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WO2025038586A1 - Composition d'extrait de cannabinoïde issu de cw1as1 pour le traitement de l'autisme et de symptômes associés - Google Patents

Composition d'extrait de cannabinoïde issu de cw1as1 pour le traitement de l'autisme et de symptômes associés Download PDF

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Publication number
WO2025038586A1
WO2025038586A1 PCT/US2024/041993 US2024041993W WO2025038586A1 WO 2025038586 A1 WO2025038586 A1 WO 2025038586A1 US 2024041993 W US2024041993 W US 2024041993W WO 2025038586 A1 WO2025038586 A1 WO 2025038586A1
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daily dose
days
administering
extract
dose
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Joel Stanley
Marcel Bonn-Miller
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Defloria LLC
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Defloria LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/348—Cannabaceae
    • A61K36/3482—Cannabis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • Botanical cannabinoid extracts with cannabidiol (CBD) as the dominant cannabinoid have the potential to be effective in the treatment of nervous system, including central nervous system (CNS), and mental diseases, conditions, disorders, and/or symptoms.
  • CNS-associated disease includes but is not limited to autism spectrum disorder (ASD). It is estimated that 1 in 68 children may have ASD (CDC 2014). ASD is characterized by deficits in social communication, irritability, repetitive behaviors, impulsivity, temper tantrums, and high caregiver burden (Lecavalier et al 2006).
  • compositions comprising a cannabinoid extract of Cannabis sativa L.
  • beta-caryophyllene at an amount that is 3% to 25% percent of the amount of beta caryophyllene in the air dried plant material from which the extract is obtained, and/or ⁇ -bisabolol at an amount that is 3% to 20% percent of the amount of ⁇ -bisabolol in the air dried plant material from which the extract is obtained and/or ⁇ - humulene at an amount that is 3% to 30% percent of the amount of ⁇ -humulene in the air dried plant material from which the extract is obtained.
  • compositions comprising a cannabinoid extract of hemp variety ‘CW1AS1’, wherein representative seeds of the variety have been deposited under NCIMB No.43291.
  • the extract is a cannabinoid and terpenoid extract of hemp variety ‘CW1AS1’.
  • the pharmaceutical compositions of the present disclosure comprise, consists of, or consists essentially of a cannabinoid extract and glyceryl monolinoleate, such as unsaturated glycerol monolinoleate, and optionally a flavoring agent.
  • the composition is not an emulsion.
  • Another aspect of the present disclosure is methods of treating autism, epilepsy, or one or more symptoms thereof by administering an effective amount of the pharmaceutical compositions of the present disclosure.
  • the methods of treating as disclosed herein are for treating a primary indication of a disease, disorder, condition, or symptom.
  • the methods of treating as disclosed herein are for treating a secondary indication of a disease, disorder, condition, or symptom.
  • the methods of treating as disclosed herein are for treating anxiety and/or irritability associated with autism.
  • the present disclosure provides methods of treating a disease, disorder, condition, and/or symptom, including symptoms associated with autism spectrum disorder, by administering the pharmaceutical composition with the cannabinoid extract of CW1AS1 being about 25 mg to about 650 mg for a ⁇ 14 year old patient daily dose and about 50 mg to about 650 mg for an adult daily dose.
  • Current autism spectrum disorder (ASD) treatments are limited in efficacy and are associated with debilitating side effects.
  • the botanical drug product of the present disclosure has the potential to have therapeutic effects in the treatment of irritability, repetitive behaviors, improved cognition, sociability, and quality of life for ASD patients.
  • FIG.1 provides an example study design for the clinical protocol of the present disclosure.
  • the term “approximately” or “about” refers to a range of values that fall within 10% in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).
  • ⁇ z refers to a terminal rate constant.
  • AE refers to an adverse event.
  • Aer refers to a cumulative amount excreted renally.
  • AESI refers to an adverse event of special interest.
  • ALP alkaline phosphatase.
  • ALT alanine aminotransferase.
  • ANOVA refers to analysis of variance.
  • ALT refers to alanine aminotransferase.
  • API refers to an active pharmaceutical ingredient.
  • ASM refers to anti-seizure medication.
  • ASD refers to autism spectrum disorder.
  • AST refers to aspartate aminotransferase.
  • AUC0-inf refers to the area under the concentration-time curve from time zero to infinity (extrapolated).
  • AUC 0-last refers to the area under the concentration-time curve from time zero until the last observed concentration.
  • AUC0-tau refers to the area under the concentration-time curve from time zero to the end of dosing interval (tau) at steady state.
  • BDP refers to a botanical drug product.
  • BDS refers to a botanical drug substance.
  • BID refers to twice a day.
  • BMI body mass index.
  • BP blood pressure.
  • BT body temperature.
  • CB G protein-coupled cannabinoid receptors.
  • CB1 cannabinoid Type 1.
  • CB2 cannabinoid Type 2.
  • CBC cannabichromene.
  • CBD cannabidiol.
  • CBDA cannabidiolic acid.
  • CBG cannabigerol.
  • CBN cannabinol.
  • CI refers to the confidence interval.
  • CK refers to creatine kinase.
  • Cl/F refers to apparent clearance.
  • Cl/F,ss refers to an apparent clearance at steady state.
  • ClR refers to renal clearance.
  • C max refers to maximal observed concentration.
  • Cmin refers to minimal observed concentration.
  • CNS refers to the central nervous system.
  • CRO refers to a contract research organization.
  • CS refers to clinically significant.
  • C-SSRS refers to Columbia suicidality severity rating scale.
  • CSR refers to clinical study report.
  • CCAE refers to Common Terminology Criteria for Adverse Events.
  • CTlast refers to concentration at last time point.
  • CTU refers to a Clinical Trial Unit.
  • CV refers to the coefficient of variation.
  • CYP refers to cytochrome P450.
  • DRF refers to dose range finding.
  • DS refers to Dravet Syndrome.
  • DSST refers to Digit Symbol Substitution Test.
  • DEQ refers to Drug Effects Questionnaire.
  • ECG electrocardiogram. Attorney Docket No.38383.0001P1
  • ECS cannabinoid system
  • eCRF electronic case report form
  • EIU EIU
  • EIU exposure in utero
  • EMA European Medicines Agency
  • ENT refers to an equilibrative nucleoside transporter.
  • EOS refers to the end of study.
  • ET refers to early termination.
  • FAAH refers to fatty acid amide hydrolase.
  • Fe% refers to the fraction of unchanged drug excreted.
  • FE refers to food-effect.
  • FDA refers to the Food and Drug Administration.
  • FSHE refers to a full spectrum hemp extract.
  • a “full-spectrum extract” refers to a CBD product that contains multiple cannabis plant extracts, including essential oils, terpenes, and other cannabinoids.
  • GACPs refers to good agriculture and collection practices.
  • GCP refers to Good Clinical Practice.
  • GTT refers to gamma-glutamyl transferase.
  • GI refers to gastrointestinal.
  • GLM refers to a general linear model.
  • GLP refers to Good Laboratory Practice.
  • GMP refers to Good Manufacturing Practice.
  • GPR55 refers to G protein-coupled receptor 55.
  • 5-HT1A refers to a 5-hydroxytryptamine 1A receptor.
  • HBsAg refers to a hepatitis B surface antigen.
  • HCV refers to hepatitis C virus. Attorney Docket No.38383.0001P1
  • HED refers to human equivalent doses.
  • HEENT refers to the head, eyes, ears, nose, and throat.
  • HERG refers to human Ether-à-go-go-Related Gene.
  • HV refers to the human immunodeficiency virus.
  • HR refers to the heart rate.
  • HREC refers to the Human Research Ethics Committee.
  • IB refers to an Investigator’s Brochure.
  • ICF refers to an informed consent form.
  • ICH refers to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.
  • ICR refers to the Institute of Cancer Research.
  • IP refers to an investigational product.
  • IUD refers to an intrauterine device.
  • IUS refers to an intrauterine system.
  • K el refers to a terminal elimination rate constant.
  • LGS refers to Lennox-Gastaut Syndrome.
  • LLC refers to a lower limit of normal.
  • MAD refers to a multiple ascending dose.
  • MCH refers to mean cell hemoglobin.
  • MCHC refers to mean cell hemoglobin concentration.
  • MCV refers to mean cell volume.
  • MDMA refers to 3,4-methylenedioxymethamphetamine.
  • MedDRA refers to Medical Dictionary for Regulatory Activities.
  • MTD refers to maximal tolerated dose.
  • NF or “(NF)” refers to National Formulary-compliant excipients. NFs are standard for the pharmaceutical industry. Traditionally, a formulary contains a collection of formulas for the compounding and testing of medication.
  • NCS refers to not clinically significant.
  • NOAEL refers to no observed adverse effect level.
  • Orphan Drug refers to the orphan status given to drugs and biologics for rare diseases that meet certain criteria as set by FDA’s Orphan Drug Designation program.
  • OTC refers to over-the-counter.
  • PASAT Paced Auditory Serial Addition Test.
  • PCP phencyclidine.
  • PICF phencyclidine.
  • PK pharmacokinetic(s).
  • PD pharmacodynamics.
  • PPND pre- and postnatal development.
  • PPAR ⁇ nuclear peroxisome proliferator-activated receptor- ⁇ .
  • po refers to oral.
  • PR refers to the PR interval.
  • QA refers to quality assurance.
  • QC refers to quality control.
  • QD refers to quaque die (once a day).
  • QT refers to the QT interval.
  • QTcF refers to Fridericia’s corrected QT interval.
  • RBC refers to a red blood cell.
  • R2D refers to Recommended Phase 2 Dose.
  • RR refers to the respiratory rate.
  • SAE refers to a serious adverse event.
  • SAD refers to a single ascending dose.
  • SAS refers to a statistical analysis plan.
  • SBA refers to statistical analysis system.
  • SBA refers to a Summary Basis of Approval (SBA) prepared by the FDA Center for Drugs and Biologics for many newly approved drugs.
  • the SBA is used to evaluate Attorney Docket No.38383.0001P1 and approve new drugs for marketing based on safety and effectiveness (efficacy), to assure that these drugs are properly labeled, and to share with the public the key facts on which approval is based.
  • SD refers to the standard deviation.
  • SOC refers to a system organ class.
  • SOP refers to a standard operation procedure.
  • SPT refers to a serum pregnancy test.
  • SRC refers to a safety review committee.
  • T1 ⁇ 2 el refers to terminal elimination half-life.
  • TEAE refers to a treatment-emergent adverse event.
  • TGA refers to Therapeutic Goods Administration.
  • THC refers to tetrahydrocannabinol.
  • THCA refers to tetrahydrocannabinolic acid.
  • T max refers to a time when the maximal concentration is observed.
  • TRPV1 refers to a transient receptor potential cation channel subfamily V member 1.
  • TRPV2 refers to a transient receptor potential cation channel subfamily V member 2.
  • UPN glucuronosyltransferase.
  • UPN refers to the upper limit of normal.
  • UPT refers to a urinary pregnancy test.
  • USP-NF refers to a combination of two compendia, the United States Pharmacopeia (USP) and the NF.
  • Vd/F,ss refers to an apparent volume of distribution at steady state.
  • VPA refers to divalproex sodium. Attorney Docket No.38383.0001P1
  • Vz/F refers to apparent volume of distribution.
  • V/F,ss refers to volume of distribution at steady state.
  • WBC refers to a white blood cell.
  • WOCBP refers to women of childbearing potential.
  • treatment refers to a method for obtaining beneficial or desired results for a patient, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, condition, disorder, and/or symptom; reducing the severity of the disease, condition, disorder, and/or symptom; stabilizing the disease, condition, disorder, and/or symptom (e.g., preventing or delaying its worsening); preventing or delaying the spread of the disease (e.g., metastasis), condition, disorder, and/or symptom; preventing or delaying the recurrence of the disease, condition, disorder, and/or symptom; delaying or slowing the progression of the disease, condition, disorder, and/or symptom; ameliorating the state of the disease, condition, disorder, and/or symptom; providing response (partial or total) to the disease, condition, disorder, and/or symptom;
  • compositions and methods of the present disclosure contemplate any one or more of these treatment aspects.
  • a “pharmaceutically effective amount” refers to an amount sufficient to treat the disease, condition, disorder, and/or symptom, such as ameliorate, reduce the rate of occurrence of, or prevent a symptom of a sign of a medical disorder.
  • Pharmaceutically effective amount also refers to an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient may vary depending on factors such as the disease to be treated, the general health of the patient, the route of method, the dose of administration, and the severity of side effects.
  • the pharmaceutically effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxic effects.
  • active ingredient refers to any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals. Active ingredients can include CBD, THC, and/or terpenoids.
  • disease refers to a pathological process having a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.
  • symptom refers to any morbid phenomenon or departure from the normal in structure, function, or sensation experienced by a patient and indicative of disease or mental disorder. With respect to mental disorders, [00177]As used herein, “disorder” refers to an abnormality, alteration, or derangement of function leading to a morbid or abnormal physical or mental state.
  • a “medical condition” refers to its use as a broad term that includes all diseases, lesions, and disorders.
  • the Diagnostic and Statistical Manual of Mental Disorders (DSM) uses the term "general medical condition” to refer to all diseases, illnesses, and injuries except for mental disorder.
  • the term medical condition is also a synonym for medical state, which describes an individual patient's current state from a medical standpoint.
  • the term “appropriate period of time” or “suitable period of time” refers to the period necessary to achieve a desired effect or result. For example, a mixture may be blended until a potency distribution is reached that is within an acceptable qualitative range for a given application or use of the blended mixture.
  • the term “dose” or “unit dose” or “unit dosage” refers to a physically discrete unit that contains a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect.
  • the unit dose or unit dosage may be in the form of a tablet, capsule, sachet, liquid dispensing device, etc. referred to herein as a “unit dosage form.”
  • Chemical Constituents of Cannabis [00173] Cannabis sativa L. is a complex plant with over 400 chemical entities of which more than 60 of them are cannabinoid compounds.
  • Atakan Z. Cannabis, a complex plant: different compounds and different effects on individuals, (Dec.2012) Ther Adv Psychopharmacol 2(6):241- 54.
  • Dried cannabis was found to contain a wide variety of compounds, including cannabinoids, terpenoids, flavonoids, hydrocarbons, fatty acids, phenols, and other miscellaneous classes of compounds and their metabolites.
  • cannabinoids terpenoids
  • flavonoids hydrocarbons
  • fatty acids fatty acids
  • phenols phenols
  • other miscellaneous classes of compounds and their metabolites A comprehensive literature analyses and the chemical analyses of mass spectral signals identified up to 62 unique compounds in the cannabis extract attributable to 22 unique signals based on the corresponding molecular weights of the compounds or the corresponding fragments. Lewis et al., (2017) ACS Omega 2, 9, 6091–6103.
  • Cannabinoids in cannabis that have been confirmed include the following: Cannabicyclols (Cannabicyclolic acid (CBLA), Cannabicyclol (CBL), Cannabicyclovarin (CBLV)); Cannabichromenes (Cannabichromene (CBC), Cannabichromevarinic acid (CBCVA), Cannabichromenic acid (CBCA), Cannabichromevarin (CBCV)); Cannabielsoins (Cannabielsoin (CBE), Cannabielsoin acid A (CBEA-A), Cannabielsoic acid B (CBEA-B)); Cannabitriols (10- Ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol, 8,9-Dihydroxy-delta-6a-tetrahydrocannabinol, Cannabitriol (CBT), Cannabitriolvarin (CBTV)); Cannabidiols (Cannabidiol (Cannab
  • THC Delta-9- Tetrahydrocannabinol
  • D8THC Cannabidiol
  • CBD Cannabinol
  • CBN Cannabichromene
  • CBG Cannabigerol
  • THCA Tetrahydrocannabinolic acid
  • CBDA Cannabidiolic Acid
  • THCV Tetrahydrocannabivarin
  • CBDDV Cannabidivarin
  • ⁇ 9 - tetrahydrocannabinol ( ⁇ 9 -THC or simply THC) is also known by its International Non-Proprietary Name (INN) as dronabinol.
  • INN International Non-Proprietary Name
  • the unsaturated bond in the cyclohexene ring is located between C-9 and C-10 in the more common dibenzopyran ring numbering system.
  • THC isomer ( ⁇ )-(6aR,10aR)-6,6,9-trimethyl-3-pentyl- 6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol.
  • Two related substances, ⁇ 9 - tetrahydrocannabinol-2-oic acid and ⁇ 9 -tetrahydrocannabinol-4-oic acid (THCA) are also present in cannabis, sometimes in large amounts.
  • Cannabis Drug Profile European Monitoring Centre for Drugs and Drug Addiction (2023) online website.
  • the cannabis plant has more than 200 terpenes, many of which are only present in trace amounts. They are the chemical building blocks of essential oils in plants. Cannabis plants produce terpenes along with cannabinoids in glands called trichomes. Besides giving cannabis its taste and aroma, some terpenoids are believed to also have beneficial effects. Terpenes are simple hydrocarbons, while terpenoids are a modified class of terpenes with different functional groups and having an oxidized methyl group moved or removed at various positions.
