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Keynote Speaker
Medical Marijuana: Improving Stability with Novel Delivery Methods
Lekhram ChangoerAXIM Biotechnologies
ExcipientFest Americas
April 26th 20172
Improving stability and bioavailability with novel delivery method
Contents
• Axim Biotechnologies
• Cannabinoids
• Isolation and semi‐synthesis of THC and CBD
• Chewing gum with cannabinoids
• Chewing effects
• Irritable Bowel Syndrome (IBS)
• MedChewRx
• Pipeline/concluding slides
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Mission Statement:
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We discover, develop, manufacture, and deliver world-class innovative bioscience solutions
Axim Today
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Leader in Cannabinoid Extraction/ Purification/ Conversion/ Microencapsulation
Leader in Cannabinoid Delivery Systems (THC/ CBD/ CBG)
All Processes Protected (IP/ TM)
11 major Patents covering pharmaceutical and biotech innovations and 20 Trademarks
MedChew RX™ and ReneCann™ in Pre‐ and Clinical Development
Selling CanChew™ in all 50 states in US and 40 countries worldwide
R&D in Pharmaceutical, Nutraceutical and Consumer Products
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Medicated Chewing Gum: MedChewRx™
MedChewRx® is a patented technology of AXIM which comprises the inclusion of active pharmaceutical ingredients (API) of the cannabinoid variety in a patented, controlled‐release, functional chewing gum formulations
Such medicated chewing gum is applicable in the field of pain management and/or neurodegenerative diseases
MedChewRx™ will be regulated as a pharmaceutical product i.e. will receive a approved NDA status by the FDA/EMA.
Phyto‐cannabinoids Endocannabinoid system
Medicinal products and supplements
Food sources
Eating behaviour Metabolic syndrome Gastro‐intestinal diseasesCachexia and disease‐related anorexia
Analgesia Anti‐inflammation Neuroprotection
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Raw Material Cannabis: Bureau of Medical Cannabis (NL)
Lynch et al., 2015 ; Genomic and Chemical Diversity in Cannabis
Enormous strain diversity enables selection for optimal strain & efficient compound isolation
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Cannabinoids (CBN’s)
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Cannabinoids act on cannabinoid receptors toinfluence neurotransmitter release, resulting in nerve transmission
• Endocannabinoids (human/animal);phytocannabinoids ; synthetic cannabinoids
• CB1 receptors: in CNS, responsible for euphoric and anticonvulsive effects of cannabis
• CB2 receptors: more peripheral, responsible for anti‐inflammatory effects
• >140 different cannabinoids from cannabis
• Most important CBN’s• THC (tetrahydrocannabinol): psycho‐active, on CB1• CBD (cannabidiol): acts also as serotonin receptoragonist; greater affinity for CB2 than CB1
More than 140 phytocannabinoids from Cannabis known to date.Major ones shown below
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Cannabinoids: a large family of compounds
Two major Cannabinoids: ∆9‐THC and CBD
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∆9‐Tetrahydrocannabinol (THC) and Cannabidiol (CBD) are the major cannabinoids
CB1 receptors are located primarily in central and peripheral neurons and CB2 receptors predominantly in immune cells.
THC, the main psychotropic constituent of cannabis, is a CB1 and CB2 receptor partial agonist and in line with classical pharmacology, the responses it elicits appear to be strongly influenced both by the expression levels, signaling efficiency and ongoing endogenous cannabinoid release.
Cannabidiol (CBD) is non‐psychotropic and displays unexpectedly high potency as an antagonist of CB1/CB2 receptor agonists in CB1‐ and CB2‐expressing cells or tissues, the manner with which it interacts with CB2 receptors providing a possible explanation for its ability to inhibit evoked immune cell migration.
Δ9‐THC extraction from Cannabis
Purification based on a tailored acid‐base extraction to provide high purity Δ9‐THC‐A (99+%) as a stable solid.
Δ9‐THC:• Unstable resin at room temperature.• Δ9‐THC‐solution in ethanol is stable at room temperature
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Crude hemp oil containing CBD‐A is obtained by extraction of cannabis flowers with organic solvent.
Purification:• CBD‐A : Column‐chromatography‐free removal of unwanted
cannabinoids and terpenes from the hemp oil by a refined acid‐base extraction.
