FORMULATIONS AND METHODS FOR ALLEVIATING SLEEP DISORDERS
CROSS-REFERENCE TO RELATED APPLICATON
[0001] This application claims priority to United States Provisional Patent Application Serial No. 63/565,658, which was filed on March 15, 2024. The disclosure of United States Provisional Patent Application Serial No. 63/565,658 is hereby incorporated by reference in its entirety.
TECHNICAL FIELD
[0002] The present disclosure is directed to formulations for alleviating a sleep disorder or improving sleep. The formulations may be adapted for oral administration. The present disclosure is also directed to methods for alleviating a sleep disorder in a subject in need thereof and to methods for improving sleep in a subject in need thereof.
BACKGROUND
[0003] Circadian rhythm sleep-wake disorders (also known as circadian rhythm sleep disorders or referred to simply as sleep disorders) are characterized by persistent or recurrent patterns of sleep disturbance related primarily to alterations of the circadian rhythm system or the misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. For example, delayed sleep-wake phase disorder is a commonly encountered circadian rhythm sleep-wake phase disorder and is characterized by a shifting of the sleep-wake cycle to later hours. Other circadian rhythm sleep disorders include jet lag disorder, shift work sleep disorder, advanced sleep-wake phase disorder, irregular sleep-wake rhythm disorder, and non-24-hour sleep-wake rhythm disorder. Sleep disorders may be encountered in subjects with various neurological conditions. Sleep disorders, irrespective of underlying cause, can have substantial negative impacts on quality of life, physiologic functioning, and overall health, and can lead to increased risk for metabolic disturbances, coronary disease, cancer, psychiatric disorders, or other chronic diseases. [0004] Melatonin may be prescribed or taken over the counter for a wide range of pediatric and adult patients to solve their sleep problems, typically by administration of a sleep-inducing amount when sleep is desired. Melatonin and melatonin receptor agonists can bind to and activate the melatonin receptors, MTi and MT2. Although melatonin and the melatonin receptor agonists may have different affinities for each of the two melatonin receptors, they are generally considered physiologically nonselective, and the melatonin receptor agonists may function similarly to melatonin itself. This notwithstanding, activation of the MT2 receptor may be more beneficial than activation of the MT 1 receptor for shifting sleep timing. Therefore, drugs with higher activity activating the MT2 receptor may be preferred in certain aspects.
[0005] Melatonin may have two modes of action. First, at various doses, melatonin may shift sleep timing earlier or later depending on when the drug is taken in the melatonin phase response curve. Second, at higher doses, melatonin may act as a weak hypnotic and may be sleep-inducing. The phase-shifting effect of melatonin may be effective at much lower doses (for example, an order of magnitude lower) than doses needed for a hypnotic effect. Melatonin receptor agonists may have similar modes of action. For circadian rhythm sleep disorders involving advancing or delaying sleep phase, melatonin or a melatonin receptor agonist may need to be taken at specific times and doses.
[0006] Despite a relatively broad acceptance of melatonin and melatonin receptor agonists being used to treat circadian rhythm sleep disorders, there remains a general lack of knowledge around melatonin as a therapeutic and the complicated nature of the timing of administration. Accordingly, the effectiveness of melatonin in treating persistent sleep disorders is limited. [0007] Other active pharmaceutical ingredients (APIs) are known to be hypnotics useful for treating sleep disorders, including benzodiazepines, non-benzodiazepine GABAA receptor agonists, orexin receptor antagonists, and some antidepressants. Other drugs outside these classes may also have hypnotic effects in addition to other therapeutic effects. For example, clonidine is an agonist of central nervous system alpha-adreno receptors or adrenergic receptors indicated for the treatment of hypertension but also exhibits hypnotic activity that may be highly effective in treating sleep disorders compared to some approved sleepinducing APIs. While hypnotics may provide insomnia relief upon administration, they often do not resolve recurring sleep disorders.
[0008] Dosing regimens of multiple APIs for sleep disorders have been explored in the past. However, it is often difficult to adhere to a regimen involving multiple dosings of the same or different drugs at different times, and such adherence is particularly difficult in individuals having swallowing problems, in children, and in situations where specific timing of each dosing is required or dosing requires waking the patient to comply with an administration protocol. As a result, such regimens often have poor adherence and results. [0009] Accordingly, a need exhibits for improved treatments for alleviating sleep disorders or for improving sleep and particularly for effective and convenient treatments for alleviating sleep disorders or improving sleep that encourage patient compliance and are effective.
SUMMARY OF THE DISCLOSURE
[0010] It is therefore an object of the present disclosure to provide formulations and methods for alleviating sleep disorders or improving sleep.
[0011] The formulations and methods may comprise, consist of, or consist essentially of the elements of the formulations and methods as described herein, as well as any additional or optional element described herein or otherwise useful in the manufacture or use of formulations or methods of treating a patient in need of improved sleep.
[0012] One aspect of the present disclosure is directed to formulations for oral administration. The formulations may comprise (a) an immediate-release layer comprising at least one of melatonin and a melatonin receptor agonist (MRA) in an amount effective to shift sleep timing in a subject to an earlier time than the subject would experience in the absence of the melatonin or MRA, (b) a delayed-release layer comprising a sleep-inducing hypnotic in an amount effective to induce sleep in the subject, and (c) an outer delayed- release component. The delayed-release component may be operable to delay release of the hypnotic until the melatonin or MRA has exhibited its effect to shift sleep timing in a subject. [0013] Another aspect according to the present disclosure is directed to methods for alleviating a sleep disorder in a subject. The methods may comprise orally administering a formulation according to the present disclosure to the subject from about one to about four hours prior to a desired sleeping time.
[0014] Another aspect according to the present disclosure is directed to methods for improving sleep in a subject. Within the present disclosure, improved sleep includes one or more of adjusting or stabilizing the timing of sleep onset, reducing the time it takes to go to sleep after bedtime (sleep onset latency [SOL]), extending sleep duration, and improving sleep quality or sleep stability (e.g., reducing number or duration of wake ups during sleep time or increasing rapid-eye-movement or REM sleep). The methods may comprise orally administering a formulation according to the present disclosure to the subject from about one to about four hours prior to a desired sleeping time.
[0015] Another aspect of the present disclosure is directed to a formulation for alleviating a sleep disorder or improving sleep. The formulation may comprise a capsule-in-capsule dose. The capsule-in-capsule dose may include (a) an outer capsule enclosing melatonin or a melatonin receptor agonist in an amount effective to shift sleep timing in a subject to an earlier time than the subject would experience in the absence of the melatonin or the melatonin receptor agonist, and (b) an inner capsule enclosing a sleep-inducing hypnotic in an amount effective to induce sleep in the subject. The outer capsule may allow for an immediate-release of the melatonin or the melatonin receptor agonist. The inner capsule may include a delayed-release component operable to delay release of the hypnotic from the inner core until the melatonin or the melatonin receptor agonist has exhibited its effect to shift sleep timing in the subject. The inner capsule may be disposed within the outer capsule to form a nested arrangement. The capsule-in-capsule dose may be adapted for oral administration.
[0016] One or more aspects according to the present disclosure may advantageously provide formulations and methods affording a combination therapy for sleep disorders or improving sleep that is effective and convenient. The formulations and methods may improve patient compliance with a prescribed or recommended dosing regimen to alleviate sleep disorders or to provide improvements in sleep, including improvements in the timing of sleep onset, sleep duration, or sleep quality or stability. In an aspect of the present disclosure, a combination therapy may require only one administration and avoid the need to wake a subject and administer a second drug to achieve these benefits. The formulations may therefore be conveniently used to improve and reinforce healthy sleep habits. These and additional advantages of the present disclosure will be more fully apparent in view of the following detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] The foregoing and other features of the present disclosure will become more fully apparent from the following description, taken in conjunction with the accompanying drawings. Understanding that these drawings depict only several aspects in accordance with the disclosure and are, therefore, not to be considered limiting of its scope, the disclosure will be described with additional specificity and detail through use of the accompanying drawings. One of skill in the art may appreciate that certain features may be optional and that features or aspects of one example may be utilized or combined with other features highlighted in another example. Further, each and every aspect shown and described may not be necessary; rather, various aspects are shown and/or described as potential example features that may be included.
