Medical Cannabis Then and Now. Jeffrey Skell, PhD

Transcription

1 Medical Cannabis Then and Now Jeffrey Skell, PhD 2016

2 Agenda A Brief History of Cannabis Drug Properties Is Cannabis Developable?

3 The Source of All That Trouble

4 Traditional Medicine in the Far East and Subcontinent Indica Body High Analgesic Muscle Relaxant Sedating Sativa Cerebral High Stimulating Anti-depressant Increase Appetite Hemp High in CBD Low in THC Muscle Relaxant Analgesic Diverse preparation methods were known Adopted by western culture up until the 30 s Currently Schedule I in the USA

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6 State Based Legalization Mid-90 s ballot initiatives covering medical Established growers transitioning from black to gray market, paying taxes Recreational use in 4 states and DC Cole memo: August 29, 2013 DOJ issued guidance covering federal departmental policy regarding state sanctioned activities Eric Holder Says DOJ Will Let Washington, Colorado Marijuana Laws Go Into Effect 08/29/2013

7 What Does That Mean Each state writes their own laws regulating growers, manufacturers, dispensaries, testing labs, distributors, packaging and labeling, and on and on No interstate transport except between adjoining states with reciprocity Widely different regulations, acceptable products and practices between states

8 Types of Cannabinoids Synthetic (synthetic phytocannabinoids) Marinol Synthetic delta 9-THC Approved by FDA in 1985 for nausea/vomiting from chemotherapy Approved by FDA in 1992 for AIDS related anorexia Endocannabinoids (naturally occurring in humans) Neuromodulatory lipids and receptors (CB1 &CB2) Variety of compounds and inhibitors with serious effects Recent phase one trial death in France- fatty acid amide hydrolase (FAAH) inhibitor (enzyme produced in the brain and elsewhere in the body that breaks down neurotransmitters known as endocannabinoids) Number of companies working on endocannabinoids, inhibitors and similar compounds to bind to receptors

9 Types of Cannabinoids Phytocannabinoids- >66 known naturally occurring compounds in plants that effect the endocannabinoid system, some of the more known or medically studied, (many found in acid form as well before drying) THC (tetrahydrocannabinol)- Psychotropic. Analgesic (pain relieving). Appetite stimulant. Bronchial dilator CBD (Cannabidiol)- Non-psychoactive. Reduces muscle spasms. Muscle relaxant. Analgesic (pain relieving) CBN (Cannabinol)- Mildly psychoactive. Non-narcotic analgesic (pain relieving) THCV (Tetrahydrocannabivarin)- Stronger, faster high effect. Appetite suppressant. Euphoria, analgesic CBC (Cannabichromene)- Sedative effect. Moderates effects of THC. Analgesic CBG (Cannabigerol)- Non-psychoactive, sleep inducing. Anti-microbial. Lowers intra-ocular pressure (IOP)

10 Chemical Structure THCA is the Naturally Occurring Form Combustion Heat vaporizes remaining THC OH

11 At Least 50% is Pyrolyzed CO2, CO, benzene, tar, free-radicals THC, CBN, others THC-A

12 Modes of Administration Inhalation Cigarette Pipe Water pipe Vaporizer Dab DPI Oral and Cutaneous Edible (foods, beverages, candies) Tincture (usually alcohol based) Sublingual (sprays, tablets) Tablet/capsule (less popular?) Local/Topical (creams, ointments) Transdermal (patches)

13 Excipients Use in Cannabinoid Delivery Excipients aid delivery and form in most available delivery platforms They play typical roles as in conventional industry Fillers, carriers and lubricants antioxidants and preservatives Viscosity modification Humectants Co-solvents penetration enhancers Bioavailability enhancement Big opportunity just like conventional pharma

14 Excipients Use in Cannabinoid Delivery PEG PEG 400 most popular grade Glycerin Used like PEG Alcohol - used in tinctures Solubilizes of cannabinoids Solid Dose Excipients MCC carrier of concentrate oil for tablets and capsules Sugars and combinations also used as carriers Gelatin gummy based edibles Topicals and Transdermals Cetyl alcohol, natural waxes, adhesives United States Cannabis market is estimated at over $700 million/yr soon to pass $1 billion/yr

15 Physico-Chemical Properties MW BP 315ºF (with decomposition) Log P > 4 (closer to 6) Water insoluble Soluble in oils, dehydrated alcohol, organic solvents, supercritical CO2 Doesn t fit the classic drug discovery criteria

16 DMPK Properties Inhalation BA 10-35% Oral BA 6-20% (highly variable) PPB >95% Significant 1 st pass metabolism to a different metabolite than inhalation Partitions into fat and skin; very slow and variable wash out time

17 Onset Depends on Route of Administration Pharmacokinetics Smoking BA is <50% (typically 10%-35%) Oral BA is <20%, highly variableand effect may last a long time

18 It Isn t All About THC Taming THC: potential cannabis synergy and phytocannabinoidterpenoid entourage effects Cannabis terpenoids: limonene, myrcene, a-pinene, linalool, b- caryophyllene, caryophyllene oxide, nerolidol and phytol. Synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections Ethan B Russo Ethan B Russo, GW Pharmaceuticals, Salisbury, Wiltshire, UK 1344 British Journal of Pharmacology (2011)

19 It Isn t All About THC Currently GW drug Epidiolex (>98% CBD, no THC) is achieving success in clinical trials for Dravet syndrome and Lennox-Gastaut syndrome (judged by reduction of epileptic siezures) High CBD strains of cannabis (most notable, charlotte s web ) have been used successfully in underground treatment for years to treat drug resistant epilepsy in children

20 Whole Plant Composition Cannabis Plant Material Sesquiterpenes Terpenes Cannabinoids Flavonoids Pigments Sugars Chlorophyll Fats Waxes Lignin Pectins Starches Cellulose *Lipids

21 What is the API Form? Dried flower 10-25% Keif/Hashish/Rosin Low potency infusions % High potency concentrates 60-95% Areas for Concern: CU, composition, pesticides, metals, residual solvents, unknown impurities, batch-batch variability

22 Dried Flower Strain: highly inbred and crossed Grow technique: indoor/outdoor, nutrients Plant to plant Bud to bud Sample size for testing Physical stability, packaging Only a fraction of the total plant material

23 High-Potency Concentrates Extraction technology has evolved, but it is not regulated by anything resembling FDA Distillation produces 95% pure THC where did the other go? Isolation of purified fractions is expensive Synthetic or natural terpene additives expensive, and stability is not monitored Branding: product in NY same as LA

24 We Need a Pharmacopoeia American Herbal Pharmacopoeia issued 1 st of a 2 part series in 2013 Schedule I complicates clinical studies Well controlled drug substance and drug product is required for clinical studies Regulatory oversight: ATF, FDA, DOJ Unified structure for medical, recreational, and care giver marketplace

25 Credits and Acknowledgements MCR Labs Skell Labs David Schaible Excipient Fest