Improvement of movement during or after sleep

Abstract

The present invention generally relates to improving sleep, behavior after sleep, or both, and more specifically to improving without inducing post-sleep effects that impair the ability of an individual to operate a machine or vehicle.

Description

Technology Field

[0001] (Cross-reference of related applications)

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 730,467, filed on September 12, 2018, which is co-pending and whose contents are incorporated herein as fully presented. Background Technology

[0003] Improving one or both of sleep quality and duration can be achieved by using medications proven to be safe and effective for such improvements. Many of these drugs act directly by reducing wakefulness, that is, by inducing a soporific effect. This soporific effect may explain the effects of these drugs wholly or in part.

[0004] Hypnotic effects persist beyond normal sleep duration and entail potential liabilities that may manifest during the treated individual's activities the following day. In such situations, these effects on the day following treatment can negatively impact the individual's ability to perform various tasks requiring wakefulness in a safe manner—that is, without causing potential harm to oneself or others as a result of reduced attention and residual drowsiness. In particular, while many of these drugs are effective in improving sleep quality or duration, they are known to affect an individual's ability to safely operate machinery or vehicles. Specifically, the marketing of these drugs is restricted through explicit warnings regarding their use when the individual must engage in such activities, such as avoiding the possibility of driving impairment or operating machinery.

[0005] For example, AMBIEN® prescribing information includes a warning that "the higher the morning blood concentration after using the 10 mg dose, the greater the risk of impaired driving and other activities requiring full attention the following day." These effects are exacerbated by the co-administration of ZOLPIDEM™ or other central nervous system depressants, and the prescribing information warns that such concomitant use "may increase drowsiness and psychomotor disturbances, including impaired driving ability."

[0006] Likewise, prescribing information for BELSOMRA® warns of the “risk of attentional and motor coordination disorders, including impaired driving,” and that this risk increases with increasing dose. Individuals taking a 20 mg dose of BELSOMRA® are explicitly warned about “driving and other activities requiring full mental attention the following day.” Clinical studies have shown “clinically significant impairment of driving performance in some subjects,” and as a result, even patients taking lower doses of BELSOMRA® are warned to be cautious about the possibility of impaired driving due to variability in individual sensitivity. means of solving the problem

[0007] The present invention relates to the preferential use of tasimelteon over other drugs known to be useful for treating sleep disorders, particularly those capable of inducing a next-day soporific effect, in patients who are willing or able to operate a car or machinery after sleep (e.g., the next day) following treatment with a sleep aid. As discussed herein, the discovery of the preferential use of tasimelteon in such situations arose from the unexpected results of a clinical study designed to evaluate the next-day adverse effects resulting from the use of tasimelteon.

[0008] Accordingly, the present invention provides a method for improving sleep, post-sleep performance, or both, of an individual who is evaluated to need treatment with a drug effective for achieving improvement in sleep, post-sleep performance, or both, said method comprising, first, a step of determining whether the individual intends to operate a vehicle or machine during the post-sleep period after treatment. Once such determination is made, if it is determined that the individual intends to operate a vehicle or machine during the post-sleep period after treatment, said individual is treated by orally administering an amount of tasimelteon effective for improving sleep, post-sleep performance, or both. Improvement of sleep may include improving one or both of the quality of sleep and the duration of sleep.

[0009] On the other hand, if such a decision is not made, the subject is subsequently treated by administering any drug known to improve sleep (e.g., sleep quality or duration of sleep) and / or sleep mobility, which is effective in achieving one or both of the improvement of sleep and sleep mobility. Accordingly, this aspect of the invention may include the step of treating the subject by administering 20 mg of tasimelteon before bedtime, by determining whether the subject has the intention or ability to operate a vehicle or machine during the post-treatment period.

[0010] Consequently, the present invention may include an improvement in a method comprising treating an individual who needs to avoid driving impairment or operate machinery during the day following sleep after drug administration to improve sleep and / or post-sleep mobility, wherein the improvement comprises using 20 mg of tasimelteon administered before bedtime as the drug.

[0011] Drugs known to improve sleep (e.g., one or both of sleep quality and sleep duration) include, for example, benzodiazepines (e.g., diazepam, estazolam, etizolam, flurazepam, lorazepam, midazolam, nitrazepam, nitrazolam, quazepam, temazepam, and triazolam), barbituates (e.g., amobarbital, pentobarbital, phenobarbital, secobarbital, and sodium thiopental), melatonin, This includes melatonin agonists (e.g., agomelatine, piromelatine, ramelteon, and tasimelteon), and non-benzodiazepine "z-drugs" (e.g., zolpidem, zopiclone, eszopiclone, and zaleplon). Likewise, the dosage of these agents and the regimen of administration for improving sleep are well known, for example, through prescribing information made publicly available by the marketers of these drugs.

