PureRx Formulas Water er-Solu lubl ble e CBD Isolate e - - PowerPoint PPT Presentation

PureRx Formulas

Water er-Solu lubl ble e CBD Isolate e

PureRxFormulas.com

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Cannabidiol (CBD)

• A non-psychoactive substance only in cannabis plants

▫ Especially abundant in industrial hemp

Pure CBD from Industrial Hemp

• Many published studies suggest desirable anti-inflammatory

properties and a potential to positively impact adverse and even life-threatening conditions

▫ Cancer, diabetes, heart disease, osteoarthritis, rheumatoid arthritis, epilepsy, inflammatory bowel disease and more ▫ Neurodegenerative diseases like multiple sclerosis, Parkinson’s disease and amyotrophic lateral sclerosis (Lou Gherig’s disease) ▫ Protect the brain after concussion ▫ Maybe trigger weight loss and lower blood sugar levels

CBD Is Safe

1 cm

CBD Crystal

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• Non-Psychoactive and Non-Addicting
• Does Not Induce Catalepsy

▫ Seizures with sensation loss, muscular rigidity, fixity of posture

• No Effects on Psychological or Motor Functions

▫ Movement, coordination, dexterity, strength, speed

• No Impact on Basic Physiological Parameters

▫ Heart rate, blood pressure, body temperature

• No Changes in Food Intake or Gastrointestinal Transit
• Chronic Use and Larger Doses (> 1,500 mg/day) Well

Tolerated – No Noticeable Side Effects

Terpenes Terpenoids Further Substances Cannabinoids

• Cannabidiol
• Δ9-Tetrahydrocannabinol
• Δ8-Tetrahydrocannabinol
• Cannabigerol
• Cannabichromene
• Cannibidiovarin
• Δ9-Tetrahydrocannabivarin
• Δ8-Tetrahydrocannabivarin
• Cannabigerovarin
• Cannabichromevarin
• Carboxylic Acid Precursors
• Cannabinol
• Cannabicyclol

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Cannabinoids have little therapeutic effect alone and instead only when combined with other substances from cannabis plants.

Entourage Effect

Terpenes Terpenoids Phytosterols Porphyrins

Chlorophyll

Flavonoids Anthocyanins Phenols Phytoestrogens

Lignans Isoflavones Coumestans

Stress Chemistry Nitrogen Compounds

Alkaloids Glucosinolates

Carotenoids

It’s Complicated

Cannabinoids

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Entourage Effect

Entourage Effect

Whole-Plant CBD Extracts ― Sigmoidal-Dose Response ―

Lower Doses Increasing Response

Pure CBD ― Bell-Shaped Dose Response ―

Higher Doses Diminishing Returns Batch-to-Batch Manufacturing Variations

Low High

Dose Response

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CBD Solubilization Effects fromOther Chemistry

Low High

Typical of Substances with Low Bioavailabilities

Entourage Effect

Is It Real? Is It Necessary? No!

• No plant chemistry
• ther than CBD
• Nothing gets into

the bloodstream

• ther than CBD

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Bioavailability

Powdered CBD (A) Liposomal CBD (B) A B Insoluble in Water Insoluble in Water Fully (100%) Soluble in Water

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Liquid CO2 CBD Oil Extract CBD Nano-Emulsion

The ability of a substance to be dissolved in water a major determinant of absorption into the bloodstream

• Arndt, D.L., and H. de Wit. 2017

. Cannabidiol Does Not Dampen Responses to Emotional Stimuli in Healthy Adults. Cannabis Cannabinoid Res. 2(1):105–113.

• Bergamaschi, M.M., R.H.C. Queiroz, A.W. Zuardi, and J.A.S. Crippa. 2011. Safety and side

effects of cannabidiol, a Cannabis sativa constituent. Curr. Drug Safety 6(4):237-249.