[0018] Fig. 1 shows a section of a schematic of a formulation in the form of a tablet according to one aspect of the present disclosure;
[0019] Fig. 2 shows a graph depicting the in vitro release of a first API (here, melatonin) and a second API (here, clonidine) from the formulation according to an aspect of the disclosure as absorbance (y-axis) as a function of time (x-axis, minutes), as described in Example 1;
[0020] Fig. 3 shows gamma scintigraphic views of a radio-labeled inner core in a formulation according to one aspect according to the present disclosure at 0, 1.5, 3 and 3.5 hours after oral administration of the formulation to a subject, as described in Example 2; and [0021] Fig. 4 shows a graph depicting blood plasma concentrations of melatonin (V) and clonidine (□) after separate administration of immediate-release formulations and of melatonin (A) and clonidine (o) after clinical administration of a formulation according to one aspect of the present disclosure, as described in Example 2.
[0022] Fig. 5 shows an example flow chart outlining a tableting process that may be used according to aspects of the present disclosure.
[0023] Fig. 6 illustrates an in vitro analysis of the release of active agents in formulations according to aspects of the present disclosure. [0024] Fig. 7A and 7B illustrate an in vitro analysis of the release of active agents tasimelteon (5 mg and 20 mg, respectively) and clonidine in formulations according to aspects of the present disclosure, Examples 2 and 3
DETAILED DESCRIPTION
[0025] In this detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative examples described in the detailed description, drawings, and potential points of novelty are not meant to be limiting. Other aspects may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented here. It will be readily understood that the aspects of the present disclosure, as described herein, and as examples are illustrated in the Figures, may be arranged, substituted, combined, and designed in a wide variety of different configurations, all of which are explicitly contemplated and make part of this disclosure.
[0026] Unless otherwise stated or context dictates otherwise, the use of the term “or” herein is the inclusive, and not the exclusive, use. For example, a list of “A, B, or C” includes either A, B, or C individually; A and B; B and C; A and C; or A, B, and C. Any percentages disclosed herein are percentages by weight unless otherwise indicated. Any reference to an amount of active ingredient refers to the active itself, notwithstanding the active being provided in a salt or other form.
[0027] As used herein, “an effective amount” refers to the amount of active agent required to confer the indicated therapeutic effect on the subject. Effective amounts vary, as recognized by those skilled in the art, depending on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size, gender and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. Empirical considerations, such as the half-life, generally will contribute to the determination of the dosage. Although it is generally preferred that a maximum dose of the individual active agent or combinations thereof be used, that is, the highest safe dose according to sound medical judgment, in some cases it may be beneficial to administer less than the maximum safe dose. Frequency of administration may be determined and adjusted over the course of therapy, and is generally, but not necessarily, based on treatment or suppression or amelioration or delay of a target disease or disorder.
[0028] Aspects of this disclosure are drawn to formulations and methods for alleviating a sleep disorder or improving sleep. The formulations may be adapted for oral administration. Example formulations may be one or more tablets, including (a) an immediate-release later of a first API, and (b) a delayed-release layer comprising a second API. The delayed-release layer may include a delayed-release component. The first API may include melatonin or a melatonin receptor agonist. The second API may include a hypnotic, such as clonidine, benzodiazepines, non-benzodiazepine GABAA receptor agonists, orexin receptor antagonists, and some antidepressants. The delayed-release component may controllably release the second API at a time after the first API has exhibited a physiological effect in a subject. Another example formulation may include one or more dual-release capsules or capsule-incapsule formulations. An inner capsule may include a second API and, optionally, a delayed- release component. A delayed-release component may be the inner capsule itself, a separate component, or a combination of the two. An outer capsule may include a first API. The inner capsule and the first API may be encapsulated within the outer capsule. The methods may comprise orally administering a formulation according to the present disclosure to the subject from about one to about four hours prior to a desired sleeping time. [0029] In some aspects of the present disclosure, a low dose of an active agent with sleepinducing or sleep phase-modifying properties may be administered to achieve the desired effects (e.g., sleep induction or sleep phase modification). In some aspects, for example, this active agent may be melatonin or a melatonin receptor agonist. In certain aspects, a low or high dose of melatonin or melatonin receptor agonist may be administered to subject to shift the sleep phase, and in additional or alternative aspects, a high dose of melatonin or melatonin receptor agonist may be administered to serve as a hypnotic to induce sleep.
[0030] Circadian rhythm disorders, sleep-wake cycle disorders, circadian misalignment, and circadian dysregulation may generally refer to abnormal timing between suprachiasmatic nucleus (SCN) rhythms and behavior. Endogenous biological clocks, orchestrated by the SCN, time the circadian rhythms that synchronize physiological and behavioral functions in humans. The circadian system is understood to be a multioscillator system. In addition to the central pacemaker in the hypothalamic SCN, the circadian system includes peripheral oscillators in many organs and cells of the body (possibly every organ and nearly every cell). The circadian system influences most physiological processes, including sleep, alertness, and cognitive performance.
[0031] Circadian rhythm dysregulation has significant deleterious health consequences. For example, circadian dysregulation affects metabolism at the genetic, cellular, and system levels, resulting in impaired glucose tolerance and insulin resistance and increased risk of metabolic syndrome, diabetes, and obesity. Further, emerging evidence points to a bidirectional relationship between circadian homeostasis and neurodegeneration, suggesting that circadian function might have an important role in the progression of neurodegenerative disorders.
[0032] The impact of the circadian system on health is much broader than sleep. Many disease states may be caused or exacerbated by exposure to circadian misalignment (e.g., impaired cognition, mood disorders, cardiovascular disease, hypertension, diabetes, obesity, gastrointestinal disorders, immune disorders, cancer, and reproductive disorders), or the consequential recurrent and chronic sleep deficiency.
[0033] Circadian misalignment can have profound adverse metabolic consequences. Circadian misalignment and disturbed sleep are independent risk factors for developing obesity and diabetes. As a component of circadian misalignment, the mistiming of food intake, i.e., during the biological night, has been shown to impair glucose tolerance and pancreatic beta cell function, and may reduce energy expenditure. Extensive evidence also links shift work with numerous gastrointestinal disorders.
[0034] The circadian system influences cardiovascular function, including blood pressure regulation, cardiac sympathovagal balance, platelet activation, and fibrinolysis. Circadian misalignment in shift work has also been linked to autoimmune disorders and impaired immune function. Other diseases that are associated with circadian misalignment and sleep disruption may be mediated by immunological mechanisms: heart disease, metabolic syndrome, stroke, and cancers all share inflammation as a risk factor or modifier.
[0035] In addition to health issues, subjects with a circadian rhythm disorder may experience difficulties with school or work, may develop other sleep issues or sleep disorders, especially chronic insomnia, may develop an alcohol or substance use disorder, or may experience daytime sleepiness and related accidents or injuries.
[0036] Specific circadian rhythm disorders include advanced or delayed sleep-wake phase disorder, irregular or non-24-hour sleep-wake rhythm disorder, and shift work, or jet lag disorder. The type of disorder is based on the pattern of sleep and wakefulness. Advanced sleep-wake phase disorder is characterized by difficulties in staying awake in the early evening and as a result, a subject wakes up too early in the morning. This can interfere with work, school, or social responsibilities. Delayed sleep-wake phase disorder, which is the most common circadian rhythm disorder, is characterized by subjects falling asleep later than desired and then finding it difficult to wake up on time. Delayed sleep-wake phase disorder similarly often interferes with work, school, or social responsibilities, and can result in a subject getting too little sleep, which can lead to daytime tiredness or anxiety. Irregular sleepwake rhythm disorder is characterized by several short periods of sleep and wakefulness (e.g., a subject may be unable to sleep during the night and take multiple naps during the day due to excessive sleepiness). Jet lag disorder, which is often a temporary disorder that may affect a subject if they travel across at least two time zones in a short period, is characterized by a sleep-wake rhythm that falls out of synchronization with the local time at a destination. Finally, non-24-hour sleep-wake rhythm disorder is characterized by a sleep-wake rhythm that is not in synchronization with a 24-hour day/night cycle.
