Ultra low dose doxepin and methods of using the same to treat sleep disorders

Abstract

The invention relates to doxepin, pharmaceutically acceptable salts and prodrugs of doxepin; compositions containing the same, and the use of any of the aforementioned for the treatment of sleep disorders.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 60 / 854,399 filed on Oct. 25, 2006 entitled ULTRA LOW DOSE DOXEPIN AND METHODS OF USING THE SAME TO TREAT SLEEP DISORDERS; U.S. Provisional Application No. 60 / 873,056, filed on Dec. 6, 2006, entitled COMBINATION THERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; and U.S. Provisional Application No. 60 / 910,586, filed on Apr. 6, 2007, entitled COMBINATION THERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; each of which applications is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The invention relates to ultra low doses of doxepin, as well as pharmaceutically acceptable salts and prodrugs of the same; compositions containing the same, and the use of any of the aforementioned for the treatment of sleep disorders.[0004]2. Description of the Related Art[0005]Sleep is essential for health and...

AI Technical Summary

Benefits of technology

[0041]It also should be mentioned that food can have an effect on the pharmacokinetics of sleep medication. The term “food effect” refers to a somewhat unpredictable phenomenon that can influence the absorption of drugs from the gastrointestinal tract following oral administration. The food effect can be designated “negative” when absorption is decreased, or “positive” when absorption is increased and manifested as an increase in oral bioavailability (as reflected by total exposure, usually defined as AUC). Alternatively, food effects can refer to changes in maximum concentration (Cmax), or the time to reach maximum concentration (Tmax)), independently of overall absorption. As a result, some drugs have to be taken in either fasted or fed conditions to achieve the optimum effect. For example, patients may be instructed to take a drug with a meal, before a meal (e.g., one hour before a meal), or after a meal (e.g., two hours after a meal). However, many drugs are unaffected by food, and thus, can be taken in a fasted or a fed condition.

[0042]Accordingly, some embodiments relate to methods of improving the pharmacokinetics of doxepin, as well as the salts and prodrugs of such substances in a patient. In particular, the time to reach maximum concentration, Tmax, can be minimized by administering the drug without food. Also, the time to reach maximum concentration can be increased by administering the substance with food. In addition, in a different embodiment, the total effective amount of drug that the patient receives can be maximized by administering the substance with food, while in other embodiments the oral bioavailability can be decreased by administering the substance without food. Because plasma concentrations and half-lives are already known to vary from patient to patient, knowledge of the food effect for a substance can help patients and physicians to eliminate this additional source of dosing uncertainty, to improve safety and tolerability, and improve therapies that utilize doxepin, or salts / prodrugs of the same. For example, as described more fully elsewhere herein, depending on the effect desired, the particular ultra low dose substance, such as an ultra low dose of doxepin, can be taken with food; it can be taken after the patient has gone without food for a period of time; and / or it can be taken some period of time prior to consuming food.

[0043]In some aspects, information regarding a food effect can be given to a patient or included with the drug. For example, instructions may be provided to patients receiving doxepin therapy or health care professionals involved in treatment of those patients that the drug should be administered with food, or at least in relatively close proximity to eating food or eating a meal (for example, within one hour or less). By way of example, such instructions could be provided orally or in written form. Some exemplary written forms include a label associated with the drug, on the container for the drug, packaged with the drug, or separately given to the patient apart from the drug. The invention further includes a package of any of the ultra low dose substances described herein with such written instructions associated therewith.

[0044]As mentioned, the ultra low dose substance can be administered without food or in a fasted state. For example, doxepin, prodrug, or salt can be administered at least about 30 minutes to about 6 hours after consuming food. More preferably, the substance can be taken at least about 1 hour to about 6 hours after consuming food. In some aspects the substance can be taken at least about 1, 2, 3, 4, 5 6 or more hours after consuming food.

[0045]Also, the ultra low dose substance can be administered at least about 30 minutes to about 6 hours before consuming any food, or more preferably, at least about 1 hour to about 3 hours before consuming food. In some aspects, the ultra low dose substance can be administered about 1, 2, 3 or more hours before food is consumed.

[0046]It should be understood that the above-mentioned “food effect” methods and uses can further include the use of doxepin, prodrugs or salts of the same in combination with other insomnia or sleep medications. For example, the methods can include the use of one or more of ramelteon, eszopiclone, zolpidem tartrate, zaleplon or the like. Further, the methods can include the use of one or more of 5-HT2 antagonists (such as ketanserin), H3 agonists, orexin antagonists, noradrenergic antagonists, galanin agonists, CRH antagonists, Gaboxadol, other GABA-A direct antagonists, GABA reuptake inhibitors (such as tiagabine), growth hormone and growth hormone agonists, estrogen and estrogen agonists, melatonin agonists or the like. Other examples of medications and substances that can be used in combination with ultra low doses as described herein can be found in U.S. Provisional Application No. 60 / 873,056, filed on Dec. 6, 2006, entitled COMBINATION THERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; and U.S. Provisional Application No. 60 / 910,586, filed on Apr. 6, 2007, entitled COMBINATION THERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; each of which applications is incorporated herein by reference in its entirety.

Problems solved by technology

Various side effects are associated with the commonly used medications.

While these agents have proven to be efficacious and relatively safe, benzodiazepines are associated with a multitude of adverse effects, including residual daytime sedation (“hangover”), amnesia, memory loss and respiratory depression.

Tolerance to the hypnotic effects of the benzodiazepines is common and abrupt discontinuation can result in withdrawal symptoms such as agitation, perceptual changes, confusion, disorientation and insomnia.

As a result, many physicians are reluctant to prescribe, and patients are reluctant to take, these drugs for chronic use in treating insomnia.

Even though there are very limited data to support the use of trazodone for insomnia and it is associated with undesirable side effects, trazodone is often prescribed because it is a non-scheduled agent, meaning non-addictive, unlike the benzodiazepines and other GABA-receptor agonists which are approved for the treatment of insomnia.