[0012] Diagnostic criteria for selecting patients to be treated with sleep aids, including medications that affect sleep quality and duration, are also known. As previously mentioned, the nature of prescribing information and accompanying safety warnings for numerous sleep aids requires a healthcare professional to diagnose the patient, select the medication for treatment, understand the nature of the patient's activities that may be affected, and prescribe medications that can cause next-day soporific effects the day after use the previous night.

[0013] Therefore, in order for a medical professional (e.g., attending physician) to appropriately inform the patient of adverse events following any sleep, if the prescribed medication may impair the ability to drive or operate machinery, it may be necessary for the attending medical professional to determine whether the patient will operate the vehicle. The machinery used herein refers to a tool capable of determining whether the use of the machinery can be performed without increasing the risk to the operating object or others due to mental attention during operation by a type or object of mechanical or electromechanical devices.

[0014] To ensure the safety of an individual considering drug treatment to address a sleep disorder, it may be necessary to caution the individual regarding driving or operating machinery the following day, or to restrict access to potentially more effective drugs resulting from safety concerns based on the effects of the following day. Accordingly, the present invention provides an alternative to current treatment practices in which tasimelteon may be selected for administration when it is determined that alternative therapies would provide adverse effects after sleep (e.g., the following day) for the individual to be treated who is capable of driving or operating machinery.

[0015] As mentioned above, one aspect of the present invention is HETLIOZ ®It may include the use of tasimelteon, also known as tasimelteon. Pharmaceutical compositions containing tasimelteon and the uses of tasimelteon are described in the art. Tasimelteon is approved for use as a human drug for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) and is available in a pharmaceutical formulation (capsule) of 20 mg directed for use before bedtime at the same time every night. Pharmaceutically, tasimelteon is an agonist of MT1R and MT2R melatonin receptors located in the suprachiasmatic nucleus (SCN), a brain region associated with the biological clock. Involvement of these receptors by melatonin is believed to regulate circadian rhythms, including the sleep / wake cycle. Tasimelteon, consistent with its receptor binding profile, demonstrates potent chronobiotic activity in preclinical models of acute phase-shifting and chronic re-entrainment.

[0016] Tasimelteon itself is claimed in Claim 7 of U.S. Patent No. 5,856,529. The '529 patent contains additional claims, including claims for a genus of compounds of which tasimelteon is a member, as well as claims for the use of this genus to treat sleep disorders as well as circadian rhythm disorders by administering an effective amount of tasimelteon. This patent describes tasimelteon as a melatonin agonist and infers that melatonin agonists would be useful for the treatment of conditions affected by melatonin activity, as well as for further studies on melatonin receptor interactions. This patent lists depression, jet lag, work-shift syndrome, and sleep disorders among other possible therapeutic uses. Elsewhere, the patent discloses that compounds within the genus of compounds in which tasimelteon is a member are useful as melatonin preparations for the treatment of sleep disorders, seasonal depression, circadian changes, melancholia, stress, appetite control, benign prostatic hyperplasia, and related conditions.

[0017] In addition to Tasimelteon, which is approved for administration at 20 mg daily before bedtime at the same time every day, U.S. Patent Application Publication No. 20090105333 reports the finding that an effective human dosage for Tasimelteon may be in the range of 10 to 100 mg / day for use in sleep disorders and circadian rhythm disorders, with the additional explanation that the exact dosage may vary depending on the particle size of Tasimelteon and the body size of the patient being treated. Furthermore, this patent describes a 20 mg oral unit formulation of Tasimelteon and clinical trials using Tasimelteon at daily doses of 10 mg, 20 mg, 50 mg, and 100 mg in a study of Tasimelteon on subjects with a sleep-wake cycle progression type that lasts for 5 hours—that is, a type of sleep-wake cycle progression that a subject traveling across the Atlantic from New York to London by jet plane might experience. The results of this study indicate that treatment produces positive outcomes compared to placebo, altering dim light melatonin onset and sleep efficacy. Specific details for implementing the invention

[0018] The effectiveness of tasimelteon in addressing post-sleep effects (e.g., the next day) observed during the use of other medications prescribed as sleep aids can be clinically demonstrated. Specifically, a clinical trial investigating the effects of tasimelteon on driving found that a 20 mg dose of tasimelteon did not affect driving the following day and did not induce results significantly different from the placebo control group. In the same study, when zopiclone was used as a positive control, driving ability was found to be significantly impaired compared to the negative placebo control group.