  • the most prominent Attorney Docket No.38383.0001P1 terpenes in cannabis plants include but are not limited to myrcene, beta-caryophyllene, limonene, linalool, pinene, humulene, terpinolene, alpha-bisabolol, eucalyptol, geraniol, terpineol, farnesene, borneol, ocimene, nerolidol, guaiol, valencene, delta-3 carene, phytol, sabinene, phellandrene, fenchol, menthol, terpinene, isoborneol, and cymene.
  • terpenes that might be present include but are not limited to octanol, isopulegol, cedrene, camphene, geranyl acetate, bergamotene, camphor, and pulegone.
  • octanol isopulegol
  • cedrene camphene
  • geranyl acetate bergamotene
  • camphor camphor
  • pulegone pulegone.
  • Liz G. The Complete List of Cannabis-Derived Terpenes (January 2, 2021) Cannabis Trends, Cannabinoids.
  • CBD Cannabidiol
  • Cannabidiol is a highly lipophilic cannabinoid-receptor allosteric modulator that interacts with the CNS, resulting in modulation of the endogenous cannabinoid system (ECS), a widespread network of G protein-coupled cannabinoid receptors (CB), synthetic and degradative enzymes, and transporters including anandamide and 2-arachidonoylglycerol, cannabinoid (CB) Type 1 (CB1) or CB Type 2 (CB2) endogenous ligands (Di Marzo & Piscitelli 2015, Mouslech & Valla 2009, Cristino et al 2020).
  • CBD is a blocker of the equilibrative nucleoside transporter (ENT) (Carrier et al 2006), the orphan G protein-coupled receptor (GPR)55 (Pertwee 2007), and the transient receptor potential cation channel subfamily M member (TRPM)8 channel (Muller 2019).
  • ENT equilibrative nucleoside transporter
  • GPR G protein-coupled receptor
  • TRPM transient receptor potential cation channel subfamily M member
  • CBD enhances the activity of the 5-hydroxytryptamine (5-HT)1A receptor (Russo et al 2005), glycine receptors (Xiong et al 2011) and the transient receptor potential cation channel subfamily A member (TRPA)1 channel (Muller et al 2019).
  • 5-HT 5-hydroxytryptamine
  • TRPA transient receptor potential cation channel subfamily A member
  • CBD activates the nuclear peroxisome proliferator-activated receptor- ⁇ (PPAR ⁇ ) and the transient receptor potential cation channel subfamily V member (TRPV)1 and TRPV2 channels (Muller et al 2019, Pertwee 2008), also inhibiting cellular uptake and fatty acid amide hydrolase (FAAH)-catalyzed degradation of the endogenous cannabinoid anandamide (Bisogno et al 2001, De Petrocellis et al 2011).
  • PPAR ⁇ nuclear peroxisome proliferator-activated receptor- ⁇
  • TRPV transient receptor potential cation channel subfamily V member
  • FAAH fatty acid amide hydrolase
  • Epidiolex® a plant-based, high-purity CBD formulated as a sesame seed oil- basedmedicine was approved by the FDA (25 June 2018), European Medicines Agency (EMA) (19 September 2019), and Therapeutics Goods Administration (TGA) (18 September 2020) as a treatment of Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS), as well as Tuberous Sclerosis Complex as ani-convulsant, in patients one year and older.
  • Epidiolex® is prescribed for chronic use in humans at up to 25 mg/kg/day (Epidiolex® SBA, Epidiolex® Package Insert), equivalent to a dose of 1750 mg/day assuming 70 kg person.
  • CBD administered intraperitoneally decreased rat locomotor activity( ⁇ 60 mg/kg) and CBD as botanical cannabinoid (100 mg/kg) reduced locomotor behavior in Institute of Cancer Research (ICR) mice (Epidiolex ® SBA,Epidiolex ® Package Insert).
  • CBD inhibited the human Ether-à-go-go-Related Gene (hERG) currents in a concentration-dependent manner (25, 50, and 75% inhibition at 64, 130, and 250 ng/mL CBD, respectively).
  • CBD (po) CBD (10, 50, and 100 mg/kg) decreased heart rate ( ⁇ 50 mg/kg po; 4 h post-dose) and increased systolic blood pressure and R-R, R-H, QRS, and Attorney Docket No.38383.0001P1 QT intervals (100 mg/kg po) in conscious, telemeterized dogs.
  • CYP3A4 Drugs such as phenobarbital, rifampicin, carbamazepine, and phenytoin induce CYP3A4, which causes a reduction in CBD bioavailability (Iffland & Grotenhermen 2017).
  • Other studies suggest a possible weak CYP2C inhibition by CBD, but no other studies were found that yielded the same results (Stout & Cimino 2014).
  • CBD may induce CYP2B isozymes in animal models, which may have implications when CBD-based therapies are administered in combination with other drugs metabolized via those isozymes such as antiepileptic drugs (e.g., valproate and clobazam) (Devinsky et al 2014).
  • antiepileptic drugs e.g., valproate and clobazam
  • CBD and botanical cannabinoids have been generally found to have a low risk of clinically significant drug interactions.
  • CBD has been extensivelyinvestigated in human clinical trials at doses ranging from ⁇ 10 mg/day to up to a single dose of 6,000 mg/day.
  • CBD showed a safe and well tolerable profile, including cardiologic and laboratory assessment deemed within normal limits.
  • the main side effect of CBD administration was sedation (Agurell et al 1986,Consroe et al 1979,Ohlsson et al 1986).
  • the safety and side effects of CBD were comprehensively reviewed (Bergamaschi et al 2011), with a subsequent update completed in 2017 (Iffland, Grotenhermen et al 2017).
  • Cannabis Hemp Extraction Methods, Extracts, and Compositions The present disclosure provides for cannabinoid extracts of Cannabis sativa L. and pharmaceutical compositions comprising the same.
  • the Cannabis sativa L is of variety ‘CW1AS1’ strain Methods of Extraction
  • a process to obtain a cannabinoid extract comprising terpenoids can comprise steps of drying in an environment wherein the average temperatures do not excess 90°F or more preferably, do not exceed 80°F and extracting with a polar organic solvent, and removing the solvent from the solvent extract and decarboxylating at temperatures that do not exceed 195°F, 190° F, 185° F, or 180 °F.
  • the process comprises: a. providing a harvested plant material of Cannabis sativa L., such as the variety ‘CW1AS1’; b.
  • the cannabinoid extracts described herein are obtained from plant material of Cannabis sativa L. Suitable plant material includes the flowers and leaves of Cannabis sativa L. In some embodiments, the cannabinoid extract comprises at least 85% by weight of flowers and leaves of Cannabis sativa L. In other words, some stem parts can be present but it does not make up a significant portion of the plant material. [00184] In some embodiments, drying the plant material is in environmental conditions having an average relative humidity less than 65% or less than 60%.
  • Drying the plant material can be in environmental conditions having an average relative humidity, for example, between 20% and 65%, 20% and 60%, 20% and 55%, 20% and 50%, 20% and 45%, 40% and 65%, 40% and 55%, or 50% and 65%.
  • the environmental conditions can have an average relative humidity, for example, of about 20%, 30%, 40%, 50%, 60%, or about 65%.
  • the time between drying and contacting with a solvent should be limited to less than 12 months and the temperature during this storage period should be t or below 80°F. In some embodiments, the dried plant material is stored for no more than 6 months at an average temperature at or below 80°F prior to contacting the plant material with solvent.
  • the dried plant material is stored for no more than 9 months at an average temperature at or below 80°F prior to contacting the plant material with solvent. In some embodiments, the dried plant material is stored for no more than 12 months at an average temperature below 80°F prior to contacting the plant material with solvent. In some embodiments, the dried plant material is stored in a sealed container.
  • the solvent is one in which cannabinoids and terpenes, such as BCP, alpha-humulene, and alpha-bisabolol, are soluble, such an alcohol, such as isopropyl alcohol or ethanol.
  • the solvent comprises, consists of, or consists essentially of an alcohol with 2 to 5 carbons or an alcohol selected from isopropyl alcohol, ethanol, and butanol.
  • the alcohol consists of or consists essentially of isopropyl alcohol and/or ethanol.
  • the solvent consists of or consists essentially isopropyl alcohol.
  • Decarboxylation is the process of removing a carboxyl Attorney Docket No.38383.0001P1 group from a carbon chain in cannabinoid acids thereby releasing CO 2 released. The loss of the carboxyl activates cannabinoids into more potent forms. Solvent removal and decarboxylation both involve adding heat to the solvent extract. Thus, these processes to some extent happen simultaneously with the methods described herein.
  • the substantial portion of the solvent is removed from the solvent extract by heating to solvent extract to a temperature of 170 °F to 195 °F or 180 to 190 °F and spraying the solvent extract in a chamber under a vacuum, wherein the chamber is in fluid communication with a condenser (e.g., a chiller) such that vapor passes to the condenser thereby condensing vapor comprising solvent and separating vaporized solvent from the solvent extract, wherein the condenser is at a temperature of 0°C to 5°C.
  • the chamber is at a pressure of 30 to 150 Torr more preferably, 30 to 50 Torr.
  • the decarboxylation process detailed herein which is performed in a vessel under vacuum, reduces the temperature required to achieve decarboxylation relative to conventional methods, such as decarboxylation in an oven.
  • the decarboxylation process comprises heating and mixing the solvent extract in a vessel to a temperature that does not exceed 85 °C, e.g., from about 75° C to 85 °C.
  • the vessel is in fluid communication with a condenser and the extract is heated at ambient pressure until no evaporated solvent condensate is visually identified in the condenser.
  • the condenser is at a temperature that is at least 50°C less than that of the solvent extract.
  • the decarboxylation process comprises heating and mixing the solvent extract in a vessel in fluid communication with a condenser to a temperature of from about 75°C to 85°C until no evaporated solvent condensate is visible in the condenser and incrementally reducing the pressure one or more times while heating, wherein between each pressure reduction no evaporated solvent condensate is visible in the condenser.
  • the decarboxylation process comprises maintaining temperature of from about 75° C to 85 °C and lowering and holding pressure in the vessel to 600 torr until no evaporated solvent condensate is visually identified in the chiller, wherein the chiller temperature is -7°C to 0°C or about -5°C.
  • the decarboxylation process is performed over a timespan of about 12 hours to about 16 hours.
  • Attorney Docket No.38383.0001P1 [00192]
  • the vessel can comprise a heat jacket configured to heat the solvent extract contained within the vessel to the desired temperature or desired temperature range and to maintain the temperature at the desired temperature or within the desired temperature range.
  • the extraction method as described above can be used to extract the cannabinoids and terpenes from Cannabis Sativa L., such as from hemp variety ‘CW1AS1’ strain. In other embodiments, said methods can be used with other strains of Cannabis Sativa plants. [00194] In some embodiments, 150 to 300 kg or 200 to 250 kg of biomass are extracted using the above described method. [00195] An aspect of the present disclosure is an extract obtained from the foregoing method. [00196] Other extraction process may also be used to obtain an extract from hemp variety ‘CW1AS1’ strain. [00197] Solvent reduced oils are also sometimes referred to as an oil, butane hash oil (BHO), CO2 extract, among other names.
  • BHO butane hash oil
  • This type of extract is made by soaking plant material in a chemical solvent capable of solubilizing one or more chemical constituents of the plant (e.g., cannabinoids and/or terpenes). After separating the solvent from plant material, the solvent can be boiled or evaporated off, leaving the extract “oil” behind.
  • Butane Hash Oil is produced by passing butane over cannabis and then letting the butane evaporate.
  • Rick Simpson Oil is produced through iso- propyl, or ethanol extraction of cannabis. The resulting substance is a wax like golden brown extract.
  • Another common extraction solvent for creating cannabis oil is CO2. Persons having skill in the art will be familiar with CO2 extraction techniques and devices, including those disclosed in US Published Patent Application Nos.
  • the present disclosure also teaches extracts produced via heat-based extraction methods, such as those disclosed in US Patent Application Nos. US 2018/0078874, US Attorney Docket No.38383.0001P1 2019/0151771, US 2019/0076753, and U.S. Pat. No. 10,159,908, each of which is hereby incorporated by reference for all purposes in their entirety.
  • the plants of the present disclosure can be extracted by exposing tissue to a hot air gas stream that volatizes cannabinoids and/or other secondary metabolites of the plant, which are then condensed and recovered in tanks.
  • the present disclosure teaches exposing plants, plant parts or plant cells to vaporizing heat.
  • vaporizing heat refers to heat sufficient to volatize one or more terpene on cannabinoid components of said plant, plant part or plant cell.
  • the boiling points for each of the cannabinoid and terpene constituents of a hemp plant are well known or readily ascertainable.
  • vaporizing heat comprises 150° F, 155° F, 160° F, 165° F, 170° F, 175° F, 180° F, 185° F, 190° F, 195° F, 200° F, 205° F, 210° F, 215° F, 220° F, 225° F, 230° F, 235° F, 240° F, 245° F, 250° F, 255° F, 260° F, 265° F, 270° F, 275° F, 280° F, 285° F, 290° F, 295° F, 300° F, 305° F, 310° F, 315° F, 320° F, 325° F, 330° F, 335° F, 340° F, 345° F, or 350° F, and all ranges and subranges therebetween.
  • Tinctures are alcoholic extracts of cannabis. These are usually made by mixing cannabis material with high proof ethanol and separating out plant material. Within the dietary supplement industry “tincture” may also describe an oil dilution of hemp extract.
  • the specialty cannabis of the present disclosure is extracted via methods that preserve the cannabinoid and terpenes. In other embodiments, said methods can be used with any cannabis plants.
  • the chemical extraction of specialty cannabis can be accomplished employing polar and non-polar solvents in various phases at varying pressures and temperatures to extract terpenes, cannabinoids, and other compounds of flavor, fragrance or pharmacological value selectively or comprehensively for use individually or combination in the formulation of our products.
  • the solvents employed for selective extraction of our cultivars may include water, carbon dioxide, 1,1,1,2-tetrafluoroethane, butane, propane, ethanol, isopropyl alcohol, hexane, and limonene, in combination or series. It is also possible to extract compounds of interest mechanically by sieving the plant parts that produce those compounds. Measuring the plant part, i.e.
  • compositions comprising at least one ingredient extracted from the ‘CW1AS1’ plant.
  • extracts from the hemp lines of the present disclosure are combined with one or more additional compounds.
  • extracts of the present disclosure such as whole hemp extracts, or a purified cannabinoid from said hemp plant, can be combined with an-other cannabinoid or terpene to produce a composition.
  • the compositions of the present disclosure encompass many forms.
  • the present disclosure provides CBD oils and tinctures.
  • the present disclosure provides CBD capsules.
  • the CBD oils comprise extracts from ‘CW1AS1’, such as solvent extracted oils, heat extracted oils.
  • the capsules comprise extracts from ‘CW1AS1.’
  • the extracts of the present disclosure may also be combined with pure compounds of interest to the extractions, e.g. cannabinoids or terpenes to further enhance or modify the resulting formulation's fragrance, flavor, or pharmacology.
  • the present disclosure teaches compositions comprising at least one ingredient extracted from the ‘CW1AS1’ plant.
  • extracts from the hemp lines of the present disclosure are combined with one or more additional compounds.
  • extracts of the present disclosure such as whole hemp extracts, or a purified cannabinoid from said hemp plant, can be combined with another cannabinoid or terpene to produce a composition.
  • compositions of the present disclosure encompass many forms.
  • the present disclosure provides CBD oils and tinctures.
  • the present disclosure provides CBD capsules.
  • the CBD oils comprise extracts Attorney Docket No.38383.0001P1 from ‘CW1AS1’, such as solvent extracted oils, heat extracted oils.
  • the capsules comprise extracts from ‘CW1AS1.’ Extract and Pharmaceutical Compositions
  • the pharmaceutical composition of the present disclosure is a botanical drug product (BDP) comprising a cannabinoid extract of the Cannabis sativa L. plant as describe herein.
  • the extract can be a full spectrum extract in that it contains the naturally occurring components of the plant that are released from the biomass during the extraction process and retained during the solvent removal process.
  • the extract can be obtained according to the process described herein, particularly with IPA or ethanol as the solvent.
  • cannabinoid extracts of the present disclosure have a high ratio of cannabidiol to THC (detla 9), such as a ratio greater than 22:1 or a ratio greater than 24:1.
  • cannabinoid extracts of Cannabis sativa L. comprise cannabinoids and terpenoids.
  • the extract comprises particular CBD and THC and one or more of beta-caryophyllene, ⁇ -bisabolol, and ⁇ -humulene.
  • the extract comprises beta-caryophyllene, ⁇ -bisabolol, and ⁇ -humulene.
  • the extract can be obtained from a process that preserves terpenes in the air dried plant material from which the extract is obtained from the freshly harvested plant material from which the extract is obtained.
  • an extract of the present disclosure can comprise beta-caryophyllene at an amount that is 3% to 25% or 5% to 20% of the amount of beta caryophyllene in the air dried plant material from which the extract is obtained, and/or ⁇ -bisabolol at an amount that is 3% to 20% or 5% to 18% of the amount of ⁇ -bisabolol in the air dried plant material from which the extract is obtained and/or ⁇ -humulene at an amount that is 3% to 30% or 5% to 28% of the amount of ⁇ -humulene in the air dried plant material from which Attorney Docket No.38383.0001P1 the extract is obtained.