[0037] Current treatment methods for circadian rhythm dysfunction may include (i) adjusting lighting; (ii) adjusting sleep behavior (e.g., making time to get enough sleep, having a bedtime routine, etc.); and (iii) administering medications. However, the current methods and medications do not meet the needs of all patients. First, as noted above, many medications require multiple dosages, which, given typical poor patient compliance, result in inadequate treatment. One or more formulations according to the present disclosure may provide significant improvements in sleep induction, latency, length, wakings after sleep onset, and sleep quality to a subject suffering from a sleep disorder. The ability to administer a single effective formulation can increase patient administration and compliance.
Additionally, owing to combination therapy, formulations according to the present disclosure may advance the sleep phase and also improve and reinforce sleep habits. For those suffering from sleep disorders, the formulations may provide a significant advance in the art.
[0038] Formulations according to the present disclosure may be adapted for oral administration. In one aspect, a formulation may be an oral formulation comprising (a) an immediate-release layer, (b) an inner core, and (c) a delayed-release component delaying release of the inner core. Fig. 1 shows a schematic of one such aspect of a formulation wherein the formulation is in the form of a tablet comprising (a) an immediate-release layer 10, (b) an inner core 20, and (c) a delayed-release component in the form of an outer coating 30 enveloping the inner core 20 that results in the delayed-release of the inner core 20. In another aspect, a formulation may be an oral formulation comprising (a) an immediate- release later of a first API, (b) a delayed-release layer comprising a second API, and (c) a release component delaying release of the second API. In another aspect, a formulation may be an oral formulation including one or more dual -release capsules or capsule-in-capsule formulations. An inner capsule may include a second API and, optionally, a delayed-release component. A delayed-release component may be the inner capsule itself, a separate component, or a combination of the two. An outer capsule may include a first API. The inner capsule and the first API may be encapsulated within the outer capsule. In another aspect, a formulation may be an oral formulation comprising (a) an immediate-release layer comprising a first API to be released immediately and (b) a delayed-release layer, wherein the delayed-release layer comprises a second API mixed with an excipient, and the excipient causes the second API to be released in a delayed-release manner or after a delay. One of ordinary skill in the art will understand however that other structural arrangements are within the scope of the formulations covered by this disclosure.
[0039] For example, in one aspect, the immediate-release layer may include or be in the form of a coating that envelopes all, substantially all, or a majority (greater than half) of the remaining components. Further, the formulation may comprise a plurality of inner cores, with each core provided with a delayed-release component, i.e., each core being surrounded by a respective delayed-release coating. In one aspect, the formulation may comprise a plurality of particles, each comprising an immediate-release layer, an inner core, and a delayed-release layer between the immediate-release layer and the inner core. Alternatively, multiple cores may be surrounded by a delayed-release component, including with all of the multiple cores surrounded by a delayed-release component, for example, a delayed-release capsule or shell having the release property as described herein, i.e., being operable to delay release of the second API from the inner core until the first API from the immediate-release layer has exhibited its physiological effect. In an example, the first API may be melatonin or a melatonin receptor agonist. In an example, the second API may be a sleep-inducing hypnotic. In an example, the physiological effect of the first API may be to shift sleep timing in a subject. The multiple cores may be of any desired size, including microparticles, or the like. [0040] In aspects of the present disclosure, a delayed-release component may include or be in the form of an osmotic pump which delays release of the second API, such as a sleepinducing hypnotic. For example, in one example, an osmotic pump comprises an outer wall formed of a semipermeable material that is permeable to the passage of external fluid, a first compartment, a second compartment, and a flexible membrane separating the first and second compartments. The flexible membrane is substantially impermeable to the passage of API and fluid. A passageway is provided in the outer wall and communicates with the first compartment for delivering the API. The first compartment contains the API, i.e., the inner core comprising the sleep-inducing hypnotic, and the second compartment contains an osmotically effective compound exhibiting an osmotic pressure gradient across the semipermeable wall against the fluid. In operation, fluid from the environment is imbibed through the wall into the second compartment in a tendency towards osmotic equilibrium at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall to continuously fill the second compartment and expand the membrane into the first compartment to force delivery of the active ingredient through the passageway at a controlled rate over a period of time. If desired, fluid from the environment may also be imbibed through the wall into the first compartment in a tendency towards osmotic equilibrium at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall to solubilize the inner core prior to delivery of the core through the passageway. Osmotic pumps are well known in the art as demonstrated by, for example, U.S. Patent No. 4,111,202 and U.S. Patent No. 6,976,981, the disclosures of which are hereby incorporated by reference. The passageway may also be filled of a material that initially blocks the passageway and is eroded or solubilized after ingestion of the formulation.
[0041] Other structural arrangements for the formulations are equally within the scope of the disclosure.
[0042] In an aspect, the immediate-release layer comprises a first API. The first API may include at least one of melatonin and a melatonin receptor agonist (MRA). Melatonin and MRAs can bind to and activate the MTi and MT2 receptors and, although melatonin and the melatonin receptor agonists have different affinities for the two melatonin receptors, they are generally considered physiologically nonselective. The MRAs are therefore considered to function similarly to melatonin itself. This notwithstanding, activation of the MT2 receptor may be more beneficial than activation of the MT 1 receptor for shifting sleep timing.
Therefore, drugs with higher activity activating the MT2 receptor may be preferred in certain aspects. The melatonin or MRA (or both) is included in the immediate-release layer in an amount effective to shift sleep timing in a subject to an earlier time than the subject would experience in the absence of the melatonin or MRA. Generally, this amount is a lower dose than would normally be taken to achieve an immediate sleep-inducing hypnotic effect and mirrors the physiological amount which shifts sleep timing, for example, to a time earlier than a preexisting sleep time for a subject experiencing difficulty in going to sleep.
[0043] Various MRAs are known in the art and suitable for use in formulations according to the present disclosure. In one aspect, the immediate-release layer may comprise melatonin or an MRA comprising tasimelteon, agomelatine, or ramelteon. In one aspect, formulations according to the present disclosure may include amounts of melatonin, MRA (tasimelteon, agomelatine, ramelteon) or combinations thereof effective to shift sleep timing in a subject to an earlier time. These effective amounts are based on the specific active ingredient(s) employed and their in-vivo pharmacokinetic properties.
[0044] In one aspect of the present disclosure, the immediate-release layer may comprise melatonin, and more specifically, may comprise from about 0.2 mg to about 2 mg melatonin, from about 0.2 mg to about 1 mg melatonin, from about 0.2 to about 0.5 mg melatonin, or from about 0.2 mg to about 0.3 mg melatonin. In another aspect, the immediate-release layer may comprise tasimelteon, and more specifically, may comprise from about 1 mg to about 25 mg tasimelteon, from about 1 mg to about 10 mg tasimelteon, from about 5 mg to about 20 mg tasimelteon, or from about 10 to about 20 mg tasimelteon. Additionally or alternatively, the immediate-release layer may comprise agomelatine, and more specifically, may comprise from about 2 mg to about 25 mg agomelatine, from about 5 mg to about 25 mg agomelatine, or from about 10 to about 25 mg agomelatine. Additionally or alternatively, the immediate- release layer may comprise ramelteon, and more specifically, may comprise from about 0.1 mg to about 5 mg ramelteon, from about 0.5 mg to about 4 mg ramelteon, or from about 1 to about 4 mg ramelteon.
