Properties of the polymeric composition e.g., thickness and dissolution rate, determine drug release.
  • the active ingredient has to diffuse through a polymeric composition (e.g., a polymeric membrane or a polymeric matrix) in order to be released.
  • the drug is encapsulated by a polymeric coating that swells and erupts from osmotic pressure, thereby releasing the drug.
  • Ion exchange formulation relies on attaching drug molecules to ionic groups. The drug molecules are then displaced by other ions and released.
  • the controlled-release formulation described herein can utilize one release mechanism or a combination of release mechanisms.
  • the above-described controlled-release formulation can be a tablet with multiple cores or layers.
  • the drug or combination of drugs for each stage of release can be surrounded by polymeric layer. The drug or combination of drugs is released as the layer dissolves.
  • a multiparticulate system is employed.
  • the active compounds are each delivered in multiple particles (e.g., small beads or microspheres ranging from 0.05 to 3.00 mm in size), each particle exhibiting the desired characteristics (e.g., release time and rate).
  • the above-described controlled-release formulation can include a plurality of particles.
  • Each particle contains a core including a compound or combination of compounds for aiding sleep and a controlled-release polymeric composition (containing one or more polymers) encapsulating the core.
  • Properties of the controlled-release polymeric composition in each particle determine the drug release profile of each particle.
  • the formulation can include uncoated particles for immediate release of a drug.
  • any of the above-described or other release mechanisms can be employed in a multiparticulate system.
  • the plurality of particles can be encapsulated in a capsule or compressed into a tablet for oral administration.
  • a three-stage release formulation can contain three types of particles, each type for each stage of release. Each dose of a drug for each stage of release is delivered by multiple particles.
  • Natural and synthetic polymers for controlled-release formulations are known in the art. Such polymers include, but are not limited to, proteins, polysaccharides, nucleotides, alginate, chitosan, heparin, xanthan gum, starch, pectin, gelatin, ⁇ / ⁇ -carrageenan, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethycellulose, methylcellulose, polyvinyl alcohol, polyacrylic acid, polyethylene oxide, poloxamers, pluronics, polymethacrylate, cellulose, collagen, nylon, polyalkylcyanoacrylate, polyethylene, polyethylene-co-vinylacetate, polyhydroxythyl methacrylate, polyhydroxypropylethyl methacrylate, polymethyl methacrylate, polyurethane, and silicon. Commercially available polymers for pharmaceutical applications include EUDRAGIT® polymethacrylates.
  • the controlled-release formulation employs an enteric coating or other coatings for delaying drug release until the drug reaches the small intestine or the colon. Delaying drug release in this manner would also control drug release time.
  • Such coatings are known in the art.
  • Each stage of release can have a specific release rate.
  • a stage can have a pulsatile-release profile, in which a drug is released rapidly and completely following a period of no release.
  • a stage can also have a first-order release rate, in which a drug is released at a 2 5 decreasing release rate.
  • a zero-order release rate i.e., a constant release rate, can also be employed.
  • An entire dose (or a significant portion thereof) of a compound can be released within a short period or over an extended period.
  • the formulation can be designed to release at least 50% (e.g., more than 60%, 70%, 75%, 80%, 85%, 90%, or 95%) of a dose of a compound within 30 minutes of the initiation of release.
  • the controlled-release formulation can also include one or more pharmaceutical excipients, e.g., binders, plasticizers, lubricants, diluents, fillers, coloring agents, flavoring agents, glidants, and preservatives.
  • pharmaceutical excipients e.g., binders, plasticizers, lubricants, diluents, fillers, coloring agents, flavoring agents, glidants, and preservatives.
  • the controlled-release formulation can be administered to a patient daily or as needed to induce and maintains sleep.
  • a formulation, in tablet or capsule form, is formulated to initiate immediate release of 50 mg of Benadryl, 10 mg of melatonin, and 25 mg of Theanine upon uptake. 2 hours thereafter, release of 5 mg of Ambien is initiated. 3 hours after the start of the release of Ambien, release of 0.5 mg of Activan and 1 mg of Xanax are initiated.
  • Hard gelatin capsules for releasing diphenhydramine HCl i.e., 2-(diphenylmethoxy)-N,N-dimethylethanamine
  • zolpidem tartrate i.e., N,N-dimethyl-2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetamide
  • lorazepam i.e., (RS)-7-Chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one
  • the capsules were designed to release the three drugs in a staged sequence controlled via pH-dependent coatings: uncoated diphenhydramine HCl for immediate release, coated zolpidem for release about 2 hours after administration, and coated lorazepam for release about 4 hours after administration.
  • Each capsule contained the following agents: (1) 50 mg of uncoated diphenhydramine HCl; (2) 5 mg of zolpidem tartrate in multiparticulate form coated with EUDRAGIT® L30 D-55, which dissolves at above pH 5.5 (with half-maximal drug release at pH 5.8 and maximal release at pH 6.3); and (3) 0.5 mg of lorazepam in multiparticulate form coated with EUDRAGIT® L/S 12,5 (1:1), which dissolves at above pH 6.5 (with half-maximal drug release at pH 7.2).
  • the coatings were selected to achieve release of zolpidem tartrate with gastric emptying and release of lorazepam when the drug reaches the intestines.
  • Example 3 The capsules described in Example 3 above were tested in dogs at CARE Research in Fort Collins, Colo. Sleep pattern of dogs is polyphasic. Each bout of sleep ranges from a few minutes to about 45 minutes. Dogs follow circadian rhythm. They fall asleep from time to time during day-time but gain most of their needed sleep during night-time.
  • each dog was orally fed with one capsule in the morning, housed individually in the same room as in Day 1, and monitored by video-cameras mounted above continuously for 24 hours.
  • EUDRAGIT® L 12,5 dissolves at above pH 6.0.
  • diphenhydramine would be released immediately and be effective for up to 4 hours.
  • Zolpidem would be released about 2 hours after administration and reach its t max (i.e., time to maximum concentration in plasma) about 2 hours later.
  • Lorazepam would be released about 4 hours after administration of the capsules and reach its t max about 6 hours post administration.

