Composition and method for aiding sleep

This application claims priority to U.S. Provisional Patent Application No. 61/936,566, filed on Feb. 6, 2014, the entire content of which is hereby incorporated by reference herein.

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 focus 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.

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 incarnata )); 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.

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 γ-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, kit-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 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.

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.