  • the cannabinoid extract of Cannabis sativa L. comprises one or more of the following terpene compounds at the specified concentration: a concentration of beta- caryophyllene is from 15 mg/mL to 70 mg/mL; a concentration of ⁇ -bisabolol of from 8 mg/mL to 50 mg/mL; and/or a concentration of ⁇ -humulene of from about 4 mg/mL to about 40 mg/mL.
  • the extract further comprises a concentration of CBD from 400 to to 700 mg/mL.
  • the extract is diluted in the preparation of the pharmaceutical composition.
  • the pharmaceutical composition comprises one or more of the following terpene compounds at the specified concentration: a concentration of beta-caryophyllene is from 1 mg/mL to 8 mg/mL; a concentration of ⁇ -bisabolol of from 0.7 mg/mL to 8 mg/mL; and/or a concentration of ⁇ -humulene of from about 0.3 mg/mL to about 6 mg/mL.
  • the composition further comprises a concentration of CBD from 40 to to 70 mg/mL.
  • the pharmaceutical composition of the present disclosure is a botanical drug product (BDP) comprising a cannabinoid extract of the Cannabis sativa L. proprietary ‘CW1AS1’ hemp cultivar, which is disclosed and claimed in U.S. Patent No. 10,653,085 and U.S. Patent No.10,736,295, both of which are herein incorporated by reference in their entireties. Representative seed of ‘CW1AS1’ has been deposited under NCIMB 43291.
  • the extract (also referred to as the botanical drug substance (BDS)) of the present disclosure is a cannabinoid extract containing cannabinoids, carbohydrates, non- cannabinoid/terpene lipids, terpenes, and proteins.
  • the primary cannabinoid is cannabidiol (CBD), along with other minor cannabinoids components including but not limited to cannabichromene (CBC), ⁇ 9-tetrahydrocannabinol (THC), cannabigerol (CBG), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerolic acid (CBGA) and cannabinol (CBN).
  • Total tetrahydrocannabinnoids i.e., THC and tetrahydrocannabinolic acid [THCA]
  • THC is controlled to ⁇ 2% in the BDS and ⁇ 0.3% w/w in the pharmaceutical composition, also referred to herein as the botanical drug product.
  • the BDS is a nonaqueous dark green to black substance, can be semi-solid at room Attorney Docket No.38383.0001P1 temperature, obtained via extraction of a proprietary strain (i.e., ‘CW1AS1’) of Cannabis sativa L.
  • the biomass is cultivated and harvested in compliance with good agriculture and collection practices (GACPs).
  • GACPs good agriculture and collection practices
  • the BDS is primarily composed of cannabinoids, followed by carbohydrates, non-cannabinoid/terpene lipids, terpenes, and proteins. Each of the molecule classes may possess activity and is expected to contribute to the overall pharmacological activity of the BDS.
  • the BDS has low aqueous solubility.
  • the BDS comprises from about 45% to about 65% CBD, from about 1% to about 5% CBC, and from about 0.5% to about 2.5% THC weight/weight% of the BDS.
  • the BDS can comprise, for example, from about 45% to about 60%, about 45% to about 55%, about 45% to about 50%, about 50% to about 65%, about 50% to about 55%, about 55% to about 65%, or about 55% to about 60% CBD weight/weight% of the BDS.
  • the BDS can comprise, for example, from about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 2% to about 4%, about 2% to about 3%, or about 3% to about 4% CBC weight/weight% of the BDS.
  • the BDS can comprise, for example, from about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 2.5%, about 1% to about 2%, or about 2% to about 2.5% THC weight/weight% of the BDS.
  • the BDS comprises about 55% CBD, 2% CBC, and about 1% to about 2% THC weight/weight% of the BDS.
  • the botanical drug product (BDP) Oral Suspension of the present disclosure comprises the cannabinoid extract in a carrier, such as a carrier comprising, consisting of, or consisting essentially of one or more oils and/or oil-like substances.
  • suitable oils include but are not limited to glyceryl monolinoleate, corn oil, olive oil, sesame oil, soybean oil (e.g., hydrogenated soybean oil), rapeseed oil, coconut oil, sunflower oil, and combinations thereof.
  • the carrier comprises, consists of, or consists essentially of a mono, di, or tri glyceride or any combination thereof, wherein the fatty acids of the glycerides have a saturated and/or unsaturated carbon chain length ranging from 8 to 20 carbons In some embodiments, the carbon chain length is 12 to 20.
  • Such glycerides can be sesame oil, modified sesame oil, corn oil, or modified corn oil.
  • the glyceride is winterized or Attorney Docket No.38383.0001P1 consists of unsaturated carbon chains.
  • the glyceride is glyceryl monolinoleate.
  • the pharmaceutical composition comprises a lipid-based formulation or lipid-surfactant based formulation comprising glyceryl monolinoleate.
  • the pharmaceutical composition comprises the botanical extract in glyceryl monolinoleate.
  • the glyceryl monolinoleate is a blend of long chain mono, di, and triglycerides.
  • the glyceryl monolinoleate is winterized.
  • glyceryl monolinoleate is Maisine CC®, manufactured by Gattefosse.
  • the glyceryl monolinoleate is a winterized oil composed of mono-, di- and triglycerides of oleic and linoleic acids (C18:1/C18:2).
  • the oils are purified oils and/or highly refined oils.
  • oils examples include but are not limited to Refined Olive Oil IV, which can be used as an excipient or API in the formulation of poorly soluble drugs, injectables, syrups, and parenteral nutrition for human and veterinary applications);Refined Sesame Oil IV-1, which can be used as an excipient in the formulation of lipophilic drugs, injectables, and syrups for human and veterinary applications; and Refined Soybean Oil IV, which can be used as an excipient or API in the formulation of poorly soluble drugs, injectables, syrups, and parenteral nutrition for human and veterinary applications. All three of these specialty oils are available from ADM®.
  • the extract is diluted with an oil, such as mono, di, and/or tri glycerides described herein, by a factor 3 to 20.
  • the dilutions factor is 5 to 15 or 8 to 14 or about 11 or about 12.
  • the purified pharmaceutical oils are also used as excipients such as during the formulation of soft gel capsules, syrups, and lotions.
  • the composition comprises a carrier, wherein the carrier comprises, consists of, or consists essentially of a mono, di, or tri glyceride or any combination thereof, wherein the fatty acids of the glycerides have a saturated or unsaturated carbon chain length ranging from 8 to 20 carbons. In some embodiments, the carbon chain length is 12 to 20. In some embodiments, the glyceride is sesame oil, corn oil, or modified corn oil. Attorney Docket No.38383.0001P1 [00225] In some embodiments, the BDP of the present disclosure comprises one or more flavoring agents including but not limited to orange flavoring, citric acid flavoring, cherry flavoring, strawberry flavoring, chocolate flavoring, mint flavoring, and combinations thereof.
  • the BDP comprises organic chocolate mint flavoring.
  • the BDP of the present disclosure can be formulated in many different forms and finished formats including but not limited to emulsifications, particle encapsulations, powders, liquids, solids, etc.
  • the oral drug product (i.e., BDP) of the present disclosure consists of BDS of 100 mg to 105 mg/ mL, such as 103 mg/mL, in glyceryl monolinoleate, National Formulary (NF), and a flavoring agent, such as an organic mint chocolate flavoring agent.
  • the manufacturing process involves mixing BDS with excipients to yield a fully homogeneous suspension or mixture.
  • Glycerol monolinoleate (C21H38O4; MW 354.5 g/mol; PubChem CID 5283469; CAS RN®: 26545-74-4) is a 1-monoglyceride that has octadecadienoyl (linoleoyl) as the acyl group. It is functionally related to linoleic acid.
  • Glycerol monolinoleate is a mixture of monoglycerides, mainly glyceryl monooleate and glyceryl monolinoleate, together with variable quantities of diglycerides and triglycerides.
  • Synonyms include 1-linoleoyl-fac-glycerol, monolinolein, 1- monolinolein, and glycerol 1-monolinolate.
  • Glyceryl monolinoleate is a natural product found in Saposhnikovia divaricate, Hycoscyamus niger, and other organisms. It can be used to enhance absorption of the drug substance, thereby enhancing bioavailability for systemic exposure.
  • USPNF Docid GUID-B60F2346-5660-41F4-97FE- 7721AECF2902_2_en-US.
  • the composition consists of or consists essentially of a cannabinoid extract of Cannabis sativa L. plant of the variety ‘CW1AS1’ strain, a mono, di, or tri glyceride or any combination thereof, wherein the fatty acids of the glycerides have a saturated and/or unsaturated carbon chain length ranging from 8 to 20 carbons, such as glyceryl monolinoleate, and a flavoring agent.
  • the compositions of the present disclosure can be stored under US Pharmacopeia (USP) Attorney Docket No.38383.0001P1 controlled room temperature conditions of about 20°C to about 25°C (about 68°F to about 77°F) with excursions permitted between about 15°C to about 30°C (about 59°F to about 86°F).
  • USP US Pharmacopeia
  • the extract, also referred to herein as the BDS and the pharmaceutical composition, also referred to herein as the BDP as such, the BDP, of the present disclosure contain numerous pharmacologically active compounds also found in cannabis, including THC, CBD and terpenoids.
  • the extract can be a full spectrum extract.
  • Cannabidiol is the primary naturally occurring cannabinoid in the BDS of the present disclosure along with minor cannabinoid components including cannabichromene (CBC), tetrahydrocannabinol (THC), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidiolic acid (CBDA), cannabidivarin (CBDV), and cannabinol (CBN).
  • cannabichromene tetrahydrocannabinol
  • CBD cannabigerol
  • CBDA cannabigerolic acid
  • CBDA cannabidiolic acid
  • CBDDV cannabidivarin
  • CBN cannabinol
  • the composition comprises a CBD concentration of from about 5% to about 8% w/w%, a THC concentration of from about 0% to about 0.3% w/w%, a CBC concentration of from about 0 to about 0.5% w/w%, and a CBG concentration of from about 0% to about 0.3% w/w% of the BDP.
  • the composition comprises a concentration of delta 9-THC is 0-0.3% w/w/of the pharmaceutical composition, a concentration of cannabichromene is 0-0.5% w/w of the pharmaceutical composition, a concentration of cannabigerol is 0 to 0.3% w/w of the pharmaceutical composition and/or wherein a concentration of total cannabinoids is 5.6-8.4% w/w of the pharmaceutical composition.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are suitable for being in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit/risk ratio.
  • a pharmaceutically acceptable substance may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • the pharmaceutically acceptable carrier or excipient preferably meets the requisite toxicological and manufacturing test standards and/or is included in the Inactive Ingredient Guide provided by U.S. Food and Drug Administration.
  • the pharmaceutical compositions disclosed herein may also comprise other conventional pharmaceutically acceptable ingredients, commonly referred to as carriers, excipients, or adjuvants.
  • excipients or adjuvants include, but are not limited to: disintegrants, binders, lubricants, glidants, stabilizers, fillers, diluents, colorants, flavoring agents, and preservatives.
  • useful additives include materials such as agents for retarding dissolution (e.g., paraffin), resorption accelerators (e.g., quaternary ammonium compounds), surface active agents (e.g., cetyl alcohol, glycerol monostearate, and sodium lauryl sulfate), adsorptive carriers (e.g., kaolin and bentonite), preservatives, sweeteners, coloring agents, flavoring agents (e.g., chocolate mint, citric acid, menthol, glycine or orange powder), stabilizers (e.g., citric acid or sodium citrate), binders (e.g., hydroxypropylmethylcellulose), and mixtures thereof.
  • agents for retarding dissolution e.g., paraffin
  • resorption accelerators e.g., quaternary ammonium compounds
  • surface active agents e.g., cetyl alcohol, glycerol monostearate, and sodium lauryl sulfate
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coating agents, surfactants, antioxidants, preservatives (e.g., antibacterial agents or antifungal agents), isotonic agents, absorption delaying agents, salts, Attorney Docket No.38383.0001P1 preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as known to those skilled in the art (see, e.g., Remington’s Pharmaceutical Sciences,18th edition, Mack Printing Company, 1990, 1289-1329).
  • the botanical extracts of the present disclosure may be a powdered botanical extract which may optionally be combined with one or more inactive, neutral compounds/ingredients which can be pharmaceutically acceptable excipients or carriers, including, but not limited to, binders, antioxidants, adjuvants, synergists and/or preservatives.
  • the botanical extract preparations of the present disclosure can further include encapsulating agents known in the art (i.e., phospholipids, cyclodextrins, etc.) to encapsulate the actives.
  • the powdered botanical extract preparations may optionally be combined with one or more additional pharmaceutically active components.
  • the optional ingredients may be added during the process of preparing the powdered preparation, for example, while the mixture is still in its liquid form and before the solid product has been obtained. Alternatively, the optional ingredients may be added to the powdered preparation after the process of preparing the powdered preparation has been completed, and before further formulation into suitable dosage forms.
  • the powdered botanical extract of the present disclosure can be further incorporated into different dosage forms in accordance with formulation processes as are known in the art.
  • the pharmaceutical compositions of the present disclosure are suitable for delivery to the respiratory tract using a metered dose inhaler (MDI).
  • MDI metered dose inhaler
  • Polar excipients are used routinely in pharmaceutical compositions for treating respiratory disorders that are delivered using MDIs. They are also sometimes referred to as solvents, co-solvents, carrier solvents and adjuvants.
  • a surfactant or the drug in the propellant can serve to solubilize a surfactant or the drug in the propellant and/or inhibit deposition of drug particles on the surfaces of the metered dose inhaler that are contacted by the Attorney Docket No.38383.0001P1 pharmaceutical composition as it passes from the container in which it is stored to the nozzle outlet.
  • They are also used as bulking agents in two-stage filling processes where the drug is mixed with a suitable polar excipient.
  • the most used polar excipient is ethanol. If a polar excipient is used, it will typically be present in an amount of from 0.5 to 10% by weight, preferably in an amount of from 1 to 5% by weight based on the total weight of the pharmaceutical composition.
  • Some embodiments of the present disclosure are directed to dosage forms that are formulated as solid articles suitable for sublingual or oral administration, such as troches, lozenges, pills, oral dissolving strips, caps, or boluses.
  • These solid dosage forms typically comprise additional excipients. They can be prepared by first mixing the powdered botanical extract of the present disclosure with one or more suitable excipients followed by molding or compressing the blended mixture. Both hard and chewable lozenges and troches are within the scope of the present disclosure.
  • the oral dosage forms are formulated as capsules in which the powdered botanical extracts are encapsulated in soft or hard gelatin capsules.
  • carrier refers to a substance that serves as a vehicle for improving the efficiency of delivery and the effectiveness of a pharmaceutical composition.
  • Some embodiments of the present disclosure are directed to dosage forms that are formulated as topical formulations, including but not limited to creams, ointments, and gel, using formulation methods as are known in the art.
  • the topical formulation is a transdermal patch, using formulation methods and technologies as are known in the art.
  • Some embodiments of the present disclosure are directed to dosage forms that are formulated as solid articles suitable for administration as vaginal ovules or rectal suppositories, using formulation methods as are known in the art.
  • Some embodiments of the present disclosure are directed to dosage forms that are formulated as liquids, including but not limited to emulsions, liposomes, dispersions, oils, and tinctures, using formulation methods as are known in the art.
  • Some embodiments of the present disclosure are directed to dosage forms that are formulated as beverages and edibles, wherein the powdered botanical extract is incorporated into food and drink products. Attorney Docket No.38383.0001P1
  • Some embodiments of the present disclosure are directed to dosage forms that are formulated as smokeable or vaporizable formulations.
  • the dosage forms of the present disclosure can be formulated, as appropriate, to include disintegrants, including but not limited to starch, cellulose derivatives and alginates, cross-linked sodium carboxymethyl cellulose (corscarmellose sodium)(e.g., AC-DI- SOL from FMC), hydroxypropylmethyl cellulose (HPMC), cross-linked polyvinylpyrrolidone (crospovidone), clay, cellulose, gum, cross-linked polymers(e.g.,crospolyvinylpyrrolidone or crospovidone, such as POLYPLASDONE XL from ISP (International Specialty Products, Wayne, N.J.)), croscarmellose calcium, soybean polysaccharide, and guar gum.
  • disintegrants including but not limited to starch, cellulose derivatives and alginates, cross-linked sodium carboxymethyl cellulose (corscarmellose sodium)(e.g., AC-DI- SOL from FMC), hydroxypropylmethyl cellulose (HP
  • the dosage forms of the present disclosure can be formulated, as appropriate, to include glidants, including but not limited to silicon dioxide, colloidal anhydrous silicon, and other silica compounds, and/or and or lubricants including stearic acid and salts thereof, such as magnesium stearate.
  • glidants including but not limited to silicon dioxide, colloidal anhydrous silicon, and other silica compounds, and/or and or lubricants including stearic acid and salts thereof, such as magnesium stearate.