[0019] In this study, 48 healthy volunteers operated a car driving simulator in the morning after being administered 20 mg of tasimelteon, 7.5 mg of zopiclone, or a placebo at bedtime. The volunteers were instructed to operate the driving simulator at a speed of 55 mph for about one hour while maintaining lane position.

[0020] Table 1 below shows the timing of relevant steps in the study design in relation to clock time and the administration of tasimelteon, zopiclone, or placebo.

[0021] [Table 1]

[0022]

[0023] Driving performance is evaluated using multiple validated metrics, including the Standard Deviation from Lateral Position (SDLP), a measure of lane weaving. The results are shown in Table 2 below.

[0024] [Table 2]

[0025]

[0026] As can be seen from the above, tasimelteon 20 mg demonstrated no driving impairment after sleep (the next day) compared to placebo when evaluated 9 hours after administration, but zopiclone 7.5 mg was associated with a significant and substantial lane weaving effect compared to placebo.

[0027] Compared to the control group, an SDLP of 4.4 cm is considered to correspond to a driving impairment associated with a blood alcohol content (BAC) of 0.05%, which is the threshold for drunk driving in many countries.

[0028] Given the expectation that tasimelteon may be useful in the treatment of jet lag (JLD), the no effect of tasimelteon 20 mg on driving the following day is significant. The tasimelteon JLD clinical program demonstrates significant benefits for subjects experiencing a circadian progression of 5 to 8 hours.

[0029] Other indications are similarly applicable to similar treatments without causing or endangering post-sleep / post-administration / next-day residual effects that may impair mobility, including mobility involving the operation of automobiles or machinery. These indications include circadian rhythm disorders and sleep disorders, such as, for example, non-24-hour sleep disorders, transient insomnia, chronic insomnia, shift work disorders, and delayed sleep stage disorders. Other such disorders will be apparent to those skilled in the art.

[0030] The terms used herein are merely for describing modes of measurement and are not intended to limit the content of this disclosure. The singular forms “a,” “an,” and “the” used herein are intended to include the plural forms unless otherwise evident from the context. It will be understood that as used herein, the terms “comprises” and / or “comprising” specify the presence of the mentioned features, integers, steps, operations, elements, and / or components, but do not make impossible the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. “Optional” or “optionally” means that an event or situation described below may or may not occur, and means that the description includes cases where the event occurs or does not occur.

[0031] The corresponding structures, materials, actions, and equivalents of all means or steps and functional elements in the following claims are intended to include any structures, materials, and actions for performing a function in combination with other specifically claimed elements. The description of this disclosure is provided for illustrative and illustrative purposes, but is not intended to be limited to or whole of the disclosed form. Many variations and modifications will be apparent to those skilled in the art without departing from the scope and spirit of this disclosure. Any selected and described embodiments are presented to best illustrate the principles and practical applications of this disclosure and to enable those skilled in the art to understand the disclosure of various embodiments having various variations suitable for the specific use being considered.

Claims

Claim 1 A pharmaceutical composition for improving post-sleep behavior in an individual who intends to operate a vehicle or machine during a post-sleep period, comprising: an amount of tasimelteon effective for improving post-sleep behavior; and a pharmaceutically acceptable excipient or carrier, wherein the post-sleep period comprises a period beginning about 9 hours after the administration of the drug, and the post-sleep behavior is behavior in operating a vehicle or machine during the post-sleep period. Claim 2 A pharmaceutical composition formulated for oral administration in claim 1. Claim 3 A pharmaceutical composition according to claim 1, comprising 20 mg of tasimelteon. Claim 4 delete Claim 5 delete Claim 6 A pharmaceutical composition according to claim 1, wherein the individual suffers from a circadian rhythm disorder or a sleep disorder. Claim 7 A pharmaceutical composition according to claim 1, wherein the individual suffers from jet lag disorder. Claim 8 A pharmaceutical composition according to claim 1, wherein improving post-sleep behavior includes avoiding driving impairment during the post-sleep period. Claim 9 A pharmaceutical composition according to claim 1, wherein improving behavior after sleep is characterized by a reduction in the next-day soporific effect. Claim 10 delete Claim 11 delete

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