Treating Sleep Apnea with CBD

Abstract

Provided is a method of treating a sleep disorder in a patient by transdermally administering an effective amount of cannabidiol (CBD) to a subject in need thereof.

Description

[Technical field]

[0001] The present disclosure relates to a method of treating a sleep disorder in a patient by transdermally administering an effective amount of cannabidiol (CBD) to a subject in need thereof. [Background technology]

[0002] Developmental and epileptic encephalopathies (DEE) are a severe group of neurodevelopmental disorders characterized by seizures and abnormal electroencephalographic activity that adversely affect development. For example, there is a need for safe and effective treatment of refractory seizures in children with DEE. This can be particularly challenging when subjects have comorbidities such as autism spectrum disorder (ASD).

[0003] Sleep disorders are a common problem associated with children with DEE, ASD and DEE-ASD. Sleep-disordered breathing, such as sleep apnea, is one type of sleep disorder seen in patients with DEE, ASD and DEE-ASD. In addition to the need to treat epilepsy in these patients, it is also desirable to improve the sleep patterns of such patients.

[0004] Sleep disorders are not limited to individuals with DEE, ASD, or DEE-ASD, as many adults also suffer from sleep disorders. Treatments that improve sleep disorders would be useful to a broader population. Summary of the Invention [Problem to be solved by the invention]

[0005] EPIDIOLEX oral CBD solution is approved for the treatment of epilepsy in children with Lennox-Gastaut and Dravet syndromes. However, oral delivery has led to gastrointestinal (GI) adverse events, such as EPIDIOLEX labeling, which reported somnolence and sedation in 32% of its patients and was dose-related. EPIDIOLEX cannabidiol oral solution labeling (June 2018). Oral CBD also has the potential to be degraded to THC in stomach acid, which may be associated with undesirable psychoactive effects. Ibid.

[0006] There is a need for effective treatments for specific targeted (refractory) seizure types in children diagnosed with autism spectrum disorder (e.g., treatment of refractory epilepsy in autism spectrum disorder). The quality of life (QoL) of children with drug-resistant epilepsy is reduced by a higher number of ASMs, greater seizure frequency, and lower IQ, further highlighting the need for new therapies. There is also a need for treatments that do not result in undesirable side effects such as somnolence, lethargy, withdrawal, or sedation. [Means for solving the problem]

[0007] The present disclosure relates to a method for treating refractory seizures in a subject, comprising transdermally administering an effective amount of CBD to the subject. The CBD can be ZYN002, a transdermal synthetic CBD gel formulation. The subject can be a child, including a child with a condition such as one or more of autism spectrum disorder (ASD), developmental and epileptic encephalopathy (DEE), or epilepsy. For example, the subject can be a child with comorbid ASD with epilepsy. Effective treatment also includes associated improvements in sleep quality, sleep onset, and sleep maintenance in children.

[0008] In some examples, the present disclosure relates to a method of treating a human suffering from autism spectrum disorder (ASD), which may include administering an effective amount of cannabidiol (CBD) to a human in need thereof to effectively treat refractory seizure types in the human with ASD.

[0009] In some instances, the refractory seizure type is focal impairment of awareness seizures (FIAS), generalized tonic-clonic seizures (GTCS), or focal onset bilateral tonic-clonic seizures (FBTCS).

[0010] In some examples, the CBD can be administered transdermally. The effective amount of CBD can range from about 250 mg to about 1000 mg total daily. The effective amount of CBD can be 250 mg total daily. The effective amount of CBD can be 500 mg total daily. The effective amount of CBD can be 750 mg total daily. The effective amount of CBD can be 1000 mg total daily. The CBD can be administered once a day. The CBD can be administered twice a day.

[0011] In some instances, treatment includes improvement of a sleep-related disorder, including improvement in sleep quality, sleep onset, total sleep, sleep onset and maintenance, sleep-wake transitions, or wakefulness and nightmare disorders.

[0012] Treatment of patients with CBD, in some embodiments, reduces the occurrence of sleep-disordered breathing (SBD), such as sleep apnea. The use of CBD can reduce the occurrence of sleep apnea and other sleep disorders in patients with DEE, ASD, or DEE-ASD. The use of CBD can also improve sleep-disordered breathing in adults and children without DEE, ASD, or DEE-ASD.

[0013] In some examples, the CBD is synthetic CBD. The CBD can be pure CBD. The CBD can be plant-derived. The cannabidiol can be (-)-cannabidiol.

[0014] In some instances, the CBD is formulated as a gel. The CBD can be formulated as a permeation enhancing gel.

[0015] In some instances, administration of an effective amount of CBD maintains or improves circadian rhythms. In some instances, administration of an effective amount of CBD does not result in intoxication and the human subject does not experience excessive somnolence.

[0016] The present disclosure relates to a method for treating refractory seizures in a human suffering from autism spectrum disorder (ASD). The method includes administering an effective amount of cannabidiol (CBD) to a human in need thereof to effectively treat refractory seizure types in a human with ASD. The human subject may include a child diagnosed with ASD. The human subject may also include a human subject with a comorbid condition of ASD and refractory epilepsy.

[0017] The present disclosure relates to a method of treating refractory seizures in children suffering from developmental and epileptic encephalopathy (DEE), which may include administering an effective amount of cannabidiol (CBD) to a child in need thereof to effectively treat refractory seizure types in children with DEE.

[0018] The present disclosure relates to a method for treating a sleep disorder in a human subject. The method may comprise administering an effective amount of cannabidiol (CBD) to a human in need thereof to treat the sleep disorder. In one embodiment, the sleep disorder is caused by episodes of sleep apnea.

[0019] Sleep disorders can be treated by transdermal CBD administration. Effective amounts of CBD range from about 250 mg to about 1000 mg total per day. Effective doses of CBD range from 10 to 25 mg / kg per dose. CBD can be administered in a single dose per day, or in two doses per day. In one embodiment, the CBD is pure CBD. The CBD can be synthetic CBD or plant-derived CBD. In one embodiment, the CBD is (-)-cannabidiol. In one embodiment, the CBD is formulated as a gel. The CBD gel can be formulated as a permeation-enhancing gel.

[0020] The use of CBD to treat sleep disorders results in improvements in sleep-related disorders, including improvements in sleep quality, sleep onset, total sleep, sleep onset and sleep maintenance, sleep-wake transitions, or wakefulness and nightmare disorders.