  • the term “binder” refers to a substance or compound that promotes, provides, or improves cohesion, i.e., a substance that causes the components of a mixture to cohere to form a solid item that possesses integrity.
  • typical binders that can be used for formulating dosage forms of the present disclosure include but are not limited to natural, synthetic, or semi- synthetic glycerides, hydrogenated coco-glycerides, mineral oil, gelatins, starches, sucrose and sucrose derivatives, lactose and lactose derivatives, cellulose, methyl cellulose, microcrystalline cellulose (e.g., AVICEL PH from FMC (Philadelphia, Pa.), hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose METHOCEL from Dow Chemical Corp., Midland, Mich.) and other cellulose derivatives, sucrose; dextrose; corn syrup; polysaccharide; gelatin, silicones (e.g., dimethicone, bis-vinyl dimethicone/dimethicone copolymer), isopropyl myristate, isostearyl palmitate, polyvinylpyrrolidone and derivatives, and polygly
  • Non-limiting examples of some specific polyglycol derivatives that can be used are: (a) PEG-laureates and dilaureates (e.g., PEG-10-, PEG-12-, PEG-20-, PEG-32-laurates, PEG-20- and PEG-32-dilaurates, PEG-20- Attorney Docket No.38383.0001P1 glyceryl-, PEG-30-glyceryl- and PEG-40-glyceryl-laurates, PEG-80-sorbitan laurate); (b) PEG- oleates, dioleates and trioleates (e.g., PEG-12-, PEG-15-, PEG-20-, PEG-32, PEG-200- and PEG- 400-oleates, PEG-20- and PEG-32-dioleates, PEG-20-trioleate, PEG-25-glyceryl trioleate, PEG- 20-glyceryl- and PEG-30-glyceryl-
  • excipient refers to a pharmacologically inactive substance that is formulated in combination with a pharmacologically active ingredient of a pharmaceutical composition and is inclusive of, but not limited to, disintegrants, lubricants, flavorings, bulking agents, binders, fillers, diluents, preservatives, antioxidants, and adjuvants, synergists and products used for facilitating drug absorption or solubility or for other pharmacokinetic considerations. See, also, The Handbook of Pharmaceutical Excipients, 4th edition, ed.
  • typical excipients that can be used for formulating dosage forms of the present disclosure include but are not limited to gelatin, sodium saccharin, mannitol, stevioside, peppermint oil, cherry flavor, lemon oil, and raspberry flavor.
  • the dosage forms of the present disclosure may optionally be formulated to further comprise one or several antioxidants.
  • antioxidants examples include but are not limited to: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite and sodium sulfite; Attorney Docket No.38383.0001P1 (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate and ⁇ tocopherol; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid and phosphoric acid.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite and sodium sulfite
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT
  • oxidants that could be used according to the present disclosure include but are not limited to ⁇ -tocopherol acetate, acetone sodium bisulfite, acetylcysteine, cysteine, tocopherol natural, tocopherol synthetic, dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thiourea and tocopherols.
  • the dosage forms of the present disclosure may optionally be formulated to further comprise one or several adjuvants or synergists.
  • the dosage forms of the present disclosure may optionally further comprise one or several preservatives.
  • non-limiting examples of those that can be used include benzalkonium chloride, benzethonium chloride, benzoic acid and salts, benzyl alcohol, boric acid and salts, cetylpyridinium chloride, cetyltrimethyl ammonium bromide, chlorobutanol, chlorocresol, chorhexidine gluconate or chlorhexidine acetate, cresol, ethanol, imidazolidinyl urea, metacresol, methylparaben, nitromersol, o-phenyl phenol, parabens, phenol, phenylmercuric acetate/nitrate, propylparaben, sodium benzoate, sorbic acids and salts, o- phenylethyl alcohol, and thimerosal.
  • Examples of pharmaceutically acceptable surfactants for use in the present disclosure include but are not limited to polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid, and lecithin.
  • Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to: silica gel, magnesium trisilicate, starch, talc, tricalcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, and microcrystalline cellulose.
  • Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to: powdered sugar, compressible sugar, glucose binding agents, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, and talc.
  • the optimal dose of each combination partner for treatment can be determined empirically for everyone using known methods and will depend upon a variety of factors, including, but not limited to: the degree of progression of the disease; the age, body weight, general health, gender, and diet of the individual; the time and route of administration; and other medications the individual is taking.
  • each combination partner that may be combined with the carrier materials to produce a single dosage form will vary depending upon the individual treated and the mode of administration.
  • the unit dosage forms containing the combination of agents as described herein will contain a certain amount of each agent of the combination that is typically administered when the agent is administered alone.
  • the drug-carrier complex disclosed herein is administered to a patient in the form of a pharmaceutical composition. In some embodiments, the drug-carrier complex disclosed herein is present in a pharmaceutically effective amount.
  • administered in combination with or “co-administration” as used herein refers to the simultaneous or separate sequential administration in any manner of a solid or liquid oral pharmaceutical dosage form containing the drug-carrier complex disclosed herein and one or more other active agents known to be useful in the treatment of nervous system and/or mental diseases, conditions, disorders, and/or symptoms.
  • other one or more active agent as used herein includes any compound or therapeutic agent known or proven to exhibit advantageous properties when administered to a patient in need of treatment Administration Attorney Docket No.38383.0001P1 [00261]
  • Administration of the extracts or pharmaceutical compositions of the present disclosure can be via any method which delivers a compound of this disclosure systemically and/or locally, including oral routes, transdermal routes, etc.
  • compositions of the present disclosure are administered orally, but the following administration methods may also be utilized where necessary and/or appropriate: parenteral administration (e.g., intravenous (IV), intramuscular, subcutaneous (SQ or Sub-Q) injections, or intramedullary), transdermal, via inhalation, topically, via suppository, sublingual administration, and buccal administration.
  • parenteral administration e.g., intravenous (IV), intramuscular, subcutaneous (SQ or Sub-Q) injections, or intramedullary
  • the administration is sublingual or directed to the side of the mouth so as to contact the cheeks with the extract or composition.
  • the extracts and the compositions are designed to produce products for human or animal consumption.
  • Modes of administration can be via inhalation (via combustion, vaporization and nebulization), buccal absorption within the mouth, oral administration (e.g., eating/drinking, such as with food or drink), and topical application delivery methods.
  • the route of administration for the compositions of the present disclosure is oral without further dilution or reconstitution.
  • such oral administration may be in a form including but not limited to capsules containing a liquid, tablets, pills, liquid, such as tinctures or sprays, lozenges, etc.
  • the dosage form is a liquid or free liquid that is orally administered for buccal absorbtion.
  • the BDP oral suspension is administered 1, 2, or 3 times a day. In a further embodiment, the BDS oral suspension is administered 2 times a day. Each administration is near the time of a meal.
  • An aspect of the present disclosure is a dosing regimen that has a starting dose of 25 mg of BDS (equivalent to approximately 13.75 mg of CBD or 0.2 mg/kg assuming a 70kg person) Attorney Docket No.38383.0001P1 with maximum expected dose level up to 618 mg of BDS (equivalent to 340 mg of CBD or 4.85 mg/kg assuming a 70kg person).
  • Another aspect of the present disclosure is a dosing regimen that has a starting dose of 226.6 mg of BDS (equivalent to 125 mg of CBD or 1.8 mg/kg assuming a 70kg person) with maximum expected dose level up to 1823.1 mg of BDS (equivalent to 1000 mg of CBD or 14.3 mg/kg assuming a 70kg person).
  • the dosing regimens of the present disclosure includes dosages of BDS of about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg,1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg,1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, and 2000 mg.
  • the BDS dosing regimens of the present disclosure range between about 25 mg to about 50 mg, about 50 mg to about 100 mg, about 75 mg to about 125 mg, about 100 mg to about 150 mg, about 125 mg to about 175 mg, about 150 mg to about 200 mg, about 175 mg to about 225 mg, about 200 mg to about 250 mg, about 225 mg to about 275 mg, about 250 mg to about 300 mg, about 275 mg to about 325 mg, about 300 mg to about 350 mg, about 325 mg to about 375 mg, about 350 mg to about 400 mg, about 375 mg to about 425 mg, about 400 mg to about 450 mg, about 425 mg to about 475 mg, about 450 mg to about 500 mg, about 475 mg to about 525 mg, about 500 mg to about 550 mg, about 525 mg to about 575 mg, about 550 mg to about 600 mg, about 575 mg to about 625 mg, about 600 mg to about 650 mg, about 625 mg to about 675 mg, about 650
  • the administered dosage of the BDS is from about 20 mg to about 400 mg per day or to about 650 mg per day.
  • the administered dosage can be, for example, from about 20 mg to about 350 mg, about 20 mg to about 300 mg, about 20 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 50 mg, about 50 mg to about 400 mg, about 50 mg to about 350 mg, about 50 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 100 mg, about 100 mg to about 400 mg, about 100 mg to about 350 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 400 Attorney Docket No.38383.0001P1 mg, about 200 mg to about 300 mg, or about 300 mg to about 400 mg.
  • the administered dosage of the BDS is about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, or about 650 mg per day.
  • the pharmaceutical composition is administered to provide BDS at an amount from about 40 mg to about 700 mg per day or about 800 mg per day.
  • the administered dosage can be, for example, from about 40 mg to about 650 mg, about 40 mg to about 600 mg, about 40 mg to about 500 mg, about 40 mg to about 400 mg, about 40 mg to about 300 mg, about 40 mg to about 200 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 80 mg to about 700 mg, about 80 mg to about 650 mg, about 80 mg to about 600 mg, about 80 mg to about 500 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 650 mg, about 200 mg to about 600 mg, about 200 mg to about 500 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, about 300 mg to about 650 mg, about 300 mg to about 600 mg, about 300 mg to about 500 mg, about 300 mg to about 400 mg, about 400 mg to about 650 mg, about 400 mg to about 600 mg, about 400 mg to about 500 mg, or about 500 mg to about 700 mg per day.
  • the administered dosage of the BDS is from about 100 mg to about 700 mg per day or to about 800 mg per day. [00272] In some embodiments, the administered dosage of the BDS is about 50 mg, about 100 mg, about 175 mg, about 250 mg, about 300 mg, about 350 mg, about 500 mg, about 600 mg, or about 700 mg per day.
  • the dose can start low and the titrate to an effective amount for the individual as a maintenance dose.
  • the maintenance dose can fall within the range of 20 mg to about 400 mg per day or to about 650 mg per day or 40 mg to 700 mg per day or 800 mg per day.
  • the BDS is administered as a titrating dose, wherein the initial dose is increased every 3, 4, or 5 days until a maintenance phase. In such embodiments, the effects and tolerability of the titrating dose are observed to determine a maintenance dose.
  • the treatment comprises administering a first daily dose of the composition that is equivalent to about 100-105 mg (such as 103 mg) of the extract to the subject for 4 to 7 days and administering a second daily dose of about 200-210 mg (such as 206 mg) for 4 to 7 days after the 4 to 7 days of administering the first daily dose, and optionally continuing administration the second daily dose as a maintenance dose after the 4 to 7 days of administering the second daily dose or resuming administration of the first daily dose after the 4 to 7 days of the second daily dose and optionally wherein a daily dose is administered twice daily.
  • the treatment comprises administering a third daily dose of the composition that is equivalent to about 360 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the second daily dose, and optionally continuing administration of the third daily dose as a maintenance dose after Attorney Docket No.38383.0001P1 the 4 to 7 days of administering the third daily dose or resuming administration of the second daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose.
  • the treatment comprises administering a fourth daily dose of the composition that is equivalent to about 515 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the third daily dose, and optionally continuing administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose or resuming administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose.
  • the treatment comprises administering a fifth daily dose of the composition that is equivalent to about 618 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the fourth daily dose, and optionally continuing administration of the fifth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose or resuming administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose.
  • the treatment comprises administering a first daily dose of the composition that is equivalent to about 53 mg of the extract to the subject for 4 to 7 days and administering a second daily dose of about 103 mg for 4 to 7 days after the 4 to 7 days of administering the first daily dose, and optionally continuing administration the second daily dose as a maintenance dose after the 4 to 7 days of administering the second daily dose or resuming administration of the first daily dose after the 4 to 7 days of the second daily dose and optionally wherein a daily dose is administered twice daily.
  • the treatment comprises administering a third daily dose of the composition that is equivalent to about 180 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the second daily dose, and optionally continuing administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose or resuming administration of the second daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose.
  • the treatment comprises administering a fourth daily dose of the composition that is equivalent to about 263 mg Attorney Docket No.38383.0001P1 of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the third daily dose, and optionally continuing administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose or resuming administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose.
  • the treatment comprises administering a fifth daily dose of the composition that is equivalent to about 314 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the fourth daily dose, and optionally continuing administration of the fifth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose or resuming administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose.
  • the dosing regimens of the present disclosure includes dosages of CBD of about 25 mg, about 50 mg, about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, and 1250 mg.
  • the CDB dosing regimens of the present disclosure range between about 25 mg to about 50 mg, about 50 mg to about 100 mg, about 75 mg to about 125 mg, about 100 mg to about 150 mg, about 125 mg to about 175 mg, about 150 mg to about 200 mg, about 175 mg to about 225 mg, about 200 mg to about 250 mg, about 225 mg to about 275 mg, about 250 mg to about 300 mg, about 275 mg to about 325 mg, about 300 mg to about 350 mg, about 325 mg to about 375 mg, about 350 mg to about 400 mg, about 375 mg to about 425 mg, about 400 mg to about 450 mg, about 425 mg to about 475 mg, about 450 mg to about 500 mg, about 475 mg to about 525 mg, about 500 mg to about 550 mg, about 525 mg to about 575 mg, about 550 mg to about 600 mg, about 575 mg to about 625 mg, about 600 mg to about 650 mg, about 625 mg to about 675 mg, about 650
  • the pharmaceutical composition is dosed at an amount to provide for CBD dosing of about 0.5 mg/kg, about 0.75 mg/kg, about 1.0 mg/kg, 1.5 mg/kg, 2.0 mg/kg, 2.5 mg/kg, 3.0 mg/kg, 3.5 mg/kg, 4.0 mg/kg, 4.5 mg/kg, 5.0 mg/kg, 5.5 mg/kg, 6.0 mg/kg, 6.5 mg/kg, 7.0 mg/kg, 7.5 mg/kg, 8.0 mg/kg, 8.5 mg/kg, 9.0 mg/kg, 9.5 mg/kg, 10.0 mg/kg, 10.5 mg/kg, 11.0 mg/kg, 11.5 mg/kg, 12.0 mg/kg, 12.5 mg/kg, 13.0 mg/kg, 13.5 mg/kg, 14.0 mg/kg, 14.5 mg/kg, 15.0 mg/kg, 15.5 mg/kg, and 16.0 mg/kg.
  • CBD dosing of about 0.5 mg/kg, about 0.75 mg/kg, about 1.0 mg/kg, 1.5 mg/kg, 2.0 mg/kg,
  • the pharmaceutical composition is dosed at an amount to provide for a CBD dose between about 0.5 mg/kg to about1.0 mg/kg, such as about 0.75 mg/kg to about 1.25 mg/kg, about 1.0 mg/kg to about 1.5 mg/kg, about 1.25 mg/kg to about 1.75 mg/kg, about 1.5 mg/kg to about 2.0 mg/kg, about 1.75 mg/kg to about 2.25 mg/kg, about 2.0 mg/kg to about 2.5 mg/kg, about 2.25 mg/kg to about 2.75 mg/kg, about 2.5 mg/kg to about 3.0 mg/kg, about 2.75 mg/kg to about 3.25 mg/kg, about 3.0 mg/kg to about 3.5 mg/kg, about 3.25 mg/kg to about 3.75 mg/kg, about 3.5 mg/kg to about 4.0 mg/kg, about 3.75 mg/kg to about 4.25 mg/kg, about 4.0 mg/kg to about 4.5 mg/kg, about 4.25 mg/kg to about 4.75 mg/kg, about 4.5 mg/kg to about 4.25 mg/kg, about 4.0 mg
  • the foregoing doses are administered twice daily.
  • the dose is titrated.
  • a patient starts at a dose of 2.5 mg/kg and after 4 to 7 days increases the dose to 5 mg/kg and so on until a dose is reached that ameliorates the symptoms.
  • the volume of the pharmaceutical composition, the BDP oral suspension, per dose is from about 0.1 mL to about 6 mL.
  • the volume of BDP oral suspension per dose can be, for example, from about 0.1 mL to about 3 mL, about 0.1 mL to about 2 mL, about 0.1 mL to about 1 mL, about 0.25 mL to about 5 mL, about 0.25 mL to about 3 mL, about 0.25 mL to about 3 mL, about 0.25 mL to about 2 mL, about 0.25 mL to about 1 mL, about 0.5 mL to about 5 mL, about 0.5 mL to about 3 mL, about 0.5 mL to about 2 mL, about 0.5 mL to about 1 mL, about 1 mL to about 5 mL, about 1 mL to about 3 mL, or about 3 mL to about 5 mL.