Landscapes

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

Abstract

Described is a controlled-release formulation for treating disturbed sleep or insomnia in a subject. The formulation is formulated to release a compound or combination of compounds in sequence at multiple stages.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This is a continuation of U.S. patent application Ser. No. 14/614,916, filed on Feb. 5, 2015, which claims priority to U.S. Provisional Patent Application No. 61/936,566, filed on Feb. 6, 2014. The contents of the prior applications in their entirety are hereby incorporated by reference herein.
    • BACKGROUND
  • In patients suffering sleep disruptions, one can observe a clear distinction between the ability to fall asleep and the ability to remain asleep long enough to feel rested. Pharmacological therapeutics for insomnia typically focuses on enabling a patient to fall asleep. Most patients taking sleeping pills wake up in the middle of night without completing the 8-hour sleep cycle. There is a need for drugs that allow a patient to fall asleep and stay asleep for a sufficient period of time.
    • SUMMARY
  • Described below is a controlled-release formulation. The formulation includes one or more compounds for aiding sleep, wherein the formulation is formulated for releasing each compound at a specific time and a specific dose in a subject after the formulation is administered to the subject.
  • In one embodiment, the formulation is formulated for two to twelve stages of release, wherein each stage initiates release of a compound or a combination of compounds in a subject at a specific time point after administration of the formulation to the subject. For example, the time interval between the initiation of each stage of release can be 0.5 to 23 hours. The first stage can be for immediate release of a compound or combination of compounds.
  • The compound or compounds can be selected from the group consisting of barbiturates (e.g., amobarbital (Amytal), pentobarbital (Nembutal), secobarbital (Seconal), and phenobarbital (Luminal); benzodiazepines (e.g., clonazepam (Klonopin N.America; Rivotril Europe, Asia), diazepam (Valium), estazolam (Prosom), flunitrazepam (Rohypnol), lorazepam (Ativan), midazolam (Versed), nitrazepam (Mogadon), oxazepam (Serax), triazolam (Halcion), temazepam (Restoril, Normison, Planum, Tenox, and Temaze), chlordiazepoxide (Librium), and alprazolam (Xanax)); non-benzodiazepine “Z-drugs” sedatives (e.g., eszopiclone (Lunesta), zaleplon (Sonata), zolpidem (Ambien), and zopiclone (Imovane, Zimovane)); antihistamines (e.g., diphenhydramine, dimenhydrinate, doxylamine, mirtazapine, and promethazine); plant components or extracts (from, e.g., Duboisia hopwoodii, chamomile, Prostanthera striatiflora, catnip, kava (Piper methysticum), valerian, cannabis, and passiflora (e.g., Passiflora incarnate)); Validol; chloral hydrate; trazodone; opiates and opioids; Suvorexant (MK-4305, Merck & Co.); glutethimide; and γ-hydroxybutyric acid.
  • In one embodiment, the formulation is a tablet or capsule for oral administration. The tablet or capsule can contain a plurality of particles, each particle including a drug core and a polymeric composition encapsulating the core, wherein the drug core contains the one or more compounds for aiding sleep.
  • Also described is a method of treating disturbed sleep or insomnia in a subject. The method includes administering the above-described formulation to a subject in need thereof.
  • The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages of the embodiments will be apparent from the description and from the claims.
    • DETAILED DESCRIPTION
  • It was unexpectedly discovered that administering certain drugs or combinations of drugs sequentially can both induce and maintain sleep in patients having disturbed sleep or insomnia. This approach extends sleep time while utilizing lower than recommended doses of the drugs, which reduces the risk of addiction and other side effects (e.g., next-morning impairment).
    • Disturbed Sleep
  • As used herein, the term “disturbed sleep”, “sleep disturbances,” or “sleep disruption” refers to a condition characterized by waking up feeling unrestored, waking up in the middle of the night, difficulty returning to sleep after waking, difficulty falling asleep, and/or waking too early. Stress, a health condition, pain, a medication, jet lag, and noise are some factors that can lead to disturbed sleep. Disturbed sleep can be acute (i.e., short-termed) or chronic in duration.
  • An individual with insomnia experiences frequent and long-term disturbed sleep with daytime impairment or distress despite having adequate opportunity and circumstance for sleep.
  • Disturbed sleep can have various negative consequences such as fatigue, lack of energy, initiative reduction, daytime sleepiness, tension headache, gastrointestinal symptoms, irritability, anxiety, mood disturbance, reduced motivation, and impairment in cognitive functions (attention, concentration, and memory).
  • Whether a subject has disturbed sleep or insomnia can be determined by a skilled practitioner in the art.
    • Controlled-Release Formulation
  • Described herein is a controlled-release formulation containing one or more compounds or compositions for aiding sleep (e.g., sedative or hypnotic agents). Such compounds or compositions for aiding sleep include, but are not limited to, barbiturates (e.g., amobarbital (Amytal), pentobarbital (Nembutal), secobarbital (Seconal), and phenobarbital (Luminal); benzodiazepines (e.g., clonazepam (Klonopin N.America; Rivotril Europe, Asia), diazepam (Valium), estazolam (Prosom), flunitrazepam (Rohypnol), lorazepam (Ativan), midazolam (Versed), nitrazepam (Mogadon), oxazepam (Serax), triazolam (Halcion), temazepam (Restoril, Normison, Planum, Tenox, and Temaze), chlordiazepoxide (Librium), and alprazolam (Xanax)); non-benzodiazepine “Z-drugs” sedatives (e.g., eszopiclone (Lunesta), zaleplon (Sonata), zolpidem (Ambien), and zopiclone (Imovane, Zimovane)); antihistamines (e.g., diphenhydramine, dimenhydrinate, doxylamine, mirtazapine, and promethazine); plant components or extracts (e.g., components or extracts from Duboisia hopwoodii, chamomile, Prostanthera striatiflora, catnip, kava (Piper methysticum), valerian, cannabis, and passiflora (e.g., Passiflora incarnata)); Validol; chloral hydrate; trazodone; opiates and opioids; Suvorexant (MK-4305, Merck & Co.); glutethimide; and y-hydroxybutyric acid. Other sedatives or hypnotic agents that target neurotransmitter receptors (e.g., histamine, GABA, and orexin receptors) can also be used in the formulation.