[0045] In another aspect according to the present disclosure, the delayed-release layer may comprise an inner core including a sleep-inducing hypnotic in an amount effective to induce sleep in the subject. Various sleep-inducing hypnotics are known in the art and suitable for use in formulations according to the present disclosure. Examples include, but are not limited to, benzodiazepines, non-benzodiazepine GABAA receptor agonists, melatonin, melatonin receptor agonists, orexin receptor antagonists, hypnotic antidepressants, and combinations of two or more thereof. Other drugs outside these classes that are also known to have hypnotic effects in addition to other therapeutic effects are also suitable for use in the inner core. For example, clonidine is an agonist of central nervous system alpha-adreno receptors indicated for the treatment of hypertension and ADHD, but clonidine also exhibits a well-established hypnotic activity that may be superior to some approved sleep-inducing APIs. Specific examples of sleep-inducing hypnotics suitable for use in formulations according to the present disclosure include, but are not limited to, clonazepam, clonidine, suvorexant, and zolpidem, and combinations of two or more thereof. In specific aspects, the sleep-inducing hypnotic in the inner core of the delay release layer may comprise from about 0.2 mg to about 0.5 mg clonazepam, from about 0.1 mg to about 0.5 mg clonidine, from about 5 mg to about 10 mg suvorexant, or from about 2 mg to about 5 mg zolpidem.
[0046] In an aspect according to the disclosure, a formulation may include an immediate- release layer comprising melatonin and a delayed-release layer comprising clonidine. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising melatonin and a delayed-release layer comprising a dual orexin-receptor antagonist. In an aspect, the dual orexin-receptor antagonist is suvorexant. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising melatonin and a delayed-release layer comprising clonazepam. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising melatonin and a delayed-release layer comprising a Z-drug. In an aspect, the Z-drug is zolpidem. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising melatonin and a delayed-release layer comprising doxepin. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising melatonin and a delayed-release layer comprising an alpha2-delta ligand. In an aspect, the alpha2-delta ligand is gabapentin. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising melatonin and a delayed-release layer comprising dipyridamole.
[0047] In an aspect according to the disclosure, a formulation may include an immediate- release layer comprising tasimelteon and a delayed-release layer comprising clonidine. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising tasimelteon and a delayed-release layer comprising a dual orexin-receptor antagonist. In an aspect, the dual orexin-receptor antagonist is suvorexant. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising tasimelteon and a delayed-release layer comprising clonazepam. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising tasimelteon and a delayed-release layer comprising a Z-drug. In an aspect, the Z-drug is zolpidem. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising tasimelteon and a delayed-release layer comprising doxepin. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising tasimelteon and a delayed-release layer comprising an alpha2-delta ligand. In an aspect, the alpha2-delta ligand is gabapentin. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising tasimelteon and a delayed-release layer comprising dipyridamole.
[0048] In an aspect according to the disclosure, a formulation may include an immediate- release layer comprising agomelatine and a delayed-release layer comprising clonidine. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising agomelatine and a delayed-release layer comprising a dual orexin-receptor antagonist. In an aspect, the dual orexin-receptor antagonist is suvorexant. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising agomelatine and a delayed-release layer comprising clonazepam. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising agomelatine and a delayed-release layer comprising a Z-drug. In an aspect, the Z-drug is zolpidem. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising agomelatine and a delayed-release layer comprising doxepin. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising agomelatine and a delayed-release layer comprising an alpha2-delta ligand. In an aspect, the alpha2-delta ligand is gabapentin. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising agomelatine and a delayed-release layer comprising dipyridamole.
[0049] In an aspect according to the disclosure, a formulation may include an immediate- release layer comprising ramelteon and a delayed-release layer comprising clonidine. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising ramelteon and a delayed-release layer comprising a dual orexin-receptor antagonist. In an aspect, the dual orexin-receptor antagonist is suvorexant. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising ramelteon and a delayed-release layer comprising clonazepam. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising ramelteon and a delayed-release layer comprising a Z-drug. In an aspect, the Z-drug is zolpidem. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising ramelteon and a delayed-release layer comprising doxepin. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising ramelteon and a delayed-release layer comprising an alpha2-delta ligand. In an aspect, the alpha2-delta ligand is gabapentin. In an aspect according to the disclosure, a formulation may include an immediate-release layer comprising ramelteon and a delayed-release layer comprising dipyridamole. [0050] In other aspects, formulations according to the present disclosure may include an immediate-release layer comprising melatonin and wherein a sleep-inducing hypnotic comprises clonidine. In additional examples, the immediate-release layer may comprise from about 0.2 mg to about 2 mg melatonin, from about 0.2 mg to about 1 mg melatonin, from about 0.2 to about 0.5 mg melatonin, or from about 0.2 mg to about 0.3 mg melatonin, and the delayed-release layer including the sleep-inducing hypnotic may comprise from about 0.1 mg to about 0.5 mg clonidine, or from about 0.1 mg to about 0.3 mg clonidine. In other aspects, the clonidine may be provided as clonidine hydrochloride, although the free base or another salt form may be used.
[0051] In other aspects, formulations according to the present disclosure may include an immediate-release layer comprising tasimelteon and the delayed-release layer including the sleep-inducing hypnotic comprises clonidine. In other aspects, the immediate-release layer may comprise from about 1 mg to about 25 mg tasimelteon, from about 1 mg to about 10 mg tasimelteon, from about 5 mg to about 20 mg tasimelteon, or from about 10 to about 20 mg tasimelteon, and the sleep-inducing hypnotic may comprise from about 0.1 mg to about 0.5 mg clonidine, or from about 0.1 mg to about 0.3 mg clonidine. In other aspects, the clonidine may be provided as clonidine hydrochloride, although the free base or another salt form may be used.
[0052] In other aspects, formulations according to the present disclosure may include an immediate-release layer comprising tasimelteon, wherein a delayed-release layer including the sleep-inducing hypnotic comprises suvorexant. In other aspects, the immediate-release layer may comprise from about 1 mg to about 25 mg tasimelteon, from about 1 mg to about 10 mg tasimelteon, from about 5 mg to about 20 mg tasimelteon, or from about 10 to about 20 mg tasimelteon, and the sleep-inducing hypnotic may comprise from about 5 mg to about
10 mg suvorexant. [0053] In other aspects according to the present disclosure, the immediate-release layer and the inner core may include one or more conventional pharmaceutical excipients. Examples include, but are not limited to, carriers, binders, disintegrants, lubricants, diluents, glidants, stabilizers/antioxidants, and the like. Formulations according to the present disclosure may also include a soluble surface coating if desired. In one example, the inner core may comprise an immediate-release composition. In such an example, the sleepinducing hypnotic may be released immediately once the delayed-release coating is eroded or dissolved. In another example, the inner core may comprise a sustained release composition that releases the sleep-inducing hypnotic over a specified, controlled period of time, for example over about one, two, or three hours. A sustained release core may be especially suitable for a formulation including a sleep -inducing hypnotic that has a very short half-life, for example, of from one to two or three hours.
[0054] Suitable pharmaceutically acceptable carriers and excipients are known in the art and are suitable for use in formulations according to the present disclosure, including as described in Remington: The Science and Practice of Pharmacy 20th Ed. (2000) Lippincott, Williams and Wilkins, Ed. K. E. Hoover. Such carriers and excipients may enhance one or more properties of the active ingredients in the compositions, e.g., bioactivity, stability, bioavailability, and other pharmacokinetics or bioactivities. To be pharmaceutically acceptable, the excipients and carriers are nontoxic to recipients at the dosages and concentrations used. Specific examples include, but are not limited to, buffers such as phosphate, citrate, and other organic acids and bases; antioxidants including ascorbic acid and methionine; preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, benzoates, sorbate and m-cresol; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, microcrystalline cellulose, and croscarmellose sodium; amino acids such as glycine, glutamine, asparagine, histidine, arginine, serine, alanine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrans; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); non-ionic surfactants such as TWEEN™ (polysorbate), PLURONICS™ (nonionic surfactants), or polyethylene glycol (PEG); anti-caking agents, adsorbents, lubricants, or glidants such as magnesium stearate, silicon dioxide, or the like.