  • the volume of BDS oral suspension per dose is about 0.25 mL, about 0.5 mL, about 1.0 mL, about 1.5 mL, about 2 mL, or about 3 mL.
  • the volume of BDP oral suspension per dose of the present disclosure includes about 0.25 mL, about 0.5 mL, about 0.75 mL, about 1.0 mL, 1.5 mL, 2.0 mL, 2.5 mL, 3.0 mL, 3.5 mL, 4.0 mL, 4.5 mL, 5.0 mL, 5.5 mL, 6.0 mL, 6.5 mL, 7.0 mL, 7.5 mL, 8.0 mL, 8.5 mL, 9.0 mL, 9.5 mL, 10.0 mL, 10.5 mL, 11.0 mL, 11.5 mL, 12.0 mL, 12.5 mL, 13.0 mL, 13.5 mL, 1
  • the volume of BDP oral suspension per dose is from about 0.5 mL to about 8 mL.
  • the volume of BDS oral suspension per dose can be, for example, from about 0.5 mL to about 6 mL, about 0.5 mL to about 3 mL, about 0.5 mL to about 1 mL, about 1 mL to about Attorney Docket No.38383.0001P1 8 mL, about 1 mL to about 6 mL, about 1 mL to about 3 mL, about 3 mL to about 8 mL, or about 3 mL to about 6 mL.
  • the volume of BDS oral suspension per dose is about 0.5 mL, 1 mL, 1.75 mL, 2.5 mL, 3 mL, 2.5 mL, 5 mL, or about 6 mL.
  • the volume of BDP oral suspension per dose of the present disclosure includes ranges between about 0.25 mL to about 0.5 mL, about0.5 mL to about 1.0 mL, about 0.75 mL to about 1.25 mL, about 1.0 mL to about 1.5 mL, about 1.25 mL to about 1.75 mL, about 1.5 mL to about 2.0 mL, about 1.75 mL to about 2.25 mL, about 2.0 mL to about 2.5 mL, about 2.25 mL to about 2.75 mL, about 2.5 mL to about 3.0 mL, about 2.75 mL to about 3.25 mL, about 3.0 mL to about 3.5 mL, about 3.25 mL to
  • the amount of BDS in the BDP is about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75 mg/mL,about 80 mg/mL, about 85 mg/mL, about 90 mg/mL, about 95 mg/mL, about 100 mg/mL, about 105 mg/mL, about 110 mg/mL, about 115 mg/mL, about 120 mg/mL, about 125 mg/mL, about 130 mg/mL, about 135 mg/mL, about 140 mg/mL, about 145 mg/mL, about 150 mg/mL, about 155 mg/mL, about 160 mg/mL, about 165 mg/mL, about 170 mg/
  • the amount is 95 to 115 mg/ ml or 100 to 110 mg/ml.
  • the amount of BDS in the BDP ranges from between about 95 mg/mL to about 110 mg/mL, about 100 mg/mL to about 105 mg/mL, about 105 mg/mL to about 110 mg/mL, or about 110 mg/mL to about 115 mg/mL.
  • the amount of BDS in the BDP ranges from between about 5 mg/mL to about 10 mg/mL, about 10 mg/L to about 15 mg/mL,about 15 mg/mL to about 20 mg/mL, about 20 mg/mL to about 25 mg/mL, about 25 mg/mL toabout 30 mg/mL,about 30 mg/mL to about 35 mg/mL, about 35 mg/mL to about 40 mg/mL, about 40 mg/mL to about 45 mg/mL, about 45 mg/mL to about 50 mg/mL, about 50 mg/mL to about 55 mg/mL, about 55 mg/mL to about 60 mg/mL, about 60 mg/mL toabout 65 mg/mL,about 65 mg/mL to about 70 mg/mL,about 70 mg/mL to about 75 mg/mL, about 75 mg/mL to about 80 mg/mL, about 80 mg/mL to about 85 mg/mL, about 85 mg/mL to about 90 mg/mL,
  • the composition comprises a concentration of cannabidiol of at least 45 mg/mL to 75 mg/mL.
  • the composition can comprise a concentration, for example, of cannabidiol of 50 mg/mL to 70 mg/mL, 50 mg/mL to 65 mg/mL of cannabidiol.
  • the composition comprises a ratio of cannabidiol:delta 9- tetrahydrocannabinol of from about 20:1 to about 40:1.
  • the composition can comprise a ratio, for example, of cannabidiol:tetrahydrocannabidiol of from about about 20:1 to about 40:1.
  • the composition comprises a ratio of cannabidiol:tetrahydrocannabidiol of from about 25:1 to about 40:1. In some embodiments, the composition comprises a ratio of cannabidiol: tetrahydrocannabinol of from about 22:1 to about 40:.
  • the composition can comprise a ratio, for example, of cannabidiol:tetrahydrocannabinol of from about 22:1 to about 35:1, about 23:1 to about 35:1, about 24:1 to about 35:1, about 25:1 to about 35:1, about 23:1 to about 40:1, about 24:1 to about 40:1.
  • the composition comprises a ratio of cannabidiol:tetrahydrocannabinol of from about 23:1 to about 38:1. In some embodiments, the composition comprises a ratio of cannabidiol:tetrahydrocannabinol of at least 25:1. [00295] In some embodiments, the composition comprises a tetrahydrocannabinol concentration of less than about 3 mg/mL.
  • the composition can comprise, for example, a tetrahydrocannabinol concentration of less than about 2.8 mg/mL, 2.7 mg/mL, 2.5 mg/mL, 2.3 mg/mL, 2.0 mg/mL, 1.8 mg/mL, 1.7 mg/mL, 1.5 mg/mL, 1.3 mg/mL, 1.0 mg/mL, 0.8 mg/mL, 0.6 mg/mL, 0.3 mg/mL, 0.1 mg/mL, or less than about 0.05 mg/mL.
  • the composition comprises a tetrahydrocannabinol concentration of from about 1 mg/mL to about 3 mg/mL.
  • the BDS and BDP of the present disclosure can be used to treat a wide range of nervous, nervous-associated, pain, pain-associated, inflammation, inflammation- associated, mental, and mental -associated diseases, conditions, disorders and/or symptoms.
  • Nervous system diseases also known as nervous system or neurological disorders, refer to over 600 medical conditions affecting the nervous system.
  • nervous system diseases, disorders, conditions, and/or symptoms include but are not limited to Acute Spinal Cord Injury, Alzheimer's Disease, Amyotrophic Lateral Sclerosis (ALS), Ataxia, Bell's Palsy Brain Tumors, Cerebral Palsy, Cerebral Aneurysm, Epilepsy, Seizures, Lennox-Gastaut syndrome (LGS), Dravet syndrome, and Tuberous Sclerosis Complex (TSC), Guillain-Barré Syndrome, Headache Head Injury, Hydrocephalus, Lumbar Disk Disease (Herniated Disk), Meningitis, Motor Neurone Disease (MND), Multiple Sclerosis, Muscular Dystrophy, Seizure Disorder, Neurofibromatosis, Neurocutaneous Syndromes, Parkinson's Disease, Stroke (Brain Attack), Cluster Headaches, Tension Headaches, Migraine Headaches, Encephalitis, Sciatica, Shingles, Septicemia, Types of Muscular Dystrophy and Neuromus
  • Autoimmune and inflammatory diseases that can be treated according to the present disclosure include but are not limited to Ankylosing Spondylitis, Antiphospholipid Antibody Syndrome, Autoimmune Encephalitis, Chronic Recurrent Multifocal Osteomyelitis, Gout, Henoch-Schonlein Purpura, Juvenile Dermatomyositis, Juvenile Idiopathic Arthritis, Juvenile Lupus (SLE), Juvenile Scleroderma, Juvenile Vasculitis, Kawasaki Disease, Lupus (Systemic Lupus Erythematosus), Mixed Connective Tissue Disease, Myositis, Poststreptococcal Inflammatory Syndromes, Psoriatic Arthritis, Reactive Arthritis, Rheumatoid Arthritis, Scleroderma, Sjogren's Syndrome, Spondyloarthritis/Spondyloarthropathy, Systemic Juvenile Idiopathic Arthritis, Undifferentiated Connective Tissue
  • compositions and treatments of the present disclosure can also be used to treat pain, including but not limited to temporary, acute, chronic, or permanent pain.
  • Acute pain is pain that Attorney Docket No.38383.0001P1 may come from inflammation, tissue damage, injury, illness, or recent surgery. It usually lasts less than a week or two. The pain usually ends after the underlying cause is treated or has been resolved.
  • Chronic pain is pain that persists for months or even years. The pain may come from inflammation, tissue damage, injury, illness, or recent surgery.
  • the pain may be associated with headaches including but not limited to the most common types of chronic headaches such as migraines, cluster headaches, and tension headaches. The pain may be low back pain.
  • pain disorders that can be treated according to the present disclosure include but are not limited to neuralgias and neuropathies that affect nerves throughout the body, pain due to damage to the central nervous system (the brain and spinal cord), as well as pain where no physical cause can be found-- psychogenic pain.
  • Common types of pain that can be treated according to the present disclosure include but are not limited to arthritis (.e.g., osteoarthritis, rheumatoid arthritis), muscle pain, bone pain, joint pain, back pain, neck pain, musculoskeletal pain, cancer pain (e.g., near a tumor), headaches, including migraines, testicular pain (orchialgia), lasting pain in scar tissue, muscle pain all over (such as with fibromyalgia), multiple sclerosis, neurogenic pain (e.g., from damage or pressure to the nerves or other parts of the nervous system), AIDS, gall bladder disease, problems with the CNS (e.g., diabetes, shingles, sciatica), and organ pain because of injuries, infections, or health problems such as inflammatory bowel disease, irritable bowel syndrome, pelvic pain, and stomach ulcers.
  • arthritis e.g., osteoarthritis, rheumatoid arthritis
  • muscle pain e.g., bone pain, joint pain, back pain, neck
  • Mental illness is a general term for a group of illnesses that may include symptoms that can affect a person’s thinking, perceptions, mood, and/or behavior. Mental illness can make it difficult for someone to cope with work, relationships, and other demands.
  • Examples of mental and/or psychiatric diseases, disorders, conditions and/or symptoms that can be treated according to the present disclosure include but are not limited to Schizophrenia, Bipolar Affective Disorder, Psychosis, Depression, Dissociation and Dissociative Disorders, Personality Disorder, Paranoia, Anxiety Disorders, Eating Disorders, Mood Disorders, Obsessive-Compulsive Disorders, Post- Traumatic Stress (PTS) Disorders, Dissociative Disorders, Panic Disorders, Substance Use Disorders, behavioral and emotional disorders in children and adults, and Schizoaffective disorder.
  • Schizophrenia Bipolar Affective Disorder
  • Psychosis Depression
  • Dissociation and Dissociative Disorders Personality Disorder, Paranoia, Anxiety Disorders, Eating Disorders, Mood Disorders, Obsessive-Compulsive Disorders, Post- Traumatic Stress (PTS) Disorders, Dissociative Disorders, Panic Disorders, Substance Use Disorders, behavioral and emotional disorders in children and adults,
  • compositions and treatments of the present disclosure can be used to Attorney Docket No.38383.0001P1 treat schizophreniform disorder (acute schizophrenic episode); schizoaffective disorder; bipolar I disorder (mania, manic disorder, manic-depressive psychosis); bipolar II disorder; major depressive disorder with psychotic feature (psychotic depression); delusional disorders (paranoia); shared psychotic disorder (shared paranoia disorder); brief psychotic disorder (other and unspecified reactive psychosis); psychotic disorder not otherwise specified (unspecified psychosis); paranoid personality disorder; schizoid personality disorder; and schizotypal personality disorder. See, e.g., US Patent No.9,017,737.
  • Disorders that can be treated according to the present disclosure include but are not limited to antisocial personality disorder, anxiety disorder, Asperger symptom/disorder, attention deficit disorder, autistic disorder, bipolar disorder, body dysmorphic disorder, borderline personality disorder, central auditory processing disorder, chromosome disorder, compulsive personality disorder, conversion disorder, cruise-associated diarrheal disorder, cumulative trauma disorder, delusional disorder, dependent personality disorder, depersonalization disorder, depressive disorder, developmental disorder, dissociative identity disorder, dysthymic disorder, eating disorder, anorexia nervosa, bulimia nervosa, binge-eating disorder, EBV-associated lymphoproliferative disorder, endometrial disorder, expressive disorder, expressive language disorder, factitious disorder, functional disorder, gender identify disorder, generalized anxiety disorder, genetic disorders, hearing disorder, histrionic personality disorder, identity disorder, internet addiction disorder, iodine deficiency disorder, language disorder, late luteal phase dysphoric disorder, lymphoproliferative disorder, major depressive
  • Autism spectrum disorder is a neurological and developmental disorder that affects how people interact with others, communicate, learn, and behave. Although autism can be diagnosed at any age, it is described as a “developmental disorder” because symptoms generally appear in the first 2 years of life. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), a guide created by the American Psychiatric Association that health care providers use to diagnose mental disorders, people with ASD often have difficulty with communication and interaction with other people; restricted interests and repetitive behaviors; and symptoms that affect their ability to function in school, work, and other areas of life.
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders
  • Autism is known as a “spectrum” disorder because there is wide variation in the type and severity of symptoms people experience. People of all genders, races, ethnicities, and economic backgrounds can be diagnosed with ASD. Although ASD can be a lifelong disorder, treatments and services can improve a person’s symptoms and daily functioning. The American Academy of Pediatrics recommends that all children receive screening for autism.
  • the compositions of the present disclosure can be used to treat or ameliorate one or more symptoms associated with autism and orphan conditions that share similar symptomatology. Examples of such symptoms include but are not limited to the following: stereotypic behavior, irritability, social anxiety, social withdrawal, inappropriate speech, hyperactivity/non-compliance, seizures, lethargy, depressive symptoms/depression.
  • cannabinoid extract and pharmaceutical compositions described herein can be used to treat autism spectrum disorder (ASD) or one or more symptoms associated therewith. It is estimated that 1 in 36 children may have ASD (Maenner et al., 2020). ASD is characterized by Attorney Docket No.38383.0001P1 deficits in social communication, irritability, repetitive behaviors, impulsivity, temper tantrums, and high caregiver burden (Lecavalier et al., 2006).
  • VPA anticonvulsant divalproex sodium
  • ASD autism spectrum disorder
  • treating ASD in a subject comprises treating one or more symptoms of ASD selected from anxiety, irritability, lethargy/social withdrawal, stereotypic behavior, hyperactivity/noncompliance, inappropriate speech, social avoidance, and sleep disturbances.
  • treating ASD in a subject comprises improving one or more deficits associated with ASD selected from cognition deficits, sensory sensitivity, social deficits, and speech and language deficits.
  • the subject is a human.
  • the human is less than 18 years of age or 5 to 17 years of age.
  • the human is at least 13 years of age or 13 to 30 years of age.
  • the subject is a human.
  • Attorney Docket No.38383.0001P1 [00308]
  • Example 1 Drying and Extraction of Cannabis sativa L. plants to form Botanical Drug Substance (BDS)
  • BDS Botanical Drug Substance
  • the plants are dried to 7% moisture or below.
  • the stems should snap cleanly before removal of flowers from stalks, or more drying is required.
  • the hemp plants are hand processed to separate the flowers and leaves from the stalks, branches, and other undesired plant material.
  • the hemp is then ran through a brush separator to remove stem material and to particle size hemp and homogenize the hemp biomass.
  • Extraction [00314] The extraction process extracts CBD and other cannabinoids from hemp cultivars of Cannabis sativa L. using isopropyl alcohol.
  • Flower and leaves of a hemp plant of the variety ‘CW1AS1’ strain is mixed with isopropyl alcohol using a CUP-15 (Delta Separations/Prospiant) centrifuge.
  • the cannabinoids are extracted from the physical biomass and brought into the Attorney Docket No.38383.0001P1 solution.
  • the solution or miscella retrieved from the centrifuge is filtered with a 50-micron bag and a 25-micron bag through a filtration system.
  • the miscella is then pumped into a storage drum, and the alcohol is substantially evaporated from the extract with spray evaporation. Alcohol recovered from the evaporation system can be used for further solvent extractions.
  • the extract isolated from the alcohol is collected.
  • Decarboxylation can be performed using a decarboxylation reactor. As many cannabinoids contain a carboxyl group, decarboxylation activates these cannabinoids to more effective forms after removal of the carboxyl group.
  • the extract placed into a 20 L vessel that is heat jacketed and heated to a temperature 180 to 190°F. Chiller columns are in fluid communication with the reactor configured to receive evaporated products from the reactor, and the vessel is placed under vacuum. A mixer is applied to the extract solution. Further evaporation of remaining alcohol solvent occurs, and application of heat converts the cannabinoids into decarboxylated cannabinoids.