  • In one embodiment, the controlled-release formulation is formulated to release one compound/composition or one combination of compounds/compositions for aiding sleep. The formulation releases the compound/composition or combination of compounds/compositions at multiple stages (e.g., 2 to 12 stages). Each stage initiates release of the compound/composition or combination of compounds/compositions at a specific time after administration of the formulation.
  • For example, the formulation can release a first dose of a compound immediately, release a second dose of the same compound 1 hour after release of the first dose, and then release a third dose of the compound 2 hours after release of the second dose.
  • In one embodiment, the controlled-release formulation releases two or more compounds/compositions or combinations of compounds/compositions for aiding sleep. The formulation releases the compounds or compositions at multiple stages (e.g., 2 to 12 stages). Each stage initiates release of a specific compound/composition or combination of compounds/compositions at a specific time after administration of the formulation to a subject.
  • For example, the formulation can release immediately a first compound, release a second compound 30 minutes after the release of the first compound, and then release a third compound and a fourth compound together 3.5 hours after the release of the second compound. In another example, the formulation can release a first compound at time 0, 2 hours, 4 hours, and 6 hours, and a second compound at time 1 hour, 3 hours, 5 hours, and 7 hours. The time interval between the initiation of each stage of release can be 30 minutes to 23 hours (e.g., 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12.5 hours, 13 hours, 15 hours, 20 hours, 22 hours, and 23 hours). Each stage can release a dose of a compound in the range of 0.01 mg to 100 mg (e.g., 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and 100 mg).
  • The first stage of release can be an immediate release, in which release of one or more active agents is initiated shortly (e.g., within 30 minutes) after administration of the formulation. The first stage of release can also be a delayed released.
  • The above-described controlled-release formulation can be a tablet (e.g., a pill) or a capsule (e.g., a hard-shelled capsule or a softgel) for oral administration. Other formulations such as implants and patches can also be used.
  • Methods for formulating and making controlled-release formulations are known in the art. See, e.g., Hong Wen and Kinam Park, 2010, Oral Controlled Release Formulation Design and Drug Delivery: Theory to Practice, John Wiley & Sons, Inc. For example, controlled-release formulations can be designed based on particular physical mechanisms, e.g., dissolution, diffusion, osmosis, and ion exchange.
  • In a dissolution system, a drug is surrounded by or distributed in a polymeric composition (e.g., a polymeric membrane or a polymeric matrix). The drug is released when the polymeric composition dissolves. Properties of the polymeric composition, e.g., thickness and dissolution rate, determine drug release. In a diffusion system, the active ingredient has to diffuse through a polymeric composition (e.g., a polymeric membrane or a polymeric matrix) in order to be released. In an osmosis-based formulation, the drug is encapsulated by a polymeric coating that swells and erupts from osmotic pressure, thereby releasing the drug. Ion exchange formulation relies on attaching drug molecules to ionic groups. The drug molecules are then displaced by other ions and released. The controlled-release formulation described herein can utilize one release mechanism or a combination of release mechanisms.
  • In one embodiment, the above-described controlled-release formulation can be a tablet with multiple cores or layers. For example, the drug or combination of drugs for each stage of release can be surrounded by polymeric layer. The drug or combination of drugs is released as the layer dissolves.
  • In one embodiment, a multiparticulate system is employed. In this system, the active compounds are each delivered in multiple particles (e.g., small beads or microspheres ranging from 0.05 to 3.00 mm in size), each particle exhibiting the desired characteristics (e.g., release time and rate). For example, the above-described controlled-release formulation can include a plurality of particles. Each particle contains a core including a compound or combination of compounds for aiding sleep and a controlled-release polymeric composition (containing one or more polymers) encapsulating the core. Properties of the controlled-release polymeric composition in each particle determine the drug release profile of each particle. The formulation can include uncoated particles for immediate release of a drug. Any of the above-described or other release mechanisms (e.g., dissolution, diffusion, and osmosis) can be employed in a multiparticulate system. The plurality of particles can be encapsulated in a capsule or compressed into a tablet for oral administration. For example, a three-stage release formulation can contain three types of particles, each type for each stage of release. Each dose of a drug for each stage of release is delivered by multiple particles.
  • Natural and synthetic polymers for controlled-release formulations are known in the art. Such polymers include, but are not limited to, proteins, polysaccharides, nucleotides, alginate, chitosan, heparin, xanthan gum, starch, pectin, gelatin, κ/τ-carrageenan, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethycellulose, methylcellulose, polyvinyl alcohol, polyacrylic acid, polyethylene oxide, poloxamers, pluronics, polymethacrylate, cellulose, collagen, nylon, polyalkylcyanoacrylate, polyethylene, polyethylene-co-vinylacetate, polyhydroxythyl methacrylate, polyhydroxypropylethyl methacrylate, polymethyl methacrylate, polyurethane, and silicon. Commercially available polymers for pharmaceutical applications include EUDRAGIT® polymethacrylates.
  • In one embodiment, the controlled-release formulation employs an enteric coating or other coatings for delaying drug release until the drug reaches the small intestine or the colon. Delaying drug release in this manner would also control drug release time. Such coatings are known in the art.
  • When a compound or composition is released, it becomes available to the body. Each stage of release can have a specific release rate. For example, a stage can have a pulsatile-release profile, in which a drug is released rapidly and completely following a period of no release. A stage can also have a first-order release rate, in which a drug is released at a 2 5 decreasing release rate. A zero-order release rate, i.e., a constant release rate, can also be employed. An entire dose (or a significant portion thereof) of a compound can be released within a short period or over an extended period. For example, the formulation can be designed to release at least 50% (e.g., more than 60%, 70%, 75%, 80%, 85%, 90%, or 95%) of a dose of a compound within 30 minutes of the initiation of release.