[0021] In one embodiment, the subject with a sleep disorder suffers from obstructive sleep apnea. Obstructive sleep apnea is associated with the subject's obesity or overweight condition. In one embodiment, the subject has a BMI greater than 25. In one embodiment, the subject is an adult. Alternatively or additionally, the subject may be between 3 and 18 years old. In some embodiments, the subject may also have ASD or DEE-ASD. In one embodiment, administration of an effective amount of CBD is initiated to maintain or improve circadian rhythm. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows the study design and treatments for cannabidiol transdermal gel according to the present disclosure. [Diagram 2] FIG. 1 illustrates the scoring of good day / bad day ratings. [Diagram 3] 1 is a graph showing the effectiveness of treatment duration. [Figure 4] 1 is a graph showing the percentage of patients with reduced seizures. [Diagram 5] Graph showing median percent reduction from baseline in seizure frequency over 28 days. [Figure 6] FIG. 1 is a graph showing the rate of patients with comorbid autism spectrum disorder (ASD) at baseline who had reduced seizures. [Figure 7] FIG. 1 shows the percentage of patients above the threshold for clinically significant sleep problems (DEE) based on the Sleep Disorders Scale for Children (SDSC) at baseline and 26 weeks of ZYN002 treatment. [Figure 8] FIG. 1 shows the proportion of patients with a threshold t-score >70 at baseline and week 26, corresponding to clinically significant sleep problems (DEE). [Figure 9] FIG. 1 shows the proportion of patients with comorbid ASD (DEE) above the threshold for clinically significant sleep problems based on the Sleep Disorders Scale for Children (SDSC) at baseline and 26 weeks of ZYN002 treatment. [Figure 10]FIG. 1 shows the proportion of patients with comorbid ASD (DEE) with a threshold t-score >70 at baseline and week 26, corresponding to clinically significant sleep problems. [Figure 11] FIG. 1 shows the distribution of good / bad day ratings at baseline and 6 months after ZYN002 treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Provided herein is a method for treating seizures, such as refractory type seizures, in a subject by administering an effective amount of CBD to the subject through the skin.The subject may have ASD as well as epilepsy (DEE).Also provided herein is a method for treating sleep disorders (e.g., sleep apnea) in any human subject.

[0024] The study summarized in the Examples – a Phase 2, open-label clinical trial – evaluated the safety, tolerability, and efficacy of transdermal CBD in DEE, a heterogeneous group of rare pediatric epilepsy syndromes, including, but not limited to, Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and West syndrome.

[0025] Fourteen children in the DEE study were prospectively identified with a comorbid diagnosis of ASD. While there may be a perception that seizures in the general population with ASD may be more easily managed medically, all children in the DEE study had difficult-to-treat and / or refractory epilepsy - and by extension, refractory epilepsy in ASD is also a rare population and may serve as a treatment indication. Refractory epilepsy is resistant to medications and treatment of refractory epilepsy fails to provide substantial seizure freedom. Similarly, refractory seizures are resistant to medications and treatment of refractory seizures fails to provide substantial seizure freedom.

[0026] Of the 14 ASD children with DEE, 11 showed overall evidence of a positive treatment benefit on total seizure number, and 11 patients were diagnosed with focal impairment of awareness seizures (FIAS) or tonic-clonic seizures (TCS), including generalized tonic-clonic seizures (GTCS) and focal onset bilateral tonic-clonic seizures (FBTCS).Of the 11 ASD children with FIAS or TCS, 8 children showed seizure improvement during open-label treatment with ZYN002 as an adjunct to stable standard care.

[0027] Transdermal administration of an effective amount of CBD can have a positive impact on the sleep of children with DEE, such as children with comorbid ASD with epilepsy (DEE). For example, transdermal administration of CBD can be used to treat disorders of sleep onset and sleep maintenance (DIMS) in ASD with epilepsy. Transdermal administration of an effective amount of CBD can increase the number of good days and decrease the number of bad days experienced by pediatric patients.

[0028] definition As used herein, the term "treating" or "treatment" refers to the alleviation, amelioration, relief, or alleviation of at least one symptom (such as a behavioral symptom) of a condition, disease, or disorder in a subject, such as a human, or the improvement in an identifiable measurement associated with the condition, disease, or disorder.

[0029] As used herein, the terms "clinical efficacy", "clinically effective", and the like refer to efficacy demonstrated in clinical trials conducted by the U.S. Food and Drug Administration (FDA) or any foreign counterpart, e.g., the European Medicines Agency (EMA).

[0030] As used herein, the term "cannabidiol" or "CBD" refers to cannabidiol; cannabidiol prodrugs; pharma- ceutically acceptable derivatives of cannabidiol, such as pharma- ceutically acceptable salts of cannabidiol, cannabidiol prodrugs, and cannabidiol derivatives. CBD includes 2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol, and its pharma- ceutically acceptable salts, solvates, metabolites (e.g., skin metabolites), and metabolic precursors. The synthesis of CBD is described, for example, in Petilka et al., Helv. Chim. Acta, 52:1102 (1969) and Mechoulam et al., J. Am. Chem. Soc., 87:3273 (1965), which are incorporated herein by reference.

[0031] ZYN002 is a pharmacopoeiaically manufactured transdermal CBD gel for the relief of seizures in a patient and for the improvement of behavioral symptoms in a patient. The patient may have other disorders in addition to ASD, epilepsy, DEE, fragile X syndrome (FXS). Some of the patients may have comorbidities with multiple disorders, such as ASD with epilepsy. In some examples, the human subject with ASD includes a child diagnosed with ASD, and the human subject may have comorbidities with ASD and epilepsy, e.g., refractory epilepsy. In some examples, the term "child or children" refers to a patient between the ages of 3 and 18.

[0032] The term "epileptic encephalopathy" refers to epileptic activity that contributes to severe cognitive and behavioral problems beyond those that might be expected from the underlying pathology alone (e.g., cortical malformations). Onset of these disorders can occur at any age.