  • Table 1 Chemical Analysis Component Amount Cannabidiol 6.49% by weight ⁇ 9-Tetrahydrocannabinol 0.24% by weight Cannabichromene 0.37% by weight Cannabigerol 0.20% by weight (-)- ⁇ -bisabolol 5700 ppm Camphene ⁇ 50 ppm (1S)-(+)-3-Carene ⁇ 50 ppm ⁇ -Caryophyllene 5100 ppm p-Cymene ⁇ 50 ppm Eucalyptol 140 ppm ⁇ -Humulene 2300 ppm (-)-Isopulegol ⁇ 50 ppm (R)-(+)Limonene 67 ppm Linalool 72 ppm beta-Myrcene ⁇ 50 ppm (E)-b-Ocimene ⁇ 50 ppm (Z)-b-Ocimene ⁇ 50
  • mice administered single oral dose of the BDS of the present disclosure of 2000 mg/kg body weight resulted in mean CBD plasma concentration of 602.3 ng/mL at 2 hours, 408.6 ng/mL at 4 hours, 350.7 ng/mL at 6 hours, and 32.2 ng/mL at 24 hours after treatment.
  • Example 4 Summary of Nonclinical Toxicology [00321]
  • GLP laboratory practice
  • DPF non-GLP dose range finding
  • the BDS contained ⁇ 55% CBD, ⁇ 2% CBC, and 1 to 2%THC.
  • a non-GLP 14-day DRF oral toxicity study was conducted in 40 Sprague-Dawley CD ® IGS rats (20 males and 20 females) at dose levels of 0 (vehicle control [olive oil]), 1000, 2000, and 4000 mg/kg/day of botanical extract (i.e., corresponding to the BDS of the present disclosure) via oral gavage, corresponding to ⁇ 63, ⁇ 125 and ⁇ 251 mg total cannabinoids/kg body weight (Study 48149). Clinical signs directly attributable to test article administration were observed in the 4000 mg/kg/day group: hypoactivity, hyperactivity, reduced food consumption, and piloerection.
  • Test article-related changes in serum chemistry values on Day 15 were observed in this dose group and consisted of increased blood urea nitrogen and creatinine.
  • Test article-related decreases in mean weekly body weights, daily body weight gain, food consumption, and food efficiency were observed in the 1000, 2000, and 4000 mg/kg/day groups.
  • Test article-related microscopic observations consisted of hepatocyte hypertrophy in the 2000 and 4000 mg/kg/day groups that correlated with an increase in liver weights, and vacuolation of the adrenal cortex in 1000, 2000, and 4000 mg/kg/day groups that correlated with dose-dependent increased adrenal weights. Based on these data, an oral dose ⁇ 1000 mg/kg/day is expected to be tolerated in a rat study of longer duration.
  • a 90-day GLP repeat-dose toxicology study was performed with male and female Sprague-Dawley rats divided into four main test and four recovery groups (i.e., 10 and 5/sex/group for the main and recovery study, respectively) (Study 48150).
  • Dose levels of 200 (low-dose), 400 (mid-dose), and 800 mg/kg/day (high-dose) of botanical extract of the present disclosure in olive oil and vehicle control (olive oil) were administered by oral gavage once a day for 93 and 94 days Attorney Docket No.38383.0001P1 to males and females, respectively, with a weekly dose adjustment based on the body weight changes.
  • the no observed adverse effect level was determined to be 800 mg/kg/day (app. ⁇ 55 mg/kg/day total cannabinoids) for females and 400 mg/kg/day ( ⁇ 27 mg/kg/day total cannabinoids) for males.
  • the BDS of the present disclosure did not show evidence of bacterial mutagenicity in a bacterial reverse mutation test (Ames) up to 5000 ⁇ g (Study 51956).
  • Example 5 Non-Interventional PK Study A non-interventional PK study was conducted with Farm Bill 2018-compliant product containing the same cannabinoid extract of the present disclosure and a similar drug product composition to the BDP of the present disclosure. There were no serious adverse events (SAEs) or withdrawals due to safety during the study, and overall data showed CBD absorption, which correlated with patterns observed in other human CBD PK studies.
  • SAEs serious adverse events
  • Example 6 A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Single and Multiple Ascending Dose Study [00325]
  • the present study is a double-blind, randomized, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the BDP of the present disclosure (i.e., an Attorney Docket No.38383.0001P1 oral suspension of the BDS of the present disclosure) in fasting and fed healthy participants. See Fig.1 for an example of the study design (i.e., schematic) for the clinical protocol.
  • the BDP of the present disclosure is a botanical cannabinoid drug substance in a suspension intended for oral delivery.
  • the BDS of the present disclosure is an oral suspension of 103 mg/mL of the BDS in glyceryl monolinoleate, National Formulary (NF), and an organic chocolate mint flavoring agent.
  • the placebo is the suspension vehicle with no drug substance and is identical in appearance to the BDP of the present disclosure.
  • the study is comprised of two parts, Part A (SAD) and Part B (MAD). Up to 8 participants will be randomized (6 participants receiving the active drug and 2 participants receiving the placebo) in each cohort of Parts A and B. Participants in Part A will receive a single dose of the BDP of the present disclosure or placebo on Day 1 while those in Part B will receive a split dose of the BDP of the present disclosure or placebo, where one dose will be administered as two equal doses taken twice daily, (BID; administered approximately every 12 hours [ ⁇ 30 minutes]) for 6 consecutive days (Day 1-Day 6), and 1 morning dose on Day 7.
  • BID administered approximately every 12 hours [ ⁇ 30 minutes]
  • Part A and Part B each have four planned dose level cohorts (A1-A4 and B1-B4).
  • Part A will include 1 cohort (A-X), which will enter a cross-over dosing scheme, where the participants will return to the clinical site on Day 14 to receive the BDP of the present disclosure or placebo following a high-fat, high-calorie breakfast on the morning on Day 15 after overnight fasting period. There will be an additional +2-day window between treatments allowed.
  • Cohorts A5/B5 and A6/B6 may be employed if maximum tolerated dose (MTD) or maximum planned dose level has not been achieved in A4/5 and B4/54 for each study Part A and B, respectively.
  • MTD maximum tolerated dose
  • Parts A and B of the study will be completed sequentially but with partial overlapping. Part B may be initiated when safety and tolerability are known and deemed acceptable for the first two cohorts in Part A (Cohorts A1-A2) at least.
  • a staggered dosing schedule will be used for dosing each cohort in Part A and will include 2 sentinel participants (1 active and 1 placebo).
  • the 2 sentinel participants will be dosed initially, and the remaining 6 participants will be dosed at least 24 hours later, contingent on the resulting safety profile and once deemed safe to move forward in the opinion of Investigator in consultation with the SRC (if required).
  • All participants will fast overnight, and no food will be allowed from at least 10 hours before dosing until at least 4 hours post-dose on Day 1 (Part A and Part B) and Day 7 (Part B). Additionally, no fluids (except for water given with the study drugs) will be allowed for 1 hour before dosing until 1-hour post-dose. No food will be allowed from at least 2 hours before until at least 1 hour after dosing for all other doses (Part B).
  • the anticipated dosing regimen is a starting dose of 226.6 mg BDS (equivalent to 125 mg CBD) with maximum expected dose level up to 1823.1 mg BDS (equivalent to 1000 mg CBD).
  • the role of the BDP of the present disclosure as adjuvant therapy is being evaluated in conditions where the available treatments are clinically insufficient or have a significant AE profile.
  • the BDP of the present disclosure is being developed for the treatment of symptoms of CNS-associated diseases, with the first indication being ASD.
  • the study includes an assessment of the potential interaction of the BDS of the present disclosure with food in healthy participants and the design follows the methodology described FDA Guidance for IndustryAssessing the Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology Considerations(June 2022). [00298]Rationale for Starting Dose and Dose Range. The no observable adverse effect levels (NOAELs) determined in the 90-day pivotal rat toxicity study and twoin vivogenetic toxicity studies are shown inTable 1, along with the corresponding maximum plasma CBD exposure from the latter two studies.
  • NOAELs no observable adverse effect levels
  • NOAEL dose levels observed in the rat toxicity study are equivalent to a minimum human equivalent dose (HED) of 4.4 and 8.9 mg/kg/day total cannabinoids for males and females, respectively, and 4.3 and 8.5 mg/kg/day CBD for males and females, respectively.
  • HED human equivalent dose
  • the observed NOAEL dose levels correspond to HEDs of 11.3/10.5 and 24.3/20.9 mg/kg/day (total cannabinoid basis/CBD), respectively.
  • the proposed BDS dose (i.e., 1.8 mg/kg as calculated above) is 2.8-fold lower than the recommended starting dosage for Epidiolex ® of 5 mg/kg/day.
  • the maximum planned dose to be evaluated in this study will be 1823.1 mgBDS, equivalent to 1000 mg CBD, a dose that is well below the maximum approved daily dose for Epidiolex ® in a 70-kg person.
  • CBD is the primary cannabinoid component of the BDS and the associated CBD doses to be delivered via the BDS of the present disclosure and evaluated in this study are well below CBD dose levels for which safety and tolerability have been established in nonclinical and clinical studies; therefore, the risk of treatment-related AEs is deemed to be low.
  • C-SSRS Columbia Suicide Severity Rating Scale
  • a sentinel group of 2 participants (1 active and 1 placebo) will be used for each cohort with the sentinel group being dosed at least 24 hours prior to dosing the remaining subjects of the cohort, and contingent on the results of ongoing safety evaluation.
  • SRC meetings will be held after safety and tolerability data up to at least Day 7 are available for all participants from a single cohort and remainder of timepoints of the preceding cohort (when applicable), in order to make decisions whether to escalate to the next dose level, decrease the next dose level, repeat a dose level, or to not evaluate any additional dose.
  • Cohort drug administrations will be separated by the minimum days required to ensure interim safety data review.
  • the primary objective of the study is toevaluate the safety and tolerability ofthe BDP of the presentdisclosure(i.e., the BDS in oral suspension) following oral administration of a single Attorney Docket No.38383.0001P1 ascending dose (SAD) and multiple ascending doses (MAD) in healthy adult participants.
  • SAD Attorney Docket No.38383.0001P1 ascending dose
  • MAD multiple ascending doses
  • SAD pharmacokinetic
  • PK parameters are evaluated for primary cannabinoids and metabolites.
  • the parameters include the following: [00315]Single Dose Parameters: minimal plasma concentration (Cmin),maximum plasma concentration (C max ), time of maximum serum concentration (T max ), Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-last),Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-inf) [including percent of area under the curve obtained by extrapolation (AUC Extrap )],terminal rate constant (l z ) , half-life (t1/2),Apparent clearance (Cl/F),Apparent volume of distribution (V z /F),and concentration at last time point (CTlast).
  • C min , C max , T max area under the concentration-time curve from time zero to the end of the dosing interval (tau) at steady state(AUC 0-tau ),l z , t1/2, apparent volume Attorney Docket No.38383.0001P1 of distribution at steady state (Vd/F,ss), and apparent clearance at steady state (Cl/F,ss) (as data allows).
  • PK parameters forthe BDP’s primary cannabinoids and metabolites, including cumulative amount excrete renally (Aer), fraction of unchanged drug excreted (fe%), and renal clearance (CLr [Ae0-t/AUC0-t])
  • DEQ Drug EffectsQuestionnaire
  • DSST Digit SymbolSubstitutionTest
  • PASAT Paced Auditory Serial Addition Test
  • Part A and Part B each have four planned dose level cohorts (A1-A4 and B1-B4).
  • Part A will include 1 cohort (A-X), which will enter a cross-over dosing scheme, where the participants Attorney Docket No.38383.0001P1 will return to the clinical site on Day 14 to receivethe BDP of the present disclosureor placebofollowing an FDA-compliant high-fat, high-calorie breakfast (vegetarians and vegans are allowed as long as an equivalent amount of fat and calories are consumed) on the morning on Day 15 after overnight fasting period.
  • Cohorts A5/B5 and A6/B6 may be employed ifmaximum tolerated dose (MTD)or maximum planned dose level has not been achieved in A4/5 and B4/54 for each study Part A and B, respectively.
  • a staggered dosing schedule will be used for dosing each cohort in Part A and will include 2 sentinel participant (1 active and 1 placebo). The 2 sentinel participants will be dosed initially, and the remaining 6 participants will be dosed at least 24 hours later, based on the contingent on the resulting safety profile and once deemed safe to move forward in the opinion of Investigator in consultation with the SRC (if required).
  • An adaptive design based on safety data will be used.
  • the planned dose range of the BDS of the present disclosure is anticipated to be 226.6 mg (equivalent to 125 mg CBD) to 1823.1 mg (equivalent to 1000 mg CBD). See Table 2. [00325] Table 2- Clinical Dosing and Equivalent Levels of Total Cannabinoids, Cannabidiol and ⁇ 9-Tetrahydrocannabinol Dose Cannabinoid Equivalents (mg) Volume BDS (mg BDS) Total Cannabinoids a CBD b ⁇ 9-THC c Oral Suspension (mL) 226.6 145.5 125 4.8 2.2 1823.1 1163.6 1000 38.5 17.7 ⁇ 9-THC: ⁇ 9-Tetrahydrocannabinol; CBD: cannabidiol a Based-on target concentration of 62% total cannabinoids b Based on target concentration of 60% cannabidiol [00339] c Based on potential maximum concentration of 2.7% ⁇ 9-tetrahydrocannabinol
  • Doses are intended to escalate and will not exceed a 3-fold SAD cohorts increase from the previous cohort. Doses may be adjusted to an intermediate (lower) or equivalent dose, on the basis of safety and tolerability data reported in the previous cohort(s). Dose level for the MAD dose levels The first MAD dose must be lower or equal to an already MAD cohorts dosed SAD cohort(s) of which safety and tolerability data are available. Doses are intended to escalate and will not exceed a 3-fold increase from the previous cohort.
  • Doses may be adjusted to an intermediate (lower) or equivalent dose, on the basis of safety and tolerability data reported in the previous cohort(s).
  • the highest daily dose level tested in MAD cohort(s) will not exceed the maximum safe dose level tested in SAD cohort(s) on any given administration day.
  • the quantity of The quantity of SAD and The planned number of different dose level cohorts is 4 for SAD and MAD MAD cohorts may be the SAD and 4 for the MAD.
  • data cohorts adapted i.e., decreased or accumulated from previous cohorts, it may be decided to increased). decrease or increase the number of cohorts in either part of the study by two.
  • Part A will include 1 cohort (A-X), which will enter a cross-over dosing scheme, where the participants will return to the clinical site on Day 14 to receivethe BDP of the present disclosureor placebo30 minutes after starting a Food and Drug Administration (FDA)-compliant high-fat, high-calorie breakfast (approximately 50% calories from fat, approximately 800-1000 kcals). Participants will be required to consume entire meal in 30 minutes or less. No food will be allowed at least 4 hours post-dose. Except for water given with the study drug and fluids provided with the high-fat, high-calorie meal, no liquids will be allowed for 1 hour before dosing until 1-hour post-dose. [00331]Participants in Part A will be admitted to clinic on Day-1 and stay until Day 3.
  • A-X Food and Drug Administration
  • Blood samples for PK analysis will be drawn on Day 1 (within 45 minutes before dosing [pre-dose]), and post-drug administration completion at approximately 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60 and 72 hours (outpatient). A blood sample will also be collected at approximately 168 hours post-dose at the Day 7 study visit. Blood samples for PK analysis for the cross-over fed dose cohort will be collected at these same timepoints as the fasted cohort. Urine will be collected over the intervals 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, and 24-48 hours post-dose on Day 1 and Day 2. The volume of urine collected at each interval will be documented.
  • Safety electrocardiograms (ECGs) for on-site interpretation will be recorded at screening, Day -1, Day 1 at pre dose (within 1.5 hours), 30 min, 1, 2 hrs ( ⁇ 10 min), 24 hours (+1 hour) and 48 hours (+1 hour) post dose and on Day 7 (Part A). Identical timepoints will apply for fed period (cohort A-X). Participants will be Attorney Docket No.38383.0001P1 discharged after their final 48-hour PK blood draw and completion of safety assessments. Participants will return to the clinic on approximately Day 7 ( ⁇ 2 days) for a final safety evaluation.
  • Part B may start while the remaining cohorts in Part A are progressing.
  • the starting dose of the Part B will be adaptive as described inTable3and will follow similar dose escalation decisions described above for the Part A; however, the dose to be administered in Part B will not exceed the higher dose levels tested in Part A.
  • Participants in Part B (B1-B4) will be admitted to clinic on Day -1 and stay until Day 9.
  • Blood samples for PK analysis will be drawn on Day 1 (within 45 minutes before dosing [pre- dose] and post-morning drug administration completion at approximately 0.5, 1, 2, 3, 4, 5, 6, 8, 12 (trough level to be drawn prior to administration of second daily dose), pre-morning dose on Days 2-6, and on Day 7 (within 45 minutes before dosing [pre-morning dose]) and post-morning drug administration completion at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 96 hours.
  • Urine will be collected over the intervals 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, and 24-48 hours post-dose on Day 7 and Day 8.
  • Safety ECGs for on-site interpretation will be recorded at screening period, Day -1, pre-dose on dosing days: Day 2, Day 3, Day 5, Day 7, Day 9, Day 11 and EOS. Electrocardiograms taken on Days 2, 3, 5, 7 and 9 should be taken at the same time of day as the first study drug dose was given on Day 1 (+ 1 hour). Participants will be discharged after their PK blood draw on Day 9 and completion of safety assessments.