  • The controlled-release formulation can also include one or more pharmaceutical excipients, e.g., binders, plasticizers, lubricants, diluents, fillers, coloring agents, flavoring agents, glidants, and preservatives.
  • The controlled-release formulation can be administered to a patient daily or as needed to induce and maintains sleep.
  • The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present disclosure to its fullest extent. All publications cited herein are hereby incorporated by reference in their entirety.
    • EXAMPLE 1 A Three-Stage Release Formulation
  • A formulation, in tablet or capsule form, releases drugs at three stages. At the first stage, release of 50 mg of Benadryl starts immediately after uptake. At the second stage, release of 5 mg of Ambien starts 2-3 hours after the initiation of the release of Benadryl. 2-3 hours after the start of the second stage, release of 0.5 mg of Activan is initiated.
    • EXAMPLE 2 A Three-Stage Release Formulation
  • A formulation, in tablet or capsule form, is formulated to initiate immediate release of 50 mg of Benadryl, 10 mg of melatonin, and 25 mg of Theanine upon uptake. 2 hours thereafter, release of 5 mg of Ambien is initiated. 3 hours after the start of the release of Ambien, release of 0.5 mg of Activan and 1 mg of Xanax are initiated.
    • EXAMPLE 3 In Vitro Release Profile of a Three-Stage Release Formulation
  • Hard gelatin capsules for releasing diphenhydramine HCl (i.e., 2-(diphenylmethoxy)-N,N-dimethylethanamine), zolpidem tartrate (i.e., N,N-dimethyl-2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetamide), and lorazepam (i.e., (RS)-7-Chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one) were manufactured.
  • The capsules were designed to release the three drugs in a staged sequence controlled via pH-dependent coatings: uncoated diphenhydramine HCl for immediate release, coated zolpidem for release about 2 hours after administration, and coated lorazepam for release about 4 hours after administration.
  • Each capsule contained the following agents: (1) 50 mg of uncoated diphenhydramine HCl; (2) 5 mg of zolpidem tartrate in multiparticulate form coated with EUDRAGIT® L30 D-55, which dissolves at above pH 5.5 (with half-maximal drug release at pH 5.8 and maximal release at pH 6.3); and (3) 0.5 mg of lorazepam in multiparticulate form coated with EUDRAGIT® L/S 12,5 (1:1), which dissolves at above pH 6.5 (with half-maximal drug release at pH 7.2). The coatings were selected to achieve release of zolpidem tartrate with gastric emptying and release of lorazepam when the drug reaches the intestines.
  • Six capsules were individually tested in beakers for pH-dependent release of each active agent. As shown in Table 1, at pH 2, more than 89% of diphenhydramine HCl was released within 30 minutes, whereas neither zolpidem tartrate nor lorazepam was released. At pH 6.4, more than 71% of zolpidem tartrate, but not lorazepam, was released within 30 minutes. At pH 7.2, more than 70% of lorazepam was released within 30 minutes.
  • TABLE 1
    pH-dependent release of diphenhydramine, zolpidem,
    and lorazepam from capsules.
    At 150 min in
    At 30 min in pH 6.4 (At At 270 min in
    pH 2 (At time 120 min changed pH 7.2 (At 240 min
    zero pH 2) to pH 6.4) changed to pH 7.2)
    % Release % Release % Release
    Cap# Diph Zolp Lora Diph Zolp Lora Diph Zolp Lora
    1 93.4 0 0 98.0 76.4 0 99.9 91.0 81.3
    2 89.8 0 0 100 68.2 0 100 98.7 77.2
    3 98.2 0 0 99.9 79.4 0 99.8 99.1 80.1
    4 98.7 0 0 100 76.2 0 99.1 100 83.2
    5 96.8 0 0 100 71.3 0 100 97.6 70.2
    6 97.3 0 0 99.9 80.1 0 99.2 99.1 72.1
    Diph: diphenhydramine
    Zolp: zolpidem
    Lora: lorazepam
    • EXAMPLE 4 Sleep Study in Dogs
  • The capsules described in Example 3 above were tested in dogs at CARE Research in Fort Collins, Colo. Sleep pattern of dogs is polyphasic. Each bout of sleep ranges from a few minutes to about 45 minutes. Dogs follow circadian rhythm. They fall asleep from time to time during day-time but gain most of their needed sleep during night-time.
  • On Day 1, four normal, untreated Beagle dogs were housed individually and monitored by video-cameras mounted above continuously for 24 hours.
  • On Day 3, each dog was orally fed with one capsule in the morning, housed individually in the same room as in Day 1, and monitored by video-cameras mounted above continuously for 24 hours.
  • Recorded videos from 12 noon to 8 pm on Day 1 and Day 3 were analyzed. Time of each sleep bout by each dog was measured and total sleep time of each dog in the course of 8 hours was tallied. Table 2 below summarizes the test results.
  • As shown in Table 2, the capsules led to a significant increase in total sleep time in all four treated Beagle dogs.
  • TABLE 2
    Effects of capsules on total sleep time in Beagle dogs.
    Total Sleep Time Difference between Day 1 and Day 3
    Day 1 Day 3 Increase %
    Dog # Placebo Treated (min) Increase
    1501 152 min 288 min 136 min 89.5%
    1502 128 min 280 min 152 min 118.8% 
    1503 145 min 256 min 111 min 76.6%
    1504 160 min 297 min 137 min 85.6%
    • EXAMPLE 5 Sleep Study in Human Subjects
  • For human studies, hard gelatin capsules identical to those described in Example 3 were manufactured, except that lorazepam was coated with EUDRAGIT® L 12,5 instead of EUDRAGIT® L/S 12,5 (1:1) to account for the slight differences between the gastrointestinal pHs of dogs and humans. EUDRAGIT® L 12,5 dissolves at above pH 6.0.
  • It is anticipated that, after administration of the capsules to human subjects, diphenhydramine would be released immediately and be effective for up to 4 hours. Zolpidem would be released about 2 hours after administration and reach its tmax (i.e., time to maximum concentration in plasma) about 2 hours later. Lorazepam would be released about 4 hours after administration of the capsules and reach its tmax about 6 hours post administration.
    • Other Embodiments
  • All of the features disclosed in this specification may be combined in any combination.
  • Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.
  • From the above description, one skilled in the art can easily ascertain the essential characteristics of the described embodiments, and without departing from the spirit and scope thereof, can make various changes and modifications of the embodiments to adapt it to various usages and conditions. Thus, other embodiments are also within the claims.