[0055] In aspects of the disclosure in which the inner core comprises a sustained release composition, examples of sustained-release matrices include polyesters, hydrogels, for example, poly(2-hydroxyethyl-methacrylate) or polyvinyl alcohol, polylactides, copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, sucrose acetate isobutyrate, and poly-D-(-)-3- hydroxybutyric acid.
[0056] Where included, the delayed-release component is effective to delay release of the hypnotic from the inner core until the melatonin or MRA has exhibited its effect to shift sleep timing in a subject, e.g., to provide a “sleepy” feeling, and to then, after such a delay, allow release of the hypnotic from the inner core. The timing of the delayed-release may therefore be dependent on the pharmacokinetic properties of the active ingredient in the immediate- release layer and, specifically, the time after oral administration to provide a “sleepy” effect. In examples, the immediate-release layer may comprise melatonin or tasimelteon and the delay of release of the sleep-inducing hypnotic may be from about 3 to about 4 hours. In other examples, the delay of release of the sleep-inducing hypnotic may be from about 1 to about 4 hours, from about 2 to about 4 hours, from about 1 to about 3 hours, or form about 2 to about 3 hours.
[0057] Various delayed-release compositions are known in the art and may be used as the delayed-release component in aspects of formulations that include a delayed-release component. In an example, the delayed-release component may be a delayed-release composition comprising an erodible wax or comprising an enteric polymer that dissolves at a pH greater than 5. The erodible wax or enteric coating may be selected based on its specific release timing in an aqueous environment.
[0058] By providing a formulation that administers a combination therapy of a sleepshifting API such as melatonin or a melatonin receptor agonist and a delayed-release sleepinducing hypnotic, administration of formulations according to the present disclosure both initiates a sleepy feeling and improves the duration and quality of sleep. Sleep phase can therefore be advanced and improved sleep can be achieved.
[0059] Formulations according to the present disclosure may have many advantages, as appreciated by a person of ordinary skill in the art. One important advantage of formulations according to the present disclosure is that the pharmacokinetic parameters of an immediately released active and a delayed-release active are similar to those of the actives administered separately. The pharmacokinetic behavior of a given drug is a function of several factors, including the active pharmaceutical ingredient itself, its formulation with excipients, its release in a given subject, and the biological status of that subject. All drugs have variable within-subject and between- subject exposure, but variability within subject is generally less than between subjects. Formulations according to the present disclosure may provide an immediate-release of a first API, such as melatonin or a melatonin receptor agonist, followed by a delayed-release of a sleep-inducing hypnotic to a subject and results in a pharmacokinetic profile similar to that of the actives administered separately. For example, a formulation that delays release of the sleep-inducing hypnotic by three hours after immediate- release of melatonin may result in pharmacokinetic properties of the actives similar to that of the actives administered separately as immediate-release formulations, but three hours apart. [0060] In formulations according to aspects of the present disclosure, upon administration to a subject, a pharmacokinetic characteristic of the first API, such as melatonin or a melatonin receptor agonist, is substantially the same as a corresponding pharmacokinetic characteristic of melatonin or the MRA in the immediate-release layer if administered separately, without the delayed-release layer; and a pharmacokinetic characteristic of the second API, such as a sleep-inducing hypnotic, may be substantially the same as a corresponding pharmacokinetic characteristic of the sleep-inducing hypnotic in the inner core administered separately, without the delayed-release coating and the immediate-release layer. In a more specific example, the pharmacokinetic characteristic of melatonin or the MRA, or of the sleep-inducing hypnotic, is at least one of the median time of maximum plasma concentration (tmax), the mean maximum plasma concentration (Cmax), or the plasma concentration area under the curve (AUCo-infmity).
[0061] In other aspects, methods according to the present disclosure may be directed to alleviating a sleep disorder in a subject. Example methods may comprise orally administering formulations according to the present disclosure to the subject from about 1 to about 4 hours before a desired sleeping time. In additional examples, the disclosure is directed to methods for phase shifting sleep in a subject. The methods may comprise orally administering formulations according to the present disclosure to the subject from about 1 to about 4 hours prior to a desired sleeping time. In any of these methods, the time for administration prior to the desired sleeping time may be selected based on the pharmacokinetic properties of the melatonin or MRA in the immediate-release layer and should approximate the time needed after administration of the formulation for the “sleepy” feeling to occur. [0062] The subject may be any individual that is suffering from a sleep disorder. In specific examples, the subject may have a circadian rhythm sleep-wake phase disorder. In additional examples, the subject is a human subject. In additional examples, the subject has a sleep disorder associated with a condition comprising Sanfilippo syndrome, Smith-Magenis syndrome, Angelman syndrome, Rett syndrome, Down’s syndrome, autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), genetic epilepsy, or delayed sleep-wake phase disorder (DSWPD). The subject may be a pediatric subject or an adult. In a specific example, the subject is a pediatric subject with Sanfilippo syndrome, Smith-Magenis syndrome, Angelman syndrome, Rett syndrome, Down syndrome, ASD, ADHD, genetic epilepsy, or DSWPD. In another example, the subject is a geriatric subject with Sanfilippo syndrome, Smith-Magenis syndrome, Angelman syndrome, Rett syndrome, Down syndrome, ASD, ADHD, genetic epilepsy, or DSWPD.
[0063] In other examples, the subject has a neurodegenerative disease or disorder, which can be selected from the group consisting of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington’s disease, major depression disorder (MDD), and a synucl ein-specific neurodegenerative disorder. In another example, the subject is a geriatric subject with such a neurodegenerative disease or disorder.
[0064] Dosing amounts may vary based on the body weight of the subject being treated. In one aspect, if the subject is a child weighing less than 50 kg, one dose of a formulation of the application may be administered to the child. In one aspect, if the subject is a child weighing more than 50 kg or an adult, two doses of a formulation of the application may be administered to such a child or adult. In one aspect, a child weighing less than 50 kg is administered a single formulation containing about 0.3 mg or less of melatonin (or an equally effective amount of an MRA) and about 0.15 mg or less of clonidine (or an equally effective amount of another hypnotic). In one aspect, a child weighing more than 50 kg or an adult is administered two dosages of a formulation containing about 0.3 mg or less of melatonin (or an equally effective amount of an MRA) and about 0.15 mg or less of clonidine (or an equally effective amount of another hypnotic).
WORKING EXAMPLES
[0065] The following examples demonstrate various features of specific aspects of the present disclosure. As described in the Working Examples below, the present formulations may surprisingly and unexpectedly provide a combination of therapeutics which effectively alleviate sleep disorders, or, more specifically, effectively treat circadian rhythm disorders. Specifically, Example la describes preparation of a formulation substantially as shown in Fig. 1, with an immediate-release layer comprising 0.25 mg of melatonin, an inner core comprising 0.15 mg clonidine hydrochloride, and a delay ed-release component in the form of a coating comprising an erodible wax and polymers. Analysis of the release of the active agents, shown in Fig. 2, demonstrates that the formulation allowed immediate-release of a relatively low dosage of melatonin, which in vivo may provide a subject with a “sleepy” feeling, and approximately three hours later, approximating the time necessary for the melatonin to exert the “sleepy” feeling effect, allowed release of the clonidine hydrochloride. This combination provides optimal timing for the sleep-inducing effect of the clonidine hydrochloride, resulting in improved quality and length of sleep.
[0066] Example lb details a study performed in which the pharmacokinetics of drug release from the formulation described in Example 1 a was compared with the pharmacokinetics of each active agent administered separately in immediate-release formulations.
[0067] Example 1c details the results of an analysis of pediatric patient records regarding the effect on sleep behavior of prescribing melatonin and clonidine. Of the 115 patients’ records, 79 patients were appropriately dosed melatonin (less than 0.5 mg) and timed for phase advancement (approximately three hours before the desired sleep time), followed by clonidine (0.3 mg or less) taken near (within approximately 30 minutes of) bedtime. Most patients reported subjective improvement in sleep at follow up.