  • Dose continuation (remaining participants within a cohort or remaining dosing for a participant) or escalation should not proceed for any of, but not limited to, the following reasons are met:if ⁇ 1 drug-related (i.e., possibly related) SAE occurs in a cohort; if ⁇ 3 participants experience a ⁇ Grade 2 drug-related (i.e., possibly related) AE in a cohort; if ⁇ 3 participants experience clinically significant changes in vital signs considered to be drug-related (i.e., possibly related) in a cohort; or if ⁇ 3 participants experience changes in ECGs (QTc greater than 500 msec with an increase from baseline greater than 60 msec) considered to be drug-related (i.e., possibly related) in a cohort.
  • ECGs QTc greater than 500 msec with an increase from baseline greater than 60 msec
  • Dose escalation will be discussed during the SRC meeting and may be stopped depending on the Investigator or Sponsor’s decision, based on but not limited to the following: if ⁇ 2 participants experience clinically significant abnormalities in physical examination, ECG, or vital signs considered to be drug-related (i.e., possibly related) in a cohort; or the occurrence of any ⁇ Grade 3 organ-specific laboratory parameters (e.g., liver and/or kidney tests) considered at least possibly related to the study drug. [00339]Clinical Trial Stopping Rules.if ⁇ 2 drug-related SAEs occur in a cohort; or the occurrence of any death attributable to the study treatment.
  • MTD Maximum Tolerated Dose and Recommended Phase 2 Dose.
  • the MTD will be determined according to the safety and tolerability review occurring during the SAD and MAD parts of the study. MTD is defined as the highest dose level reached per the stopping rules. Attorney Docket No.38383.0001P1 [00341]If MTD is reached at the lowest dose in the SAD or MAD; in that case, the Investigator and Sponsor will determine if an additional lower dose cohort should be evaluated based on the safety, PK, and PD data. If MTD is not reached in the A4/B4, the Investigator, and Sponsor will determine if an additional cohort should be evaluated, or the Recommended Phase 2 Dose (RP2D) determined based on the available safety, PK, and PD data.
  • R2D Recommended Phase 2 Dose
  • the dose to be administered in the given cohorts will not exceed the maximum dose of 2150.0 mgof the BDS of thepresent disclosure as currently outlined in the protocol.Observations made at previous dose cohort levels will also be considered (i.e., data in its aggregate form will be used to define the presence of possible trends that may not be apparent from an assessment of individual data).
  • Blinding.Thefollowing controls will be employed to maintain the double-blind status of the study during each cohort: [00343]For Parts A and B, the participants and the clinical personnel involved in the collection, monitoring, revision, or evaluation of AEs, or personnel who could have an impact on the outcome of the study will be blinded with respect to the participant’s treatment assignment (BDP or placebo).
  • a staggered dosing schedule will be used and will include 2 sentinel participants randomized in a 1:1 ratio (1 active and 1 placebo) dosed initially, and the remaining 6 participants (5 active and 1 placebo) dosed at least 24 hours later.
  • One randomization scheme will be produced for each cohort separately.
  • Participants will be administered each treatment according to the 2-period, block randomization scheme.
  • Randomization will be performed by a computer-generated randomization schedule. The participant and the study team (except for necessary pharmacy staff) will remain blinded to the treatment arm at least until the clinical phase of the study is completed (i.e., when reporting and evaluation of all AEs have been completed, for all cohorts.
  • Participants to be included in this study must meet the following inclusion criteria: (1) Provide signed ethics committee (EC)-approved consent form prior to any study procedures, can understand and comply with the requirements of the study, and are able to communicate with the Investigator; (2) Males and females, aged 18 and 65 years (inclusive), with body mass index (BMI) of 18-32.0 kg/m 2 and body weight ⁇ 50.0 kg at screening; (3) No known allergic reaction to cannabis products and formulation components (glyceryl monolinoleate (NF), and organic chocolate mint flavoring agent); (4) Medically healthy with no clinically significant medical history (fully resolved childhood asthma and mild asthma that does not require a reliever Attorney Docket No.38383.0001P1 more than once per month, and does not require a preventer or any additional therapies is not considered clinically significant and permissible), physical examination, laboratory profiles, vital signs, or ECG, as deemed by the Investigator; (5) Must have hepatic and renal clinical laboratory test results (ALT, AST, total bilirubin [including direct and indirect bilirubin results
  • CBD Ceretyl-containing products within 60 days of start of study (Day 1);(19)Serious illness in the 30 days preceding the beginning of treatment on Day 1 (i.e., that resulted in hospitalization);(20)Receipt of treatment for any type of internal cancer within the 5 years prior to enrollment (fully treated and resolved basal cell carcinoma and or squamous cell carcinoma are permissible);(21)Females who are pregnant, plan to become pregnant during the study, or are breastfeeding a child;(22)Positive alcohol breath testor urine drug screenat screening or at admissions on Day -1;(23)Blood or plasma donation (500 mL) within the past month, or receipt of blood transfusion within 1 month prior to Day 1;and (24)Employee, family member, or student of the Investigator or clinical site(s).
  • ParticipantWithdrawal and Replacement Participants will be informed that they have the right to withdraw from the study at any time for any reason, without prejudice to their medical care. Over the course of the study the Investigator also has right to withdraw any participant from the study for one of thefollowingreasons:intolerance/unacceptable AEs;death;needs for medication which may interfere with study measurements;non-compliance with protocol requirements or non- Attorney Docket No.38383.0001P1 adherence to study drug;significant protocol deviation;unwillingness to continue in the study;participant lost to follow-up;and any other reason based upon the medical judgment of the Investigator.
  • a participant is withdrawn from the study for any reason, whether related to the study drug or not, or if a participant voluntarily withdraws before or after receiving the study drug, such participant will be considered an early termination participant.
  • the reason for study withdrawal is to be documented in the participant’s source documents and electronic case report form (eCRF).
  • eCRF electronic case report form
  • the Investigator will make every effort to ensure that early termination participants who have received the study drug complete all scheduled safety assessments, including all follow-up visit assessments in the relevant treatment period.
  • a PK blood sample may be collected at the time of withdrawal if deemed required by the Investigator.
  • Vital signs will be collected with the participant supine and after they have been resting for 5 minutes. Vital signs will be taken at screening, Day -1, Day 1: pre-drug administration (within 1 hour), and at 15 minutes, 1 hour, 4 hours, and 12 hours post-dose ( ⁇ 10 minutes up to and including 12 hour); Day 2: 24 hours post-dose ( ⁇ 30 minutes); Day 3 and 7. Vitals should be collected prior to blood draws. Additional vital signs may be taken at any time during study as needed.The same timepoints for vitals will occur in the fasting and fed assessments of one SAD cohort. b. A full physical examination to be conducted at screening, with symptom-directed physical examinations thereafter. c.
  • Electrocardiograms will be taken during Screening Period, Day -1, Day 1 at pre dose (within 1.5 hours), 30 min, 1, 2 hrs ( ⁇ 10 min), 24 hours (+1 hour) and 48 hours (+1 hour) post dose and on Day 7. Identical timepoints will apply for fed period (cohort A-X). d. The same timepoints for blood sample collection for PK analysis will occur in the fasting and fed SAD cohorts. SeeTable 6for PK sample collection times and windows.Note, 72 hour blood draw is outpatient. e.
  • Urine collection will occur for 1) drug and cotinine screen at screening and Day -1and Day 14 (for fed portion of the study); 2) urine will be collected over the intervals 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, and 24- 48 hours post-dose on Day 1 to Day 2 and Day 15 to Day 16 for the fed cohort for PK analysis; 3) immunoassay (IA) drug testing to detect the presence of THC on Day 7and Day 21 for the fed cohort. The volume of urine collected at each interval will be recorded. f. Randomizationoccurson Day 1. g.
  • the Drug Effects Questionnaire and cognitive/psychomotor assessments will be completed pre-morning dose on Day 1 and at 1 hour (+10 minutes), 2 hours (+10 minutes), 4 hours (+10 minutes), 6 hours (+10 minutes),8 hours (+10 minutes) and 12 hours (+10 minutes) post-dose.
  • the Drug Effects Questionnaire (only) will also be completed on Day 3 prior to discharge.
  • Adverse events are collected upon signing the ICF through the last study visit; those that occur before dosing Attorney Docket No.38383.0001P1 will be recorded as medical history instead of as an AE, however, if their condition deteriorates at any time during the study, it will be recorded as an AE.
  • Vital signs will be collected with the participant supine and after they have been resting for 5 minutes. Vital signs will be taken at screening, Day -1, Days 1 and 7 (at pre-morning dose [within 1 hour], 4 hours [ ⁇ 10 minutes], and 8 hours [ ⁇ 10 minutes] post-first dose of the day) and on Days 2-6 (within 1 hour prior to each post-morning dose), at 24 hours, 48 hours and 96 hours [ ⁇ 30 minutes] post-administration on Day 7 and at the EOS visit (Day 14). Additional vital signs may be taken at any time during study as needed.
  • Electrocardiograms will be taken during Screening Period, Day -1, pre-dose on dosing days: Day 2, Day 3, Day 5, Day 7, Day 9, Day 11 and EOS. Electrocardiograms taken on Days 2, 3, 5, 7 and 9 should be taken at the same time of day as the first study drug dose was given on Day 1 (+1 hour).
  • d SeeTable 7for PK sample collection times and windows.
  • Urine collection will occur for 1) drug and cotinine screen at screening and Day -1; 2) urine will be collected over the intervals 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, and 24-48 hours post-dose on Day 7 to Day 8 for PK analysis; 3) immunoassay (IA) drug testing to detect the presence of THC onDay 9 discharge and Day 14.
  • the volume of urine collected at each interval will be recorded.
  • Randomization may occuron Day 1 due to pending repeat tests.
  • the Drug Effects Questionnaire and cognitive/psychomotor assessments will be completed pre-morning dose on Days 1, 3, and 7 and at 1 hour (+10 minutes), 2 hours (+10 minutes), 4 hours (+10 minutes), 6 hours (+10 minutes), 8 hours (+10 minutes) and 12 hours (+10 minutes) post-dose.
  • the Drug Effects Questionnaire (only) will also be completed on Day 9 prior to discharge.
  • Participants will receive a split dose with twice daily dosing (approximately every 12hours [ ⁇ 30 minutes]) for6 days, then only 1 morning dose on the seventh day. i.
  • Body Weight and Height.Body weight (kilograms), wearing light clothes, no shoes, and height (centimeters) will be measured at the screening visit to allow the calculation of BMI (rounded to one decimal place).
  • Virtual Serology.HIV antibodies, hepatitis B surface antigen and hepatitis C antibody will be measured at screening.
  • Safety and Tolerability Assessments.Safety and tolerability will be evaluated by performing physical examinations, vital signs measurements, ECG measurements, clinical laboratory safety tests, C-SSRS, concomitant medication and AE monitoring.
  • Physical Examination.Full physical examinations will be performed at screening, with symptom-directed physical examinations thereafter.
  • the physical examination will include examination of the following: general appearance, head, ears, eyes, nose, throat, neck (including thyroid), skin, cardiovascular system, respiratory system, gastrointestinal system, musculoskeletal system, lymph nodes and nervous system. Any findings made during the physical examination must be noted regardless if they are part of the participant’s medical history. Additional symptom-directed physical examinations may also be performed at any time through the study as clinically indicated.
  • Vital Signs Measurements will include systolic and diastolic blood pressure (mm Hg), pulse rate (beats/minute), respiratory rate (breaths/minute) and body temperature (tympanic; °C).
  • vital signs will be recorded after the participant has rested comfortably (supine position) for at least 5 minutes and using consistent methods between participants. Testing for any out-of-range values may be repeated at the discretion of the Investigator.
  • the Investigator or a qualified observer at the investigational site) will interpret the vital signs using one of the following categories: within normal limits, abnormal not clinically significant (NCS), or abnormal clinically significant (CS). All CS findings will be recorded as AEs.
  • Systolic BP 90 to Attorney Docket No.38383.0001P1 140 mmHg
  • Diastolic BP 40 to 90 mmHg
  • Heart rate 40 to 100 beats/minute
  • Respiratory rate 10 to 22 breaths/minute
  • Temperature 35.5 to 37.5 °C.
  • Electrocardiograms taken on Days 2, 3, 5, 7 and 9 should be taken at the same time of day as the first study drug dose was given on Day 1 ( ⁇ 1 hour).
  • the following ECG parameters will be assessed: heart rate, PR interval, RR interval, QRS duration, QT interval and QTcF.
  • the mean value for the triplicate will be utilized. Testing for any out-of-range values may be repeated once at the discretion of the Investigator.
  • the Investigator (or a qualified observer at the investigational site) will interpret the ECG using one of the following categories: within normal limits, abnormal NCS, or abnormal CS. All CS findings will be recorded as AEs.
  • Heart rate 40 to 100 beats/minute
  • PR interval ⁇ 120 to ⁇ 220 msec
  • QRS duration ⁇ 120 msec
  • QTcF interval ⁇ 450 msec (for both genders).
  • Clinical Laboratory Safety Tests.Blood and urine samples will be collected according to the clinical site SOPs at the times specified inTable 4 for Part A (SAD) and for Part B (MAD), and analyzed and assessed by a certified local laboratory, using their reference’s ranges.
  • the clinical laboratory assessments to be performed are listed inTable 8 below.
  • the C-SSRS is a questionnaire designed for the assessment of suicidal ideation and behavior in adolescents and adults. The questionnaire must be administered by the Investigator or other individual that is suitably qualifiedfor education or training. When administered, all responses recorded on the scale must be provided by the participant either verbally or by gesture. The baseline version of the C-SSRS will be used during screening to assess lifetime suicidality. At all other protocol- specified timepoints, the C-SSRS – Since Last Visit version will be used to assess the participant’s suicidality since the last assessment.
  • Pregnancy Test A serum pregnancy test ( ⁇ -human chorionic gonadotropin) will be performed at screening for all female participants of childbearing potential to confirm negative pregnancy results and urine pregnancy test subsequently as perTable 4 for Part A (SAD) andTable 5 for Part B (MAD).
  • SAD serum pregnancy test
  • MAD Type 5 for Part B
  • Prior/Concomitant Medications All medications, including prescription drugs, herbal products, vitamins, minerals, and OTC drugs, taken within 30 days (or 5 half-lives, whichever is longer) prior to the start of the study will be recorded as prior medications. All medications taken after the first dose of the study drug and through the EOS visit will be recorded as concomitant therapy.
  • BDS cannabinoids and metabolites including Cannabidiol (CBD),Cannabichromene (CBC),Cannabigerol (CBG), Cannabidiolic acid (CBDA), ⁇ 9- Tetrahydrocannabinol (THC),7-hydroxy-CBD (7-OH-CBD), 7-carboxy-CBD (7-COOH-CBD), 11-hydroxy-THC (11-OH-THC), and 11-carboxy-THC (11-COOH-THC).
  • PASAT Paced Auditory Serial Addition Test
  • the PASAT measures working memory and higher order cognition.
  • the PASAT is presented on audiocassette tape or compact disk to control the rate of stimulus presentation. Single digits are presented either every 3 seconds or every 2 seconds and the participant must add each new digit to the one immediately prior to it. The test result is the number of correct sums given (out of 60 possible).
  • Example 7 A Maximum Tolerated Dose and 7-Day Dose Range Finding Study
  • MTD maximum tolerated dose
  • BDP BDP of the present disclosure
  • Table 4 Study Design for MTD and 7-Day Dose Range Finding Dose Level Dose Dose Main Study Group Test (mg/kg/), Volume Concentration No. Article No. of No.
  • BDS a (mL/kg) (mg/mL) Males
  • the first day of dosing for each dose level was designated as Day 1.
  • the same animals were administered up to 3 additional doses of the BDS (CBD), with a 5-day washout period between each dose level, as warranted.
  • the proposed dose levels were increased or decreased based on the responses to the preceding dose level(s) until the dose-limiting toxicity was observed (MTD). Doses did not exceed 100 mg/kg (limit dose).
  • Table 5 Study Design for MTD and 7-Day Dose Range Finding Dose Level Dose Dose Main Study Group Test (mg/kg/day), Volume Concentration No. Article No. of No. of BDS (mL/kg) (mg/mL) Males Females 5 Vehicle 10 5 0 2 2 6 BDP 30 5 2 2 2 7 BDP 50 5 6 2 2 8 BDP 100 5 10 2 2 [00342]
  • the following parameters and endpoints were evaluated in this study: mortality, clinical signs, body weights, food consumption, clinical pathology parameters (hematology, coagulation, and clinical chemistry), toxicokinetic (TK) parameters of cannabidiol (CBD) and other analytes, ( ⁇ )-cannabichromene (CBC), 7-hydroxy-cannabidiol (7OHCBD), 7-carboxy-cannabidiol (7COOHCBD), delta-9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11OHTHC), and 11- carboxy
  • Example 8 A 4-Week Study by Oral Gavage Administration in Beagle Dogs with a 2-Week Recovery Period
  • the objectives of this study were to determine potential toxicity of the BDP of the present disclosure (i.e., an oral suspension of the BDS of the present disclosure), when given via oral (gavage) daily for up to 4 weeks to dogs and to evaluate the potential reversibility of any findings following a 2-week recovery period.