Claims (20)

What is claimed is:
1. A controlled-release formulation, comprising one or more compounds for aiding sleep, wherein the formulation is formulated for releasing each compound at a specific time and a specific dose in a subject after the formulation is administered to the subject.
2. The formulation of claim 1, wherein the formulation is formulated for releasing different compounds or different combinations of compounds at different time points in a subject after the formulation is administered to the subject.
3. The formulation of claim 1, wherein the formulation is formulated for releasing the one or more compounds at two or more stages, wherein, at each stage, release of a compound or a combination of compounds is initiated at a specific time in a subject after the formulation is administered to the subject.
4. The formulation of claim 3, wherein the formulation is formulated for two to twelve stages of release.
5. The formulation of claim 4, wherein the time interval between the initiation of each stage of release is 0.5 to 23 hours.
6. The formulation of claim 5, wherein the first stage is for immediate release of one or more compounds.
7. The formulation of claim 3, wherein the one or more compounds are selected from the group consisting of a barbiturate, diazepam, estazolam, flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam, triazolam, temazepam, chlordiazepoxide, alprazolam, eszopiclone, zaleplon, zolpidem, zopiclone, diphenhydramine, dimenhydrinate, doxylamine, mirtazapine, promethazine, a plant component or extract, Validol, chloral hydrate, trazodone, an opiate, an opioid, Suvorexant, glutethimide, and γ-hydroxybutyric acid.
8. The formulation of claim 7, wherein the formulation contains 0.01 mg to 100 mg of each of the one or more compounds.
9. The formulation of claim 8, wherein the formulation is a tablet or capsule for oral administration.
10. The formulation of claim 9, wherein the tablet is a multi-layered or multi-cored tablet.
11. The formulation of claim 9, wherein the tablet or capsule contains a plurality of particles, each particle including a drug core and a polymeric composition encapsulating the core, wherein the drug core contains one or more compounds for aiding sleep.
12. The formulation of claim 3, wherein the formulation is formulated for a first stage immediate release of an antihistamine, a second stage release of a benzodiazepine that starts 2-3 hours after initiation of the first stage, and a third stage release of a non-benzodiazepine sedative that starts 2-3 hours after initiation of the third stage.
13. The formulation of claim 12, wherein the antihistamine is diphenhydramine HCl, the benzodiazepine is zolpidem tartrate, and the non-benzodiazepine sedative is lorazepam.
14. The formulation of claim 13, wherein the formulation contains 50 mg of diphenhydramine HCl, 5 mg of zolpidem tartrate, and 0.5 mg of lorazepam.
15. The formulation of claim 14, wherein the formulation is a tablet or capsule for oral administration.
16. The formulation of claim 15, wherein the tablet or capsule contains a plurality of particles, each particle including a drug core and a polymeric composition encapsulating the core, wherein the drug core contains zolpidem tartrate or lorazepam.
17. The formulation of claim 16, wherein the polymeric composition includes a polymethacrylate.
18. The formulation of claim 13, wherein the formulation contains diphenhydramine HCl, zolpidem tartrate, and lorazepam as the only three active compounds.
19. A method of treating disturbed sleep or insomnia in a subject, comprising administering the formulation of claim 1 to a subject in need thereof.
20. The method of claim 19, wherein the formulation is formulated for a first stage immediate release of an antihistamine, a second stage release of a benzodiazepine that starts 2-3 hours after initiation of the first stage, and a third stage release of a non-benzodiazepine sedative that starts 2-3 hours after initiation of the third stage.
US15/234,620 2014-02-06 2016-08-11 Composition and method for aiding sleep Abandoned US20160346216A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US15/234,620 US20160346216A1 (en) 2014-02-06 2016-08-11 Composition and method for aiding sleep