[0033] The term "developmental and epileptic encephalopathies" or "DEE" refers to severe epilepsy disorders that develop during infancy and childhood. DEE is characterized by the presence of multiple focal and generalized seizure types and severe cognitive and behavioral problems. In DEE, cognitive and behavioral problems can occur independent of seizure activity even before seizures become frequent, suggesting a developmental component in addition to the epileptogenic component of DEE. Such disorders may occur early or worsen over time. Scheffer, "ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology" Epilepsia 58(4):512-521, 2017. DEE includes genetic epilepsies, such as CDKL5, SCN1A- and STXBP1-related disorders. They include Lennox-Gastaut syndrome (LGS), Ohtahara syndrome, West syndrome, Landau-Kleffner syndrome, Douzet syndrome, Dravet syndrome (DS) and Infantile Spasms (IS). DEE with onset before 18 months of age has an incidence of 1 in 2000 births.

[0034] As used herein, the term "transdermally administering" refers to contacting the CBD with the skin of a patient or subject under conditions effective for the CBD to penetrate the skin.

[0035] The term developmental and epileptic encephalopathies (DEE) was introduced by the International League Against Epilepsy (ILAE) Special Committee on Classification and Terminology (Scheffer et al., 2017) to more fully describe the clinical manifestations of coexisting developmental disorders and epileptic encephalopathies. Historically, epileptic encephalopathies was used in a broader sense to encompass both concepts, without the term "developmental". In 2001, the ILAE recognized epileptic encephalopathies as a separate category. Engel, "A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology" Epilepsia 42:796-803 (2001). The ILAE defined epileptic encephalopathies as conditions in which "epileptiform EEG abnormalities are themselves thought to contribute to progressive impairment of brain function." In 2010, the ILAE redefined epileptic encephalopathy as a condition that may worsen over time in which epileptic activity itself may contribute to severe cognitive and behavioral problems beyond those that might be expected from the underlying pathology alone (e.g., cortical malformations). Berg et al., “Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009” Epilepsia 51:676-685(2010).

[0036] The change to include "developmental" in this description was made to allow for the specific recognition of patients who present with both developmental disorders and epileptic encephalopathies, and patients with developmental disorders without the high frequency of epileptic activity associated with a developmental disorder or epileptic encephalopathy without pre-existing development of a disorder. A key element of this concept is that amelioration of epileptic activity may have the potential to improve the developmental outcome of the disorder (Scheffer et al., 2017).

[0037] The overall incidence and prevalence of developmental epileptic encephalopathies is low. Patients with DEE include, but are not limited to, those with Lennox-Gastaut syndrome, Dravet syndrome, Douzet syndrome (epilepsy with myoclonic atonic seizures (EMAS)), West syndrome (infantile spasms), Landau-Kleffner syndrome, or genetic disorders such as CDKL5 encephalopathy and CHD2 encephalopathy.

[0038] Seizures are generally refractory to antiseizure medications (ASMs), such as standard antiepileptic drugs (AEDs). For example, seizures in patients with DEE are generally refractory to AEDs. As a result, more aggressive adjunctive use of AEDs (e.g., benzodiazepines, valproic acid, and lamotrigine), immunomodulatory therapies (e.g., corticosteroids, intravenous immunoglobulin [IVIG], plasmapheresis), ketogenic diets, and surgical options that are believed to be effective in suppressing interictal epileptiform discharges, are often considered. Furthermore, oral administration of AEDs can be difficult due to behavioral and cognitive impairments.

[0039] Although patients with DEE can present with a variety of seizure types and subdisorders, Lennox-Gastaut syndrome, Dravet syndrome, and infantile spasms are the only DEE subtypes for which one or more AEDs are currently approved by the US FDA for adjunctive treatment (Table 1). Children with DEE may be medically fragile and may have multiple comorbidities, including motor and cognitive disorders, ASD, and sleep disorders, which further increase disability. In some instances, children are defined as those aged 3 to <18 years.

[0040] [Table 1]

[0041] Given the limited number of approved drugs with treatment refractoriness and evidence from controlled trials, clinicians are often forced to use standard AEDs on a trial-and-error basis, based primarily on clinical experience or open-label studies. Lennox-Gastaut syndrome and Dravet syndrome are the DEE subtypes for which the greatest amount of evidence from controlled trials of antiepileptic drugs has been generated.

[0042] Similar to DEE, children with ASD have refractory seizure types, for example, there is a need for treatment of refractory epilepsy in ASD.

[0043] Table 2 shows descriptive information related to the QoL assessments of the BELIEVE study (Figure 1, discussed further below, shows the study design and procedures for the BELIEVE study). QoL assessments were caregiver-rated and included the ELDQOL scale, a daily "good day / bad day" rating, and qualitative feedback (Table 2 and Figure 2).

[0044] [Table 2]

[0045] Table 3 shows a description of the Sleep Disorders in Children Scale (SDSC), an assessment administered by caregivers to evaluate children's sleep problems.

[0046] [Table 3]

[0047] For example, reducing sleep disturbances by reducing sleep apnea is believed to be associated with both improved nighttime sleep (e.g., sleep transitions and sleep maintenance) and better daytime wakefulness for better nighttime sleep. Better sleep in individuals, particularly those with DEE, ASD, or DEE-ASD, can lead to better daytime functioning, better daytime cognition, and better educational performance.

[0048] Transdermal Pharmaceutical Composition Transdermal delivery of cannabinoids (e.g., CBD) has advantages over oral dosing because it allows the drug to be absorbed directly into the bloodstream through the skin. This avoids first-pass hepatic metabolism, allowing for lower dosage levels of the active pharmaceutical ingredient as well as higher bioavailability and improved safety profiles. Transdermal delivery also avoids the gastrointestinal tract, reducing the chance of CBD being degraded to THC by gastric acid, which may be associated with GI-related adverse events and undesirable psychoactive effects. Additionally, transdermal delivery of CBD reduces the intensity and frequency of somnolence adverse events typically present with oral dosing of CBD. Transdermal delivery of CBD can avoid liver function adverse events typically present with oral dosing of CBD. In some embodiments, transdermal administration of an effective amount of CBD reduces the intensity of at least one adverse event by about 15% to about 95% compared to oral administration of CBD. Exemplary transdermal cannabinoid delivery systems are described in U.S. Pat. Nos. 8,435,556 and 8,449,908, both of which are incorporated herein by reference.

[0049] The CBD may be in gel form and may be pharma- ceutical manufactured as a transparent gel, such as a permeation-enhancing gel designed to provide transdermal controlled drug delivery with once or twice daily administration. The CBD gel may be 1% (wt / wt) CBD to 7.5% (wt / wt) CBD. The CBD gel may have, for example, 4.2% (wt / wt) CBD or 7.5% (wt / wt) CBD. The CBD gel may be applied topically by the patient or a caregiver to the patient's upper arms and shoulders, back, thighs, or any combination thereof.

[0050] The CBD gel may include diluents and carriers, as well as other conventional excipients such as wetting agents, preservatives, and suspending and dispersing agents. The CBD may be synthetic CBD. The CBD may be pure CBD. The CBD may be plant-derived. The CBD may be (-)-cannabidiol.

[0051] The transdermal formulation may be a cream, salve, lotion or ointment. The CBD may be delivered by a bandage, pad or patch.

[0052] The CBD can be administered transdermally to the subject's upper arms and shoulders. In some embodiments, the CBD is administered transdermally to the subject's thighs or back.

[0053] The CBD gel may include solubilizers, permeation enhancers, dissolution aids, antioxidants, bulking agents, thickeners, and / or pH adjusters. The composition of the CBD gel may be, for example: a. cannabidiol present in an amount of about 0.1% to about 20% (wt / wt) of the composition; b. a lower alcohol having 1-6 carbon atoms present in an amount of about 15% to about 95% (wt / wt) of the composition; c. a first penetration enhancer present in an amount of about 0.1% to about 20% (wt / wt) of the composition; and d. water in an amount sufficient to bring the composition to a total of 100% (wt / wt). Other formulations of CBD gels may be found in International Publication No. WO 2010 / 127033, the entire contents of which are incorporated herein by reference.

[0054] In some instances, there may be other ways to provide the CBD gel, for example, via a pump or as an alternative transdermal formulation.

[0055] The effective amount of CBD may range from about 250 mg to about 1000 mg total daily, which may be administered in a single daily dose or twice daily doses. For example, the effective amount of CBD may be about 250, 500, 750, or 1000 mg total daily, which may be administered in a single daily dose or twice daily doses. For example, a total daily dose of 1000 mg may be administered in two doses of 500 mg per day.

[0056] In some instances, the administration of an effective amount of CBD maintains or improves circadian rhythm. The administration of an effective amount of CBD does not cause addiction in at least some, if not all, patients. In addition to the advantage of not developing addiction when the administration of an effective amount of CBD is started, human subjects, e.g., patients, may not experience excessive drowsiness.

[0057] sleep apnea Sleep apnea is a sleep disorder characterized by one or more pauses in breathing or shallow breathing during sleep. Each pause in breathing, called an apnea, can last from a few seconds to a few minutes and can occur from 5 to 30 or more times per hour. In moderate to severe sleep apnea, the most common treatment is the use of continuous positive airway pressure (CPAP), which helps maintain an open airway during sleep by a constant flow of pressurized air to the patient's mouth and / or nose. Patients typically wear a mask that covers the nose and / or mouth and is connected by a flexible tube to a small bedside compressor. This type of treatment, although effective, can be uncomfortable.

[0058] There is some correlation between obstructive sleep apnea (OSA) and body weight. The prevalence of OSA in obese or severely obese patients is about twice that of adults with normal weight. Furthermore, mild OSA patients who gain 10% of their baseline body weight have a 6-fold increased risk of developing OSA, and an equivalent weight loss can result in more than 20% improvement in OSA severity (Peppard et al., Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA. 2000; 284(23): 3015-3021). Furthermore, the higher prevalence of OSA in obese subjects is not limited to adults. Recent data indicate that obese children have a 46% prevalence of OSA when compared with children seen in general pediatric clinics (33%) (Rudnick et al. Prevalence and ethnicity of sleep-disordered breathing and obesity in children. Otolaryngol Head Neck Surg. 2007;137(6):878-882).

[0059] Fat deposits in certain areas may affect sleep apnea. Fat deposits in the tissues surrounding the upper airway may lead to smaller passages and increased collapse of the upper airway, predisposing a person to apnea. Fat deposits around the chest (trunk obesity) may reduce chest compliance and functional residual capacity, increasing oxygen demand. (Romero Corral et al. Interactions Between Obesity and Obstructive Sleep Apnea Chest. 2010 Mar;137(3):711-719).

[0060] Although excess weight is one of the main causes of sleep apnea, there are other causes of sleep apnea that are unrelated to weight. Some patients may have pre-existing anatomical or neurological conditions that can cause sleep apnea. For example, central sleep apnea is a disorder in which an individual's breathing stops and starts repeatedly during sleep because the brain does not send the appropriate signals to the muscles that control breathing during sleep. People with thick necks or narrow throats may have narrow airways, leading to sleep apnea. Enlarged tonsils or adenoids can block the airway, especially in children. All of these conditions can cause sleep apnea episodes in individuals, regardless of weight or BMI.

[0061] In one embodiment, a sleep disorder in a human subject is treated by administering an effective amount of cannabidiol (CBD) to a human in need thereof to treat the sleep disorder. In some embodiments, the sleep disorder is caused by an episode of sleep apnea. In one embodiment, CBD is administered transdermally as described above. Typical doses of transdermal CBD range from about 10 mg / kg to about 25 mg / kg. In some embodiments, an effective amount of CBD ranges from about 250 mg to about 1000 mg total per day. CBD can be administered once a day or twice a day. In some embodiments, CBD is administered at least 8 hours, at least 6 hours, or at least 4 hours before the patient's expected bedtime. CBD used to treat a sleep disorder can be administered between about 9:00 a.m. and 4:00 p.m., 10:00 a.m. and 3:00 p.m., or 11:00 a.m. and 2:00 p.m.

[0062] In one embodiment, the subject with a sleep disorder suffers from obstructive sleep apnea. Obstructive sleep apnea is associated with the subject's obesity or overweight condition. In one embodiment, the subject has a BMI greater than 25. In one embodiment, the subject is an adult. Alternatively or additionally, the subject may be between 3 and 18 years old. In some embodiments, the subject may also have ASD or DEE-ASD. In one embodiment, administration of an effective amount of CBD is initiated to maintain or improve circadian rhythm. EXAMPLES

[0063] [Example 1] Study of ZYN-002 in Children with DEE This was a sequential, multiphase, open-label, multinational, multicenter, multiple-dose study to evaluate the long-term safety, tolerability, and efficacy of ZYN002 (transdermal CBD gel) in child and adolescent epilepsy patients aged 3 to 18 years with seizures associated with developmental and epileptic encephalopathies (DEE) according to the International League Against Epilepsy (ILEA) classification (Scheffer et al., 2017). The study was conducted to evaluate the efficacy of ZYN002 in DEE patients with ASD. The study objectives also included evaluating the effect of ZYN002 transdermal CBD gel on QoL, sleep, and caregiver qualitative assessments in child and adolescent patients with DEE.

[0064] Figure 1 illustrates the study design and treatment of Example 1 of cannabidiol transdermal gel in BELIEVE (ZYN2-CL-025) according to the present disclosure. ZYN002 was administered at a total daily dose of 250mg to 1000mg over an initial 26 week treatment period (Period A), followed by an extension period of up to 46 weeks (Period B). Results through 12 months for Period A and Period B, as well as safety results through 72 weeks, are discussed herein.

[0065] Approximately 48 patients enrolled in Period A, and 40 patients progressed to complete open-label treatment in Period A. In Period A, patients underwent a 4-week baseline period, followed by a 4-week titration period, and a flexible dosing maintenance period of 22 weeks. Patients were treated for a total of 26 weeks in Period A.

[0066] Approximately 29 patients entered Period B, and 28 patients progressed to completion. One patient withdrew consent at week 42. In Period B, patients continued to receive ZYN002 at the same maintenance dose they were receiving at week 26 (i.e., end of Period A) for up to an additional 46 weeks.

[0067] Patients received study medication twice daily (every 12 hours ± 2 hours) for a 26-week treatment period and a 46-week extension period (total treatment period of 72 weeks).

[0068] Enrolled patients received an initial weight-based dose of ZYN-002 of 250 mg / day or 500 mg / day. Patients weighing 25 kg or less could be titrated up to a maximum of 750 mg / day, and patients weighing more than 25 kg could be titrated up to a maximum of 1,000 mg / day.

[0069] Diagnosis and inclusion criteria Patients enrolled in this study had a diagnosis of developmental and epileptic encephalopathy. Patients were males and females between the ages of 3 and 18 years, with a body mass index between 13 and 35 kg / m2. 2 and weighed more than 12 kg.

[0070] Patients had a diagnosis of developmental and epileptic encephalopathy (DEE) as defined by the International League Against Epilepsy classification (Scheffer 2017) and had generalized motor (i.e., generalized tonic-clonic, tonic-clonic, atonic, epileptic spasms), focal awareness-preserving motor, focal awareness-impaired, or focal-onset bilateral tonic-clonic seizures. Enrolled examples of DEE included, but were not limited to, Lennox-Gastaut syndrome, Dravet syndrome, West syndrome / infantile spasms, and Douzé syndrome. The diagnosis must have been established for more than one year and must be substantiated by review of medical history and examination and appropriate testing, including electroencephalogram (EEG), magnetic resonance imaging (MRI) scan, or genetic testing.

[0071] A stable regimen of 1–4 ASM for patients was maintained from the baseline period throughout the study.

[0072] Patients had a total of 5 or more of the following types of seizures during the baseline period: generalized motor (i.e., generalized tonic-clonic, tonic, clonic, atonic, epileptic spasms), focal awareness-preserving motor, focal awareness-impaired, or focal onset bilateral tonic-clonic seizures. Clusters of epileptic spasms were counted as a single seizure.

[0073] Patients had a history of developmental delay with regression, slowing, or plateau in at least one domain of development after seizure onset as determined by the investigator.

[0074] Exclusion criteria Patients were excluded from the study for the following reasons, including: use of tetrahydrocannabinol or CBD products within 12 weeks prior to screening; treatment with strong inhibitors / inducers of CYP3A4; change in ASM regimen or epilepsy diet within the past 4 weeks; or alanine aminotransferase, aspartate aminotransferase, or total bilirubin levels ≥3x the upper limit of normal (ULN).

[0075] Applicable area The approved application sites for the gel were the left and right upper arms, as shown in Table 4.

[0076] [Table 4]

[0077] If redness occurred at the application site, ZYN002 was temporarily applied to the left or right upper thigh in consultation with the investigator. For patients with lower BMI and / or smaller arms, ZYN002 could be applied to the right or left upper thigh. The application sequence was one sachet each on the left and right upper arms / shoulders, and one sachet each on the left and right upper thighs.

[0078] If applied to the right and / or left upper thigh, the procedure was the same as described for the left and right upper arms / shoulders. The parent / caregiver applying the gel wore gloves. The parent / caregiver ensured that the gel was rubbed in completely, that no gel was left on the gloves, and that the skin surface where the gel was applied was no longer shiny and dry to the touch before donning. The parent / caregiver could apply an approved moisturizing lotion 2 hours after dosing.

[0079] Products, Dosages and Modes of Administration The product was ZYN002 (Cannabidiol: CBD), 4.2% gel, topical, and the drug was supplied as a sachet containing 2.98 g of gel to deliver 125 mg of CBD / sachet, applied by using 1-4 sachets in the morning and evening to achieve the appropriate total daily dose for each patient based on treatment group.

[0080] The treatment was as follows: Treatment A - 125 mg CBD Q12H (± 2 hours); total daily dose was 250 mg CBD (1 sachet in the morning and 1 sachet in the evening). Treatment B - 250 mg CBD Q12H (± 2 hours); total daily dose was 500 mg CBD (2 sachets in the morning and 2 sachets in the evening). Treatment C- 375 mg CBD Q12H (± 2 h); total daily dose was 750 mg CBD (3 sachets in the morning and 3 sachets in the evening). Treatment D-500 mg CBD Q12H (± 2 hours); total daily dose was 1000 mg CBD (4 sachets in the morning and 4 sachets in the evening).

[0081] Period A: Baseline period During a 4-week baseline period, parents and / or caregivers recorded the number of the following types of seizures in a seizure diary: Generalized tonic-clonic ("primary generalized tonic-clonic") seizures Focal consciousness impairment seizures Focal onset bilateral tonic-clonic seizures Focal aware seizures with motor signs Tonic seizures -Clonic seizures Cataplexy Epileptic spasms (clusters of epileptic spasms were counted as single seizures).