• CBD : Crystallization provides CBD as stable solid (97‐98% pure)
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Cannabidiol (CBD) extraction from Cannabis
Adsorption of THC and CBD to the chewing gum• Pure chewing gum not feasible due to lipophilicity of both THC and CBD
• Carrier‐approach with double layered chewing gum tablet anticipated
Stability issues with THC• Coating silica gel and maltose with THC unsuccessful due toinstability of THC (picture)
• Solution: employ a protective environment for THC: preformulation approach
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Issues of THC and CBD in chewing gum
Solutions for the 2 issues identified
Continue with a combination of chewing gum and tablet excipients
• Not a dual‐layer tablet but a true mixture of gum base and excipientsto prevent separation of both layers upon chewing
Protect THC (and CBD) by applying micro‐encapsulation(preformulation approach)
• 3 preformulations chosen to be applied in the chewing gum• Choice to be made on the basis of pre‐set criteria (stability, ease of release, taste, etc.)
• Increasing bioavailability of Cannabinoids
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Preformulation 1: coating
Coat a particle with THC (CBD) and coat the formedparticle with a protective layer
The carrier particle may be maltose or silica gel
Use of fluid bed coater
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Preformulation 2: encapsulation
Encapsulate the THC (CBD) in a polymeric matrix using a spray‐drier
• Technique used to encapsulate vulnerableproteins/antibodies/biosimilars
• Processed under nitrogen
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Preformulation 3: absorption
Liquisolid technology• Silica gel with large pores is to absorb a solution of THC (CBD) in a liquid mixture of excipients
• The excipients are selected for their ability to form a micro‐emulsion in contact with water
• This serves to release the THC (CBD) from the pores in thesilica gel
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Preformulation: how to choose
The choice will be made on the following criteria
• Stability
• Potential to release the active from the formulation
• Down stream manufacturability
• Taste
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Chewing gum tablets
The chewing gum tablets will be made from the followingexcipients
• Preformulation • Gum base powder (Health‐in‐Gum, Cafosa) 50‐80%• Excipients (lactose, maltose, silica gel)• Flavors
Tablets will be 1.5‐2.0 gram so these can be chewed and noteasily swallowed
Tablets will contain 5 mg of THC and CBD each
Other formulations in development• Synthetic THC gum• Opiods and Cannabidiol• etc
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Functional chewing gum with cannabinoids
Feeding
Food supplements – Nutraceuticals
Rx drug: Medication
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Physiology of chewing
Neurotransmitters release (serotonin, dopamine)
Increase of salivary production
Increase in intestinal motility (implications in ileus)
Increase in cerebral perfusion (MCA velocity studies during
chewing)
Shortening of the hypophiseal/ suprarenal axis (return to
eustress)
Form of physical exercise (increase in HR and BP during chewing).
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Chewing advantages: Physiology
Psychological effects:
• Improves short and long term memory
• Improves focus
• decreases anxiety
• decreases stress
• improves mood; “feel good”
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Chewing advantages: Psychological
Chewing gum containing controlled release of CBN’s
Vastly improved delivery system (bypass of 1st pass, hepatic
metabolism, hence decreased 11‐hydroxy‐THC). It is directly
absorbed into the oro‐pharyngeal capillary bed similar to the
entry of the smoked CBN’s through the alveolar (lung) circulation.
Increase of production of saliva, which is important in patients on
multiple meds, e.g. baclofen in MS who suffer dry mouth as a
sequence to these meds.
Neuroprotective effects will be increased due to the anti‐
inflammatory effects of the CBN’s as well as these provided by
the act of mastication where we believe 1+1=3
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Chewing advantages: with cannabinoids (CBN)
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Chewing and the brain
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Chewing and cognition
Alertness
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Chewing and stress
Preservation of chewing function is important for
Nourishment status Reduction stress Reduction pain Enriched environment Quality of life Prevention disease progression
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Conclusion
IBS clinical study University of Wageningen (NL)
Probably the most common intestinal condition
incidence 15 ‐ 20 % among women (15 ‐ 65 years)
men (15 ‐ 65 years) : 5 ‐ 20 %
Chronic or recurrent colonic symptoms without a clear etiology
Characterized by chronic or recurrent abdominal pain, bloating, mucus in the feces and an erratic disturbance of defecation
Associated with : stress, sensoric hypersensitivity, motility disturbance
Currently available medical or nutritional options very limited
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IBS: Phase 2 clinical study
Carried out at the University of Wageningen (NL)
CBD used as active substance
Potent anti‐inflammatory (analgesic, anti‐proliferative) cannabinoid
Non psycho‐active
Long tradition of safe use in humans; several clinical studies ongoing
Preclinical data and clinical observations strongly underline potential for GI indications (IBD and IBS)
...Clear demand for specific formulations ...