[0068] This data shows both that a combination of active agents as employed in formulations according to the present disclosure provides statistically significant improvement in sleep, but that individual administration of the actives in an optimal protocol is challenging. This is because it is often difficult to administer two treatments to patients who may have difficulty swallowing, or to properly time administration of a second active. The present invention satisfies the need for a single formulation that optimizes timing of the release of each active agent for the benefits of sleep phase shifting for improved sleep induction and improved sleep quality and length. Advantageously, formulations according to the present disclosure avoid any need to disrupt the sleep of a subject in order to administer a second, separate sleep-inducing hypnotic as is the case in some conventional dosing regimens.
[0069] Drug combinations may not always desirable as such combinations can produce undesirable toxicity or incompatible pharmacokinetics, as well as an inflexible fixed dose ratio. Data described herein surprisingly and unexpectedly demonstrates that the combinations according to formulations of the present disclosure do not exhibit undesirable toxicity and present compatible pharmacokinetics. Further, and importantly, the range of fixed dose ratios may produce desirable therapeutic effects. Co-administered drugs that have the potential for drug-drug interactions are often separated in their administration times. Combining two drugs in the formulations according to the present disclosure enforces the temporal separation of each drug’s release in the gastrointestinal tract and avoids accidental coadministration with accompanying potential for drug-drug interaction. Therefore, in the formulations according to the present disclosure, release of the sleep-inducing hypnotic may be separated from the release of the melatonin or the MRA by the use of the delayed-release mechanism to avoid potential drug-drug interactions between two drugs with such a potential.
Example la
[0070] In this example, a formulation with the structure shown schematically in Fig. 1 was prepared. The immediate-release layer contained 0.25 mg melatonin and excipients comprising microcrystalline cellulose, calcium hydrogen phosphate dehydrate, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. The immediate- release layer was developed by evaluating several formulations and blending processes (shown in Tables 1-2 below). Formulation M-003/004 (Table 1) and Process P (Table 2) provided the optimal release characteristics.
Table 1 : Melatonin Formulations for Immediate-Release Layer
Table 2: Evaluated Blending Processes for Immediate-Release Layer Having Melatonin
[0071] The hypnotic in the delay ed-release layer contained a 0.15 mg clonidine hydrochloride tablet (Clonistada (STADA)), which included excipients comprising calcium hydrogen phosphate hydrate, lactose, magnesium stearate, corn starch, sodium starch glycolate, povidone K90, and silicon dioxide. The delayed-release coating comprised a mixture of glyceryl behenate and low-substituted hydroxypropyl celluloses, known as the OralogiK™ formulation. The optimal delayed-release parameters were identified by evaluating the effect on clonidine release (in three in vitro release media - pH 1.2 HCL, 0.01N HC1 and pH 6.8 potassium phosphate buffer) of different thicknesses of the OralogiK™ formulation shown in Table 3 below:
Table 3: Delayed-Release Coating
[0072] Table 4 below shows the following OralogiK™ weights and compression parameters (1, 2 and 3) using 10.5mm Natoli tooling; all were evaluated. The two OralogiK™ weights listed represent the mass of delayed-release coating material above and the clonidine within the delayed-release coating: Table 4: Initial Tablet-in-Tablet Compression Parameters
[0073] Parameters 1, 2, and 3 resulted in clonidine release with too-short delay times, high variability, and some sustained release from the core, the last potentially due to distortion of the marketed tablet core upon second compression. Two additional tablets were therefore manufactured with increased tablet size (11 mm diameter) and increased quantities of OralogiK™ weights (200 and 230 mg), and with all other manufacturing parameters remaining the same (parameter 4). This process resulted in timed-release clonidine tablets with close to (but slightly longer than) the target 3 -hour delay ed-release of clonidine (3 hr 15 min and 3 hr 5 min post-dissolution start, for each tablet, respectively).
[0074] Once the melatonin-containing immediate-release layer and clonidine-containing delayed-release layer were optimized as described above, a dual-pulse (melatonin and clonidine) tablet meeting the required profile was manufactured by compressing an immediate-release melatonin layer (Process P formulation) onto the final delayed-release clonidine tablets. For the final dual-pulse tablets, the OralogiK™ delayed-release layer weights were adjusted slightly downwards to 190 mg and 220 mg (for top and bottom layers, respectively) to achieve the target ~3 hour delay. The final tableting parameters were as shown in Table 5 below: Table 5: Final Dual -Phase Tablet Parameters
[0075] Fig. 5 shows an example flow chart outlining the tableting process discussed above. In the flow chart, EBL refers to erodible barrier layer and is another name for the delayed-release coating used in this example.
[0076] The formulation was subjected to an in vitro analysis of the release of the active agents, typical results of which are shown in Fig. 2. More specifically, the release profile was evaluated in water, pH 1.2 HC1, 0.01N HC1 and pH 6.8 potassium phosphate buffer. The release profile is shown in Fig. 6, with the initial (immediate) increase in absorbance reflecting the melatonin release and the delayed (~3-hour) increase in absorbance reflecting the clonidine release. Release profiles were similar, regardless of conditions, indicating that the delayed-release lag time should consistently be approximately 3 hours irrespective of whether the tablet is retained and fully releases in the stomach or if release completes later in the GI tract. This expectation was confirmed during clinical evaluation (Example lb). The delay from time zero in clonidine release from the dual -release (tab-in-tab) tablets is enumerated in Table 6 below. Table 6: Dissolution Release Characteristics for Dual-Release Tablet; USP II (50 RPM), 500 ml, in Various Media, n=6 or n=18
[0077] To confirm that release of drug into the in vitro buffers did not change the pH of the buffers, the post-release pH values were measured after the melatonin and clonidine releases and are presented in Table 7 below. Substantial pH change effects were also not observed due to either API, even in unbuffered water.
Table 7: pH Values for Dual-Release Tablet in Various Dissolution Media Post-Release
[0078] Significantly, the formulation developed and described above allowed immediate- release of the relatively low dosage of melatonin, which in vivo will result in a subject having a “sleepy” feeling at the appropriate time of day (i.e., entraining to the appropriate circadian phase) and allowed release of the clonidine hydrochloride approximately three hours later, for its hypnotic (sleep-inducing) effect. [0079] This formulation comprising the combination of active ingredients provides optimal timing for the sleep-inducing effect of the clonidine hydrochloride, resulting in reduced sleep onset latency, as well as improved quality and length of sleep.
Example lb
[0080] A two arm, crossover, open label study was performed in which the pharmacokinetics of drug release from the final dual-release tablet formulation described in Example la was compared with the pharmacokinetics of each active agent administered separately in immediate-release formulations.
[0081] The following treatments were dosed during the study:
Treatment A: One 0.25 mg melatonin immediate-release tablet
Treatment B: One 0.15 mg clonidine HC1 tablet (Clonistada (STADA))
Treatment C: One formulation as described in Example la containing an immediate-release layer with 0.25 mg melatonin, an inner core comprising 0.15 mg clonidine (comprising a Clonistada® tablet), and a delayed-release coating on the inner core. The formulation was radiolabeled in the core with a small amount of 4 MBq 99mTc to monitor exposure and disintegration of the core in vivo using gamma scintigraphy. The plasma concentrations of melatonin and clonidine were also measured over time.
[0082] In their first visit, 12 healthy adults subjects were administered with treatment A two hours after consumption of a standard dinner, followed by administration of treatment B three hours later. After a washout period of at least three days but no longer than 14 days, the subjects returned for a second visit and were administered treatment C alone.
