medical cannabis -...
TRANSCRIPT
Medical Cannabis
Then and Now
Jeffrey Skell, PhD
2016
Agenda
A Brief
History of
Cannabis
Drug
Properties
Is
Cannabis
“Developable?”
The
Source of
All That
Trouble
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
http://www.slate.com/content/dam/slate/blogs/the_vault/2015/05/13/LgMedicinalPlants.jpg
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
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
http://il8.picdn.net/shutterstock/videos/8510101/thumb/1.jpg
Types of Cannabinoids
• 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
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)
Types of Cannabinoids
• 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)
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)
Chemical Structure
THCA is the Naturally Occurring Form
Combustion
Heat vaporizes
remaining THC
www.mcrlabs.com
OH
At Least 50% is Pyrolyzed
CO2, CO, benzene,
tar, free-radicals
THC, CBN, others
THC-A
Inhalation
• Cigarette
• Pipe
• Water pipe
• Vaporizer
• Dab
• DPI
Modes of Administration
Oral and Cutaneous
• Edible (foods, beverages, candies)
• Tincture (usually alcohol based)
• Sublingual (sprays, tablets)
• Tablet/capsule (less popular?)
• Local/Topical (creams, ointments)
• Transdermal (patches)
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
• 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
Excipients Use in Cannabinoid
Delivery
United States Cannabis
market is estimated at over
$700 million/yr soon to pass
$1 billion/yr
Physico-Chemical Properties
• MW 314.5
• 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
DMPK Properties
• Inhalation BA 10-35%
• Oral BA 6-20% (highly variable)
• PPB >95%
• Significant 1st pass metabolism to a different
metabolite than inhalation
• Partitions into fat and skin; very slow and
variable wash out time
Onset Depends on Route of
Administration
Smoking BA is <50% (typically 10%-35%)
Oral BA is <20%, highly variableand effect may last a long time
Pharmacokinetics
It Isn’t All About THC
Taming THC: potential cannabis
synergy and phytocannabinoid-
terpenoid 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, GW Pharmaceuticals, Salisbury, Wiltshire, UK
1344 British Journal of Pharmacology (2011) 163 1344–1364
Ethan B Russo
http://bjcardio.co.uk/files/uploads/2015/02/Ethan-2010-Headshot.jpeg
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
http://www.gwpharm.com/
• Sesquiterpenes
• Terpenes
• Cannabinoids
• Flavonoids
• Pigments
• Sugars
• Chlorophyll
• Fats
• Waxes
• Lignin
• Pectins
• Starches
• Cellulose
• *Lipids
Whole Plant Composition
Cannabis Plant Material
http://www.tetralabs.com/ca/about-puregold
What is the API Form?
• Dried flower 10-25%
• Keif/Hashish/Rosin
• Low potency infusions 0.25-5%
• High potency concentrates 60-95%
Areas for Concern:
CU, composition, pesticides, metals, residual
solvents, unknown impurities, batch-batch
variability
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
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
We Need a Pharmacopoeia
• American Herbal
Pharmacopoeia issued 1st 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
http://www.herbal-ahp.org/order_online.htm
Credits and Acknowledgements
https://skunkpharmresearch.com/about/
David
Schaible
MCR
Labs
Skell
Labs
Excipient
Fest