• Babalonis, S., M. Haney, R.J. Malcolm, M.R. Lofwall, V.R. Votaw, S. Sparenborg, and S.L.
• Walsh. 2017

. Oral cannabidiol does not produce a signal for abuse liability in frequent marijuana smokers. Drug Alcohol Depend. 172:9–13.

• Grotenhermen, F., and K. Iffland. 2017

. An update on safety and side effects of cannabidiol: A review of clinical data and relevant animal studies. Cannabis Cannabinoid

• Res. 2(1):139-154.
• Manini, A.F., G. Yiannoulos, M.M. Bergamaschi, S. Hernandez, R. Olmedo, A.J. Barnes, G.

Winkel, R. Sinha, D. Jutras-Aswad, M.A. Huestis, and Y.L. Hurd. 2015. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J. Addict. Med. 9(3):204-210.

• Ren, Y., J. Whittard, A. Higuera-Matas, C.V. Morris, and Y.L. Hurd, 2009. Cannabidiol, a

nonpsychotropic component of cannabis, inhibits cue-induced heroin-seeking and normalizes discrete mesolimbic neuronal disturbance. J Neurosci. 29(47): 14764–14769.

• Rong, C., Y. Lee, N.E. Carmona, R.M. Ragguett, J.D. Rosenblat, R.B. Mansur, R.C. Ho, and

R.S. McIntyre. 2017 . Cannabidiol in medical marijuana: Research vistas and potential

CBD Is Safe: References

• pportunities. Pharmacol. Res. 121:213-218.

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Regular CBD Is a Problem

• Insoluble in Water

▫ Solubility in water crucial for efficiently getting from the mouth into bloodstream ▫ Solubility essential to beveragemanufacture

• Very Low Bioavailability

▫ Only minor amounts can reach the bloodsteam and therefore sites of action in the body

• Most Regular CBD Is Instead Wasted

▫ Either degrades in the stomachor passed in feces

Problems Uniquely Resolved with Proprietary GRAS1 Nano-Micelles(nextCBD)

1GRAS = generally recognized as safe, an FDA label for safe, edible substances

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• Agurell, S., S. Carlsson, J.E. Lindgren, A. Ohlsson, H. Gillspie, and L. Hollister. 1981. Interaction
• f THC with cannabinol and cannabidiol following oral administration in man. Assay of

cannabinol and cannabidiol by mass fragmentography. Experientia 37(10):1090–1092.

• Atsmon, J., D. Heffetz, L. Deutsch, F

. Deutsch, and H, Sacks. 2017. Single-dose pharmacokinetics of oral cannabidiol following administration of PTL101: A mew formulation based on gelatin matrix pellets technology. Clin. Pharmacol. Drug Dev. Nov 10. [Epub ahead

• f print]
• Devinsky, O., M.M. Cilo, H. Cross, J, Fernandez-Ruiz, J.French, C. Hill, R. Katz, V

. Di Marzo, D. Justras-Aswad, W.G. Notcutt, J Maartinez-Orgado, P .J. Robson, B.G. Rohrback, E. Thiele, B. Whalley, and D. Friedman. 2014. Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55(6):791-802.

• Grotenhermen, F

. 2003. Clinical pharmacokinetics of cannabinoids. J. Cannabis Therapeutics 3(1):3-50.

• Grotenhermen, F

. 2003. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin.

• Pharmacokinet. 42(4):327-360.

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CBD Insolubility & Low Bioavailability: References

• Hložek, T., L. Uttl, L. Kadeřábek, M. Balíková, E. Lhotková, R.R. Horsley, P

. Nováková,

• K. Šíchová, K. Štefková, F. Tylš, M. Kuchař, and Páleníček T

. 2017. Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary,

• ral, and subcutaneous administration in rats and confirmation of conversion in

vivo of CBD to THC. Eur. Neuropsychopharmacol. 27(12):1223-1237.

• Manini, A.F., G. Yiannoulos, M.M. Bergamaschi. S. Hernandez, R. Olmedo, A.J.

Barnes, G. Winkel, R. Sinha, D. Jutras-Aswad, M.A. Huestis MA and Y.I.Hurd. 2015. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J. Addict. Med. 9(3):204-210.