[0083] Fig. 3 presents the results of the gamma scintigraphy measurement of one subject and is representative of the measurements of each subject. As shown in Fig. 3, the radiolabeled inner core was released after approximately three hours. [0084] The plasma pharmacokinetic profiles (Tmax, Cmax and AUCo-infmity) of melatonin and clonidine were measured in each subject during both visits. In the first visit, the pharmacokinetics were from melatonin and clonidine administered as separate, immediate- release tablets, with the clonidine administered three hours after the melatonin (treatments A and B, respectively). In the second visit, the pharmacokinetics were from administration as a single formulation with immediate-release of the melatonin and delayed-release of the clonidine (Treatment C). The results are shown in Fig. 4 wherein plasma concentrations of melatonin (V) and clonidine (□) after separate administration of immediate-release formulations, and of melatonin (A) and clonidine (o) after administration of a formulation according to the invention are shown. Significantly, the profiles were found to be substantially similar, showing that the delayed-release coating had successfully delayed the release of the inner core containing clonidine by approximately three hours, but that otherwise the pharmacokinetic parameters were similar.
[0085] One skilled in the art will appreciate that a formulation according to the present disclosure can therefore provide significant improvements in both sleep induction and in the length and quality of sleep to a subject suffering from a sleep disorder. The ability to administer a single effective formulation can increase patient administration and compliance. Additionally, owing to the combination therapy, the formulation can advance the sleep phase and improve and reinforce sleep habits. For those suffering from sleep disorders, the formulation provides a significant advance in the art.
Study Results
[0086] Pediatric patients at Cincinnati Children’s Hospital Medical Center were administered melatonin and clonidine as separate tablets for the treatment of sleep issues. The records were then evaluated for the effect on sleep behavior of prescribing melatonin and clonidine in pediatric patients. A summary of findings is provided in Table 1. Of the 115 patients’ records reviewed, 79 patients were appropriately dosed melatonin (less than 0.5 mg) and timed for phase advancement (approximately three hours before the desired sleep time), followed by clonidine (0.3 mg or less) taken near (within approximately 30 minutes of) bedtime. Of the 79 patients who were administered melatonin and clonidine according to this protocol, clinical follow-up information was available for 57. The majority of patients or patient families (42/57, 74%) reported subjective improvement in sleep at follow up. None reported worsening or significant side effects:
Table 8
Cases _ Protocol _ Follow up Improved No change Worse
115 79 57 42 15 0
[0087] The effect was statistically significant as shown in Table 2, based on a chi-square test against an assumed no-treatment effect of 33% improved, 33% no change and 33% worse:
Table 9 Chi-square
Chi-square, df 47.68, 2
P value < 0.0001
[0088] The demographics of the 57 patients with follow-up are shown in Table 10 below:
Table 10: Patient Demograhics [0089] Before beginning the protocol, the patients had been on the medications in Table 11 below and were still having chronic sleep issues:
Table 11 : Prior Medications
* Z drugs include: zolpidem, zopiclone, zaleplon and eszopiclone
[0090] The protocol according to this example was highly effective, regardless of diagnosis, as shown in Table 12 below:
Table 12: Patient Improvements by Diagnosis
[0091] The protocol according to this example was highly effective, regardless of prior treatments, as shown in Table 13 below:
Table 13: Patient Improvements by Prior Therapy
[0092] The protocol according to this example was highly effective, regardless of patient age, as shown in Table 14 below:
Table 14: Patient Improvements by Age
Examples 2-3
[0093] Example 2 was prepared using the same structure shown in Fig. 1 and with the same formulation as described in Example la, except that the melatonin in the immediate- release layer was replaced by 20mg of tasimelteon. Example 3 was prepared using the same structure shown in Fig. 1 and with the same formulation as described in Example la, except that the melatonin in the immediate-release layer was replaced by 5mg of tasimelteon. The compositions of the immediate-release layer of Examples 2-3 are shown in Table 15 below:
Table 15
[0094] Also as in Example la, the delay ed-release component in Examples 2-3 was the OralogiK™ composition prepared using the process described with regard to Example la. The hypnotic in Examples 2-3 was 0.15 mg clonidine. The total composition of Example 2 is depicted in Table 16 below:
Table 16: Composition of Example 2 [0095] The total composition of Example 3 is depicted in Table 17 below:
Table 17: Composition of Example 3 [0096] The release profiles of tasimelteon and clonidine from Examples 2 and 3 were evaluated using a USP II apparatus at 50 rpm in 500 ml, pH 1.2 HC1 buffer and mean n=6, as shown in Fig. 7A and Fig. 7B. pH 1.2 HC1 buffer is: 2.9225 g NaCl + 6.36 mL concentrated (37%) HC1 dissolved in 1 liter of distilled water (pH is adjusted, if necessary, by adding diluted HC1 or NaOH solution).
[0097] Fig. 7A illustrates the release profile of dual-phase tasimelteon (5 mg, immediate- release layer) and clonidine HC1 (delay ed-release layer) tablet according to Example 3. Fig. 7B illustrates the release profile of dual-phase tasimelteon (20 mg, immediate-release layer) and clonidine HC1 (delayed-release layer) tablets according to Example 2.
[0098] In both Example 2 and Example 3, more than 80% of the tasimelteon was released within an hour, and the clonidine was released beginning at about 3 hours, and more than 80% of the tasimelteon was released by about 3.5 hrs, indicating that the target release profile had been achieved.
[0099] These data show both that a combination of active agents as employed in the present formulations provides statistically significant improvement in sleep, and that individual administration of the actives in an optimal protocol is challenging. As discussed, it is often difficult to administer two treatments to patients who may have difficulty swallowing, or to properly time administration of a second active. The present disclosure satisfies the need for a single formulation according to the disclosure that optimizes timing of the release of each active agent for the benefits of sleep phase shifting for improved sleep induction and improved sleep quality and length.
PROPHETIC EXAMPLES
[0100] Additional formulations are within the spirit and scope of this disclosure. Other combinations of hypnotics in a delayed-release layer are expected to be combined with melatonin or a melatonin receptor agonist (such as tasimelteon) similar to Working Examples 1-3. In each of the following examples, the formulation may be made such that the melatonin or melatonin receptor agonist is in an immediate-release layer in an amount sufficient to exhibit a circadian effect (e.g., entrainment) at an appropriate time before the patient’s desired bedtime, with a hypnotic in a delayed-release layer configured to release the hypnotic at a predetermined time after ingestion of the formulation (e.g., the hypnotic is released about
2-3 hours following ingestion).
[0101] In one example, a formulation may comprise an immediate-release layer comprising about 0.25 mg melatonin and pharmaceutically acceptable excipients (e.g., as described with respect to Working Example la), and the delayed-release layer may comprise between about 5mg to about 20mg suvorexant (or an amount of a dual orexin receptor antagonist sufficient to exhibit a hypnotic effect in a patient). The delayed-release layer may include pharmaceutically acceptable excipients and an acceptable delayed-release component (e.g., the delayed-release component described with respect to Working Examples 1-3).
[0102] In another example, a formulation may comprise an immediate-release layer comprising about 20 mg tasimelteon and pharmaceutically acceptable excipients (e.g., as described with respect to Working Example 2), and the delayed-release layer may comprise between about 5mg to about 20mg suvorexant (or an amount of a dual orexin receptor antagonist sufficient to exhibit a hypnotic effect in a patient). The delayed-release layer may include pharmaceutically acceptable excipients and an acceptable delayed-release component (e.g., the delayed-release component described with respect to Working Examples 1-3).
[0103] In another example, a formulation may comprise an immediate-release layer comprising about 5 mg to about 10 mg tasimelteon and pharmaceutically acceptable excipients (e.g., as described with respect to Working Example 3), and the delayed-release layer may comprise between about 5mg to about 20mg suvorexant (or an amount of a dual orexin receptor antagonist sufficient to exhibit a hypnotic effect in a patient). The delayed- release layer may include pharmaceutically acceptable excipients and an acceptable delayed- release component (e.g., the delayed-release component described with respect to Working Examples 1-3).