  • the doses and concentrations were based on the content of cannabidiol (CBD) present.
  • CBD cannabidiol
  • TK toxicokinetic
  • the study design was as shown in Table 6: Table 6: Study Design Dose Level Dose Dose Main Study Recovery Study Group Test (mg/kg/day), Volume Concentration No.
  • TK parameters were determined on Days 1 and 28 for CBD, ( ⁇ )- cannabichromene (CBC), 7-hydroxy-cannabidiol (7OHCBD), 7-carboxy-cannabidiol (7COOHCBD), delta-, 11-hydroxy-THC (11OHTHC), and 11-carboxy-THC (11COOHTHC).
  • All dose formulation results were within approximately 4% of the target BDS concentration as measured by the primary CBD component.
  • the analytical data demonstrated acceptable performance of the method for all reported results and that dose formulations were prepared at the intended target concentration and were homogeneous. Vehicle control samples were below the limit of quantitation ( ⁇ 0.2000 mg/mL).
  • Veterinary intervention was required (food enrichment, gastrointestinal (GI) blend canned food) each day of the study until the feces and/or body conditions of the animal normalized. Thin body condition and loss of body weight (up to approximately -23.5% in males and up to -12.0% in females compared to controls) were likely secondary to fecal changes and decreased appetite (up to -91.1% in males and up to -96.1% in females compared to controls). [00357] The magnitude and timing of the observations varied throughout the dosing period. However, these observations fully resolved or trended toward resolution during the recovery period and were therefore not considered adverse.
  • BDP-related changes were observed in hematology parameters in males and/or females and included mildly lower mean reticulocyte counts at > 30 mg/kg/day accompanied by minimally to mildly lower erythrocyte mass (red blood cell count [RBC], hemoglobin concentration, and/or hematocrit) at 50 mg/kg/day.
  • RBC red blood cell count
  • Minimally to mildly lower mean lymphocyte, eosinophil, basophil, and total white blood cell counts were noted at 50 mg/kg/day.
  • Minimally to mildly higher mean platelet (PLT) counts were observed at > 10 mg/kg/day.
  • BDP-related minimally shortened mean Attorney Docket No.38383.0001P1 activated partial thromboplastin times (APTT) were observed in males at > 10 mg/kg/day and females at 50 mg/kg/day.
  • BDP-related changes in chemistry parameters were observed in males and/or females as mildly to moderately higher mean alkaline phosphatase (ALP) at ⁇ 10 mg/kg/day and minimally higher gamma glutamyl-transferase (GGT) at ⁇ 30 mg/kg/day.
  • ALP alkaline phosphatase
  • GTT gamma glutamyl-transferase
  • Non-adverse BDP-related microscopic findings were noted in the liver and thymus. In the liver, minimal to mild hepatocellular hypertrophy was present in all BDP dose groups in both sexes. Hepatocellular hypertrophy correlated with higher mean liver/gallbladder weights and higher hepatobiliary clinical chemistry parameters at > 10 mg/kg/day. BDP-related decreased lymphoid cellularity of thymus in all dose groups of both sexes was considered an indirect effect secondary to stress.
  • Non-adverse BDS-related microscopic findings were present in the liver and thymus were observed in males and females and correlated with clinical pathology findings.
  • the no-observed-adverse-effect-level (NOAEL) for males and females for the BDS was considered to be 50 mg/kg/day based on the CBD content, the highest dose level tested, and was associated with a mean plasma CBD Cmax of 3850 ⁇ 1470 ng/mL and AUC0-24h, of [00367] 47700 ⁇ 18900 hr•ng/mL in males and females combined on Day 28.
  • Example 9 A Phase 2 Study to Investigate the Safety, Tolerability, and Effectiveness of the BDP in Adolescents and Adults with Autism Spectrum Disorder [00368] This is a multicenter open-label study to investigate the safety, tolerability, and effectiveness of the BDP disclosed herein with ASD. Subjects will be enrolled to receive the BDP. This study will utilize a flexible-dose design, with doses individualized to each subject based on safety and tolerability. Doses will be titrated up from the starting dose over an approximately 3-week Titration Period, with dose adjustments taking place approximately every 4 days.
  • the Titration Period will be followed by one more week of dosing (Maintenance Period) for a total Treatment Period of 4 weeks, and a 2-week Safety Follow-up Period. Safety and efficacy assessments will take place during each clinic visit. Assessments made during the Titration Period will be conducted by telephone or videoconference. [00372] Dose Titration Guideline.
  • Table 7 Dose Titration Amount of Titration Period Study Medication Day 1 Day 5 Day 9 Day 13 Day 17 Day 21 Day 22-29 Per dose 0.5 mL 1.0 mL 1.75 2.5 mL 3.0 mL Check-in to confirm Maintenance mL maintenance dose Per day 1.0 mL 2.0 mL 3.5 mL 5.0 mL 6.0 mL Check-in to confirm Maintenance maintenance dose [00373] This table is a guideline only for the Investigator; the actual titration will depend on the individual subject’s response to treatment, i.e., decisions to increase each subject’s dose will be based on tolerability and safety.
  • the BDP should be taken twice per day (BID), in the morning and evening (approximately every 12 ⁇ 2 hours) within one hour after eating a meal (e.g., breakfast and dinner).
  • BID twice per day
  • the Titration Period is expected to take up to 3 weeks, with dose adjustments to be made approximately every 4 days. Some subjects may reach a dose limit based on safety and tolerability (based on Investigator judgment) in less than 3 weeks at which point they would remain at that dose through Week 4 of the study.
  • Inclusion Criteria To, subjects must meet ALL of the following inclusion criteria prior to enrollment: Males or females 13-30 years of age at Screening, Diagnosis of ASD confirmed by Mini International Neuropsychiatric Interview (MINI), ABC-I score of ⁇ 18 at Screening and Baseline, CGI-S of irritability associated with ASD score of >4 at Screening and Baseline. Description of Investigational Product.
  • the IP is a BDP containing FSHE-L.
  • the BDS is primarily composed of cannabinoids ( ⁇ 48%) followed by carbohydrates ( ⁇ 40%), non-cannabinoid/terpene lipids ( ⁇ 6%), terpenes ( ⁇ 5%), and proteins ( ⁇ 1%). While efficacy is expected to be derived from the cannabinoids, each of the molecule classes may possess activity and is expected to contribute to the overall pharmacological activity of the BDS.
  • the BDP is a brown oil-based solution consisting of 103 mg/mL BDS in Glyceryl Monolinoleate, NF and a chocolate mint flavoring.
  • BDP i.e., BDS in Oral Suspension
  • Participants will be administered BDP (i.e., BDS in Oral Suspension) 30 minutes after startingan FDA-compliant high-fat, high-calorie breakfast (approximately 50% calories from fat, approximately 800-1000 kcals). Participants will be required to consume entire meal in 30 minutes or less. No food will be allowed at least 4 hours post-dose.
  • AE is defined as any untoward medical occurrence in a patient or clinical trial participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment.
  • An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product.
  • CTU clinical trial unit
  • outpatient study visits or upon review of participant data by a study monitor.
  • SAE Serious Adverse Event.An SAE is any untoward medical occurrence that at any dose: results in death; is life-threatening (i.e., the participant is at immediate risk of death at the time the event occurred; it does not refer to an event which might hypothetically have caused Attorney Docket No.38383.0001P1 death had it been more severe);requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is a medically important event or reaction.
  • hospitalization for social reason e.g., caregiver relief
  • hospitalization for surgery/procedure planned prior to study entry hospital visits less than 24 hours (e.g., held for observation or treatment, but duration of stay less than 24 hours); and/or treatment at hospital or center for minor procedures (e.g. laser eye surgery).
  • the causal relationship of the study drug to an AE will be ratedrelationship categories: Nonetheless, possibly, unlikely, and unrelated.
  • the definitions for the relationship categories are as follows: [00421]Table11- Adverse Event Relationship Categories Category of Casual R elationship Definition ⁇ ⁇ ⁇ Cannot be reasonably explained by an alternative explanation, e.g. concomitant drug(s), concomitant disease(s). Hence ⁇ ⁇ ⁇
  • the relationship in time to study drug is very suggestive with improvement on cessation of study drug or reduction in dose.
  • Adverse Events Recording of Adverse Events.Adverse events and medical history will be collected and documented from the time of signing the Participant information and informed consent form (PICF) and throughout the study until the EOS. Any medical condition that is present at the time that the participant is screened until the drug administration will be considered part of their medical history and not reported as an AE. However, if their condition deteriorates at any time following the drug administration, it will be recorded as an AE. [00423]Adverse events will be recorded and evaluated for their seriousness, severity, and relationship to the study drug. All AEs, regardless of seriousness, severity, or presumed relationship to the study drug, will be assessed by the Investigator (or medically qualified sub- Investigator).
  • AE/SAE AE/SAE
  • the Investigator must review all documentation (e.g., hospital progress notes, laboratory, and diagnostic reports) relative to the event and record all relevant information using medical terminology in the eCRF and/or other sources.
  • diagnoses should be given when signs and symptoms are due to a common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion) may be reported as “upper respiratory infection”.
  • Investigators must record in the eCRF the date of onset of the event, their opinion concerning the relationship of the event to the study drug, the severity of the event, whether the event is serious or nonserious, actions taken to manage the event, the outcome of the event, and date of resolution where applicable.
  • the frequency of AEs (the number of AEs, the number of participants experiencing an AE, and the percentage of participants experiencing an AE) will be summarized by treatment, Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC), and preferred term (PT).
  • MedDRA Medical Dictionary for Regulatory Activities
  • SOC system organ class
  • PT preferred term
  • the summary and frequency AE tables will be presented for all causalities and for those considered Attorney Docket No.38383.0001P1 related to the study drug (those that have a relationship of possibly related or definitely related). Serious AEs will be tabulated.
  • Clinical blood and urine laboratory parameters will be summarized by treatment.
  • all blood and urine laboratory data outside the clinical reference ranges will be listed by parameter and treatment. Values for any laboratory or urine values outside the clinical reference ranges will be listed and flagged on the listings.
  • Source documentation must be available to substantiate participant identification, eligibility, and participation; proper informed consent procedures; protocol-specified medical history; dates of visits; adherence to protocol procedures; record of safety and efficacy parameters, adequate reporting and follow-up of AEs; administration of concomitant medication; study drug receipt/dispensing/return records; study drug administration information; and date of participant completion, discontinuation from treatment, or withdrawal from the study, and the reason if appropriate.
  • Direct access includes examining, analyzing, verifying, and reproducing any records and reports that are important to the evaluation of the study. The Investigator is obligated to inform the participant and obtain their consent to permit named representatives to have access to his/her study-related records without violating the confidentiality of the participant.
  • the revised PICF prepared by the Investigator, must be approved by the HREC.
  • No deviations to the protocol are permitted except in instances when issue relating to the safety of study participant arise which requires a deviation from the protocol. If there is a need for such a deviation the Investigator must notify the Sponsor and the responsible HREC of the facts and circumstance causing the deviation as soon as is reasonably practical, but in any event no later than 5 working days after the change is implemented. The nature and reasons for the protocol deviations will be recorded in the participant’s eCRF. The Sponsor may not reimburse the Investigator for cases in which the study procedures and evaluations are conducted such that they result in major protocol violations.
  • Example 10 An Open-Label, Safety, Tolerability, and Effectiveness Study of the BDP disclosed herein in Children and Adolescents with Autism Spectrum Disorder (ASD) [00380]
  • This open-label Phase 2 study is being conducted to evaluate the safety, tolerability, and effectiveness of the BDP disclosed herein in pediatric patients with ASD.
  • the BDP is a cannabinoid extract of CW1AS1 strain in Macine CC oil. The extract was obtained via the solvent extraction and decarboxylation process described herein using isopropyl alcohol. [00381] .
  • the BDP will be studied for its effectiveness to treat irritability, repetitive behaviors, and improve cognition, sociability, and quality of life for ASD patients.
  • Doses will be administred orally for buccal absorptoion, preferably sublingually but this can depend on the patient’s level of cooperation.
  • the following dose levels will be evaluated: Attorney Docket No.38383.0001P1 [00386]
  • the first 10 subjects (Group 1) will begin with 0.25 mL (i.e., 25.75 mg BDS; equivalent to 14.2 mg CBD and 0.55 mg THC) administered BID for a total daily dose of 0.5 mL and will titrate up to a maximum dose of 1.5 mL (i.e., 154.5 mg BDS; equivalent to 85.2 mg CBD and 3.25 mg THC) BID for a total daily dose of 3.0 mL.
  • the subsequent 10 subjects will begin with 0.5 mL (i.e., 51.5 mg BDS; equivalent to 28.4 mg CBD and 1.1 mg THC) administered BID for a total daily dose of 1.0 mL, and will titrate up to a maximum dose of 3.0 mL (i.e., 309 mg BDS; equivalent to 170.4 mg CBD and 6.5 mg THC) BID for a total daily dose of 6.0 mL.
  • Doses will be titrated up from the starting dose over an approximately 3-week Titration Period, with upward dose adjustments to take place approximately every 4 days, based on assessments of safety and tolerability and in the judgment of the Investigator.
  • Titration Period will be followed by an approximately 9-week Maintenance Period (for a total Treatment Period of 12 weeks), and a 2-week Follow-up Period. If at any point during the Maintenance Period a subject experiences intolerable adverse effects, the Investigator may decrease the dose until tolerability is achieved. In-person clinic visits are scheduled to take place on Days 29 ⁇ 3 days, 57 ⁇ 3 days, and 85 ⁇ 3 days and the final safety follow-up visit will take place on Day 99 ⁇ 3 days by telephone or videoconference. [00390] Inclusion Criteria.
  • a pharmaceutical composition comprising an oral suspension of a full spectrum hemp extractderived from Cannabis sativa hemp variety ‘CW1AS1’, wherein representative seed of the variety has been deposited under NCIMB No.43291.
  • a method of treating a nervous system or mental disease, disorder, condition, or symptom by administeringan effective amount of the pharmaceutical composition ofembodiment 1, 2, or 3 to a subject in need thereof. 5. The method of claim 4, wherein the disease, disorder, condition, or symptom is a primary indication. 6.
  • the method ofembodiment 4, wherein the disease, disorder, condition, or symptom is a secondary indication. 7. The method ofembodiment 4, wherein the nervous system disease, disorder, condition, or symptom is a CNS-associated disease, disorder, condition, or symptom. 8. The method ofembodiment 7, wherein the CNS-associated disease, disorder, condition, or symptom is autism. 9. The method ofembodiment 4, wherein the nervous system disease, disorder, condition, or symptom is epilepsy. 10. The method ofembodiment 4, wherein the mental disease, disorder, condition, or symptom is anxiety and/or irritability associated with autism. Attorney Docket No.38383.0001P1 11.
  • Bih CI Chen T, Nunn AVW, et al. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics.2015;12:699-730.
  • Bisogno T Hanus L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol.2001;134:845-852.
  • Carrier EJ, Auchampach JA Hillard CJ.
  • Cannabidiol pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia.2014;55(6):791-802.
  • Di Marzo V Piscitelli F. The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics.2015;12:692-698.
  • Epidiolex ® Summary Basis of Approval (Drug Approval Package: Epidiolex (Cannabidiol) (fda.gov)). [00414] Epidiolex ® Package Insert, January 2023 [00415] Hollander E, Chaplin W, Soorya L, Wasserman S, Novotny S, Rusoff J, Feirsen N, Pepa L, Anagnostou E. Divalproex sodium vs placebo for the treatment of irritability in children and adolescents with autism spectrum disorders. Neuropsychopharmacology.2010;35(4):990-8.
  • Pertwee RG The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: D9-tetrahydrocannabinol, cannabidiol and D9-tetrahydrocannabivarin. Br J Pharmacol.2008;153:199-215. [00430] Risperdal ® Package Insert, August 2022 [00431] Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res.2005;30(8):1037-1043. [00432] Russo EB.
  • Taming THC potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol.2011;163(7):1344-64. [00433] Russo, E. and G.W. Guy, A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses, 2006.66(2): p.234-46. [00434] Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev.2014;46(1):86-95.

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Abstract

La présente divulgation concerne des compositions médicamenteuses botaniques et des procédés d'utilisation de celles-ci pour traiter des maladies, affections, troubles et/ou symptômes mentaux et/ou associés au système nerveux.
PCT/US2024/041993 2023-08-11 2024-08-12 Composition d'extrait de cannabinoïde issu de cw1as1 pour le traitement de l'autisme et de symptômes associés Pending WO2025038586A1 (fr)

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SURAEV A. ET AL: "Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community", SCIENTIFIC REPORTS, vol. 8, no. 1, 1 December 2018 (2018-12-01), XP055853595, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033872/pdf/41598_2018_Article_28127.pdf> DOI: 10.1038/s41598-018-28127-0 *

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