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201461936566P 2014-02-06 2014-02-06
US14/614,916 US9427409B2 (en) 2014-02-06 2015-02-05 Composition and method for aiding sleep
US15/234,620 US20160346216A1 (en) 2014-02-06 2016-08-11 Composition and method for aiding sleep

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US14/614,916 Continuation US9427409B2 (en) 2014-02-06 2015-02-05 Composition and method for aiding sleep

Publications (1)

Publication Number Publication Date
US20160346216A1 true US20160346216A1 (en) 2016-12-01

Family

ID=53753899

Family Applications (2)

Application Number Title Priority Date Filing Date
US14/614,916 Active US9427409B2 (en) 2014-02-06 2015-02-05 Composition and method for aiding sleep
US15/234,620 Abandoned US20160346216A1 (en) 2014-02-06 2016-08-11 Composition and method for aiding sleep

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US14/614,916 Active US9427409B2 (en) 2014-02-06 2015-02-05 Composition and method for aiding sleep

Country Status (21)

Country Link
US (2) US9427409B2 (en)
EP (2) EP3102189B1 (en)
JP (1) JP6338683B2 (en)
KR (1) KR101774721B1 (en)
CN (2) CN110604727A (en)
AU (1) AU2015214285B2 (en)
BR (1) BR112016017742A2 (en)
CA (1) CA2934595C (en)
DK (1) DK3102189T3 (en)
ES (1) ES2759452T3 (en)
HR (1) HRP20192119T8 (en)
HU (1) HUE047654T2 (en)
MX (2) MX373821B (en)
MY (1) MY177906A (en)
NZ (1) NZ720813A (en)
PL (1) PL3102189T3 (en)
PT (1) PT3102189T (en)
RS (1) RS59800B1 (en)
SG (1) SG10202004858TA (en)
TW (1) TWI730939B (en)
WO (1) WO2015120006A1 (en)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10398662B1 (en) 2015-02-18 2019-09-03 Jazz Pharma Ireland Limited GHB formulation and method for its manufacture
WO2020096569A1 (en) * 2018-11-06 2020-05-14 Sequential Medicine Limited Composition and method for aiding sleep
US10758488B2 (en) 2010-03-24 2020-09-01 Jazz Pharmaceuticals, Inc. Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
US11400052B2 (en) 2018-11-19 2022-08-02 Jazz Pharmaceuticals Ireland Limited Alcohol-resistant drug formulations
US11400065B2 (en) 2019-03-01 2022-08-02 Flamel Ireland Limited Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state
US11426373B2 (en) 2017-03-17 2022-08-30 Jazz Pharmaceuticals Ireland Limited Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
US11504347B1 (en) 2016-07-22 2022-11-22 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11583510B1 (en) 2022-02-07 2023-02-21 Flamel Ireland Limited Methods of administering gamma hydroxybutyrate formulations after a high-fat meal
US11602512B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11602513B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11779557B1 (en) 2022-02-07 2023-10-10 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11839597B2 (en) 2016-07-22 2023-12-12 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11986451B1 (en) 2016-07-22 2024-05-21 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12138233B2 (en) 2020-02-21 2024-11-12 Jazz Pharmaceuticals Ireland Limited Methods of treating idiopathic hypersomnia
US12186296B1 (en) 2016-07-22 2025-01-07 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12440449B2 (en) 2022-02-11 2025-10-14 Jazz Pharmaceuticals Ireland Limited Alcohol-resistant drug formulations

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2015214285B2 (en) * 2014-02-06 2020-07-23 Lan Bo Chen Composition and method for aiding sleep
EP3452020A4 (en) * 2016-05-06 2020-02-19 Physician's Seal, LLC BALDRIAN COMPOSITION AND RELATED PROCEDURES
CN110075302A (en) * 2019-04-19 2019-08-02 陶燃 It is a kind of to treat depression and the composition of insomnia and application thereof
WO2025111679A1 (en) * 2023-11-30 2025-06-05 Prati, Donaduzzi & Cia Ltda Oral pharmaceutical form for biphasic release, composed of a multiparticulate system, process for preparing same and therapeutic use of oral form

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9427409B2 (en) * 2014-02-06 2016-08-30 Sequential Medicine Limited Composition and method for aiding sleep