[0104] In another example, a formulation may comprise an immediate-release layer comprising about 0.25 mg melatonin and pharmaceutically acceptable excipients (e.g., as described with respect to Working Example la), and the delayed-release layer may comprise between about Img to about lOmg doxepin. In specific aspects, the delayed-release layer may comprise between about 3mg to about 6mg doxepin. The delayed-release layer may include pharmaceutically acceptable excipients and an acceptable delayed-release component (e.g., the delayed-release component described with respect to Working Examples 1-3).
[0105] In another example, a formulation may comprise an immediate-release layer comprising about 20 mg tasimelteon and pharmaceutically acceptable excipients (e.g., as described with respect to Working Example 2), and the delayed-release layer may comprise between about Img to about lOmg doxepin. In specific aspects, the delayed-release layer may comprise between about 3mg to about 6mg doxepin. The delayed-release layer may include pharmaceutically acceptable excipients and an acceptable delayed-release component (e.g., the delayed-release component described with respect to Working Examples 1-3).
[0106] In another example, a formulation may comprise an immediate-release layer comprising about 5 mg to about 10 mg tasimelteon and pharmaceutically acceptable excipients (e.g., as described with respect to Working Example 3), and the delayed-release layer may comprise between about Img to about lOmg doxepin. In specific aspects, the delayed-release layer may comprise between about 3mg to about 6mg doxepin. The delayed- release layer may include pharmaceutically acceptable excipients and an acceptable delayed- release component (e.g., the delayed-release component described with respect to Working Examples 1-3). [0107] In another example, a formulation may comprise an immediate-release layer comprising about 0.25 mg melatonin and pharmaceutically acceptable excipients (e.g., as described with respect to Working Example la), and the delay ed-release layer may comprise between about lOOmg to about 900mg gabapentin (or an amount of an alpha2-delta ligand or A2D ligand sufficient to exhibit a hypnotic effect or other intended therapeutic effect such as relief of restless legs syndrome or periodic limb movement disorder in a patient). In a small child, the amount of gabapentin in the delayed-release layer may be as low as 50mg. In children, the amount of gabapentin in the delayed release layer may be approximately 5mg/kg to approximately 15mg/kg. The delayed-release layer may include pharmaceutically acceptable excipients and an acceptable delayed-release component (e.g., the delayed-release component described with respect to Working Examples 1-3). Such a formulation may be particularly useful in treating patients with restless legs syndrome, periodic limb movement disorder, restless sleep disorder, and insomnia resulting from a medical condition or pain. [0108] In another example, a formulation may comprise an immediate-release layer comprising about 20 mg tasimelteon and pharmaceutically acceptable excipients (e.g., as described with respect to Working Example 2), and the delayed-release layer may comprise between about lOOmg to about 900mg gabapentin (or an amount of an alpha2-delta ligand or A2D ligand sufficient to exhibit a hypnotic effect or other intended therapeutic effect such as relief of restless legs syndrome or periodic limb movement disorder in a patient). In a small child, the amount of gabapentin in the delayed-release layer may be as low as 50mg. In children, the amount of gabapentin in the delayed release layer may be approximately 5mg/kg to approximately 15mg/kg. The delayed-release layer may include pharmaceutically acceptable excipients and an acceptable delayed-release component (e.g., the delayed-release component described with respect to Working Examples 1-3). Such a formulation may be particularly useful in treating patients with restless legs syndrome, periodic limb movement disorder, restless sleep disorder, and insomnia resulting from a medical condition or pain. [0109] In another example, a formulation may comprise an immediate-release layer comprising about 5 mg to about 10 mg tasimelteon and pharmaceutically acceptable excipients (e.g., as described with respect to Working Example 3), and the delayed-release layer may comprise between about lOOmg to about 900mg gabapentin (or an amount of an alpha2-delta ligand or A2D ligand sufficient to exhibit a hypnotic effect or other intended therapeutic effect such as relief of restless legs syndrome or periodic limb movement disorder in a patient). In a small child, the amount of gabapentin in the delayed-release layer may be as low as 50mg. In children, the amount of gabapentin in the delayed release layer may be approximately 5mg/kg to approximately 15mg/kg. The delayed-release layer may include pharmaceutically acceptable excipients and an acceptable delayed-release component (e.g., the delayed-release component described with respect to Working Examples 1-3). Such a formulation may be particularly useful in treating patients with restless legs syndrome, periodic limb movement disorder, restless sleep disorder, and insomnia resulting from a medical condition or pain.
[0110] In another example, a formulation may comprise an immediate-release layer comprising about 0.25 mg melatonin and pharmaceutically acceptable excipients (e.g., as described with respect to Working Example la), and the delayed-release layer may comprise between about 50mg to about 400mg dipyridamole. The delayed-release layer may include pharmaceutically acceptable excipients and an acceptable delayed-release component (e.g., the delayed-release component described with respect to Working Examples 1-3). Such a formulation may be particularly useful in treating patients with restless legs syndrome. [OHl] In another example, a formulation may comprise an immediate-release layer comprising about 20 mg tasimelteon and pharmaceutically acceptable excipients (e.g., as described with respect to Working Example 2), and the delayed-release layer may comprise between about 50mg to about 400mg dipyridamole. The delayed-release layer may include pharmaceutically acceptable excipients and an acceptable delayed-release component (e.g., the delayed-release component described with respect to Working Examples 1-3). Such a formulation may be particularly useful in treating patients with restless legs syndrome.
[0112] In another example, a formulation may comprise an immediate-release layer comprising about 5 mg to about 10 mg tasimelteon and pharmaceutically acceptable excipients (e.g., as described with respect to Working Example 3), and the delayed-release layer may comprise between about 50mg to about 400mg dipyridamole. The delayed-release layer may include pharmaceutically acceptable excipients and an acceptable delayed-release component (e.g., the delayed-release component described with respect to Working Examples 1-3). Such a formulation may be particularly useful in treating patients with restless legs syndrome.
[0113] Other hypnotics as described in this disclosure may additionally or alternatively be used in the delayed-release layer. A person of ordinary skill in the art may recognize alternative formulations that may similarly exhibit the desired dual -phase release characteristics, such as a capsule-in-capsule formulation or a sprinkles formulation. A sprinkles formulation refers to a type of pharmaceutical dosage form designed to make medication administration easier, especially for populations like infants, young children, and older adults who may have difficulty swallowing traditional tablets or capsules. These formulations may comprise small multi-particulates, often contained within a capsule. The capsule can be opened, and the multi-particulates, or "sprinkles," can be dispersed in liquid or soft food for easier consumption. [0114] The disclosure further contemplates any formulation that allows for precise dosing requirements that also allows for mixing with food or drinks, for example to make the formulation more palatable.
[0115] Unless expressly indicated otherwise, it may be appreciated that patients of different sizes may require different doses of a formulation to be effective. For example, a small child may require a smaller dosage than an average adult, and an average adult may require a larger dosage than a small child. Formulations may be created having differing amounts of melatonin or MRA in the immediate-release layer and differing amounts of hypnotic in the delayed-release layer. Those of ordinary skill in the art may recognize different effective amounts of active ingredients for different patients, for example, based on patient age, patient size, and patient condition. As an example, hypnotics such as clonidine, suvorexant, doxepin, clonazepam, and zolpidem may be more useful for patients having a sleep disorder. Similarly, hypnotics such as gabapentin may be more useful for patients with restless legs syndrome, periodic limb movement disorder, restless sleep disorder, and insomnia resulting from a medical condition or pain. As another example, dipyridamole may be more useful for patients with restless legs syndrome.
[0116] The specific examples described herein are exemplary only and are not limiting to the aspects of the disclosure defined by the claims. 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. It is, therefore, to be understood that the foregoing examples are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive aspects may be practiced otherwise than as specifically described, and the disclosure should be construed as encompassing those aspects.
[0117] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, patent application, or item of information was specifically and individually indicated to be incorporated by reference. To the extent publications, patents, patent applications, and items of information incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede or take precedence over any such contradictory material.
[0118] What is claimed is: