WO2023272335A1

WO2023272335A1 - Cannabidiol formulation comprising a matrix pellet forming excipient

Info

Publication number: WO2023272335A1
Application number: PCT/AU2022/050542
Authority: WO
Inventors: Adam James
Original assignee: Emyria
Current assignee: Emyria
Priority date: 2021-06-30
Filing date: 2022-06-02
Publication date: 2023-01-05
Anticipated expiration: 2023-12-30

Abstract

A method for treating or preventing symptoms or conditions such as psychological distress, pain and insomnia, by administering an oral pharmaceutical composition containing a prophylactically or therapeutically effective amount of CBD and a matrix pellet forming excipient such as gelatin.

Description

Cannabidiol Dosing Regime TECHNICAL FIELD

[0001] The present invention relates to a method of treating a condition such as psychological distress, pain and insomnia, comprising administering the cannabidiol with a matrix pellet forming excipient.

BACKGROUND ART

[0002] Anxiety, depression and stress are symptoms of psychological distress and are the most prevalent psychiatric symptoms, being associated with a high burden of illness. For example, up to one-third of women and one-fifth of men will experience anxiety at some point in their lives. Insomnia is a further significant health burden, often associated with psychological distress.

[0003] There are a number of psychological and medical treatments available to alleviate anxiety, stress and depression, and insomnia.

[0004] Psychological treatments include cognitive behavioural therapy (CBT), counselling and behavioural therapy. These can be effective, but are time intensive and costly, and not easily accessed for some subjects, particularly in rural areas.

[0005] Medical treatments include the administration of antidepressant medications (including tricyclic antidepressants, SSRIs and SNRIs), beta blockers and benzodiazepines. However, many of these medications can have significant side effects such as nausea, drowsiness, weight gain and addiction.

[0006] The global burden of pain is large and growing. One in five Australians aged under 65 live with chronic pain, leading to financial and social exclusion, poor quality of life and impacts on mental health. Pain is the most common reason patients seek medical care.

[0007] Medical treatments for pain include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, opioids, some anticonvulsant drugs (gabapentin and pregabalin), and some antidepressant medications. Like those for psychological distress and insomnia, they can have significant side effects such as nausea, drowsiness, weight gain and addiction.

[0008] The present invention seeks to provide a composition and method to reduce or prevent symptoms of psychological distress such as anxiety, stress and/or depression, insomnia and pain, or to provide the consumer with a useful or commercial choice.

[0009] The previous discussion of the background art is intended to facilitate an understanding of the present invention only. The discussion is not an acknowledgement or admission that any of the material referred to is or was part of the common general knowledge as at the priority date of the application. SUMMARY OF INVENTION

[0010] The present invention provides a method for treating or preventing at least one symptom of a condition in a subject in need thereof, the method comprising the step of: administering an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition.

[0011] Preferably the first prophylactically or therapeutically effective amount of CBD is at a ratio to the second equally prophylactically or therapeutically effective amount of CBD of 1 :3, 1 :2.5, 1 :2 or 1 :1.5.

[0012] Preferably the is condition chosen from the list comprising: insomnia, pain, and psychological distress.

[0013] Preferably the method reduces the subject’s score on the validated scale for anxiety or reduces the anxiety biomarker and/or reduces the subject’s score on the validated scale for stress or reduces the stress biomarker and/or reduces the subject’s score on the validated scale for depression or the depression biomarker. Preferably the method reduces the subject’s score on the validated scale for anxiety and/or reduces the subject’s score on the validated scale for stress and/or reduces the subject’s score on the validated scale for depression.

[0014] Preferably the method reduces the subject’s score on the validated scale for insomnia or reduces the insomnia biomarker.

[0015] Preferably the method reduces the subject’s score on the validated scale for pain or reduces the pain biomarker.

[0016] Preferably the matrix pellet forming excipient is chosen from the list comprising: gelatine, medium chain triglycerides, long chain triglycerides, hydroxypropyl methylcellulose (HPMC), starch and modified starch, carrageenan, hydroxy propyl cellulose (HPC), pullulan, polyvinyl alcohol (PVA), and alginate.

[0017] The present invention further provides an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition for the treatment or prevention at least one symptom of a condition in a subject in need thereof.

[0018] The composition is preferably administered for at least one month.

[0019] According to another aspect of the invention, there is provided the use of an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition for the treatment or prevention of at least one symptom of a condition in a subject in need thereof.

[0020] According to another aspect of the invention, there is provided the use of a first prophylactically or therapeutically effective amount of and matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition, in the manufacture of an oral composition for the treatment or prevention of at least one symptom of a condition in a subject in need thereof.

[0021] There is further provided a kit for at least one symptom of a condition in a subject in need thereof, comprising: a) an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition; b) instructions for use.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Further features of the present invention are more fully described in the following description of several non-limiting embodiments thereof. This description is included solely for the purposes of exemplifying the present invention. It should not be understood as a restriction on the broad summary, disclosure or description of the invention as set out above. The description will be made with reference to the accompanying drawings in which: Figure 1 is the DASS-21 questionnaire and assessment criteria.

Figure 2 is the ISI questionnaire and assessment criteria.

Figure 3 is the BPI-Short Form Pain questionnaire and assessment criteria.

Figure 4 provides a Schedule of Assessments a: Review Visits are at Doctor's discretion. Suggested one / month for first 6 months but can be more or less b: May occur at any time after the patient has ceased treatment c: Optional visits as clinically indicated d: Obtain if possible e: As applicable.

Figure 5 is a graph of the change in anxiety scores from initial visit to first follow-up and cannabidiol dosage (oil and capsule). Higher values of change indicate less anxiety. The solid fitted line represents a LOESS curve with 95% confidence intervals.

Figure 6 is a graph of the change in anxiety scores from initial visit to first follow-up and cannabidiol dosage (capsule only). Higher values of change indicate less anxiety. The solid fitted line represents a LOESS curve with 95% confidence intervals.

Figure 7 is a graph comparing the mean changes in anxiety scores between patients on CBD capsules and those on CBD oils for (i) the full (unmatched) sample, (ii) a subsample matched by baseline anxiety scores as well as a 1 :1 (capsule to oil) CBD dosage ratio, and (iii) a subsample matched by baseline anxiety scores as well as a 1 :2 (capsule to oil) CBD dosage ratio.

Figure 8 is a graph comparing the respective mean changes in survey scores for depression, stress, insomnia, pain severity, and pain interference between patients on CBD capsules and those on CBD oils in a subsample of patients matched by the corresponding baseline survey scores as well as a 1 :2 (capsule to oil) CBD dosage ratio.

Figure 9 is a graph of the pharmacokinetics of matrix pellet encapsulated 10 mg cannabidiol compositions (PTL101-10mg) compared to a commercial reference (Sativex™), as shown by mean CBD plasma levels following oral administering to healthy volunteers (N=14). Matrix pellet encapsulated cannabidiol compositions (grey curve), Sativex™ reference (black curve), both containing 10 mg CBD.

Figure 10 is a graph of drug loading capacity of matrix pellet encapsulated cannabidiol compositions (PTL101-10mg, PTL101-100mg), when comparing mean CBD plasma levels following oral administering to healthy volunteers (N=14) at two doses, 10 mg CBD (·) and 100 mg CBD ( * ).

Figure 11 is a graph of bioavailability of matrix pellet encapsulated cannabidiol compositions (PTL101) (grey) compared to a commercial reference (Sativex™, black), when administered to healthy volunteers (N=14). Relative bioavailability as was calculated from the ratios of Area Under concentration-time Curve (AUC) normalized to dose.

DESCRIPTION OF INVENTION

Detailed Description of the Invention

Method of Treatment

[0023] Administration of cannabidiol can assist with treating or preventing one or more symptoms of a number of diseases or conditions in a subject. However, it is the policy of most pharmaceutical regulatory bodies that the lowest dose of any active agent should be used. Therefore, it would be advantageous to provide to a subject desiring the relief provided by cannabidiol, the lowest dose that would provide that relief.

[0024] The present inventors have surprisingly found that delivery of a dose of cannabidiol in the form of matrix pellets provides the same treatment or prevention of symptoms of the condition that a higher dose of cannabidiol in the form of an oil provides. Thus, a lower dose of cannabidiol provided in the form of matrix pellets provides the same relief of symptoms of psychological distress, insomnia or pain as a higher dose of cannabidiol provided in the form of an oil.

[0025] The present method therefore provides a method of treating or preventing at least one symptom of a condition in a subject in need thereof comprising the step of: administering an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition

[0026] Preferably the first prophylactically or therapeutically effective amount of CBD is at a ratio to the second equally prophylactically or therapeutically effective amount of CBD of 1 :3, 1 :2.5,1 :2 or 1 :1.5.

[0027] Preferably the prevention or treatment of at least one symptom of a condition is prevention or treatment of the symptoms of psychological distress such as anxiety, stress and/or depression, insomnia and pain. In the present invention, the terms “disease”, disorder” and “condition” may be used interchangeably.

[0028] Administration of cannabidiol in the present method can assist with treating or preventing one or more symptoms of psychological distress in the form of anxiety, stress and/or depression. [0029] The present method provides a method of treating or preventing one or more symptoms of psychological distress in a subject comprising the step of: administering an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition wherein the subject has symptoms of at least one of anxiety, stress and/or depression when assessed by a validated scale or biomarker for identifying symptoms of anxiety, stress and/or depression. Preferably, the subject has symptoms of two or more of anxiety, stress and/or depression.

[0030] Preferably for the treatment of symptoms of at least one of anxiety, stress and/or depression the first prophylactically or therapeutically effective amount of CBD is at a ratio to the second equally prophylactically or therapeutically effective amount of CBD of 1 :3 to 1 :2, preferably 1 :2.5.

[0031] The present method provides a method of treating or preventing one or more symptoms of insomnia in a subject comprising the step of: administering an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition wherein the subject has symptoms of at least one of insomnia when assessed by a validated scale or biomarker for identifying symptoms of insomnia.

[0032] Preferably for the treatment of symptoms of insomnia the first prophylactically or therapeutically effective amount of CBD is at a ratio to the second equally prophylactically or therapeutically effective amount of CBD of 1 :2 or 1 :1 .5.

[0033] The present method provides a method of treating or preventing one or more symptoms of pain in a subject comprising the step of: administering an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition wherein the subject has symptoms of pain when assessed by a validated scale or biomarker for identifying symptoms of pain.

[0034] Preferably for the treatment of symptoms of pain the first prophylactically or therapeutically effective amount of CBD is at a ratio to the second equally prophylactically or therapeutically effective amount of CBD of 1 :2.5 to 1 :1 .5, more preferably 1 :2.0 or 1 :1 .9.

[0035] Preferably the oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient comprises from 25 mg to 200 mg cannabidiol.

[0036] Preferably the matrix pellet forming excipient is chosen from the list comprising: gelatine, medium chain triglycerides, long chain triglycerides, hydroxypropyl methylcellulose (HPMC), starch and modified starch, carrageenan, hydroxy propyl cellulose (HPC), pullulan, polyvinyl alcohol (PVA), and alginate.

[0037] Preferably the solubility of cannabinoid in the matrix pellet forming excipient is similar to that of cannabinoid in gelatine. For example, the solubility of cannabinoid in the matrix pellet forming excipient may be within 2% of the solubility of cannabinoid in gelatine, within 5%, within 10%, within 15%, within 20%, within 25% or within 30% of the solubility of cannabinoid in gelatine.

[0038] Preferably the solubility of CBD in the matrix pellet forming excipient is similar to that of CBD in gelatine. For example, the solubility of CBD in the matrix pellet forming excipient may be within 2% of the solubility of CBD in gelatine, within 5%, within 10%, within 15%, within 20%, within 25% or within 30% of the solubility of CBD in gelatine.

[0039] Preferably the matrix pellet forming excipient is capable of forming a solid or semi-solid pellet at a temperature of less than 60 °C, for example from at least 20 °C to 60 °C.

[0040] Preferably the matrix pellet forming excipient is a liquid at a temperature that is within the range that CBD remains stable and does not degrade. For example, preferably the matrix pellet forming excipient is a liquid at a temperature above 60 °C. The matrix pellet forming excipient may be a liquid at a temperature above 70 °C, 80 °C, 90 °C, or 100 °C. [0041 ] In some embodiments, the matrix pellets of the invention have a diameter size in the range of at least about 0.5-3.0 mm, or 1-2 mm. Preferably the matrix pellets of the invention have a diameter size from 2 mm or less.

[0042] In further embodiments, the matrix pellets of the invention have a weight in the range of at least about 0.1-10 mg, or 0.5-5 mg.

[0043] In some embodiments, a matrix pellet of the invention can comprise an amount of cannabinoid active ingredient that is up to about 30% (w/w). In one embodiment, the amount of active ingredient in a single matrix pellet is from 20-24%, or more preferably 22% (w/w). In another embodiment, the amount of active ingredient in a single matrix pellet is from 2-4%, or more preferably 3% (w/w).

[0044] In some embodiments, a matrix pellet of the invention can comprise an amount of cannabinoid active ingredient that is up to about 0.6 mg per pellet. In one embodiment, the amount of cannabinoid in a single matrix pellet is from 0.2mg to 0.6 mg per pellet. The amount of cannabinoid in a single matrix pellet is more preferably from 0.35 to 0.4 mg per pellet or 0.375 mg per pellet; or from 0.45 mg to 0.5 mg per pellet or 0.46 mg per pellet.

[0045] The present invention thus provides a method of treating or preventing one or more symptoms of psychological distress in a subject comprising the step of: administering an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition wherein the subject has symptoms of at least one of anxiety, stress and/or depression when assessed by a validated scale or biomarker for identifying symptoms of anxiety, stress and/or depression; wherein:

- the first prophylactically or therapeutically effective amount of CBD is 100 mg; and

- the second prophylactically or therapeutically effective amount of CBD is 250 mg.

[0046] Administration of cannabidiol in the present method can assist with treating or preventing one or more symptoms of insomnia.

[0047] The present method therefore provides a method of treating or preventing insomnia in a subject in need thereof comprising the step of: administering an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition wherein the subject has symptoms of insomnia as assessed by a validated scale or biomarker for identifying symptoms of insomnia.

[0048] The present invention thus provides a method of treating or preventing one or more symptoms of insomnia in a subject comprising the step of:

[0049] administering an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition wherein the subject has symptoms of insomnia when assessed by a validated scale or biomarker for identifying symptoms of insomnia; wherein:

- the first prophylactically or therapeutically effective amount of CBD is 150 mg; and

- the second prophylactically or therapeutically effective amount of CBD is 225 mg.

[0050] Administration of cannabidiol in the present method can assist with treating or preventing pain.

[0051 ] The present method therefore provides a method of treating or preventing pain in a subject comprising the step of: administering an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition wherein the subject has symptoms of pain as assessed by a validated scale or biomarker for identifying symptoms of pain.

[0052] The present invention thus provides a method of treating or preventing one or more symptoms of pain in a subject comprising the step of:

[0053] administering an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition wherein the subject has symptoms of pain when assessed by a validated scale or biomarker for identifying symptoms of pain; wherein:

- the first prophylactically or therapeutically effective amount of CBD is 120 mg; and

- the second prophylactically or therapeutically effective amount of CBD is 230 mg.

[0054] Preferably, the dose is administered in a single composition once per day. Alternatively, the dose may be delivered two, three or four times in separate compositions, to a total daily dose of between 25 mg and 200 mg cannabidiol.

Disease or Condition

[0055] In one embodiment, the subject does not have a current diagnosis of a mental disorder corresponding to the DSM-5 criteria for: depressive disorders, trauma- and stressor-related disorders, obsessive-compulsive and related disorders. In one embodiment, the subject does not have a current diagnosis of a mental disorder corresponding to the DSM-5 criteria for anxiety disorders. In this embodiment, the subjects may have had a previous diagnosis of the relevant DSM-5 mental disorder, but the diagnosis is not current at the time of treatment by the present method.

• Psychological Distress

[0056] The symptoms of psychological distress include anxiety, stress and/or depression.

[0057] Preferably the validated scale for identifying symptoms of anxiety, stress and/or depression is chosen from the list comprising: Depression Anxiety Stress Scales (DASS-21 , DASS-42), Penn State Worry Questionnaire, Kessler’s psychological distress scale 10 (K-10), Hospital Anxiety and Depression Scale (HAD), Hospital Anxiety and Depression Scale- Anxiety Subscale (HADS-A), Beck Anxiety Inventory (BAI), Mood and Anxiety Symptom Questionnaire (MASQ), Generalized Anxiety Disorder Scale (GAD-7), Four-Dimensional Symptom Questionnaire (4DSQ), State-Trait Anxiety Inventory (STAI), Liebowitz Social Anxiety Scale (LSAS), Overall Anxiety Severity and Impairment Scale (OASIS), Patient Health Questionnaire-4 (PHQ-4), Social Interaction Anxiety Scale (SIAS), Social Phobia Inventory (SPIN), Social Phobia and Anxiety Inventory (SPAI), Brief Fear of Negative Evaluation Scale (BFNE), Zung Self-Rating Anxiety/Depression Scale (SAS/SDS), Westside Test Anxiety Scale Validation, Revised Children’s Anxiety and Depression Scale (RCADS), Spence Children’s Anxiety Scale (SCAS), Anxiety Likert or Visual Analog Scale (VAS), Hamilton Anxiety Rating Scale (HAM-A). In one form, the validated scale is DASS (DASS-21 or DASS-42). Preferably, the validated scale is not HAM- A.

[0058] Preferably the validated scale can be administered and scored by non-psychologists. Preferably the validated scale is a self-reported assessment used to isolate and identify aspects of emotional disturbance; for example, to assess the degree of severity of the core symptoms of depression, anxiety or stress. For example, the scale may be DASS (DASS-21 or DASS-42), or K-10.

[0059] In one aspect, the validated scale is not a psychological questionnaire used by qualified psychologists to rate the severity of a patient's anxiety. Preferably the validated scale is not a clinical rating of the extensiveness of anxiety intended for individuals that have already been diagnosed with an anxiety disorder or anxiety neurosis. Preferably, the validated scale is not HAM-A.

[0060] Preferably the method reduces the subject’s score on the validated scale for anxiety or reduces the anxiety biomarker. Preferably the method also reduces the subject’s score on the validated scale for stress and/or depression or reduces the stress and/or depression biomarker(s). Preferably the method reduces the subject’s score on the validated scale for anxiety and/or reduces the subject’s score on the validated scale for stress and/or reduces the subject’s score on the validated scale for depression.

[0061] The “symptoms of anxiety” include excessive anxiety and worry (apprehensive expectation) about events or activities (such as social events; work or school performance). The anxiety may be associated with restlessness or feeling keyed up or on edge; being easily fatigued; difficulty concentrating or mind going blank; irritability; muscle tension and/or sleep disturbance (difficulty falling or staying asleep; or restless unsatisfying sleep). The term preferably covers undiagnosed or common anxiety, that is anxiety not diagnosed as an Anxiety Disorder by a qualified health care provider or physician. However, the term may also include diagnosed disorders such as generalized anxiety disorder, agoraphobia, social anxiety disorder, separation anxiety disorder, selective mutism, specific phobia, panic disorder, agoraphobia, substance/medication-induced anxiety disorder, and anxiety disorder due to another medical condition. The anxiety may be an anxiety disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

[0062] The “symptoms of depression” include feeling sad or having a depressed mood; loss of interest or pleasure in activities once enjoyed; changes in appetite; weight loss or gain unrelated to dieting; trouble sleeping or sleeping too much; loss of energy or increased fatigue; increase in purposeless physical activity (e.g., inability to sit still, pacing, handwringing) or slowed movements or speech; feeling worthless or guilty; difficulty thinking, concentrating or making decisions; thoughts of death or suicide. The term preferably covers undiagnosed depression. However, the term may also include depression diagnosed by a qualified health care provider or physician. The depression may be Major Depressive Disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

[0063] The “symptoms of stress” include feeling overwhelmed; inability to concentrate; poor judgment; seeing only the negative; anxious or racing thoughts; constant worrying; agitation; moodiness, irritability, or anger; feeling overwhelmed; loneliness and isolation; aches and pains; diarrhea or constipation; nausea, dizziness; chest pain, rapid heart rate; loss of sex drive; frequent colds or flu; eating more or less; sleeping too much or too little; withdrawing from others; procrastinating or neglecting responsibilities; nervous habits (e.g. nail biting, pacing); using alcohol, cigarettes, or drugs to relax. The term preferably covers stress which has not been diagnosed as a major heath issue by a qualified health care provider or physician. However, the term may also include stress which has been diagnosed as a major heath issue by a qualified health care provider or physician, for example a Trauma- and Stressor-Related Disorder as defined in the DSM-5.

[0064] Preferably the subject has symptoms of anxiety, stress and/or depression secondary to a medical condition, more preferably a chronic medical condition. The medical condition may be one of the following: cancer, cancer treatment, chronic diseases such as heart and lung disease or diabetes, migraine, insomnia or sleep disorder, chronic pain; gastrointestinal disorder; neurological disorder, osteoarthritis or inflammatory arthritis. The medical condition may be mental illness that is not a mental disorder corresponding to the DSM-5 criteria for: depressive disorders, anxiety disorder trauma- and stressor-related disorders, obsessive-compulsive and related disorders.

[0065] Preferably the anxiety is not associated with obsessive-compulsive disorder, acute stress disorder, or posttraumatic stress disorder.

• Insomnia

[0066] Insomnia may present as disturbed sleep, inability to get to sleep, inability to stay asleep and/or sleep that leaves the subject tired upon waking. The insomnia may be assessed using the Insomnia Seventy Index (ISI) 7-item self-report questionnaire. Notably, the ISI has been clinically validated to identify and isolate aspects of insomnia severity based on several indicators, such as difficulty falling asleep, staying asleep, waking up too early, degree of impairment with daytime functioning or satisfaction with sleep. More importantly perhaps, this global measure has been employed in number of recent clinical trials to assess the responses in insomnia to a wide variety of treatments.

[0067] Preferably the validated scale for identifying symptoms of insomnia is the Insomnia Severity Index (ISI) 7-item self-report questionnaire. Alternative rating sales such as the Pittsburgh Sleep Quality Index (PSQI), Medical Outcomes Study (MOS) Sleep Scale, Regensburg Insomnia Scale (RIS), Bergen Insomnia Scale (BIS), Athens Insomnia Scale (AIS), sleep diary or sleep apps may be used. The method for identifying symptoms of insomnia may be actigraphy and/or polysomnography (PSG). Preferably the validated scale can be administered and scored by non-psychologists. Preferably the validated scale is a self-reported assessment used to isolate and identify aspects of insomnia and sleep disturbance.

[0068] Preferably the method reduces the subject’s score on the validated scale for insomnia or reduces the insomnia biomarker.

[0069] The “symptoms of insomnia” include finding it hard to go to sleep; frequent waking during the night; problems returning to sleep after awakenings; waking up early and being unable to go back to sleep; still feeling tired after waking up; finding it hard to nap during the day even though the subject is tired; feeling tired and irritable during the day. The term preferably covers insomnia which has not been diagnosed as a major heath issue by a qualified health care provider or physician. However, the term may also include insomnia which has been diagnosed as a major heath issue by a qualified health care provider or physician, for example insomnia or an insomnia disorder as defined in the International Classification of Sleep Disorders, 3rd edition (ICSD-3) and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition (DSM-5).

• Pain

[0070] Pain stems from activation of the nervous system and can range from annoying to debilitating. Pain can be chronic or acute. Acute pain generally happens quickly, has a specific and treatable cause and goes away once the cause is resolved. Chronic pain generally lasts longer than three months and can continue when the injury or illness has been treated.

[0071] Preferably the pain treated by the present invention is chronic pain.

[0072] Preferably the validated scale for identifying symptoms of pain is the Brief Pain Inventory Short Form (BPI-Short Form). Alternative rating sales such as the numeric rating scale (NRS), visual analogue scale (VAS), Wong Baker Faces Pain Rating Scale, McGill Pain Questionnaire (MPQ), 13-item Pain Catastrophizing Scale, Abbey Pain Scale, Behavioural Pain Scale, FLACC Behavioural Pain Scale, Mankowski Pain Scale, Rolan-Morris Back Pain Questionnaire, Neck Pain and Disability Scale, COMFORT Scale, Pain Self-Efficacy Questionnaire, Pain Disability Index (PDI), Multidimensional Pain Inventory, Oswestry Disability Index (ODI), Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale, Douieur Neuropathique en 4 questions (DN4), PainDETECT and Clinical Global impression (CGI) pain scale may be used. Preferably the validated scale can be administered and scored by non physicians and/or non-psychologists. Preferably the validated scale is a self-reported assessment used to isolate and identify aspects of pain.

[0073] Preferably the method reduces the subject’s score on the validated scale for pain or reduces the pain biomarker.

[0074] The “symptoms of pain” include having pain that interferes with normal activity, pain that interferes with the subject’s mood, pain that interferes with the subject’s ability to walk, pain that interferes with the subject’s normal work or housework routine, pain that interferes with subject’s strength or energy, pain that interferes with the subject’s ability to interact with other people, pain that interferes with subject’s appetite, pain that interferes with the subject’s sleep and pain that interferes with the subject’s enjoyment of life.

Cannabidiol

[0075] Cannabidiol, as used herein, refers to 2-[3-methyl-6-(1 -methylethenyl)-2-cyclohexen-1 -ylj- 5-pentyl-1 ,3-benzenediol. The synthesis of cannabidiol is described, for example, in Petilka etal., Helv. Chim.Acta , 52: 1102 (1969) and in Mechoulam et al., J. Am. Chem. Soc., 87:3273 (1965), which are hereby incorporated by reference.

[0076] The term “cannabidiol” may include pre-cursors of cannabidiol such as cannabidiolic acid (CBDA or CBD-A). In one form of the invention the term “cannabidiol” only covers cannabidiol per se. In another form of the invention, the term “cannabidiol” covers both cannabidiol and precursor compounds. In another form of the invention, the term “cannabidiol” covers both cannabidiol and the precursor compound, cannabidiolic acid.

[0077] Preferably the oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient comprises from 25 mg to 200 mg cannabidiol. More preferably the composition comprises from 25 mg to 150 mg, or 50 mg to 150 mg cannabidiol. The composition may comprise from 60 mg to 200 mg, 60 mg to 150 mg, 70 mg to 200 mg, 70 mg to 150 mg, 80 mg to 200 mg, 90 mg to 200 mg, 90 mg to 150 mg, 100 mg to 200 mg, 100 mg to 150 mg. The composition may be in a single dose form (for examples matrix pellets in a capsule) or the composition may be in several dosage forms (eg several capsules containing matrix pellets). [0078] The oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient may comprise 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg. More preferably the composition comprises 50 mg cannabidiol.

[0079] The dose of cannabidiol being administered to the subject may be increased from a lower dose to a higher dose over a time period. For example, the subject may be first administered a dose of 50 mg per day. Over the course of several weeks, this dose may be increased to 60 mg, or 100 mg, or 150 mg. The increase is dosage may be carried out for a range of reasons, including a wish to avoid side-effects caused by initial administration of high doses of cannabidiol to a subject unused to such doses, and increasing the dose if the subject is not responding sufficiently to the initial lower dose.

[0080] In addition to cannabidiol, the composition may contain more than one cannabinoid. For example, the composition of the present invention may contain a combination of two, three or more cannabinoids.

[0081] Preferably the composition comprise a majority of one cannabinoid. More preferably, the composition may comprise at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% of one cannabinoid. The remaining % of the composition may be other cannabinoids or other impurities. Preferably the majority cannabinoid is cannabidiol (CBD).

[0082] For example, the composition may comprise greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) other cannabinoids. The less than or equal to 2% (w/w) other cannabinoids may comprise the cannabinoids tetrahydrocannabinol (THC); cannabidivarin (CBDV); cannabinol (CBN); cannabigerol (CBG); tetrahydrocannabivarin; (THCV); cannabichromene (CBC); nantradol hydrochloride; nabilone and other naturally occurring cannabinoids.

[0083] Suitable pharmaceutically acceptable salts of cannabinoids for which a salt can be made include conventionally used non-toxic salts, for example a salt with an inorganic base such as an alkali metal salt (such as sodium salt and potassium salt), an alkaline earth metal salt (such as calcium salt and magnesium salt), an ammonium salt; or a salt with an organic base, for example, an amine salt (such as methylamine salt, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino) ethane salt, monomethyl-monoethanolamine salt, procaine salt and caffeine salt), a basic amino acid salt (such as arginine salt and lysine salt), tetraalkyl ammonium salt and the like, or other salt forms that enable the cannabinoid to remain soluble in a liquid medium, or to be prepared and/or effectively administered in a liquid medium, preferable an aqueous medium. The above salts may be prepared by a conventional process, for example from the corresponding acid and base or by salt interchange.

[0084] Examples of suitable pharmaceutically acceptable salts of cannabinoids for which a salt can be made include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methansulfonate, p-toluenesulfonate, and ascorbate; salts with acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,N'-dibenzylethylenediamine salt; and salts with basic amino acid such as lysine salt and arginine salt. The salts may be in some cases hydrates or ethanol solvates.

[0085] In one embodiment at least a portion of at least one of the cannabinoids present in the composition is isolated from cannabis plant material. Preferably at least a portion of the CBD present in the composition is isolated from cannabis plant material.

[0086] In a further embodiment of the invention substantially all of at least one of the cannabinoids present in the composition is isolated from cannabis plant material. Preferably substantially all of the CBD present in the composition is isolated from cannabis plant material.

[0087] In a further embodiment of the invention substantially all of the cannabinoids present in the composition are isolated from cannabis plant material.

[0088] Preferably the cannabis plant material is from Cannabis sativa, Cannabis indica, or Cannabis ruderalis plants. Preferably the cannabis plant is a high-CBD containing cannabis chemotype.

[0089] In a further embodiment of the invention at least a portion of at least one of the cannabinoids present in the composition is prepared synthetically. Preferably at least a portion of the CBD present in the composition is prepared synthetically.

[0090] In a further embodiment of the invention substantially all of at least one of the cannabinoids present in the composition is prepared synthetically. Preferably substantially all of the CBD present in the composition is prepared synthetically.

[0091] Preferably substantially all of the cannabinoids present in the composition are prepared synthetically.

[0092] If at least a portion or substantially all of the CBD present in the composition is synthetic, then preferably the synthetic CBD only contains the (-) CBD enantiomer. [0093] The composition may contain both cannabinoids isolated from cannabis plant material and synthetically prepared cannabinoids. For example, the composition may contain synthetically prepared CBD and a mixture of other cannabinoids isolated from cannabis plant material.

[0094] Preferably the composition comprises not more than 2.0% or 1 .5% (w/w) THC based on total amount of cannabinoid in the preparation. More preferably the composition comprises about 0.01% to about 0.1% (w/w) THC based on total amount of cannabinoid in the preparation. More preferably the composition comprises about 0.02% to about 0.05% (w/w) THC based on total amount of cannabinoid in the preparation. More preferably the composition comprises 0% (w/w) THC.

Matrix Pellet Forming Excipient

[0095] The matrix pellet forming excipient is an excipient that is mixed with the cannabidiol to form matrix pellets comprising CBD distributed, preferably homogenously, in the solid matrix pellet forming excipient. The CBD is therefore essentially protected in a three-dimensional matrix, which does not need a shell or an additional filling material.

[0096] CBD is highly lipophilic and has very low aqueous solubility, is susceptible to degradation and is poorly absorbed through the gastrointestinal system with low oral bioavailability. Preferably, the matrix pellet forming excipient is adapted to improve the delivery of lipophilic CBD, allow greater gastric absorption and provide sustained release of CBD.

[0097] Preferably the matrix pellet forming excipient is chosen from the list comprising: gelatine, medium chain triglycerides, long chain triglycerides, hydroxypropyl methylcellulose (HPMC), starch and modified starch, carrageenan, hydroxy propyl cellulose (HPC), pullulan, polyvinyl alcohol (PVA), and alginate.

[0098] Preferably the solubility of CBD in the matrix pellet forming excipient is similar to that of CBD in gelatine. For example, the solubility of CBD in the matrix pellet forming excipient may be within 2% of the solubility of CBD in gelatine, within 5%, within 10%, within 15%, within 20%, within 25% or within 30% of the solubility of CBD in gelatine.

[0099] Preferably the matrix pellet forming excipient is capable of forming a solid or semi-solid pellet at a temperature of less than 60 °C, for example from at least 20 °C to 60 °C.

[00100] Preferably the matrix pellet forming excipient is a liquid at a temperature that is within the range that CBD remains stable and does not degrade. For example, preferably the matrix pellet forming excipient is a liquid at a temperature above 60 °C. The matrix pellet forming excipient may be a liquid at a temperature above 70 °C, 80 °C, 90 °C, or 100 °C.

[00101] In some embodiments, the matrix pellet forming excipient is gelatine. It should be appreciated that in certain embodiments the gelatine may be of bovine or fish origin, characterized in terms of certain Bloom strength (defined as known in the art). In some embodiments, the gelatine Bloom can be in the range of 100 to 240 Bloom, and in other embodiments, in the range of 140 to 200 Bloom.

[00102] Preferably the matrix pellet forming excipient comprises at least 50% (w/w) of the matrix pellet of the present invention. For example, the amount of matrix pellet forming excipient may be from 50% to 99%, from 50% to 95%, from 50% to 90%, from 50% to 85%, from 50% to 80%, from 50% to 75%, from 50% to 70%, from 50% to 65%, from 50% to 60%, or from 50% to 55% (w/w) of the matrix pellet. The matrix pellet forming excipient may comprise 50% (w/w), 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% (w/w) of the matrix pellet of the present invention.

[00103] In some embodiments, the matrix pellets of the invention have a diameter size in the range of at least about 0.5-3.0 mm, or 1-2 mm. In some embodiments, the diameter size of each matrix pellet can be in the ranges of at least about 0.5-1 .0 mm, 1 .0-1 .5 mm, 1 .5-2.0 mm. In a preferred embodiment, the diameter may be in the range of at least about 2.0-2.5 mm, and 2.5- 3.0 mm. Preferably the diameter of the matrix pellets is from 2 mm or less.

[00104] In further embodiments, the matrix pellets of the invention have a weight in the range of at least about 0.1 -10 mg, or 0.5-5 mg. In some embodiments, the weight of each matrix pellet can be in the range of at least about 0.1 -1 mg, 1 -2 mg, 2-3 mg, 3-4 mg, 4-5 mg, 5-6 mg, 6- 7 mg, 7-8 mg, 8-9 mg or 9-10 mg. In some embodiments, the weight may be in the range of about 0.5-5 mg, 1-4.5 mg, 1 .5-4 mg, 2-3.5 mg or 2.5-3 mg.

[00105] The matrix pellets of the compositions of the present invention may optionally contain water. For example, in an embodiment a matrix pellet of the invention has a moisture content of up to about 15%, by weight (w/w). In some embodiments, the moisture content in each matrix pellet can be up to at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12, 13%, 14%, 15%. Alternatively, the matrix pellets may contain no water.

[00106] In some embodiments, a matrix pellet of the invention can comprise an amount of CBD active ingredient that is up to about 30% (w/w). In some embodiments, the amount of active ingredient in a single matrix pellet can be up to at least about 1%, 5%, 10%, 15%, 20%, 25% and 30% (w/w) or more, and further in the range of at least about 0.1 -1%, 1 -5%, 5-10%, 10-15%, 15- 20%, 20-25%, 25-30% (w/w) or more. In one embodiment, the amount of active ingredient in a single matrix pellet is from 20-24%, or more preferably 22% (w/w). In another embodiment, the amount of active ingredient in a single matrix pellet is from 2-4%, or more preferably 3% (w/w).

[00107] In some embodiments, a matrix pellet of the invention can comprise an amount of cannabinoid active ingredient that is up to about 0.6 mg per pellet. In one embodiment, the amount of cannabinoid in a single matrix pellet is from 0.2mg to 0.6 mg per pellet. The amount of cannabinoid in a single matrix pellet is more preferably from 0.35 to 0.4 mg per pellet or 0.375 mg per pellet; or 0.45 mg to 0.5 mg per pellet or 0.46 mg per pellet.

[00108] A plurality of matrix pellets can be packed into a capsule, such as a hard two-piece capsule or soft or semi-solid one-piece capsule. The capsule may include an external gastro- resistant coating, if desired.

[00109] Optionally, in one embodiment, the matrix pellets can be manufactured by:

- adding an amount of an active ingredient to a matrix pellet forming excipient solution to obtain a mixture and pelletizing said mixture to form matrix pellets;

- adding a pre-defined amount of the active ingredient to a matrix pellet forming excipient solution to obtain a mixture and pelletizing said mixture in a cooling fluid and/or liquid to form matrix pellets;

- adding a pre-defined amount of the active ingredient to the hot matrix pellet forming excipient solution to obtain a mixture and pelletizing said mixture by dropping the mixture into a cooling fluid and/or liquid to form matrix pellets;

- obtaining a hot matrix pellet forming excipient solution, adding a pre-defined amount of the active ingredient to the hot matrix pellet forming excipient solution to obtain a mixture, homogenizing the mixture (e.g., by stirring) and pelletizing the homogenous mixture to form matrix pellets.

[00110] The manufacture may further comprise the step of filtering off the pellets. The manufacture may further comprise the step of removing residual cooling liquid by washing it away with an organic solvent, by centrifugation or by drying the matrix pellets with an air stream or (inert) gas stream.

Carrier Oil

[00111] In some embodiments, the CBD can be pre-dissolved in an oil, such as an organic oil or oils comprising at least one lipid or a triglyceride, prior to mixing into the matrix pellet forming excipient. Non-limiting examples of such oils include linseed oil, hemp oil, sesame oil, olive oil, castor oil, chia ( Salvia hispanica L.) seed oil, cotton oil, corn oil, coconut oil, a medium chain triglyceride, a long chain triglyceride, sunflower oil, soybean oil, canola oil.

[00112] It should be noted that linseed oil, castor oil and sesame oil are particularly used in some of the embodiments of the formulations. In some embodiments, the oil is linseed oil.

[00113] Preferably the oil is present in an amount from 0% to 15% (w/w) of each matrix pellet. For example, the oil may be present in an amount from 0-14%, 0-13%, 0-12%, 0-10%, 0- 9%, 0-8%, 0-7%, 0-6%, 0-5%, 0-4%, 0-3%, 0-2%, or 0-1% (w/w). The amount of oil may be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% (w/w) of each matrix pellet.

[00114] Alternatively, the oil may be present in an amount from 30%-50% (w/w) of the amount of active. For example, the oil may be present in an amount from 30-50%, 30-45%, 30- 40%, 35-50%, 35-45% or 35-40% (w/w). The amount of oil may be 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% or 50% (w/w) of the amount of active.

[00115] Exemplary compositions of the present invention include:

(A) active ingredient(s) - up to 30% matrix pellet forming excipient - at least 60% oil - up to 10% (or 35-45% of the active ingredients) water - up to 15%

(B) active ingredient (CBD) - up to 30% matrix pellet forming excipient (gelatine) - at least 60% oil (hemp) - up to 10% (or 35-45% of the CBD) water - up to 15%

(C) active ingredient (CBD) - 10mg matrix pellet forming excipient (gelatine) - 320.3mg oil (hemp) - 4.3mg water - 5.1 mg

(D) active ingredient (CBD) - 10Omg matrix pellet forming excipient (gelatine) - 290.3mg oil (hemp) - 42.8mg water - 17.7mg Gastro-resistant Coating

[00116] The term “controlled release” herein is meant a property or a modification enabling the achieve time-dependent release, sustained release, prolonged release, pulse release or delayed release of the drug.

[00117] The matrix pellets may be coated with a gastro-resistant coating, using GRAS- based materials. A plurality of these matrix pellets can be packed, e.g., in a seamless two-piece hard capsule, further including an external gastro-resistant coating, if desired, thus providing a solid cannabinoid dosage form. [00118] The term “gastro-resistance” herein is meant a property or a modification enabling pH-controlled drug release, gastrointestinal targeting, colon delivery, protection of acid-sensitive actives, and/or protection of gastric mucosa from aggressive actives. In this sense, gastro- resistance includes targeted drug release. It is further contemplated that for the purpose of certain embodiments, the matrix pellet, being optionally of gelatine, can further include a specific coating or other ingredients contributing to gastro-resistance and/or controlled release.

[00119] Improved gastro-resistance and/or controlled release can be achieved by modification of the matrix pellet forming excipient itself and/or coating of a matrix pellet using various pharmacological technologies.

[00120] For example, poly(meth)acrylate coatings have been widely used in the pharmacological industry to achieve targeted and controlled drug release; and example of this coating is EUDRAGIT™.

[00121] The matrix pellets can further comprise or be coated with hydrophilic or hydrophobic polymers. In certain embodiments, matrix pellets of the invention can comprise matrix modifying/controlled release materials such as: glycerides, waxes, fatty acids, methyl acrylate, methylmethacrylate, ethyl cellulose, poly(vinyl alcohol) (PVA), poly(vinyl pyrrolidone) (PVP), starch, polysaccharides, and others.

[00122] In some embodiments, the matrix pellets of the invention can be coated with hydroxypropyl methylcellulose, poly(meth)acrylates, methyl acrylate-methacrylic acid copolymers, cellulose acetate, polyvinyl acetate phthalate, and other types of coatings.

[00123] For coating, one or more substances are applied in layers to a matrix pellet. The layering process is similar to a film coating process. The term “layering” may be applied to a range of technologies encompassing substances applied in layers to the core as a solution, suspension (Suspension/Solution layering) or powder (Dry powder layering). Further, various characteristics of the active substance layer can be achieved by adding suitable supplementary materials. Certain solid oils can be added to facilitate controlled release, such as mono, di and triglycerides oils, in general, and trilaurin, tricaprin, tripalmitin, trimyristin, glyceryl, hydrogenated palm oil distearate, hydrogenated castor oil, hydrogenated vegetable oil, in particular.

Oral Solid Cannabinoid Dosage Form Delivery

[00124] The matrix pellets of the invention may be packaged in various optional forms, such as capsules, being one of the most popular and convenient methods of drug delivery.

[00125] The matrix pellets of the present invention comprising cannabidiol and matrix pellet forming excipient may be further be packaged in a capsule to form an oral solid cannabinoid dosage. The capsule may be a two-piece hard capsule, or a soft or semi-solid single piece capsule. Optionally the capsule may confer gastro resistance.

[00126] The oral solid cannabinoid dosage may comprise a plurality of matrix pellets comprising distinct active ingredients defined as above. The term “plurality” is meant to convey any number of matrix pellets in the range of at least about 50-400 beads, and more specifically, 50-100, 100-150, 150-200, 200-250, 250-300, 300-350 and 350-400 beads or more. The plurality may be further construed as a population of the same or different groups of matrix pellets according to the invention. In this connection, groups of pellets or populations are characterized with certain constitution, in terms of size, form, type of matrix pellet forming excipient, type of active ingredient, dosage thereof, and further, matrix modifying/controlled release or coating material.

[00127] In an embodiment, an oral solid dosage form of the invention comprises matrix pellets with at least one of the following features:

(i) a diameter size in the range of at least about 1 -2 mm, as referred to above,

(ii) a weight in the range of at least about 0.5-5 mg, as referred to above, and/or

(iii) a moisture content of up to about 15%, (w/w), as referred to above contained within a capsule.

[00128] The oral solid dosage form of the invention, being composed of matrix pellets, can comprise a pre-defined amount of total active ingredients up to about 30% (w/w). In some embodiments, the amount of an active ingredient comprised in the oral cannabinoid dosage form may be up to at least about 1%, 5%, 10%, 15%, 20%, 25% and 30% (w/w) or more, and further in the range of at least about 0.1 -1%, 1-5%, 5-10%, 10-15%, 15-20%, 20-25%, 25-30% (w/w) or more. Exemplary embodiments of this particular feature have been demonstrated in oral solid cannabinoid dosage forms containing 10 mg, 50mg or 100 mg CBD.

[00129] In another embodiment, the matrix pellets of the invention can be packaged in a bag or a bottle, ready to mix with food or drink. In further embodiments, the solid cannabinoid dosage form can be provided in a secondary package, such as a blister pack (PVC/PVDC-Alufoil), a bottle, an aluminium pouch, etc.

Treatment and prevention

[00130] In certain embodiments the administration of cannabidiol is expected to treat or prevent one or more symptoms of psychological distress in a subject wherein the subject has symptoms of anxiety, stress or depression or insomnia. For example, the cannabidiol may reduce the incidence and/or severity of episodes of anxiety, stress or depression or insomnia. Therapeutic effects of the present invention include, but are not limited to, reduction in frequency and/or severity of episodes of anxiety, stress or depression or insomnia.

[00131] The present invention may treat the symptoms of anxiety, stress or depression or insomnia by reducing the incidence and/or severity of one or more of the symptoms of anxiety, stress or depression or insomnia, such as those listed above in relation to “symptoms of anxiety”, “symptoms of depression”, “symptoms of stress”, “symptoms of insomnia” and/or “symptoms of pain”. The present invention may prevent the onset of one or more of the symptoms of anxiety, stress or depression, insomnia or pain, such as those listed above in relation to “symptoms of anxiety”, “symptoms of depression”, “symptoms of stress”, “symptoms of insomnia” and/or “symptoms of pain”.

[00132] In certain embodiments, the administration of cannabidiol is expected to improve the symptoms of anxiety, stress or depression, insomnia or pain. By “improve”, it is meant that there is a reduction in frequency and/or severity of episodes of anxiety, stress or depression, insomnia or pain.

[00133] Preferably, the treatment reduces one or more symptoms of psychological distress, insomnia or pain in a subject wherein the subject has symptoms when assessed using a validated scale by a drop from a higher score or category to a score or lower category for at least one of anxiety, stress or depression, insomnia or pain. In this respect, it does not matter what the original score or category was in the validated scale, merely that the treatment has reduced that score or category to a lower score or category. More preferably, the treatment reduces the symptoms of anxiety, stress or depression by a drop from a higher score or category to a lower score or category for at least two of anxiety, stress or depression. For example, if DASS is being used, the treatment may reduce the anxiety score from a category of “very severe” to “severe”, or reduce the depression score from “moderate” to “mild”. The treatment further preferably reduces the symptoms of insomnia by a drop from a higher score or category to a lower score or category. For example, if ISI is being used, the treatment may reduce the insomnia score from a category of “severe” to “moderate”.

[00134] Preferably, the subject being treated scores at least: a) 8 for anxiety (mild-moderate); b) 15 for stress (mild-moderate); and/or c) 10 for depression (mild-moderate) on at least one of the categories of anxiety, stress or depression when assessed by the Depression Anxiety Stress Scale (DASS-21 or DASS-42); and the treatment reduces the subject’s DASS score on at least one of the categories of anxiety, stress or depression. [00135] Preferably, the subject being treated scores at least 8 for insomnia when assessed by the Insomnia Severity Index (ISI) 7-item self-report questionnaire; and the treatment reduces the subject’s ISI score.

[00136] Preferably, the subject being treated scores at least 1 for pain when assessed by the BPI-Short Form self-report questionnaire; and the treatment reduces the subject’s BPI-Short Form score.

[00137] As the symptoms of psychological distress (anxiety, stress or depression), insomnia and pain are often linked, it is preferred that a reduction in scores for one set of symptoms is associated with a reduction in scores for a second set of symptoms. For example, without being held to any theory, as the symptoms of anxiety, stress and/or depression may lead to symptoms of insomnia and equally the symptoms of insomnia may lead to symptoms of anxiety, stress and/or depression, it is preferred that reduction in one or more of the symptoms results in a reduction in at least one other symptom. For example, reducing the symptoms of anxiety may assist in reducing the symptoms of insomnia, or reducing the symptoms of insomnia may assist in reducing the symptoms of stress. Reducing the symptoms of pain may assist is reducing the symptoms of insomnia.

[00138] The reduction in the symptoms of psychological distress of anxiety, stress or depression, insomnia or pain may not occur immediately after administration of the first dose of cannabidiol. The reduction in the symptoms of psychological distress of anxiety, stress or depression, insomnia or pain may take days, weeks or months to be detectable by use of a validated scale. In one embodiment, the reduction in the symptoms of anxiety, stress or depression is detectable by a drop from a higher score or category to a score or lower category for at least one of anxiety, stress or depression over a time period of one month. In one embodiment, the reduction in the symptoms of insomnia is detectable by a drop from a higher score or category to a score or lower category for insomnia over a time period of one month. In one embodiment, the reduction in the symptoms of pain is detectable by a drop from a higher score or category to a score or lower category for pain over a time period of one month.

[00139] Preferably, the reduction in the symptoms of anxiety, stress or depression is detectable by a drop from a higher score or category to a score or lower category for at least one of anxiety, stress or depression is maintained for at least as long as the cannabidiol is being administered. For example, the reduction in the symptoms of anxiety, stress or depression may be maintained for at least 1 month, 2 months, 6 months, 12 months, 2 years or indefinitely whilst the cannabidiol is being administered. In addition, the reduction in the symptoms of anxiety, stress or depression or insomnia may be maintained for at least 1 month, 2 months, 6 months, 12 months, 2 years or indefinitely after administration of the last dose of cannabidiol. [00140] Preferably, the reduction in the symptoms of insomnia is detectable by a drop from a higher score or category to a score or lower category for insomnia is maintained for at least as long as the cannabidiol is being administered. For example, the reduction in the symptoms of insomnia may be maintained for at least 1 month, 2 months, 6 months, 12 months, 2 years or indefinitely whilst the cannabidiol is being administered. In addition, the reduction in the symptoms insomnia may be maintained for at least 1 month, 2 months, 6 months, 12 months, 2 years or indefinitely after administration of the last dose of cannabidiol.

[00141] Preferably, the reduction in the symptoms of pain is detectable by a drop from a higher score or category to a score or lower category for pain is maintained for at least as long as the cannabidiol is being administered. For example, the reduction in the symptoms of pain may be maintained for at least 1 month, 2 months, 6 months, 12 months, 2 years or indefinitely whilst the cannabidiol is being administered. In addition, the reduction in the symptoms of pain may be maintained for at least 1 month, 2 months, 6 months, 12 months, 2 years or indefinitely after administration of the last dose of cannabidiol.

[00142] The composition may be administered daily for at least one month. The daily administration may be continued for two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months or twelve months. The daily delivery may be administered for one or a few months, then there may be a break in delivery for several months, until symptoms of psychological distress of anxiety, stress or depression, insomnia or pain recur and treatment is resumed.

[00143] A primary advantage of the present invention is expected to be the improvement in the mental wellbeing of the subject with a reduction or absence in the typical side effects of conventional therapies such as antidepressant medications (including SSRIs and SNRIs), beta blockers, benzodiazepines, opioids and NSAIDs.

[00144] Those skilled in the art will appreciate that the term “dosage form” or “unit dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms. [00145] Those skilled in the art will appreciate that the term “dosing regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[00146] The exact regimen for administration of the cannabidiol may depend on the needs of the individual subject being treated, the type of treatment administered, and/or the judgment of the attending medical specialist. As used herein, the terms “subject” and “patient” includes both humans and animals. In some embodiments, the subject or patient is a human adult, human adolescent, human child, or human infant. As those skilled in the art will appreciate, the dosage administered will depend upon the condition being treated, the age, health and weight of the recipient, the type of concurrent treatment, if any, and the frequency of treatment.

[00147] The present compositions may also be tailored such that a therapeutically effective amount of the total active ingredient(s) is personalized. In this context, the term “personalized dose” refers to a method wherein the therapeutically effective dose is tailored to an individual patient, based on the individual's predicted response and alleviation of symptoms of a disease and other consideration. Diagnostic testing can be employed for selecting appropriate and optimal therapies based on the context of a patient's molecular or biochemical analyses and other personalization measures (potentially including genetics). As such, the matrix pellet technology is particularly advantageous, as various doses and cannabinoid combinations can be administered by packaging a suitable amount of matrix pellets and/or by mixing matrix pellets of different types (e.g. different gastro-resistant coatings, different cannabinoids) in the oral solid dosage forms. The preparation can be done on-demand. Alternatively, matrix pellets can be prepared with more than one cannabinoid in the same matrix pellet. This personalized approach can be further extended to incorporate additional nutrients and therapeutic agents. [00148] In some embodiments, a composition or a pharmaceutical composition comprising CBD may be administered in a therapeutically effective amount. A therapeutically effective amount may be administered according to a dosing regimen comprising one or more unit doses. Generally, a therapeutically effective amount is sufficient to achieve a benefit to the subject (e.g., prophylaxis, treating, modulating, curing, preventing and/or ameliorating a disease or condition).

[00149] Generally, the term “therapeutically effective amount” refers to an amount of the active ingredient that induces a change in a condition treated by a dosage form of the invention, as measured by relevant definition criteria. This may be monitored in an animal model or in a clinical setting. In this sense, the therapeutic effect is also a pharmacodynamic effect. A therapeutically effective amount (and/or unit dose) of a composition for any particular subject may depend upon a variety of factors including the disease or condition being treated; disease or condition severity; the activity of the specific composition employed; the specific composition employed; the age; body weight; fitness; comorbid conditions (e.g., other than the diseases or condition(s) being treated) general health; sex; and diet of the patient; personal history; genetic characteristic; lifestyle parameter; severity of cardiac defect and/or level of risk of cardiac defect; the time of administration; route of administration; concomitant treatments or medications; and/or rate of excretion or metabolism of the specific composition employed; the duration of the treatment; combinations thereof; as well as other factors well known in the medical arts. In view of the present disclosure, one of ordinary skill in the art will be readily able to determine appropriate dosages depending on these and other related factors. In addition, both objective and subjective assays may optionally be employed to identify optimal dosage ranges. In some particular embodiments, appropriate doses or amounts to be administered may be extrapolated in view of the instant disclosure from dose-response curves derived from in vitro or animal model test systems.

[00150] A therapeutically effective amount (also pharmacologically or pharmaceutically or physiologically effective amount) also means an amount of active ingredient (a cannabinoid or a combination) that is needed to provide a desired level of active agent in the bloodstream or at a target organ or to provide an anticipated physiological response. The precise amount will depend upon numerous factors, e.g. type of an agent, activity of a composition, intended patient use (e.g. number of doses per day), patient considerations, and others, which can readily be determined by one skilled in the art. An effective amount of an agent can be determined using standard clinical procedures for determining appropriate amounts and timing of administration. It is understood that the effective amount can be the result of empirical and/or individualized (case-by-case) determination on the part of the treating health care professional and/or individual.

[00151 ] The present invention contemplates dosing regiments comprising single as well as multiple administrations of a composition as described. The composition can be administered at regular intervals, depending on the nature, severity and extent of the subject’s condition. In some embodiments, the composition may be administered periodically at regular intervals (e.g., once every year, once every six months, once every five months, once every three months, bimonthly (once every two months), monthly (once every month), biweekly (once every two weeks), weekly, daily, multiple times each day, or continuously).

[00152] A therapeutically effective amount of cannabidiol may be administered according to a dosing regimen that may comprise multiple unit doses. For any particular composition, a therapeutically effective amount (and/or an appropriate unit dose within an effective dosing regimen) may vary, for example, depending on route of administration, or combination with other pharmaceutical agents.

[00153] In some embodiments, the composition as described may be administered as a single dose. In some embodiments, a composition or a pharmaceutical composition as described may be administered at regular intervals. Administration at an “interval,” as used herein, indicates that the therapeutically effective amount is administered periodically (as distinguished from a one time dose). The interval can be determined by standard clinical techniques. In some embodiments, the composition as described may be administered bimonthly, monthly, twice monthly, triweekly, biweekly, weekly, twice weekly, thrice weekly, daily, twice daily, every six hours, every four hours, every two hours, or hourly. The administration interval for a given individual need not be a fixed interval, but may be varied over time, depending on the needs of the individual.

[00154] In some embodiments, the composition as described is administered at regular intervals indefinitely. In some embodiments, the composition is administered at regular intervals for a defined period.

[00155] It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the cannabidiol and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed invention.

[00156] As used herein, “improve”, “increase”, “inhibit” or “reduce”, or grammatically comparable comparative terms, indicate values that are relative to a comparable reference measurement. For example, in some embodiments, an assessed value achieved with an agent of interest may be “improved” relative to that obtained with a comparable reference agent. Alternatively or additionally, in some embodiments, an assessed value achieved in a subject or system of interest may be “improved” relative to that obtained in the same subject or system under different conditions (e.g., prior to or after an event such as administration of an agent of interest), or in a different, comparable subject (e.g., in a comparable subject or system that differs from the subject or system of interest in presence of one or more indicators of a particular disease, disorder or condition of interest, or in prior exposure to a condition or agent, etc.)· In some embodiments, comparative terms refer to statistically relevant differences (e.g., that are of a prevalence and/or magnitude sufficient to achieve statistical relevance). Those skilled in the art will be aware, or will readily be able to determine, in a given context, a degree and/or prevalence of difference that is required or sufficient to achieve such statistical significance.

[00157] In some embodiments, a change in the condition being treated is identified if there is at least 5% improvement, or 10% improvement, or at least 25%, or at least 50%, or at least 75%, or at least 100% improvement. The change can be based on improvements in the severity of the treated condition in an individual, or on a difference in the frequency of improved conditions in populations of subjects with and without treatment with dosage forms of the invention, or with dosage forms of the invention in combination with other drugs.

[00158] “Prevent or prevention” as used herein when used in connection with the occurrence of anxiety, stress or depression, insomnia or pain, refers to reducing the risk of developing anxiety, stress or depression, insomnia or pain and/or to delaying onset of one or more characteristics or symptoms of anxiety, stress or depression, insomnia or pain. Prevention may be considered complete when onset of anxiety, stress or depression, insomnia or pain has been delayed for a predefined period of time.

[00159] According to the present invention, “symptoms are reduced” when one or more symptoms of anxiety, stress or depression, insomnia or pain is reduced in magnitude (e.g., intensity, severity, etc.) and/or frequency. For purposes of clarity, a delay in the onset of a particular symptom is considered one form of reducing the frequency of that symptom.

[00160] As used herein, the term “treat”, “treatment”, or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of anxiety, stress or depression, insomnia or pain. In some embodiments, treatment refers to administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of anxiety, stress or depression, insomnia or pain. Treatment may be administered to a subject who does not exhibit signs of anxiety, stress or depression, insomnia or pain. In some embodiments, treatment may be administered to a subject who exhibits only early signs of anxiety, stress or depression, insomnia or pain, for example for the purpose of decreasing the risk of developing pathology associated with anxiety, stress or depression, insomnia or pain. [00161] As used herein, the term “subject” or “patient” refers an organism, typically a mammal (e.g., a human). In some embodiments, a subject or patient refers to any organism (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.) to which a provided compound or composition is administered in accordance with the present disclosure e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. In some embodiments, a subject is suffering from anxiety, stress or depression, insomnia or pain. In some embodiments, a subject has symptoms associated with anxiety, stress or depression, insomnia or pain. In some embodiments, a subject is susceptible to anxiety, stress or depression, insomnia or pain or symptoms associated with anxiety, stress or depression, insomnia or pain. In some embodiments, a subject displays one or more symptoms or characteristics of anxiety, stress or depression, insomnia or pain. In some embodiments, a subject does not display any symptoms or characteristics of anxiety, stress or depression, insomnia or pain. In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of anxiety, stress or depression, insomnia or pain. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and/or therapy is and/or has been administered. "Individual", "patient" and "subject" are used interchangeably.

Composition

[00162] According to one aspect of the invention, there is provided a composition comprising a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition for the treatment or prevention of one or more symptoms of a condition in a subject wherein the subject.

[00163] Preferably the prevention or treatment of at least one symptom of a condition is prevention or treatment of the symptoms of psychological distress such as anxiety, stress and/or depression, insomnia and pain.

[00164] According to one embodiment, there is provided a composition comprising a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition for the treatment or prevention of one or more symptoms of psychological distress in a subject wherein the subject has symptoms of at least one of anxiety, stress and/or depression when assessed by a validated scale or biomarker for identifying symptoms of anxiety, stress and/or depression.

[00165] Preferably, the subject has symptoms of two or more of anxiety, stress and/or depression. Preferably the method reduces the subject’s score on the validated scale for anxiety or reduces the anxiety biomarker. Preferably the method also reduces the subject’s score on the validated scale for stress and/or depression or reduces the stress and/or depression biomarker(s). Preferably the method reduces the subject’s score on the validated scale for anxiety and/or reduces the subject’s score on the validated scale for stress and/or reduces the subject’s score on the validated scale for depression.

[00166] There is further provided a composition comprising a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition for the treatment or prevention of one or more symptoms of insomnia in a subject wherein the subject has symptoms of insomnia when assessed by a validated scale or biomarker for identifying symptoms of insomnia.

[00167] Preferably the method reduces the subject’s score on the validated scale for insomnia.

[00168] There is further provided a composition comprising a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition for the treatment or prevention of one or more symptoms of pain in a subject wherein the subject has symptoms of pain when assessed by a validated scale or biomarker for identifying symptoms of pain.

[00169] Preferably the method reduces the subject’s score on the validated scale for pain.

[00170] The composition may be delivered once per day, or more than once per day (for example, twice per day, three times per day or four times per day) for a total daily dose of between 25mg and 200 mg of cannabidiol.

[00171] The composition may be administered orally, by nasal or pulmonary administration, or administered via the oral mucosa. Delivery

[00172] In one embodiment of the invention, cannabidiol is administered to the subject using a dosing regimen selected from the group consisting of: three times daily; two times daily; daily; every second day, every third day, once weekly; once fortnightly and once monthly.

[00173] In accordance with certain embodiments, the composition is administered regularly until treatment is obtained. In one preferred embodiment, the composition is administered to the subject in need of such treatment using a dosing regimen selected from the group consisting of: every hour, every 2 hours, every 3 hours, once daily, twice daily, three times daily, four times daily, five times daily, once weekly, twice weekly, once fortnightly and once monthly. However, other application schedules may be utilized in accordance with the present invention. Preferably, the composition of the treatment regimen is administered to the subject between one and five times per day, more preferably once or twice per day.

[00174] The composition may be administered daily for at least one month. The daily administration may be continued for two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months or twelve months. The daily delivery may be administered for one or a few months, then there may be a break in delivery for several months, until symptoms of psychological distress, insomnia or pain recur and treatment is resumed.

[00175] In one aspect, the composition used in the method for the treatment or prevention of psychological distress, insomnia or pain in a subject is an oral pharmaceutical composition comprising cannabidiol. The oral treatment method may comprise the administration of cannabidiol to the gastrointestinal (Gl) tract of the subject. Preferably, the cannabidiol enters the blood stream via absorption in the Gl tract and is systemically available to the subject.

Additional Excipients

[00176] The compositions of the invention may optionally include pharmaceutically acceptable nontoxic excipients and carriers. As used herein, a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, suspending agent, excipient or vehicle for delivering the cannabidiol to the subject. The carrier may be liquid or solid and is selected with the planned manner of administration in mind.

[00177] The composition of the invention may be selected from the group consisting of: an immediate release composition, a delayed release composition, a controlled release composition and a rapid release composition.

[00178] The compositions described herein may be formulated by including such dosage forms in an oil-in-water emulsion, or a water-in-oil emulsion. In such a composition, the immediate release dosage form is in the continuous phase, and the delayed release dosage form is in a discontinuous phase. The composition may also be produced in a manner for delivery of three dosage forms as hereinabove described. For example, there may be provided an oil-in-water-in- oil emulsion, with oil being a continuous phase that contains the immediate release component, water dispersed in the oil containing a first delayed release dosage form, and oil dispersed in the water containing a third delayed release dosage form.

[00179] The compositions described herein may be in the form of a liquid composition. The liquid composition may comprise a solution that includes a therapeutic agent (e.g. cannabidiol) dissolved in a solvent. Generally, any solvent that has the desired effect may be used in which the therapeutic agent dissolves and which can be administered to a subject. Generally, any concentration of therapeutic agent that has the desired effect can be used. The composition in some variations is a solution which is unsaturated, a saturated or a supersaturated solution. The solvent may be a pure solvent or may be a mixture of liquid solvent components. In some variations the solution formed is an in-situ gelling composition. Solvents and types of solutions that may be used are well known to those versed in such drug delivery technologies.

[00180] The composition may or may not contain water. Preferably, the composition does not contain water, i.e. it is non-aqueous. In another preferred embodiment, the composition does not comprise a preservative.

[00181 ] The pharmaceutical composition may be formulated according to the conventional pharmaceutical practice (see, for example, Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed; A. R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds; J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York; Remington's Pharmaceutical Sciences, 18^th Edition, Mack Publishing Company, Easton, Pennsylvania, USA).

[00182] Generally, examples of suitable carriers, excipients and diluents include, without limitation, water, saline, ethanol, dextrose, glycerol, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphates, alginate, tragacanth, gelatine, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, polysorbates, talc magnesium stearate, mineral oil or combinations thereof. The compositions can additionally include lubricating agents, pH buffering agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.

[00183] The composition may be in the form of a controlled-release composition and may include a degradable or non-degradable polymer, hydrogel, organogel, or other physical construct that modifies the release of the cannabidiol. It is understood that such compositions may include additional inactive ingredients that are added to provide desirable colour, stability, buffering capacity, dispersion, or other known desirable features. Such compositions may further include liposomes, such as emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like. Liposomes for use in the invention may be formed from standard vesicle-forming lipids, generally including neutral and negatively charged phospholipids and a sterol, such as cholesterol.

Oral Compositions

[00184] Contemplated for use herein are oral solid dosage forms, which are described generally in Martin, Remington's Pharmaceutical Sciences, 18th Ed. (1990 Mack Publishing Co. Easton PA 18042) at Chapter 89, which is herein incorporated by reference. Solid dosage forms include tablets, capsules, pills, troches or lozenges, cachets or pellets. Also, liposomal or proteinoid encapsulation may be used to formulate the present compositions (as, for example, proteinoid microspheres reported in U.S. Patent No. 4,925,673). Liposomal encapsulation may be used and the liposomes may be derivatised with various polymers ( E.g ., U.S. Patent No. 5,013,556). A description of possible solid dosage forms for the therapeutic is given by Marshall, in Modern Pharmaceutics, Chapter 10, Banker and Rhodes ed., (1979), herein incorporated by reference. In general, the composition will include therapeutic agents (e.g. cannabidiol), and inert ingredients which allow for protection against the stomach environment, and release of the cannabidiol in the intestine.

[00185] For the cannabidiol of the invention, the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available compositions that will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. In one aspect, the release will avoid the deleterious effects of the stomach environment, either by protection of the composition or by release of the cannabidiol beyond the stomach environment, such as in the intestine.

[00186] It is believed that the oral bioavailability of cannabinoids is only 4% to 12% and absorption is highly variable. Although most cannabinoids are generally easily absorbed due to their high partition coefficient (P), they are subject to degradation in the stomach and significant first-pass metabolism. Therefore, preferably, the cannabidiol of the present invention is released in the lower gastrointestinal tract.

[00187] The oral dosage method may be provided using an oral sustained release pharmaceutical composition comprising a therapeutically effective pharmaceutical composition according to the invention, and a release retardant.

[00188] In one aspect of the present invention the release retardant is a water-soluble, water swellable and/or water insoluble polymer. In particular, water-soluble polymers may be selected from the group comprising ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose. The release retardant may be an enteric coating or a semipermeable membrane. In another aspect of the invention the release retardant is a non-polymeric release retardant. More particularly, the non-polymeric release retardant may be hydrogenated castor oil. The compositions of the invention may be milled or granulated and compressed into tablets or encapsulated into capsules according to conventional procedures known in the art.

[00189] To ensure full gastric resistance, a coating impermeable to at least pH 5.0 is used. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and Shellac. These coatings may be used as mixed films.

[00190] A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This includes without limitation sugar coatings, or coatings that make the tablet easier to swallow. Exemplary capsules include hard shell capsules (such as gelatine) for delivery of dry therapeutics such as powders, or soft gelatine shells for liquid therapeutic forms. The shell material of cachets in certain aspects is thick starch or other edible paper. For pills, lozenges, moulded tablets or tablet triturates, moist massing techniques are also contemplated, without limitation.

[00191 ] As used herein, the term "sustained release" means the gradual but continuous or sustained release over a relatively extended period of the therapeutic compound content after oral ingestion. The release may continue after the pharmaceutical composition has passed from the stomach and through until and after the pharmaceutical composition reaches the intestine. The phrase “sustained release” also means delayed release wherein release of the therapeutic compound is not immediately initiated upon the pharmaceutical composition reaching the stomach but rather is delayed for a period of time, for example, until when the pharmaceutical composition reaches the intestine. Upon reaching the intestine, the increase in pH may then trigger release of the therapeutic agent from the pharmaceutical composition.

[00192] Though term "release retardant" is used herein, means a substance that reduces the rate of release of a therapeutic agent from a pharmaceutical composition when orally ingested. The release retardant may be a polymer or a non-polymer. The release retardant may be used according to any one of several sustained release systems including, for example, a diffusion system, a dissolution system and/or an osmotic system.

[00193] In certain aspects, the therapeutic agent (e.g. cannabidiol) is included in the composition as fine multi-particulates in the form of granules or pellets of particle size about 1 mm. The composition of the material for capsule administration is, in certain aspects, a powder, lightly compressed plug, or even as a tablet. In one aspect, the composition comprising the therapeutic agent could be prepared by compression.

[00194] Colourants and flavouring agents may optionally be included. For example, compositions may be formulated (such as, and without limitation, by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavouring agents.

[00195] The volume of the composition may be diluted or increased with an inert material. These diluents could include carbohydrates, especially mannitol, alpha-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts are also optionally used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.

[00196] In other embodiments, disintegrants are included in the solid dosage form compositions of the present invention. Materials used as disintegrants include but are not limited to starch including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatine, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite are also contemplated. Another form of the disintegrants is the insoluble cationic exchange resins. Powdered gums are also optionally used as disintegrants and as binders and these include, without limitation, powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[00197] Binders are contemplated to hold the cannabidiol together to form a hard tablet and include, without limitation, materials from natural products such as acacia, tragacanth, starch and gelatine. Other binders include, without limitation, methylcellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) are contemplated for use in alcoholic solutions to granulate the therapeutic.

[00198] An antifrictional agent may be optionally included in the compositions of the invention to prevent sticking during the composition process. Lubricants may be optionally used as a layer between the therapeutic and the die wall, and these can include but are not limited to: stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Exemplary soluble lubricants may also be used such as include sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, and Carbowax 4000 and 6000. [00199] Glidants that might improve the flow properties of the compound during composition and to aid rearrangement during compression might be optionally added. The glidants may include without limitation starch, talc, pyrogenic silica and hydrated silicoaluminate.

[00200] To aid dissolution of the therapeutic agent (e.g. cannabidiol) into the aqueous environment, a surfactant might be added in certain embodiments as a wetting agent. Surfactants may include, for example and without limitation, anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents might be optionally used and could include, without limitation, benzalkonium chloride or benzethomium chloride. The list of potential nonionic detergents that could be included in the composition as surfactants are lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. When used, these surfactants could be present in the composition of the therapeutic agent either alone or as a mixture in different ratios.

[00201] Additives which that potentially enhance uptake of the therapeutic agent include, without limitation, the fatty acids oleic acid, linoleic acid and linolenic acid.

[00202] Controlled release composition may be desirable. In certain aspects, the therapeutic agents could be incorporated into an inert matrix that permits release by either diffusion or leaching mechanisms i.e., gums. In some aspects, slowly degenerating matrices may also be incorporated into the composition. Another form of a controlled release of this therapeutic is by a method based on the Oros therapeutic system (Alza Corp.), i.e. the drug is enclosed in a semipermeable membrane which allows water to enter and push drug out through a single small opening due to osmotic effects. Some enteric coatings also have a delayed release effect.

[00203] In other aspects, a mix of materials might be used to provide the optimum film coating. Film coating may be carried out, for example, in a pan coater or in a fluidized bed or by compression coating.

Use

[00204] According to another aspect of the invention, there is provided the use of an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition for the treatment or prevention of at least one symptom of a condition in a subject in need thereof. [00205] According to another aspect of the invention, there is provided the use of a first prophylactically or therapeutically effective amount of and matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition, in the manufacture of an oral composition for the treatment or prevention of at least one symptom of a condition in a subject in need thereof.

[00206] Preferably, the subject has symptoms of two or more of anxiety, stress and/or depression. Preferably the method reduces the subject’s score on the validated scale for anxiety or reduces the anxiety biomarker. Preferably the method also reduces the subject’s score on the validated scale for stress and/or depression or reduces the stress and/or depression biomarker(s). Preferably the method reduces the subject’s score on the validated scale for anxiety and/or reduces the subject’s score on the validated scale for stress and/or reduces the subject’s score on the validated scale for depression.

[00207] Preferably the method reduces the subject’s score on the validated scale for insomnia or reduces the insomnia biomarker.

[00208] Preferably the method reduces the subject’s score on the validated scale for pain or reduces the pain biomarker.

[00209] The composition may be delivered once per day, or more than once per day (for example, twice per day, three times per day or four times per day) for a total daily dose of between 25mg and 200 mg of cannabidiol.

Kits

[00210] According to one aspect of the invention, there is further provided a kit for at least one symptom of a condition in a subject in need thereof, comprising: a) an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition; b) instructions for use.

[00211] Preferably, the subject has symptoms of two or more of anxiety, stress and/or depression. Preferably the method reduces the subject’s score on the validated scale for anxiety or reduces the anxiety biomarker. Preferably the method also reduces the subject’s score on the validated scale for stress and/or depression or reduces the stress and/or depression biomarker(s). Preferably the method reduces the subject’s score on the validated scale for anxiety and/or reduces the subject’s score on the validated scale for stress and/or reduces the subject’s score on the validated scale for depression.

[00212] Preferably the method reduces the subject’s score on the validated scale for insomnia or reduces the insomnia biomarker.

[00213] Preferably the method reduces the subject’s score on the validated scale for pain or reduces the pain biomarker.

[00214] Kits of the invention include one or more containers comprising cannabidiol as described herein, and instructions for use in accordance with any one of the methods described herein. The kit may further comprise a description for selecting a subject suitable for treatment based on identifying whether that individual has symptoms of anxiety, stress and/or depression, insomnia or pain when assessed by a validated scale or biomarker for identifying symptoms of anxiety, stress and/or depression , insomnia or pain. The kit may further comprise a description of administering cannabidiol as described herein to an individual at risk of developing symptoms of anxiety, stress and/or depression , insomnia or pain when assessed by a validated scale or biomarker for identifying symptoms of anxiety, stress and/or depression , insomnia or pain.

[00215] The composition may be delivered once per day, or more than once per day (for example, twice per day, three times per day or four times per day) for a total daily dose of between 25mg and 200 mg of cannabidiol.

[00216] The instructions generally include information as to dosage, dosing schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e.g. multi-dose packages) or sub-unit doses. Instructions supplied in the kits of the invention are typically written instructions on a label or package insert. The label or package insert indicates that the composition is used for treating and/or preventing symptoms of anxiety, stress and/or depression , insomnia or pain. Instructions may be provided for practising any of the methods described herein.

General

[00217] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. The invention includes all such variation and modifications. The invention also includes all of the steps, features, formulations and compounds referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features. [00218] Each document, reference, patent application or patent cited in this text is expressly incorporated herein in their entirety by reference, which means that it should be read and considered by the reader as part of this text. That the document, reference, patent application or patent cited in this text is not repeated in this text is merely for reasons of conciseness.

[00219] Any manufacturer’s instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention.

[00220] The present invention is not to be limited in scope by any of the specific embodiments described herein. These embodiments are intended for the purpose of exemplification only. Functionally equivalent products, formulations and methods are clearly within the scope of the invention as described herein.

[00221 ] The invention described herein may include one or more range of values (eg. Size, displacement and field strength etc). A range of values will be understood to include all values within the range, including the values defining the range, and values adjacent to the range which lead to the same or substantially the same outcome as the values immediately adjacent to that value which defines the boundary to the range. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. Hence “about 80 %” means “about 80 %” and also “80 %”. At the very least, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[00222] Throughout this specification, unless the context requires otherwise, the word “comprise” or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. It is also noted that in this disclosure and particularly in the claims and/or paragraphs, terms such as “comprises”, “comprised”, “comprising” and the like can have the meaning attributed to it in U.S. Patent law; e.g., they can mean “includes”, “included”, “including”, and the like; and that terms such as “consisting essentially of’ and “consists essentially of’ have the meaning ascribed to them in U.S. Patent law, e.g., they allow for elements not explicitly recited, but exclude elements that are found in the prior art or that affect a basic or novel characteristic of the invention.

[00223] Other definitions for selected terms used herein may be found within the detailed description of the invention and apply throughout. Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs. The term “active agent” may mean one active agent or may encompass two or more active agents.

[00224] The following examples serve to more fully describe the manner of using the above- described invention, as well as to set forth the best modes contemplated for carrying out various aspects of the invention. It is understood that these methods in no way serve to limit the true scope of this invention, but rather are presented for illustrative purposes.

EXAMPLES

[00225] Further features of the present invention are more fully described in the following non limiting Examples. This description is included solely for the purposes of exemplifying the present invention. It should not be understood as a restriction on the broad description of the invention as set out above.

Example 1

Treatment of psychological distress

Methods

[00226] Detailed demographic information and validated standardised questionnaires were collected as part of routine care. Written informed consent to treatment was obtained from all patients, as well as additional consent to participate in Emyria’s clinical data registry, data from participating patients were anonymised, aggregated, and analysed to establish clinical efficacy.

[00227] Clinically validated tools were used to monitor patients for management of symptoms, quality of life, physical/emotional functioning, and concomitant medication usage. Patients were asked about their cannabis history and initially pre-screened for any illicit cannabis use before commencing on medicinal cannabis treatment using the Cannabis Use Condition Identification Test (CUDIT), a urine screen was performed to confirm negative result for cannabis in their urine before they commence treatment. After they commenced on medicinal cannabis treatment they were initially treated with low doses and monitored for safety and efficacy of treatment before dose escalation is considered.

[00228] Patients are excluded from treatment with medicinal cannabis if they: were pregnant or breast-feeding; have untreated heart disease, heart failure or arrhythmia; a history of severe psychiatric conditions; active suicidal ideation; a history of dependence on cannabis; a history of dependence or abuse of psychoactive substances; detectable urinary THC before commencement of medicinal cannabis.

Exclusion Criteria

[00229] A potentially eligible individual who met any of the following criteria will be excluded from participation if the following criteria is met:

1. Clinically recorded cannabis drug addiction, or cannabis use condition including individuals with scores 8 or more on the Cannabis Use Condition Identification Test (CUDIT).

2. Untreated cardiovascular disease, arrhythmias (other than well controlled atrial fibrillation), or severe heart failure. 3. History of suicide attempts or suicidal ideation.

4. History of psychotic episode, schizophrenia or other psychotic conditions.

[00230] Patients were assessed monthly by the clinical team (doctor and nurse) and a visit schedule protocol was followed for each patient. A full medical history was conducted at the initial visit, including a detailed history of the clinical indication (including duration symptoms), comorbidities mental and cardiac health conditions, previous procedures, medications and therapies tried. Patients were reviewed as per the Schedule of Assessments (Figure 2). Cannabinoid dose and Adverse events were also recorded at each visit after treatment began and categorised as mild (no product change indicated), moderate (product change indicated), severe (product cessation indicated) or serious (life-threatening/medical emergency).

Dosing of Medicinal Cannabis Products

[00231] The doctors treating patients prescribed orally-based medicinal cannabis standardised products as per approval under the Therapeutic Goods Administration (TGA) through the Special Access Scheme (SAS) Category B and Authorised Prescriber (AP) scheme. The prescribing doctor will decide which product type including THC/CBD ratio and CBD only, based on TGA guidance documents (ie for pain THC/CBD type is generally prescribed) [see https://www.tga.gov.au/medicinal-cannabis-guidance-documents], but also will factor in patient’s circumstances such as driving (then CBD only prescribed).

[00232] T reatment dosing by the prescribing doctor was in accordance with Emyria (Emerald Clinics) experience, well-tolerated with minimal side effects. Doctors reviewed patients after the 14 day (2 week), see the Schedule of Assessments (Figure 2). Following the 2-week dosing review where a doctor may increase/decrease the dosage or change product type, patients were then seen regularly (generally monthly) as per the Schedule of Assessments (Figure 2). Patients taking CBD only products were prescribed either oil or capsules.

Population Criteria Collected for Evaluation

• Population descriptors

- Age

- Sex

- Ethnicity

- Work Status

- Comorbidities

- Family history of diseases • Condition being treated:

- Primary condition being treated

- Any relevant co-morbidities that are being managed that are relevant to the primary condition.

- Prior treatments trialled including medications, surgery and management interventions.

• Prior Treatments:

- Concurrent medications

- Surgical procedures

- Other concurrent management interventions (peer support, directly observed therapy)

• Comorbidities

- Mental health condition (PTSD, Anxiety, Depression, Other)

- Diabetes

- Cancer

- Heart and circulation problems (including Heart Disease, Pacemaker, Blood Disease)

- Muscle, bone and joint problems

- Respiratory problems (including asthma, lung disease, COPD, sleep apnoea)

- Neurological problems (including stroke, epilepsy, multiple sclerosis, Parkinson’s Disease)

- Digestive problems (including IBS, GORD, stomach ulcers, reflux, bowel disease)

- Liver, kidney and pancreas problems (including pancreatitis, kidney disease)

- Thyroid problems (including hyperactive or hypoactive thyroid, Graves’ disease)

- Sleep issues (ie trouble falling or staying asleep, restless legs, snoring, terrors, falling asleep without warning)

- Bacterial, fungal, viral or parasitic disease

- Ear, nose, throat, mouth or eye disease

- Skin or connective tissue disease

- Substance abuse

- Wounds or Injuries

- Conditions present at birth

- Other health conditions • Treatment outcome

- Self-reported adherence to cannabis-based therapy expressed as a proportion of all prescribed doses taken

- Self-reported pain, mood (anxiety, depression, stress), sleep and quality of life (QoL) score using clinically validated questionnaires reported monthly for the first year, with regular follow up. See the Schedule of Assessments (Figure 2).

- Safety Data (recording of Adverse events) at each visit.

- Cannabinoid dose (recording of dose and frequency) at each visit.

- Concomitant medications (recording of medications) at each visit.

- Vital Signs (at each clinic visit)

- Any clinical assessments, laboratory and pathology assessments conducted by GP or specialist as part of their standard treatment of their clinical indication.

Safety Evaluations

[00233] Adverse events (AE) were recorded at each of the visits. AEs were categorised as either: Mild (required no change in dose or product), Moderate (required change in dose or product), Severe (required cessation of product) or Serious (medical emergency).

[00234] All AEs reported during treatment were recorded. Assessments included monitoring of any or all of the following parameters: the participant’s clinical symptoms, laboratory, pathological, radiological or surgical history, physical examination findings, and/or or findings from blood/urine tests. The nature, time of onset, duration and severity will be documented, together with the Investigator’s opinion of the relationship to the Medicinal cannabis product.

[00235] Any pre-existing conditions or signs and/or symptoms present in a participant prior to the start of treatment (i.e., before informed consent obtained) were recorded as Medical/Surgical History. In addition, any medical occurrence that is reported after informed consent was obtained, but prior to first starting the medicinal cannabis product, were documented as baseline signs and symptoms.

[00236] The screening visit also provided a baseline general health assessment including blood pressure and any pre-existing conditions requiring assessments of kidney and liver function. Participants were monitored for any medications that may interact with medicinal cannabis.

[00237] Review of the dose and side effects was conducted by the doctor at 2 weeks; the doctors then advise whether to increase/or decreases doses. Reviews and clinical visits beyond the 2 weeks occurred monthly or more often as required by the patient due to efficacy and side effects. [00238] There were 234 patients with DASS-21 scores in the initial (baseline) visit and follow-up after taking CBD for at least one month with age range 7-95 years (Table 1).55% of the patients were female and 45% of patients were male.

[00239] Table 1 presents baseline (before treatment) descriptive statistics for patients treated with a CBD product (both capsule and oil).

able 1 : Baseline summary statistics of patients prescribed cannabidiol (n=234).

otes: a Mental health conditions are patient-identified, whereas primary diagnoses displayed in Panel B are identified by the treating doctor. Notice that the specifindications of chronic non-cancer pain and mental health problems do not necessarily add up to the total proportion of cases within the sample (i.e. 0.55 and 0.48), a atients may display multiple indications (in addition to non-specified indications being omitted).

4

0

Dose

[00240] Patients were administered between 3 mg and 600 mg cannabidiol per day. Table 2: Prescribed cannabinoid doses

Results

[00241] Figures 5 and 6 investigate the respective dose-response of CBD (both capsule and oil) and CBD capsule-only on symptoms of anxiety (as measured by the DASS-21 ). In particular, the figures plot the relationship between daily dose amounts of CBD and changes in DASS-21 anxiety scores from baseline (before treatment) to the first follow-up visit (8 weeks after). Notice that lower values indicate less symptoms of anxiety. The relationships (displayed as the solid fitted lines) are derived using a locally estimated scatterplot smoothing (LOESS) regression approach (95 percent confidence intervals around the fitted line).

[00242] Overall, Figure 5 shows a negative relationship between cannabidiol dose and anxiety symptoms with an initial dip at approximately at daily dose of 60mg and then a subsequent dose amount around 140mg. Figure 6 reveals that the drop in anxiety score is driven by CBD capsule treatment alone.

[00243] To investigate the relationship further, regression-equation checks were undertaken. Table 3 displays fixed effects regression results predicting the short-term therapeutic effect of CBD capsules on DASS-21 anxiety scores at the first follow-up visit. Column (1 ) first presents results from a univariate specification with a time specific dummy variable capturing the first follow-up visit (i.e., Visit 1) as the sole explanatory variable. Most notably, the coefficient of interest is negative and statistically significant at the 1 percent level, confirming an overall decline in symptoms of anxiety across the 8-week treatment period.

Table 3: Main regression results, predicting anxiety score change (lower values indicate less anxiety symptoms).

Notes: The data are from Visit 0 (baseline) and Visit 1 (first follow-up) of patients who (i) report DASS-21 anxiety scores, and (ii) are prescribed a CBD only product. Columns (1 )-(3) focus on patients taking a CBD capsule, whereas columns (4)-(5) are dedicated to individuals on a CBD oil. Outcome is the short-term change in DASS-21 anxiety score between Visit 0 and Visit 1 . Standard errors clustered at the patient level are displayed in parentheses. *p< 0.10, **p< 0.05, ”*p< 0.01 .

[00244] In terms of magnitude, treatment with capsules of approximately 55 days, on average, is suggested to lower a DASS-21 anxiety score by -2.647. To place the size of this effect into context, such a reduction would correspond to a 28.4 percent drop when considering the mean anxiety score of 9.324 at baseline (before treatment).

[00245] Columns (2) and (3) then move from an overall treatment dummy variable of taking CBD capsules to including daily dose amounts (both linear and squared). Note that the coefficient on CBD dose is negative whereas the corresponding squared term is positive, confirming the non linearity seen in Figure 2. Computing the turning point from the coefficients in column (3), 107mg in CBD capsules per day is associated with the maximum decline in anxiety symptoms.

[00246] To compare these results to those produced by other CBD products, columns (4) and (5) of Table 3 repeat the regression analysis for patients on CBD oil. The estimated CBD daily dose amount required to achieve the maximum drop in anxiety score is suggested to be at 239mg per day.

[00247] Table 4 directly compares the performance of CBD capsules and oils.

able 4: Robustness checks, comparing capsule to oil

Outcome: DASS-21 Anxiety

Unmatched Matched (1 :1 dosage ratio)⁰_ Matched (1 :2 dosage ratio)⁰

Both Capsule Oil Both Capsule Oil Both Capsule Oil

(1 ) (2) (3) (4) (5) (6) (7) (8) (9)

Visit 1 -2.647” -2.647” -3.325” _2 0 7 -2.647” -1.706* -2.647”* -2.647” -2.147*

(0.730) (0.735) (0.603) (0.732) (0.732) (0.679) (0.732) (0.732) (0.826)

Visit 1 ^c CBD oil -0.678 0.941 0.500

(0.947) (0.998) (1.104)

Patient fixed effects Yes Yes Yes Yes Yes Yes Yes Yes Yes u

# of patients 234 68 166 136 68 68 136 68 68

# of visits 2 2 2 2 2 2 2 2 2 N 468 136 332 272 136 136 272 136 136

Mean of outcome (baseline) 10.821 9.324 11 .434 9.338 9.324 9.353 9.118 9.324 8.912 Mean of prescribed dosage 120.075 91.324 131.852 91.507 91 .324 91.691 134.154 91.324 176.985 otes: The data are from Visit 0 (baseline) and Visit 1 (first follow-up) of patients who (i) report DASS-21 anxiety scores, and (ii) are prescribed a CBD only producutcome is the short-term change in DASS-21 anxiety score between Visit 0 and Visit 1. ^a ln addition to being matched at the corresponding CBD dosage ratiosolumns (4)— (9) are also paired by baseline anxiety scores. Standard errors clustered at the patient level are displayed in parentheses. * p< 0.05, ** p< 0.01 , ***p.001.

[00248] Columns (1) to (3) show an unmatched comparison between the two products. Columns (4) to (6) then present matched comparison (both in terms of average daily dose and baseline anxiety scores). Noticeably, the drop in anxiety score is substantially larger for patients on a CBD capsule than those on an oil product. Finally, columns (7) to (9) report results comparing capsules to oils, where the average prescribed daily dose is twice as large for oils (176.99mg) than capsules (91.32mg). Nevertheless, the larger drop in anxiety for CBD capsules persists compared to oils.

[00249] Figure 7 visualises the results shown in Tables 4. Figure 4 shows that the drop in anxiety score is notably larger for those on CBD capsules once prescribed daily dosages and baseline scores are matched.

[00250] Figure 8 shows that this pattern emerges for other survey scores as well. In particular, those on CBD capsules experience comparable (and in most cases, larger) declines in depression, stress, insomnia, pain severity, and pain interference scores than patients prescribed twice the daily dose amount of CBD in oil form.

Example 2

Pharmacological profile of matrix pellet encapsulated cannabidiol

[00251 ] Clinical trials have been conducted to assess the pharmacokinetic (PK) properties and bioavailability of matrix pellet encapsulated cannabidiol compositions containing 10mg and 100 mg CBD, in 14 healthy volunteers. The matrix pellet encapsulated cannabidiol compositions were compared to the commercial reference product Sativex™, an oral spray.

Matrix Pellet formulations

[00252] The above matrix pellets were packed into two-piece hard gastro-resistant capsules.

[00253] The Sativex™ dose was four actuations of the spray, two under the tongue and two inside the cheek. Results

Table 5: Summary of pharmacokinetics parameters

[00254] Human study demonstrated significantly higher CBD plasma levels in the matrix pellet encapsulated cannabidiol compositions compared to a commercial standard CBD preparation, Sativex™. The matrix pellet encapsulated cannabidiol compositions further demonstrated superior pharmacokinetic values and bioavailability. Consistent values of 134% higher bioavailability of CBD were obtained for the matrix pellet encapsulated cannabidiol compositions compared to Sativex™. Further, this study demonstrated a significant dose response comparing the matrix pellet encapsulated cannabidiol 10 mg and 100 mg compositions.

Claims

1 . A method for treating or preventing at least one symptom of a condition in a subject in need thereof, the method comprising the step of: administering an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition.

2. The method of claim 1 wherein the first prophylactically or therapeutically effective amount of CBD is at a ratio to the second equally prophylactically or therapeutically effective amount of CBD of 1 :3, 1 :2.5, 1 :2 or 1 :1.5.

3. The method of claim 1 wherein the is condition chosen from the list comprising: insomnia, pain, and psychological distress.

4. The method of claim 1 wherein the method: i. reduces the subject’s score on the validated scale for anxiety or reduces the anxiety biomarker and/or reduces the subject’s score on the validated scale for stress or reduces the stress biomarker and/or reduces the subject’s score on the validated scale for depression or the depression biomarker. Preferably the method reduces the subject’s score on the validated scale for anxiety and/or reduces the subject’s score on the validated scale for stress and/or reduces the subject’s score on the validated scale for depression; ii. reduces the subject’s score on the validated scale for insomnia or reduces the insomnia biomarker; and/or iii. reduces the subject’s score on the validated scale for pain or reduces the pain biomarker.

5. The method of claim 1 wherein the matrix pellet forming excipient is chosen from the list comprising: gelatine, medium chain triglycerides, long chain triglycerides, hydroxypropyl methylcellulose (HPMC), starch and modified starch, carrageenan, hydroxy propyl cellulose (HPC), pullulan, polyvinyl alcohol (PVA), and alginate.

6. The method of claim 1 wherein the oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD is administered for at least one month.

7. An oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition for the treatment or prevention at least one symptom of a condition in a subject in need thereof.

8. Use of an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition for the treatment or prevention of at least one symptom of a condition in a subject in need thereof.

9. Use of a first prophylactically or therapeutically effective amount of and matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition, in the manufacture of an oral composition for the treatment or prevention of at least one symptom of a condition in a subject in need thereof.

10. A kit for at least one symptom of a condition in a subject in need thereof, comprising: a) an oral pharmaceutical composition containing a first prophylactically or therapeutically effective amount of CBD in a first pharmaceutical composition comprising a matrix pellet forming excipient wherein the first prophylactically or therapeutically effective amount of CBD is lower than a second equally prophylactically or therapeutically effective amount of CBD, wherein the second prophylactically or therapeutically effective amount of CBD does not comprise the matrix pellet forming excipient of the first pharmaceutical composition; b) instructions for use.