• Ohlsson, A., J. Lindgren, and S. Andersson. 1984. Single dose kinetics of cannabidiol

in man. Pp. 219-225 in The Cannabinoids: Chemical, Pharmacologic, and Therapeutic Aspects. 1st Ed. Academic Press, New York, 932p.

• Samara, E., M. Bialer, and R. Mechoulam. 1988. Pharmacokinetics of cannabidiol in
• dogs. Drugs Metab. Dispos. 16(3):469-472.
• Zgair, A., J. Lee, J. C. Wong, P

. M. Fischer, D. A. Barrett, C. S. Constantinescu, and P .

• Gershkovich. 2015. Effect of long-chain triglyceride formulation on the oral

bioavailability of cannabidiol. American Association of Pharmaceutical Scientists, Annual Meeting, Poster.

CBD Insolubility & Low Bioavailability: References

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• Receptacle 1/1600

Width of a Hair

• Made with Safe,Edible

GRAS1 Materials

CBD CBD

+

High Solubility & Bioavailablity

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Empty Nano-Shell Regular CBD PureRx CBD

• Low Bioavailability
• Barely Gets into the

Body (Bloodstream) when Taken by Mouth

• Insoluble in Water
• CBD-Loaded Nano-Shell
• Elevated Bioavailability
• Entry Into the Body

(Bloodstream) Greatly Amplified

• 100% Water Soluble

Entry of CBD Into the Body Greatly Enhanced with Patented nextCBD Technology

Cryo-Electron Microscopy

50 nm 50 nm

Transmission Electron Microscopy at -200 oC (-330 oF) Nano-Shell

Empty Nano-Shells Loaded Nano-Shells (nextCBD)

• PureRX CBD -- Very Small CBD-Loaded Vessels, 10–20 nmDiameter, Optimally Sized

for Maximizing the Entry of CBD Into theBody

• Smaller than the Wavelength of Visible Light (500 nm) –Cannot Be Seen with a

LightMicroscope

• Human Hair – 80,000 nm Thick, Red Blood Cell – 7,500nm Diameter, Flu Virus

– 100 nm Diameter 13

.. ..

1 2 3

. .

4 5 6

... .. .

• = CBD

CBD-Loaded Nano-Shell Emptied Nano-Shell Membrane Bloodstream

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How PureRx CBD Is Transported from the Small Intestine to the Bloodstream

• CBD Molecules Passes

Through Membranes

• f the Intestinal Wall &

Into the Bloodstream

• The GRAS Nano-Shell

Does Not

• CBD’s Entry Into the

Body is Greatly Enhanced

CBD in Plasma ng/mlv

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10 mg/kg Dose N = 10 in Each Group PureRx CBD Regular CBD in Olive Oil

More Gets Into the Body

Taken by Mouth Amount in the Bloodstream at 30 Min.

2.0 Hours

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PureRx CBD N = 10 In Each Group 25 mg/kg Dose Regular CBD in Olive Oil 0.5 Hours CBD in Blood Plasma ng/ml

More Gets Into the Body

Taken by Mouth Amount in the Bloodstream at 0.5 & 2.0 Hours

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The statements made herein have not been evaluated by the U.S. Food and Drug Administration and are not intended for diagnosing, treating, curing or preventing any disease or medical condition.

Regular CBD No Treatment PureRx CBD

Ear Thickness (μm)

N = 10 in Each Group

CBD & Inflammation Swollen Tissue

• Inflammation in Rats -- DTH Model
• Inflammation Measured as Thickness of a

Swollen Ear

• Regular and Nano-Micellar CBD Given by Mouth
• Inflammation Reduced

About 4X More with Nano-Micellar CBD Versus Regular CBD

• A Major Inflammation-Causing Protein

▫ Made by immune system cells

• A Cause or Factor in Many Diseases

▫ Rheumatoid arthritis, osteoarthritis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, atherosclerosis, heart attack, diabetes

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CBD & Inflammation Tumor Necrosis Factor Alpha (TNF-α)

3D Model of TNF-α Protein

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treating, curing or preventing any disease or medical condition.