Family Cites Families (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE229807T1 (en) * 1996-10-11 2003-01-15 Medichemie Ag CHRONIC USE OF LORAZEPAM AND DIPHENHYDRAMINE
EP1005863A1 (en) * 1998-12-04 2000-06-07 Synthelabo Controlled-release dosage forms comprising a short acting hypnotic or a salt thereof
EP1165054A4 (en) * 1999-04-06 2005-02-09 Pharmaquest Ltd Pharmaceutical dosage form for pulsatile delivery of methylphenidate
EP1064937A1 (en) * 1999-06-28 2001-01-03 Sanofi-Synthelabo Timed dual release dosage forms comprising a short acting hypnotic or a salt thereof
EP1352647A1 (en) * 1999-08-26 2003-10-15 Neurocrine Biosciences, Inc. Controlled-release sedative hypnotic compositions and method related thereto
US6485746B1 (en) * 2000-08-25 2002-11-26 Neurocrine Biosciences, Inc. Controlled-release sedative-hypnotic compositions and methods related thereto
KR100540035B1 (en) * 2002-02-01 2005-12-29 주식회사 태평양 Multi-stage oral drug controlled-release system
US20050038042A1 (en) * 2002-11-15 2005-02-17 Jenet Codd Modified release composition comprising a short-acting hypnotic for treatment of sleep disorders
US20050031688A1 (en) * 2003-08-04 2005-02-10 Ayala William J. Positive wakeup pharmaceutical sleep system with compatible pre-bedtime administration
CA2543164A1 (en) * 2003-11-05 2005-05-19 Santarus, Inc. Combination of proton pump inhibitor and sleep aid
US20060084659A1 (en) * 2004-10-19 2006-04-20 Michael Davis Augmentation of psychotherapy with cannabinoid reuptake inhibitors
GB0423964D0 (en) * 2004-10-28 2004-12-01 Jagotec Ag Dosage form
CA2590802A1 (en) * 2004-12-20 2006-06-29 Collegium Pharmaceutical, Inc. Pharmaceutical compositions for sleep disorders
WO2006133349A2 (en) * 2005-06-08 2006-12-14 Alpharma, Inc. Orally disintegrable sleep aid formulations
US20070020333A1 (en) * 2005-07-20 2007-01-25 Chin-Chih Chiang Controlled release of hypnotic agents
FR2889811B1 (en) * 2005-08-19 2009-10-09 Sanofi Aventis Sa ASSOCIATION OF A HYPNOTIC AGENT HAS LONG LASTING ACTION AND A SHORT-ACTING HYPNOTIC AGENT, A PHARMACEUTICAL COMPOSITION CONTAINING THE SAME AND ITS THERAPEUTIC USE.
US20070190130A1 (en) * 2006-02-16 2007-08-16 Mark William A Protein hydrolysate excipients
WO2008075372A1 (en) * 2006-12-18 2008-06-26 Lupin Limited Controlled release dosage forms of zolpidem
US20080248106A1 (en) * 2007-04-05 2008-10-09 Marvin Heuer Melatonin-based composition for improved sleep
US20080254121A1 (en) 2007-04-10 2008-10-16 Iomedix Sleep International Srl Multi-layer melatonin composition
US20080311162A1 (en) * 2007-05-16 2008-12-18 Olivia Darmuzey Solid form
CA2767576C (en) * 2009-07-08 2020-03-10 Charleston Laboratories Inc. Pharmaceutical compositions comprising an antiemetic and an opioid analgesic
GB201003731D0 (en) * 2010-03-05 2010-04-21 Univ Strathclyde Immediate/delayed drug delivery
IT1401142B1 (en) * 2010-07-26 2013-07-12 Ambros Pharma S R L PROCEDURE FOR THE PREPARATION OF CONTROLLED TABLETS INCLUDING MELATONIN
US20130078304A1 (en) * 2011-09-28 2013-03-28 Taiwan Biotech Co., Ltd. Controlled release formulation for treating sleep disorders
CN103550775B (en) * 2013-10-18 2017-08-25 广州共禾医药科技有限公司 A kind of anti-insomnia composition and its application and the multiphase pulse prepared using said composition understand suddenly preparation and preparation method thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9427409B2 (en) * 2014-02-06 2016-08-30 Sequential Medicine Limited Composition and method for aiding sleep

Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10758488B2 (en) 2010-03-24 2020-09-01 Jazz Pharmaceuticals, Inc. Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
US10813885B1 (en) 2010-03-24 2020-10-27 Jazz Pharmaceuticals, Inc. Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
US10959956B2 (en) 2010-03-24 2021-03-30 Jazz Pharmaceuticals, Inc. Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
US10966931B2 (en) 2010-03-24 2021-04-06 Jazz Pharmaceuticals, Inc. Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
US10987310B2 (en) 2010-03-24 2021-04-27 Jazz Pharmaceuticals, Inc. Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
US11090269B1 (en) 2010-03-24 2021-08-17 Jazz Pharmaceuticals, Inc. Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
US11207270B2 (en) 2010-03-24 2021-12-28 Jazz Pharmaceuticals, Inc. Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
US10398662B1 (en) 2015-02-18 2019-09-03 Jazz Pharma Ireland Limited GHB formulation and method for its manufacture
US11077079B1 (en) 2015-02-18 2021-08-03 Jazz Pharmaceuticals Ireland Limited GHB formulation and method for its manufacture
US11147782B1 (en) 2015-02-18 2021-10-19 Jazz Pharmaceuticals Ireland Limited GHB formulation and method for its manufacture
US11364215B1 (en) 2015-02-18 2022-06-21 Jazz Pharmaceuticals Ireland Limited GHB formulation and method for its manufacture
US11896572B2 (en) 2016-07-22 2024-02-13 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12186296B1 (en) 2016-07-22 2025-01-07 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12263150B2 (en) 2016-07-22 2025-04-01 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12263151B2 (en) 2016-07-22 2025-04-01 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12257223B2 (en) 2016-07-22 2025-03-25 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11504347B1 (en) 2016-07-22 2022-11-22 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12239625B2 (en) 2016-07-22 2025-03-04 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11602512B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11602513B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11766418B2 (en) 2016-07-22 2023-09-26 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12226389B2 (en) 2016-07-22 2025-02-18 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11826335B2 (en) 2016-07-22 2023-11-28 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11839597B2 (en) 2016-07-22 2023-12-12 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12226388B2 (en) 2016-07-22 2025-02-18 Flamel Ireland Limited Modified release gamma- hydroxybutyrate formulations having improved pharmacokinetics
US11986451B1 (en) 2016-07-22 2024-05-21 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12097176B2 (en) 2016-07-22 2024-09-24 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12097175B2 (en) 2016-07-22 2024-09-24 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12109186B2 (en) 2016-07-22 2024-10-08 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12115143B2 (en) 2016-07-22 2024-10-15 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12115145B2 (en) 2016-07-22 2024-10-15 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12115144B2 (en) 2016-07-22 2024-10-15 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12115142B2 (en) 2016-07-22 2024-10-15 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12128021B1 (en) 2016-07-22 2024-10-29 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12186298B2 (en) 2016-07-22 2025-01-07 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12138239B2 (en) 2016-07-22 2024-11-12 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12144793B2 (en) 2016-07-22 2024-11-19 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11426373B2 (en) 2017-03-17 2022-08-30 Jazz Pharmaceuticals Ireland Limited Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
WO2020096569A1 (en) * 2018-11-06 2020-05-14 Sequential Medicine Limited Composition and method for aiding sleep
CN113271929A (en) * 2018-11-06 2021-08-17 序列医学有限公司 Compositions and methods for aiding sleep
US11400052B2 (en) 2018-11-19 2022-08-02 Jazz Pharmaceuticals Ireland Limited Alcohol-resistant drug formulations
US11400065B2 (en) 2019-03-01 2022-08-02 Flamel Ireland Limited Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state
US12226377B2 (en) 2019-03-01 2025-02-18 Flamel Ireland Limited Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state
US12167991B2 (en) 2019-03-01 2024-12-17 Flamel Ireland Limited Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state
US12167992B2 (en) 2019-03-01 2024-12-17 Flamel Ireland Limited Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state
US12303478B2 (en) 2019-03-01 2025-05-20 Flamel Ireland Limited Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state
US12138233B2 (en) 2020-02-21 2024-11-12 Jazz Pharmaceuticals Ireland Limited Methods of treating idiopathic hypersomnia
US11779557B1 (en) 2022-02-07 2023-10-10 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11583510B1 (en) 2022-02-07 2023-02-21 Flamel Ireland Limited Methods of administering gamma hydroxybutyrate formulations after a high-fat meal
US12295926B1 (en) 2022-02-07 2025-05-13 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12440449B2 (en) 2022-02-11 2025-10-14 Jazz Pharmaceuticals Ireland Limited Alcohol-resistant drug formulations

