Nanotecnologia
aplicada ao
canabidiol: Desafios
de um pesquisador
Prof. Dr. Sócrates Egito
Universidade Federal do Rio Grande do Norte
(UFRN)
[email protected]
WhatsApp – 84 994318816
Nanotecnologia
aplicada ao
canabidiol: Desafios
de um pesquisador
Prof. Dr. Sócrates Egito
Universidade Federal do Rio Grande do Norte
(UFRN)
[email protected]
WhatsApp – 84 994318816
Cannabis sativa
• Endemic from Asia;
• Medicinal use:
• Female flowers of the plant: high
amount of glandular trichomes
that contain pharmacologically
active compounds.
Cannabidiol (CBD)
Cannabis sativa
• More than 85 active cannabinoids identified
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Cannabis sativa
• More than 85 active cannabinoids identified
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Cannabidiol (CBD)
• Second-largest component of Cannabis sativa;
• Low molecular weight: 314,47 g/mol.
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Cannabidiol (CBD)
• Chemical Formula: C21H30O2
• Molecular Weight: Approximately 314.46 g/mol
• Solubility: CBD is sparingly soluble in water but highly soluble in organic solvents such as ethanol and
dimethyl sulfoxide (DMSO).
• Melting Point: CBD has a melting point of around 66-67 °C (150-152 °F).
• Boiling Point: It has a boiling point of approximately 160-180 °C (320-356 °F) at reduced pressure.
• pKa Value: The pKa (acid dissociation constant) of CBD is around 10.6, indicating it acts as a weak
base.
• Isomerization: CBD can isomerize or convert to another compound, particularly when exposed to heat,
light, or acidic conditions, resulting in the formation of THC (Tetrahydrocannabinol) under acidic
conditions.
Cannabidiol (CBD)
• Chemical Formula: C21H30O2
• Molecular Weight: Approximately 314.46 g/mol
• Solubility: CBD is sparingly soluble in water but highly soluble in organic solvents such as ethanol
and dimethyl sulfoxide (DMSO).
• Melting Point: CBD has a melting point of around 66-67 °C (150-152 °F).
• Boiling Point: It has a boiling point of approximately 160-180 °C (320-356 °F) at reduced pressure.
• pKa Value: The pKa (acid dissociation constant) of CBD is around 10.6, indicating it acts as a weak
base.
• Isomerization: CBD can isomerize or convert to another compound, particularly when exposed to heat,
light, or acidic conditions, resulting in the formation of THC (Tetrahydrocannabinol) under acidic
conditions.
These properties are relevant for various applications of CBD in chemistry, pharmacology, and
medicine.
Cannabidiol (CBD)
• Lipophilic molecule: LogP= 6.3;
• Low water solubility: 12,6 mg/L;
• Soluble in organic solvents.
Cannabidiol (CBD)
• First commercially available in the world as health and food supplement.
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Cannabidiol (CBD)
• Medicinal properties:
- analgesia
- anti-inflammatory
- anticonvulsant
- antitumor
- anxiolytic
Ramalho, I.; et al. Expert Opin Drug Deliv, 2021.
CBD’s drawbacks
• Low and unpredictable oral bioavailability;
• Variable pharmacokinetic profiles;
• Poor stability on physiologic fluids;
• Class II Drug: low water solubility and high
permeability.
• Low permeation on gastrointestinal tissues;
• Conversion to THC;
• Regulatory issues.
Tan, S.; et al. Pharmaceutics, 2021.
CBD’s drawbacks
• Low and unpredictable oral bioavailability;
• Variable pharmacokinetic profiles;
• Poor stability on physiologic fluids;
• Class II Drug: Low water solubility and high
permeability.
• Low permeation on gastrointestinal tissues;
• Conversion to THC;
• Regulatory issues.
Tan, S.; et al. Pharmaceutics, 2021.
CBD conversion to Delta-9-
Tetrahydrocannabinol (Δ-9 THC)
• Similar chemical structures, but different effects on brain;
• Both can bind to cannabinoid receptors.
*Cyclohexene ring (A-C) and aromatic ring
(B) Martinez, N.; et al. Molecules, 2023.
CBD conversion to Delta-9-
Tetrahydrocannabinol (Δ-9 THC)
• Psychoactive;
• Non-psychoactive;
• Non-intoxicating. X • The majoritary special metabolite of C. sativa;
• The chronic use increase the incidence of
mental health diseases.
Martinez, N.; et al. Molecules, 2023.
CBD conversion to Delta-9-
Tetrahydrocannabinol (Δ-9 THC)
• A significant amount of CBD transforms to (Δ9-THC) in a • Might CBD be degraded into psychotropic
hot GC injection system when acidic precipitation agents (THC) cannabinoids in vivo?
are used for plasma protein precipitation.
• It is certain that CBD degrades to psychotropic
• Depends on the temperature of the GC injector, the products in acidic environments
concentration of the precipitation agent and the
incubation time of plasma
Storage stability of commercial formulations requires more attention in the future.
CBD in the world
MARKETED PRODUCTS
Countries Regulatory agency Number of CBD products Formulation Concentration
United States of
FDA 1
America (USA) Oral oily solution 100 mg/mL
European Union (EU) EMA
European Medicines Agency - EMA, 2019.
Food and Drug Administration - FDA, 2018.