[0082] The following types of seizures were recorded in the daily diary at the same time and for the same duration each day as determined by the investigator (e.g., 10 minutes at 6:00 PM): Myoclonic seizures -Yawning attacks Focal aware seizures without motor signs (e.g., focal sensory seizures)

[0083] Period A: Gradual increase period The initial dose for patients <25 kg was 125 mg CBD Q12H (± 2 hours) with a total daily dose of 250 mg CBD over a 4-week titration period. At the week 4 visit (Visit 4), at the investigator's discretion, the dose remained at 250 mg CBD daily or was increased to 250 mg CBD Q12H (± 2 hours) for a total daily dose of 500 mg CBD (4 sachets) for the remaining 22 weeks of the treatment period.

[0084] Patients weighing >25 kg received 250 mg CBD Q12H (± 2 hours) for a total dose of 500 mg CBD daily over the 4-week titration period. At the week 4 visit (Visit 4), at the investigator's discretion, the dose remained at 500 mg CBD daily or was increased to 375 mg CBD Q12H (± 2 hours) for a total dose of 750 mg CBD (6 sachets) daily for the remaining 22 weeks of the treatment period.

[0085] Period A: Maintenance Period At week 10, patients taking 500 mg CBD per day could be increased to 750 mg CBD per day (6 packets), and patients taking 750 mg CBD per day could be increased to 1000 mg CBD (8 packets).

[0086] Investigators reduced doses as needed based on safety and tolerability after patients began the maintenance period. Patients taking CBD 250 mg Q12H (± 2 hours); total daily dose 500 mg CBD could reduce their dose to 125 mg CBD Q12H (± 2 hours); total daily dose 250 mg CBD. Patients taking CBD 375 mg Q12H (± 2 hours); total daily dose 750 mg CBD could reduce their dose to 250 mg CBD Q12H (± 2 hours); total daily dose 500 mg CBD. Patients taking CBD 500 mg Q12H (± 2 hours); total daily dose 1000 mg CBD were allowed to reduce their dose to CBD 375 mg Q12H (± 2 hours); total daily dose 750 mg or 250 mg CBD Q12H (± 2 hours); total daily dose 500 mg CBD. Patients whose weight changed during the course of the study were allowed to increase or decrease their dose.

[0087] Depending on the patient's dose at the time of discontinuation, a tapering period ranging from 1 to 3 weeks was completed. After tapering, patients were also required to complete a 4-week telephone follow-up period.

[0088] Evaluation criteria Safety Assessments: Safety assessments included collection of AEs, physical and neurological examinations, vital signs, electrocardiogram (ECG), skin check tests (investigator) and diaries (parent / caregiver), and laboratory tests.

[0089] Endpoints Seizure Frequency The efficacy endpoint was the median percent change from baseline in mean monthly (28-day) seizure frequency (SF28) sum ("countable seizures") over 26 weeks (Period A) for the following types: Focal Impaired Awareness Seizures (FIAS) Tonic-clonic seizures (TCS), e.g. ·Generalized tonic-clonic seizures (GTCS) Focal onset bilateral tonic-clonic seizures (FBTCS) Recorded the number of patients who met 35% and 50% reduction in FIAS and TCS.

[0090] QoL Efficacy Endpoints: Change in ELDQOL from baseline to the end of period A Change from baseline in "good day / bad day" ratings:

[0091] Sleep Efficacy Endpoints: Change from baseline to the end of period A in SDSC

[0092] Qualitative Caregiver Endpoints: Qualitative descriptions of parents and caregivers at the end of Period A

[0093] Analysis Populations: The safety analysis set included all patients who received at least one dose of study drug. Patients who received study drug for at least 80 days and completed at least 80% of seizure diaries were included in the efficacy analysis and were identified as the modified intent-to-treat (mITT) population.

[0094] result The data show that ZYN-002 reduced seizure frequency in many types of difficult-to-treat developmental and epileptic encephalopathies, including refractory seizure types such as focal impairment of awareness seizures (FIAS), generalized tonic-clonic seizures (GTCS), or focal onset bilateral tonic-clonic seizures (FBTCS).

[0095] These results show a meaningful reduction in seizures and improvement in many of the challenging behaviors and symptoms, such as sleep-related disorders, seizure intensity, fatigue, social isolation, cognitive impairment, and speech disorders. For example, patients experienced improvements in sleep-related disorders, including improvements in sleep quality, sleep onset, total sleep, sleep onset and sleep maintenance, sleep-wake transitions, or wakefulness and nightmare disorders.

[0096] Of the 48 patients enrolled in BELIEVE (ZYN2-CL-025), 40 patients completed Period A and 28 completed through Month 12 of Period B (Table 5). Only one subject withdrew consent during Period B.

[0097] [Table 5]

[0098] Baseline characteristics and seizure frequency The mean age of the 48 patients enrolled in BELIEVE and included in the safety analysis set was 10.5 years (see Table 6). One-quarter of patients had Lennox-Gastaut syndrome (LGS) or Dravet syndrome.

[0099] Clinically significant comorbid conditions were present in all patients and included gait and mobility disorders (45.8%), sleep disorders (39.6%), chronic respiratory conditions / infections (37.5%), ASD (29.2%), and percutaneous endoscopic gastrostomy (14.6%).

[0100] The mITT population included 46 patients (2 patients were excluded from efficacy analyses due to not completing 80% of the diary or not using study medication for 80 days). Thirty-three patients had FIAS and / or TCS at baseline and constituted the population in which the seizure frequency efficacy endpoint was measured.

[0101] [Table 6] TIFF2024505212000007.tif106166

[0102] Seizure frequency Efficacy endpoint Figure 3 is a graph showing efficacy over the treatment period. Specifically, Figure 3 shows the median percent reduction from baseline in 28-day frequency of FIAS and TCS by time point for patients with FIAS and / or TCS at baseline. Over the 12-month treatment period, the median percent reduction from baseline in monthly frequency of FIAS and TCS ranged from 44% at 3 months to 73% at 12 months.

[0103] When analyzed by seizure type, the median reductions from baseline in FIAS, GTCS, and FBTCS at 6 months were 45%, 60%, and 59%, respectively. At 12 months, the median reductions in FIAS, GTCS, and FBTCS were 100%, 83%, and 59%, respectively.

[0104] FIG. 4 is a graph showing the percentage of patients with reduced seizures. Specifically, FIG. 4 shows the percentage of patients with FIAS and / or TCS at baseline who achieved a 35% and 50% reduction in FIAS and TCS by time point. A significant percentage of patients achieved a 35% or greater and a 50% or greater reduction in FIAS and TCS by month 3 of the follow-up to month 12. For example, the percentage of patients who achieved 35% or greater increased from 58% at month 3 to 89% at month 12. Similarly, the percentage of patients who achieved 50% or greater increased from 46% at month 3 to 83% at month 12.

[0105] Figure 5 is a graph showing the median percent reduction from baseline in 28-day seizure frequency. Specifically, Figure 5 shows the median percent reduction from baseline in 28-day frequency of FIAS and TCS by time point for patients with comorbid ASD at baseline. For patients with comorbid ASD, the median percent reduction from baseline in 1-month frequency of FIAS and TCS ranged from 44% at 3 months to 68% at 12 months over the 12-month treatment period.

[0106] FIG. 6 is a graph showing the rate of patients with reduced seizures with comorbid autism spectrum disorder (ASD) at baseline. Specifically, FIG. 6 shows the rate of patients with 35% and 50% reductions in FIAS and TCS by time point for patients with comorbid ASD at baseline. The rate of patients achieving 35% or more and 50% or more reductions in FIAS and TCS increased over time. For example, the rate of patients achieving 35% or more increased from 65% at 3 months to 88% at 12 months. Similarly, the rate of patients achieving 50% or more increased from 41% at 3 months to 75% at 12 months. Eight out of nine (8 / 9) parents / caregivers provided descriptions of improvement, and one out of nine (1 / 9) parents / caregivers did not mention benefits. Improvements reported by caregivers included focus, engagement, attention, and reduced sleepiness at school.

[0107] ELDQOL Statistically significant reductions from baseline in mean ELDQOL subscale scores for seizure severity, behavior, and mood were observed at week 26 (Table 7).

[0108] [Table 7]

[0109] Sleep score Sleep disorders affect many patients with DEE, ASD, or both DEE-ASD. Sleep disorders include, but are not limited to, sleep onset and sleep maintenance disorders (DIMS), sleep-disordered breathing (SBD), awakening / nightmare disorder (DA), sleep-wake transition disorder (SWTD), hypersomnolence disorder (DOES), and sleep hyperhidrosis. Sleep onset and sleep maintenance disorders (DIMS) are disorders in which a patient has difficulty falling asleep or staying asleep (e.g., insomnia). Sleep-disordered breathing (SBD) are disorders involving difficulty breathing during sleep (e.g., obstructive sleep apnea). Awakening / nightmare disorder (DA) are mental or motor events that occur during non-REM sleep. Typical DA include sleep walking and nightmares. In most cases, DA events are not remembered by the patient upon full awakening. Sleep-wake transition disorder (SWTD) includes events that occur during the transition from sleep to wakefulness and may include rhythmic movement disorder, sleep talking, and leg spasms. Disorder of excessive somnolence (DOES) is characterized by sleepiness (hypersomnia) during normal waking hours. Hyperhidrosis of sleep is characterized by excessive sweating while falling asleep or at night.

[0110] Figure 7 shows the percentage of all patients above the threshold for clinically significant sleep problems based on the Sleep Disorders Scale for Children (SDSC) at baseline and at 26 weeks of ZYN002 treatment. For Figure 7, the left bar is the percentage of patients at baseline and the right bar is the percentage of patients at 26 weeks (see also Table 8). Figure 8 shows the percentage of patients with a threshold t-score >70 at baseline and at 26 weeks, which corresponds to clinically significant sleep problems. For Figure 8, the left bar is the percentage of patients at baseline and the right bar is the percentage of patients at 26 weeks. Statistically significant improvements from baseline in sleep scores were observed in total score, sleep onset or maintenance disorder (DIMS), awakening / nightmare disorder (DA), and sleep-wake transition disorder (SWTD) (see also Table 9).

[0111] Figure 9 shows the percentage of patients with comorbid ASD (DEE) above the threshold for clinically significant sleep problems based on the Sleep Disorder Scale for Children (SDSC) at baseline and at 26 weeks of ZYN002 treatment. For Figure 9, the left bar is the percentage of patients at baseline and the right bar is the percentage of patients at 26 weeks. (See also Table 10). Figure 10 shows the percentage of patients with comorbid ASD (DEE) with a threshold t-score >70 at baseline and at 26 weeks, which corresponds to clinically significant sleep problems. For Figure 10, the left bar is the percentage of patients at baseline and the right bar is the percentage of patients at 26 weeks. Statistically significant improvements from baseline in sleep scores were observed in total score, sleep onset or sleep maintenance disorder (DIMS), awakening / nightmare disorder (DA), and sleep-wake transition disorder (SWTD) (see also Table 11).

[0112] [Table 8]

[0113] [Table 9]

[0114] [Table 10]

[0115] [Table 11]

[0116] Good Day / Bad Day Rating FIG. 11 shows the distribution of good / bad day ratings at baseline and at 6 months of ZYN002 treatment. For FIG. 11, the percentage of patients at baseline was 3.00% very poor, 9.30% very poor, 35.70% neither good nor bad, 45.70% good, and 6.30% very good. The percentage of patients at 6 months was 0.50% very poor, 3.20% poor, 25.90% neither good nor bad, 59.80% good, and 10.60% very good. Comparing baseline to 6 months, the combined percentage of reports of "good days" and "very good days" increased from 52.0% at baseline to 70.4%, and the combined percentage of reports of "very bad days" and "bad days" decreased from 12.3% at baseline to 3.7% (FIG. 11).

[0117] Qualitative caregiver feedback: Qualitative caregiver ratings were administered to 43 parents / caregivers of the 46 patients in the mITT population. 84% (n=36) of parents / caregivers provided 1 or more statements of improvement and 60% (n=26) provided 1 or more statements of deterioration (Table 8). Improvements in the qualitative summary measures were observed in most patients for most measures: - Any improvement: 84% (n=36) -Improved vitality: 58% (n=25) - Seizure improvement: 51% (n=22) -Improved cognition / concentration: 47% (n=20) -Improvement of social avoidance behavior: 44% (n=19) -Improvement of excitability: 33% (n=14) -Improvement of school life: 28% (n=12) -Medical improvement: 14% (n=6)

[0118] Table 12 shows the most frequent positive and negative qualitative statements (n>8) made by parents and caregivers in Period A, the mITT population (N=43).