Also Published As

Publication number Publication date
HK1222580A1 (en) 2017-07-07
CA2934595A1 (en) 2015-08-13
CA2934595C (en) 2022-06-21
BR112016017742A2 (en) 2018-06-26
EP3102189A4 (en) 2017-07-12
PL3102189T3 (en) 2020-05-18
NZ720813A (en) 2021-12-24
DK3102189T3 (en) 2019-12-02
KR101774721B1 (en) 2017-09-04
AU2015214285B2 (en) 2020-07-23
TW201538160A (en) 2015-10-16
HRP20192119T8 (en) 2020-08-21
CN105899194B (en) 2019-10-25
WO2015120006A1 (en) 2015-08-13
JP6338683B2 (en) 2018-06-06
AU2015214285A1 (en) 2016-06-23
US9427409B2 (en) 2016-08-30
EP3632416A1 (en) 2020-04-08
RS59800B1 (en) 2020-02-28
MX2016010051A (en) 2017-05-04
EP3102189B1 (en) 2019-09-04
MX373821B (en) 2020-03-24
CN105899194A (en) 2016-08-24
TWI730939B (en) 2021-06-21
HUE047654T2 (en) 2020-05-28
PT3102189T (en) 2019-12-11
JP2016536371A (en) 2016-11-24
US20150216811A1 (en) 2015-08-06
KR20160057479A (en) 2016-05-23
HRP20192119T1 (en) 2020-03-06
SG10202004858TA (en) 2020-06-29
MX2020003139A (en) 2020-07-28
MY177906A (en) 2020-09-25
EP3102189A1 (en) 2016-12-14
CN110604727A (en) 2019-12-24
ES2759452T3 (en) 2020-05-11

Similar Documents

Publication Publication Date Title
US9427409B2 (en) Composition and method for aiding sleep
AU2005307052B2 (en) Taste-masked multiparticulate pharmaceutical compositions comprising a drug-containing core particle and a solvent-coacervated membrane
AU2006281334B2 (en) Combination of a long-acting hypnotic agent and a short-acting hypnotic agent and therapeutic use of same
CN103417505B (en) There is huperzine controlled release preparation of two-phase drug release behavior and preparation method thereof
US20110003005A1 (en) Methods of Treating PDNV and PONV with Extended Release Ondansetron Compositions
CN103648485A (en) Pharmaceutical composition of rosuvastatin calcium
MX2012013119A (en) PHARMACEUTICAL COMPOSITIONS THAT INCLUDE HYDROMORPHONE AND NALOXONE.
US20110135724A1 (en) Ondansetron Orally Disintegrating Tablet Compositions for Prevention of Nausea and Vomiting
HK1230943A1 (en) Composition and method for aiding sleep
HK1230943B (en) Composition and method for aiding sleep
HK40013826A (en) Composition and method for aiding sleep
HK1222580B (en) Composition and method for aiding sleep
US20080312166A1 (en) Reversal core pharmaceutical system and method
US20200138748A1 (en) Composition and method for aiding sleep
EP3876915A1 (en) Composition and method for aiding sleep
US11759471B2 (en) Modified release pharmaceutical composition and method for the treatment of mental disorders
WO2018044895A1 (en) Immediate release dosage forms with abuse deterrence and alcohol resistance
TW202017565A (en) Composition and method for aiding sleep
US20200306193A1 (en) Melatonin mini-tablets and method of manufacturing the same
Lancaster Which interventions help individuals to stop smoking?

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION