WO2025210605A1 - Cannabidiol compositions for anxiety disorders - Google Patents

Abstract

The present invention relates to pharmaceutical compositions of cannabidiol comprising less than 0.3% of THC for treating various anxiety disorders. The invention also discloses evaluation of efficacy, safety and pharmacokinetics of these compositions for treating mild to moderate anxiety disorders.

Description

CANNABIDIOL COMPOSITIONS FOR ANXIETY DISORDERS

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions of cannabidiol comprising less than 0.3% of THC for treating various anxiety disorders. The invention also discloses evaluation of efficacy, safety and pharmacokinetics of these compositions for treating mild to moderate anxiety disorders.

BACKGROUND OF THE INVENTION

The worldwide adoption of the non-psychoactive phytocannabinoid cannabidiol (CBD) is on the rise because of its wide-ranging therapeutic benefits in managing various health issues. In 2018, the FDA granted approval to Epidiolex, the pharmaceutical grade CBD medication, for treating Dravet syndrome and Lennox - Gastaut syndrome.

Anxiety disorders, including generalized anxiety disorder (GAD), panic disorder (PD) with or without agoraphobia, social anxiety disorder (SAD), specific phobias, selective mutism, anxiety not otherwise specified, and separation anxiety disorder, are common mental health conditions that have a considerable impact on both individuals and society. They affect over 301 million people worldwide. In India, the prevalence of anxiety was documented at a rate of 3,006 per 100,000 individuals between 1999 and 2019.

The effectiveness of existing treatments for anxiety disorders is hindered by low response rates, ongoing symptoms, heightened addiction risks, and adverse effects. Given the widespread occurrence of anxiety disorders and the limitations associated with their treatment, it is crucial to prioritize the development of innovative therapies. SUMMARY OF THE INVENTION

One aspect of the present invention is to provide oral compositions of cannabidiol for treatment of anxiety disorders wherein the compositions have less than 0.3% THC, preferably less than 0.1% THC.

Another aspect of the present invention is to provide oral compositions of cannabidiol for treatment of anxiety disorders by administering a composition in the form of solution, emulsion, suspension or capsules.

Yet another aspect of the invention is to provide oral cannabidiol composition with reduced food effect for effective treatment of anxiety disorders.

Yet another embodiment is to provide a cannabidiol oral composition for treating anxiety disorders comprising cannabidiol in a concentration of 0.01% to 60% w/w of the total weight of the composition, wherein the composition contains less than 0.3% THC and is administered in a dose ranging from 150mg to 600mg.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Generalized Anxiety Disorder-7 (GAD-7) item score

IA) GAD-7 score at different visits in CBD treatment and placebo groups

IB) GAD-7 scores at baseline and Visit 11 (end of study)

Figure 2: Hamilton Anxiety (HAM- A) score

2A) HAM-A scores at different visits in CBD treatment and placebo groups

2B) HAM-A scores at baseline and Visit 11 (end of study) DETAILED DESCRIPTION OF THE INVENTION

Cannabidiol (CBD) is a potential therapeutic option for several disorders like seizures, chemotherapy-induced nausea and vomiting, spasticity, post-traumatic stress disorder and neuropathic pain.

Despite the therapeutic benefits of CBD compositions, the presence of THC in the compositions may lead to numerous undesirable side effects. The severity of these adverse events tends to rise with prolonged exposure during treatment. The compositions of the invention are designed to contain minimal or no THC content and are effective in treating anxiety disorders without the associated side effects.

One embodiment of the present invention discloses oral compositions of cannabidiol with less than 0.3% THC, preferably less than 0.1% THC.

Another embodiment of the invention provides oral compositions of cannabidiol with less than 0.3% THC for the treatment of mild to moderate anxiety disorders, and mild to moderate anxiety disorders associated with mild to moderate depression and sleep quality disturbances.

The present invention provides oral compositions comprising one or more lipids one or more surfactants, one or more cosolvents, one or more oils and other pharmaceutically acceptable excipients, for the treatment of mild to moderate anxiety disorders, depressive disorders and sleep disturbance disorders.

Yet another embodiment of the present invention provides oral compositions of cannabidiol comprising cannabidiol (0.01-60%), one or more lipids (0.5-90%), one or more fatty acids or their derivatives, one or more surfactants (0.5-85%), one or more cosolvents (0.5-20%), and one or more oils (0.5-60%) of total weight of the composition and other pharmaceutically acceptable excipients, for the treatment of mild to moderate anxiety disorders, depressive disorders and sleep disturbance disorders.

The compositions of the present invention can be in the form of solution, emulsion, suspension, liquid filled hard or soft gelatin capsules.

The oral compositions comprise cannabidiol in the concentration range of 0.01% - 60% w/w of total weight of the composition. Preferably cannabidiol ranges from O.lmg/ml to 600 mg/ml in the composition. More preferably it ranges from 50 to 300 mg/ml. Most preferably it ranges from 100-200mg/ml in the composition.

The compositions are designed to administer cannabidiol in the range of 150mg to 600mg per dose. The quantity of the composition can be measured to arrive at the required dose, facilitating easy administration for patients with special needs.

The oral composition of the invention comprises one or more lipids in the range of 0.1 to 90 % w/w of total weight. Lipids may be selected from the group comprising of lipids, decanoic acid (DA), pentadecanoic acid (PDA), alpha lipoic acid, capric acid, cholesterol, Monosteol (propylene glycol monostearate), pegylated lipid including Lipoid PE 18:0/18 :0-PEG 2000 (N-(Carbonyl- methoxypolyethylenglycol-2000)- 1 ,2-distearoyl-sn-glycero phosphoethanolamine, MPEG-2000-DSPE, Na-salt): PEG-PE, Solutol HS-15 (polyethylene glycol-15- hydroxy stearate), Gelucire® 48/16 (polyethylene glycol monostearate) and the like, fatty acid derivatives, fatty alcohol derivatives, free fatty acids or fatty alcohols, and choline derivatives of fatty acids, PEGylated or propylene glycol derivatives of oils, free fatty acids or free fatty alcohols.

Surfactant is a compound that reduces the surface tension of water and can be nonionic, anionic, cationic, or amphoteric in nature based on its charge. The oral composition of the invention comprises of one or more surfactants in the range of 0.5%-85% w/w of total weight of the composition. The surfactants may be chosen from poly-amino acids, alpha lecithin; phospholipids like soy lecithin, Lipoid E 80 S (egg lecithin), Egg Lipoid 80 W (egg lecithin), Lipoid E 80 (phospholipids); DMPC (modified phospholipids derivatives of dimyristoyl phosphatidylcholine), DPPC (l,2-dipalmitoyl-rac-glycero-3-phosphocholine), hydrophilic surfactants like Poloxamer-188, sodium oleate, salts of fatty acids, Polysorbates, Span, Cremophor RH 40, and sucrose esters of fatty acids (ex: sucrose laurate) and Kolliphor RH 40, polyethoxylated derivatives of fatty acids or fatty alcohols.

The poly-amino acids are selected from natural polymers, such as protein-based polymers and polysaccharides selected from but not limited to collagen, albumin, gelatin, casein, silk, wool, starch, cellulose, agarose, alginate, carrageenan, hyaluronic acid, dextran, chitosan, cyclodextrins, polyesters such as polyhydroxyalkanoates, and others such as natural rubber, lignin and shellac. Synthetic biodegradable polymers selected from but not limited to polyesters such as poly(lactic acid), poly(glycolic acid), poly(hydroxy butyrate), poly(s- caprolactone), poly(P-malic acid), poly(dioxanes), polyanhydrides such as poly(sebacic acid), poly(adipic acid), poly(terphthalic acid) and various copolymers, polyamides such as poly(imino carbonates), polyamino acids, phosphorus-based polymers such as polyphosphates, polyphosphonates, polyphosphazenes and other polymers such as poly(cyano acrylates), polyurethanes, polyortho esters, poly dihydropyrans, polyacetals. Synthetic non- biodegradable polymers selected from but not limited to acrylic polymers such as polymethacrylates, poly(methyl methacrylate), poly hydro(ethyl methacrylate), cellulose derivatives such as carboxymethyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate propionate, hydroxyl propyl methyl cellulose, silicones such as polydimethyl siloxane, colloidal silica and others polymers such as polyvinyl pyrrolidone, ethyl vinyl acetate, poloxamers, poloxamines.

The composition may comprise one or more cosolvents in the range of 0.5-20% w/w of total weight of the composition. They may be selected from group comprising of alcohols like ethanol, dehydrated alcohol, glycerol, propylene glycol, Poloxamer, and polyethylene glycol and esters of alcohols.

The composition comprises of one or more oils in the range of 0.5%-60% w/w of total weight selected from group comprising of medium chain triglycerides NF, Labrafac Lipophile WL 1349 (MCT oil), caprylic acid and the like, fish oil, soybean oil, olive oil, corn oil, vitamin E, grapeseed oil, walnut oil, avocado oil, flax seed oil, coconut oil, olive oil, hemp seed oil, ginger oil, sesame oil, poppy seed oil, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and other omega fatty acids (OFA).

The present composition may additionally comprise of pharmaceutically acceptable excipients such as stabilizers, chelating agents, preservatives, buffers, viscosity modifiers, tonicity modifiers, organoleptic additives, antioxidants, chelating agents, preservatives, oils, bulking aids, fillers, complexing agents, disintegrants, fatty acid salts, polymers, gelatin derivatives, collagen derivatives, alginate derivatives and drug carriers or vehicles such as Tricaprin (captex 1000), MCT oil.

The organoleptic additives can be sweeteners such as sucrose, xylitol, mannitol, sorbitol, lactitol and maltitol, acesulfame-potassium, aspartame, erythritol, neohesperidine dihydrochalcone, neotame, saccharin, sucralose, stevia and flavouring agents such as peppermint supreme, strawberry, pineapple, vanilla, spearmint, menthol, cinnamon, mango, orange, apple, lemon, lime, Masking agent 2522 and Masking agent 2521.

The present invention further may comprise of antioxidants such as DL-Alpha tocopherol (Vitamin E), Vitamin E acetate (alpha-tocopherol acetate), monothioglycerol (MTG), ascorbic acid, citric acid, tartaric acid, ascorbyl palmitate, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). Chelating agents in the present invention comprise of 1,4,7,10- Tetraazacyclododecane- 1,4,7, 10-tetraacetic acid (DOT A), disodium ethylene diamine tetraacetic acid (EDTA) and diethylenetriaminepentaacetatic acid (DTPA).

Preservatives comprise of potassium sorbate, methyl paraben, propyl paraben, ethyl paraben, butyl paraben chlorbutanol, benzoic acid, sodium benzoate and sorbic acid.

Anxiety disorders represent the most prevalent mental health issue, resulting in social withdrawal, clinical depression, panic attacks, fear and overall unease, all of which can disrupt daily functioning. Screening for various anxiety disorders relies on these symptoms, with assessments conducted using tools such as the Generalized Anxiety Disorder Scale (GAD-7), Hamilton Rating Scale for Anxiety (HAM-A), Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression- Severity (CGI-S), Patient Health Questionnaire-9 (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), and The Depression, Anxiety, and Stress Scale - 21 Items (DASS-21).

The scales of anxiety are classified as below:

Table 1: GAD-7 (Generalized Anxiety Disorder 7 -item scale)

Table 2: HAM-A (Hamilton Anxiety Rating Scale)

The composition of the present invention was administered to evaluate the efficacy, safety, and pharmacokinetics in subjects with mild to moderate anxiety, cannabidiol oral composition (150 mg/ml) and placebo oral solution were prepared by mixing required dose volume of each with 150ml of water and administered about 30 minutes after food intake in a 1:1 ratio to a total of 178 randomized participants who were screened based on ICD-11 criteria for anxiety disorders and DASS-21 anxiety scale. The dose of CBD was titrated, starting from 300mg/day to 600mg/day, and increased based on a CGI-I score>3 in each of the visits. The study lasted approximately 15 weeks.

The study was evaluated using primary outcomes (GAD-7 and HAM-A). Secondary outcomes were based on the improvements in the overall severity of symptoms and functioning at the conclusion of the treatment period.

Results

Primary Endpoints:

Table 3: GAD-7 score (Figure 1 - A & B)

The treatment difference in GAD-7 score at end of treatment and baseline for CBD arm vs Placebo arm is -7.02 (S.E: 0.25, 95% CI -7.52; -6.52), p-value <0.0001.

The mean (SD) GAD-7 scores gradually decreased in the CBD group from week 2 (visit 4), which continued till week 13 (visit 11). At Visit 10 (Week 12) the drug was tapered to 150 mg/day and at the end of the study Visit 11 (Week 13), there was no increase in anxiety scores.

Table 4: HAM- A score (Figure 2- A & B)

The treatment difference in HAM-A score at end of treatment when compared to baseline for CBD arm vs Placebo arm is -11.9 (S.E: 0.33, 95% CI -12.6; -11.3), p- value <0.0001. The mean (SD) HAM-A scores gradually decreased in the CBD group from week 2 (visit 4), which continued till week 13 (visit 11).

At Visit 10 (Week 12) the drug was tapered to 150 mg/day and at the end of the study Visit 11 (Week 13), there was no increase in anxiety scores.

Table 5: Secondary Endpoints: It is evident from the study results that the cannabidiol composition of present invention reduced GAD-7 and HAM-A scores (primary outcome), reduced CGI-I. CGI-S. PHQ-9. and PSQI scores (secondary outcomes) achieving superior efficacy when compared to the placebo group during the treatment of anxiety disorders with no serious adverse effects reported.

The cannabidiol formulation of present invention showed therapeutic efficacy, excellent safety, and tolerability in treating not only mild to moderate anxiety disorders (primary end point of the study) but also associated depression and disturbances in sleep quality (Secondary endpoint of the study) with no incidences of withdrawal anxiety upon dose tapering and at the end of the treatment.

CBD reduced GAD-7 and HAM-A scores (primary outcome). CBD reduced CGI- I, CGI-S, PHQ-9, and PSQI scores (secondary outcomes). Therefore, CBD Oral Solution was effective in treating mild to moderate anxiety and showed good tolerability, with no serious adverse events.

The CBD oral solution (150 mg/mL) formulation showed therapeutic efficacy, excellent safety, and tolerability in treating not only mild to moderate anxiety disorders (primary end point of the study) but also associated depression and disturbances in sleep quality (Secondary endpoint of the study) with no incidences of withdrawal anxiety upon dose tapering and at the end of the treatment.

Single dose pharmacokinetics study

This study was conducted using 2ml of present cannabidiol 150mg/ml formulation (i.e., 300mg/dose). CBD oral solution was dispersed in 150ml of water and administered to 18 participants (both fasting and fed state). In the fed state, the medication was given about 30 minutes after standardized high calorie meal. Various pharmacokinetic parameters such as Cmax, T_max, ti/2, AUCo-t and AUCo were evaluated. Cmax increased during fed state, with a geometric mean Cmax at 332.9 (CV 40.7%) and 239.6 ng/ml (CV 30.7%) at fasting. The Cmax ratio of fed vs fasted was about 1.5. The Cmax ratio is less than 3 and the Tmax is less than 5 hours.

Geometric mean AUC 0-t and AUC 0-co are 3-fold higher in fed state (1575.6 ng*hr/ml (CV 25%), & 1626.4 ng*hr/ml (CV 24.9%)) vs. fasting (508.5 ng*hr/ml (CV 31.8%), & 535.8 ng*hr/ml (CV 31.4%)).

The administration of cannabidiol composition of the present invention showed enhanced therapeutic efficacy, excellent safety, tolerability and better pharmacokinetic profile in treating mild to moderate anxiety disorders and mild to moderate anxiety disorders associated with mild to moderate depression and sleep quality disturbances.

Below are a few exemplary examples that do not limit the scope of the present invention.

Example 1 Manufacturing process:

1. Accurately weighed quantity of MCT oil, egg phospholipid (E80) and Cremophor RH 40 were taken into a glass vial to which capric acid and PEG-PE were added and the contents were dissolved by heating on a water bath at 40°C. 2. Then, required quantity of cannabidiol was added to the above mixture and dissolved by further heating at 40°C to give a homogenous oil matrix which was then cooled to room temperature.

3. In another vial weighed quantity of dehydrated alcohol was taken to which required pharmaceutically acceptable excipients were added and dissolved by stirring for 5 min at 400 rpm.

4. The above alcoholic mixture was transferred to the vial containing cooled oil matrix and the resultant mixture was mixed for 2 min at 400 rpm.

Example 2 Manufacturing process:

1. Accurately weighed quantity of ethanol was taken into a manufacturing vessel, followed by addition of Neotame under stirring until a clear solution is obtained.

2. Required quantity of PEG-PE was added to the above solution, followed by addition of following ingredients one by one along with stirring: MCT oil, decanoic acid, Kolliphor RH 40, egg lecithin, peppermint supreme, menthol were added until a clear solution was obtained.

3. In a separate container required quantity of methyl paraben was added, followed by addition of DL- Alpha Tocopherol and mixed well. 4. Transfer the above solution mixture into the manufacturing vessel and stir, followed by addition of cannabidiol under stirring until clear solution was obtained.

5. Finally make up the volume to 100% by using the remaining quantity of MCT oil and stirred until a clear solution was obtained.

Table 6: Stability data of Example 2 Note: BLQ: Below Level of Quantification Example 3

Manufacturing process:

1. Accurately weighed quantity of ethanol was taken into a manufacturing vessel, followed by addition of Neotame under stirring until a clear solution is obtained.

2. Required quantity of PEG-PE was added to the above solution, followed by addition of following ingredients one by one along with stirring: MCT oil, decanoic acid, Kolliphor RH 40, egg lecithin, peppermint supreme, menthol, potassium sorbate were added until a clear solution was obtained. 3. Add cannabidiol into the manufacturing vessel under stirring until clear solution was obtained.

4. Finally make up the volume to 100% by using the remaining quantity of MCT oil and stirred until a clear solution is obtained. Table 7: Stability data of Example 3

Example 4: Formulations of cannabidiol oral capsule

Manufacturing process

1. Required quantity of Labrafac Lipophile WL 1349 (MCT Oil) and Captex-1000 were added to manufacturing vessel, followed by addition of Egg Lecithin (Egg Lip

80 W) and PEG-PE and dissolved by heating at about 40°C.

2. To the above mixture pentadecanoic acid, decanoic acid and Kolliphor RH 40/Cremophor RH 40 were added subsequently and dissolved by stirring, followed by addition of menthol and methyl paraben under stirring until dissolved and addition of alpha tocopherol and cannabidiol under stirring until dissolved.

3. Finally make up the volume to 100% using MCT oil. 4. The above homogeneous composition is to be filled into capsules, made of gelatine or cellulose or HPMC or other suitable polymers.

Claims

We Claim:

1) A cannabidiol oral composition for treating anxiety disorders comprising cannabidiol in a concentration of 0.01% to 60% w/w of total weight of the composition, wherein the composition a) contains less than 0.3% THC and b) is administered in a dose ranging from 150mg to 600mg c) has ratio of geometric mean maximum plasma concentration (Cmax) of fed and fast state is less than 3.

2. The composition of claim 1, wherein the duration of treatment is carried out for about 1 week to 15 weeks.

3. The composition as claimed in claim 1, where the time to attain maximum plasma concentration, Tmax, is less than 5 hours.

4. The composition as claimed in claim 1, wherein the composition is in the form of solution.

5. The composition as claimed in claim 1, wherein the composition is in the form of emulsion.

6. The composition as claimed in claim 1, wherein the composition is in the form of suspension.

7. The composition as claimed in claim 1, wherein the composition is in the form of liquid filled hard or soft gelatin capsules.

8. The composition of claim 1, comprising 0.5% to 85% w/w of surfactants.

9. The composition of claim 1, comprising 0.5% to 90% w/w of lipids.

10. The composition of claim 1, comprising 0.5% to 60% w/w oils.