CBD in Brazil
MARKETED PRODUCTS
• Resolução da Diretoria Colegiada (RDC) 327/2019
Country Regulatory agency Number of CBD products Formulation Concentrations
17.18 mg/mL; 20 mg/mL;
23.75 mg/mL; 34.36 mg/mL;
Brazil ANVISA 19 Oral oily solution
50 mg/mL; 100 mg/mL;
150 mg/mL; 200 mg/mL.
Agência Nacional de Vigilância Sanitária - Anvisa, 2022.
< 0.2 % THC
CBD marketed products
MARKETED PRODUCTS
Brazil EUA and
19 X UE
1
Regulatory aspects to CBD
RESOLUÇÃO DA DIRETORIA COLEGIADA - RDC Nº 327, DE 9 DE
DEZEMBRO DE 2019
Oral oily solution problems
Inaccurate dose Unplesant organoleptic Susceptible to oxidation and Low solubility in
charateristics microbiological growth
GIT
Need for researchers to develop new pharmaceutical dosage forms for CBD delivery
Nanotechnology Research
NANOTECHNOLOGY
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Nanotechnology Research
NANOCARRIERS
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Nanotechnology Research
MICROEMULSIONS
• Microemulsions is a nanotechnological drug delivery
system, homogeneous transparent, thermodynamically
stable dispersion of water and oil, stabilized by a
surfactant, usually in combination with a co-surfactant.
MCCLEMENTS, D., Soft Matter, 2012.
Microemulsion - Composition and
Surfactant Behavior
Lindman, B., et al. J. Colloid. Surf. 1981
Microemulsion - Excipients
Commonly used excipients for microemulsion manufacturing
Surfactants
Polyoxyethylene
Lecithin Spans Tweens
Stearates
Concentration 0.1 – 10% 0.1 – 15% 0.1 – 15% 0.5 – 10%
Inhalations, IM Oral, parenteral,
Oral, parenteral,
Oral and topical injections, and topical
Administration and topical
formulations ophthalmic, oral, pharmaceutical
products
topical products formulations
Regulatory status FDA Inactive Ingredients Database
Rowe, R., et al. Handbook of Pharmaceutical Excipients, 2009.
Microemulsion - Excipients
Commonly used excipients for microemulsion manufacturing
Oils
Mineral oil Castor oil Soybean oil Miglyol
Intramuscularly as
oral,
Orally, drug vehicle or as a
parenteral,
Administration Orally and topically parenterally and component of
and topical
topically emulsions used in
products
parenteral nutrition
Regulatory status FDA Inactive Ingredients Database
Rowe, R., et al. Handbook of Pharmaceutical Excipients, 2009.
Microemulsions
DROPLET SIZE
COMPARISON
CALLENDER, P. et al. Inter. J. Pharm., 2017.
Microemulsions
DROPLET SIZE COMPARISON
CALLENDER, P. et al. Inter. J. Pharm., 2017.
Microemulsions
SURFACE BEHAVIOR
CALLENDER, P. et al. Inter. J. Pharm., 2017.
Microemulsions
AIR
Surface
AIR/AQUEOUS
PHASE
Interface
OIL/AQUEOUS
PHASE
AQUEOUS
PHASE
Bancroft’s Law
SURFACTANT
Microemulsions – Drug Loading
Interface
Water phase
Droplet core
Droplet core
Water phase
Interface Droplet core
Microemulsions
ADVANTAGES
Improve the apparent
Increase the Increase the rate of Helpful in taste masking
solubility of Class II and
bioavailability
Class IV drugs absorption
Cannabidiol microemulsion (CBD-
ME)
FORMULATION CHOICE
Quantity
Components Function
(%)
Lipoid® S100 6,3 Surfactant
CBD loading
Tween® 80 14,7 Surfactant
Purified water 68 Aqueous phase
Miglyol® 812 N 11 Oily phase
Cannabidiol microemulsion (CBD-
ME)
Cannabidiol microemulsion (CBD-
ME)
PHISICOCHEMICAL CHARACTERIZATION
ME CBD-ME
pH 6.2 ± 0.07 6.1 ± 0.09
Droplet Size 20 ± 0.4 22 ± 0.6 nm
PdI 0.151 ± 0.07 0.127 ± 0.08
Conductivity 148 ± 22 µS/cm 140 ± 16 µS/cm
Cannabidiol microemulsion (CBD-
ME)
Encapsulation Efficiency
Ideal CBD concentration
15mg/ml
Cannabidiol microemulsion (CBD-
ME)
Stability after freeze drying (FD) process
Formulations Droplet Size (nm) ± SD PdI ± SD
ME 20,0 ± 0,4 0,151 ± 0,07
ME + 5% MT (Maltose) 47,7 ± 0,8 0,143 ± 0,03
ME + 5% MT after FD 20,8 ± 0,6 0,142 ± 0,01
CBD-ME 22,0 ± 0,6 0,127 ± 0,01
CBD-ME + 5% MT 46,9 ± 0,9 0,178 ± 0,04
CBD-ME + 5% MT after FD 21,7 ± 0,5 0,172 ± 0,09
Next steps
Scale up process Safety and
Clinical trials
Industrial production Toxicicological
studies
Perspectives
Education concerning Studies for CBD quality New research
the medicinal use of assessment development
CBD
Difficulties in working with
cannabidiol
Raw material Conversion of CBD into Legal aspects
purity THC
New areas of research in
Psychotropics:
DM
T
DMT - dimethyltryptamine
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