PureRx CBD

CBD & Inflammation

Nano-Micellar CBD Greatly Decreases TNF-α Levels

N = 10 in Each Group

• 50-mg Regular CBD versus 5-mg nextCBD
• 70% less TNF-α with 5-mg nextCBD

The statements made herein have not been evaluated by the U.S. Food and Drug Administration and are not intended for diagnosing,

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CBD: Conversion to THC in the Stomach

Cannabidiol (CBD)

Acid hydrolysis in the Stomach

Tetrahydrocannabinol (THC)

Loss of CBD, lower bioavailability, possible psychoactive side effects, etc.

0.2 0.4 0.6 0.8 1 1.2 20 40 60 80 100 120 140 160 180 200 ] 0 C [C / ati

• n

tr n e c n

• c

e ati v l e R Time [min] MeOH AX1

1.2 1.0 0.8 0.6 0.4 0.2

Relative Concentration [C/C0]

20 40 60 80 100 120 140 160 180 200

Time (Minutes)

PureRx CBD Regular CBD

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CBD Degradation in Gastrointestinal Fluid

• Nano-Micellar

PureRx CBD, Reactive Site of the CBD Molecule Protected

• No Evident Conversion or

Degradation as a Result

• Almost All CBD Can

Reach the Small Intestine

UNKNOWN substances Now Identified

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CBD Conversion in Gastrointestinal Fluid

∆8-THC and ∆9-THC Prominent

• Breakthrough technology – Only tool worldwide for

accelerated and reliable, product stability testing

• Instabilities detected 2300X faster and more accurately
• Precise stability and shelf-life determinations in minutes
• r hours, not months or years

Hundreds of Sensors

Light Source Sample Sensor

Concentration Stable –No Breakdown Flocculation Aggregation Coalescence Demulsification Sedimentation

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LUMifuge™ Stability Analysis

• Breakdown detected as changes in light transmission

• No Breakdown
• Shelf Life 2 Years at

Room Temperature Diluted – 15% in Water

• No Breakdown

Even When Diluted

• Same Shelf Life as

Full-Strength nextCBD

Sensors Turning On Sensors Turning Off

Full Strength

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LUMIfuge Analysis -- Nano-Micellar CBD

Regular CBD Is Unstable

• Considerable Degradation
• Lesser, Questionable Shelf Life

LUMIfuge Analysis -- Regular CBD

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A Typical Commercial Product

Sizable Levels of: Flocculation Aggregation Coalescence Demulsification Sedimentation

4 oC 39 oF 25 oC 77 oF 40 oC 104 oF Day 0 Day 15 Day 30 Day 68

% ) w t ( ti

• n

a tr n

6 1 2 3 4

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Stable Across Temperatures

• Over a Time Span of 68 Days, No Obvious Nano-Micellar

CBD Degradation – Even at Higher Temperatures

6 5

CBD Concentration (wt%)

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Powdered CBD – Nearly Insoluble in Water

• Lipophilic CBD has virtually no solubility in water-based

solutions ▫ Regular CBD precipitates from aqueousmixtures

• Attempts by others to make It water compatible

▫ Emulsifiers and liposomal or micellar vessels oftentried ▫ Allunstable ▫ Constructs rapidly degrade -- CBD drops out ofsolution

CBD in Aqueous Solutions: A Technical Challenge

Nano-Micellar CBD Regular CBD With an Emulsifier

80% 10% 80% 10%

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100% Water Solubility with Nano-Micellar CBD – But Not with Regular CBD

• Fully Water Soluble
• Clear – Transparent
• Bacteriostatic, Inhibits

Bacterial Growth

• Poorly Water Soluble
• Turbid – Opaque
• Supports Bacterial

Growth

• Solubility Uniquely Suited for Aqueous Solutions
• Prolonged Stability