[0119] [Table 12]

[0120] The improvement seen by caregivers may be related to both improved nighttime sleep (e.g., sleep transition and sleep maintenance) and better daytime wakefulness for better nighttime sleep. Daytime wakefulness is believed to be correlated with both better nighttime sleep and the daytime pharmacological effects of CBD. CBD is preferentially administered in the morning or early afternoon because it may have a stimulating effect when first administered. As can be seen from the caregiver feedback in Figure 11 and Table 12, the combination of better sleep and the stimulating effect of CBD has been shown to result in better daytime functioning, better daytime cognition, and better educational performance. Both "better" days and other quality of life improvements are believed to be related to or caused by improved sleep, including improved symptoms of sleep-disordered breathing.

[0121] safety ZYN-002 was well tolerated in the BELIEVE clinical trial of ZYN002. Most treatment-emergent adverse events (TEAEs) (any events whether unrelated or related to the study drug) were mild or moderate. There were 30 serious adverse events reported by 14 patients over the 72-week treatment period, of which two (lower respiratory tract infection and status epilepticus) were considered potentially drug-related. One patient with a history of keratosis pilaris discontinued study drug due to an AE (severe application site erythema); dermatological patch testing indicated this was not caused by ZYN002-derived allergic contact dermatitis but was likely an irritant contact dermatitis complicated by a secondary bacterial infection. There were no clinically significant changes in vital signs, ECGs, or laboratory findings, except for one patient with a benign isolated alkaline phosphatase elevation (1.69 x ULN) at week 26 that was not considered related to study drug.

[0122] BELIEVE is the first clinical trial of ZYN002 (transdermal CBD) in DEE. Data suggest a meaningful reduction in FIAS and TCS with ZYN002 treatment over 12 months. In a subgroup of ASD patients, ZYN002 demonstrated a meaningful reduction in FIAS and TCS attacks, with most children reaching the 35% or 50% responder threshold by 3 and 6 months, respectively.

[0123] Treatment with ZYN002 may be associated with clinically meaningful improvements in seizure severity, behavior and mood; sleep onset and maintenance, wake / nightmare disorders, sleep-wake transitions, and overall sleep; as well as energy, cognition / concentration, and social avoidance behaviors.

[0124] ZYN002 was well tolerated over 18 months of treatment in medically fragile children and adolescents with DEE. There is a positive benefit / risk profile for ZYN002, as demonstrated in this BELIEVE clinical trial in patients with DEE and FIAS and TCS.

[0125] sleep apnea While testing the effect of CBD on sleep disorders in DEE and DEE-ADS patients, it was found that there is a significant difference in sleep disordered breathing between patients with DEE and patients with DEE with comorbid ASD. Referring to Table 8, which contains the combined data from patients with DEE and patients with DEE-ASD, it can be seen that there is no significant change in SBD for the combined group. However, in the data for the DEE-ASD group (Table 10), which excludes DEE patients without ASD, there is a substantial decrease in SBD (-3.9, p=.072). This trend is also seen in patients with a total SDSC score above 70. In Table 9 (all patients with DEE), there is no significant change in SBD relative to baseline. In Table 11, which presents data from DEE-ASD patients only, the decrease in SBD for DEE-ASD patients is -6.7 (p=.018).

[0126] Without being bound by any theory, it is believed that this change is related to physiological differences between DEE and DEE-ASD patients. Typically, DEE patients have a relatively low body weight / body mass index (BMI) compared to the general population. In contrast, DEE-ASD patients and general ASD patients have a significantly higher body weight / BMI when compared to DEE patients. (Hill et al., Obesity and Autism, Pediatrics, 2015 Dec; 136(6): 1051-1061). This suggests that CBD improves obstructive sleep apnea. It is also believed that sleep apnea can be generally treated with CBD, regardless of whether there are any other underlying causes of the sleep disorder (such as DEE and / or ADS).

[0127] Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. This description should therefore be interpreted as illustrative only and for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It should be understood that the forms of the invention shown and described herein should be interpreted as examples of embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and methods may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention. Changes may be made to the elements described herein without departing from the spirit and scope of the invention as set forth in the following claims.

Claims

1. 1. A pharmaceutical composition for use in a method of treating a sleep disorder in a human subject, comprising: The method comprises administering an effective amount of cannabidiol (CBD) to a human in need thereof to treat the sleep disorder.

2. 2. The method of claim 1, wherein the sleep disorder is caused by episodes of sleep apnea.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the CBD is administered transdermally.

4. 4. The pharmaceutical composition of claim 1, wherein the effective amount of CBD is in the range of about 250 mg to about 1000 mg total daily.

5. 5. The pharmaceutical composition of claim 1, wherein the effective dose of CBD is within the range of 10-25 mg / kg per dose.

6. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the CBD is administered in a single daily dose.

7. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the CBD is administered in two doses per day.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the treatment comprises amelioration of sleep-related disorders.

9. 9. The pharmaceutical composition of claim 8, wherein the improvement of sleep-related disorders comprises improvement in sleep quality, sleep onset, total sleep, sleep onset and sleep maintenance, sleep-wake transition or wakefulness, and nightmare disorders.

10. 10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the CBD is pure CBD.

11. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the CBD is synthetic CBD.

12. 10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the CBD is derived from a plant.

13. 13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the cannabidiol is (-)-cannabidiol.

14. 14. A pharmaceutical composition according to any preceding claim, wherein the CBD is formulated as a gel.

15. 15. The pharmaceutical composition of claim 14, wherein the CBD is formulated as a permeation enhancing gel.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the subject suffers from obstructive sleep apnea.

17. 17. The pharmaceutical composition of claim 16, wherein the obstructive sleep apnea is associated with an obese or overweight condition in the subject.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the subject is an adult.

19. The pharmaceutical composition according to any one of claims 1 to 17, wherein the subject is between 3 and 18 years old.

20. The pharmaceutical composition of any one of claims 1 to 19, wherein the subject has ASD.

21. The pharmaceutical composition of any one of claims 1 to 20, wherein the subject has DEE-ASD.

22. The pharmaceutical composition of any of claims 1 to 21, wherein the subject has a BMI of greater than 25.

23. The pharmaceutical composition according to any one of claims 1 to 22, wherein circadian rhythm is maintained or improved upon initiation of administration of an effective amount of CBD.

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