Local : Site‐specific release Systemic : slow release & avoid first pass effect
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IBS clinical study: design
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IBS clinical study: PK study
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PP01: 10 mg CBD PP04: 30 mg CBD
IBS clinical study: Phase 2
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• Drug: CanChew gum 50mg CBD; dosage: up to 6 gums/day
• Patients: 40 subjects (18‐55 yrs)
• Duration: 8 weeks randomized double blind cross over trial
• Endpoints: pain reduction (VAS); QOL (IBD‐QOL);
• Estimated time completion study: May 2017
https://clinicaltrials.gov/ct2/show/NCT03003260?term=canchew&rank=1
Next steps: Inflammatory bowel diseases (IBD)(IBD)
Two main forms: Crohn’s disease (CD) and Colitis Ulcerosa(Ulcerative colitis, UC)
Incidence rises (Europe : CD = 20‐40 per 100,000 ; UC = 70‐150 per 100,000 ) Chronic and relapsing diseases Significantly impairing quality of life Signs and complications
• Diarrhoea, abdominal pain • Depression• Food restriction, weight loss, impaired growth in children
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Mayo endoscopic score for ulcerative colitis(A) Score 0=normal; endoscopic remission(B) Score 1=mild; erythema, decreased vascular pattern, mild friability(C) Score 2=moderate; marked erythema, absent vascular pattern, friability, erosions(D) Score 3=severe; spontaneous bleeding, ulceration.
Ordas et al. The Lancet Volume 380, Issue 9853 (2012), 1606 ‐ 1619
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Next steps: Ulcerative Colitus
IBD work program
Development of CBD (&CBG ?) rectal formulation (intermediate, experimental formulation)
Small‐scale PK pilot in healthy volunteers
Dose‐escalating pilot in patients suffering from distal colitis
In parallel (now running) development of test based on saliva analysis to monitor disease activity
Ultimate goaldevelopment of colon‐specific rectal CBD (or CBG) formulation for IBD (UC and Crohn)
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MedChewRx clinical trial on MS patients‐1
Phase 1: PK/PD biocomparison trial
• Drug: MedChewRx 5 mg THC/5 mg CBD; Sativex 2,7 mg THC/2,5 mg CBD
• Healthy volunteers: 15 (18‐55 yrs)
• Phase 1 center: QPS Phase 1 unit Groningen (NL)
• Design: open label, randomized, 5 period cross over study with a washout of 1 wk
• Analysis: PK/PD incl metabolites (11‐OH‐THC); (S)AE’s, clinical chemistry, hematology, urine analysis, vital signs
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No MedChewRx Sativex Charcoal
A SD 10 min
B SD 20 min
C SD 20 min X
D DD
E DD X
MedChewRx clinical trial on MS patients‐2
Phase 2/3
• Drug: MedchewRx 5 mg THC/5 mg CBD
• Patient: 100 (18‐55 yrs)
• Multicenter: Switzerland, VU Amsterdam, UK Plymouth, USA.
• Duration: screening phase (1 wk)open titration effective dose (2 wk)double blind cross over period each (2 wk); total 7 wk + follow up 2 wk= 9 wk
• Design: Randomised double blind, placebo controlled, multidose, multi‐site
• Endpoints: pain score by NRS (PI & PID); Spasticity score by NRS; Oridinal Rating Scale Spasm Frequency; Motricity Index Score; PGIC, QOL (EQ5D),
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Axim’s overall clinical development program
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Management Team
George Anastassov, MD, DDS, MBA
Chairman, Chief Executive and Financial Officer
Co‐founder, CEO of CanChew Biotechnologies, LLC and Director and GP of Sanammad Foundation and Sanammad Pharmaceuticals, BV
Research and Development in Medicine and Biotechnologies since 1987
Philip van Damme, DMD, MD, PhD
Director, Chief Medical Officer
Co‐founder, CEO of CanChew Biotech and Director and GP of Sanammad Foundation and Sanammad Pharmaceuticals, BV
Research and Development in Medicine and Biotechnologies since 1983
Dr. Lekhram Changoer, MSC, BSC
Director, Chief Technology Officer
Co‐founder, CSO of CanChew Biotech and Director and Partner of Sanammad Foundation and Sanammad Pharmaceuticals, BV
Co‐founded several intellectual property‐based pharmaceutical and dental companies, and over 20 years experience in sales & marketing, product development, quality assurance, and research and development
Axim is Led by a Credible and Proven Management Team
END
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North American Address:18 East 50th Street, 5 Floor
New York, NY 10022+1 844 294 6246
European Address:Boelewerf 32, Unit 3
2987 VD Ridderkerk, The Netherlands+31 10 8209 227
For further information, please contact:www.aximbiotech.com
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