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Cannabidiol - Transdermal delivery and anti-inflammatory effect in a murine model

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  • Houston Methodist Research Institute, Institute of Academic Medicine

Abstract and Figures

Cannabidiol (CBD) is a new drug candidate for treatment of rheumatic diseases. However, its oral administration is associated with a number of drawbacks. The objective of this study was to design a transdermal delivery system for CBD by using ethosomal carriers. CBD ethosomes were characterized by transmission electron microscopy, confocal laser scanning microscopy and differential scanning calorimetry. Results indicated that CBD and phosphatidylcholine form an eutectic mixture. In vivo application of ethosomal CBD to CDI nude mice produced a significant accumulation of the drug in the skin and in the underlying muscle. Upon transdermal application of the ethosomal system to the abdomen of ICR mice for 72 h, steady-state levels were reached at about 24 h and lasted at least until the end of the experiment, at 72 h. Furthermore, transdermal application of ethosomal CBD prevented the inflammation and edema induced by sub-plantar injection of carrageenan in the same animal model. In conclusion, ethosomes enable CBD's skin permeation and its accumulation in a depot at levels that demonstrate the potential of transdermal CBD to be used as an anti-inflammatory treatment.
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Cannabidiol—transdermal delivery and anti-inflammatory effect in
a murine model
M. Lodzki
a
, B. Godin
a
, L. Rakou
a
, R. Mechoulam
b
,
R. Gallily
c
, E. Touitou
a,
*
a
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
b
Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem,
Jerusalem, Israel
c
The Lautenberg Center for Immunology, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
Received 24 June 2003; accepted 3 September 2003
Abstract
Cannabidiol (CBD) is a new drug candidate for treatment of rheumatic diseases. However, its oral administration is
associated with a number of drawbacks. The objective of this study was to design a transdermal delivery system for CBD by
using ethosomal carriers. CBD ethosomes were characterized by transmission electron microscopy, confocal laser scanning
microscopy and differential scanning calorimetry. Results indicated that CBD and phosphatidylcholine form an eutectic
mixture. In vivo application of ethosomal CBD to CDI nude mice produced a significant accumulation of the drug in the skin
and in the underlying muscle. Upon transdermal application of the ethosomal system to the abdomen of ICR mice for 72 h,
steady-state levels were reached at about 24 h and lasted at least until the end of the experiment, at 72 h. Furthermore,
transdermal application of ethosomal CBD prevented the inflammation and edema induced by sub-plantar injection of
carrageenan in the same animal model. In conclusion, ethosomes enable CBD’s skin permeation and its accumulation in a depot
at levels that demonstrate the potential of transdermal CBD to be used as an anti-inflammatory treatment.
D2003 Elsevier B.V. All rights reserved.
Keywords: Ethosomes; Transdermal; Cannabinoids; Delivery system; Anti-inflammatory; Rheumatoid arthritis
1. Introduction
Recently, cannabidiol (CBD) intra-peritoneal and
oral administrations have shown the symptomatic
amelioration of collagen-induced rheumatoid arthritis
(RA) in mice [1]. RA is a common chronic, progres-
sive, systemic, inflammatory and destructive arthrop-
athy characterized by symmetric, erosive, and
disabling polyarthritis and a wide array of extraartic-
ular complications. As the disease progresses, irre-
versible joint damage may lead to loss of function
and to deformity. RA cannot be cured and has
substantial personal, social and economic costs.
CBD’s particular properties make it a good candidate
for such treatment: first of all, the lack of psycho-
activity associated with CBD allows it to be admin-
istered in higher doses than would be possible with
psychotropic cannabinoids, such as tetrahydrocannab-
0168-3659/$ - see front matter D2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jconrel.2003.09.001
* Corresponding author. Tel.: +972-2-6758660; fax: +972-2-
6757611.
E-mail address: touitou@cc.huji.ac.il (E. Touitou).
www.elsevier.com/locate/jconrel
Journal of Controlled Release 93 (2003) 377 – 387
inol (THC); second, CBD is not toxic, even when
chronically administered to humans or given at high
doses of 10 mg/kg/day [1 –3].
However, a major obstacle in the way of devel-
opment treatments with CBD is its low oral bio-
availability across species. Possible reasons for this
include extensive first pass hepatic metabolism,
instability in the acidic gastric pH and/or low water
solubility, leading to incomplete absorption [4,5].A
therapy that will overcome these drawbacks, such as
transdermal administration, could, therefore, be a
reasonable solution. Furthermore, the transdermal
route of administration has a high patient compli-
ance, which derives from its being non-invasive and
from the long interval between applications. Trans-
dermal administration also provides a means to
obtain constant systemic drug levels. However,
since CBD is a highly lipophilic molecule (log
K
o/w
f8) [6], it tends to accumulate within the
upper skin layer, the stratum corneum, and poorly
permeates to deeper strata [7,8]. Hence, its skin
transport can only be obtained by efficient perme-
ation enhancement.
In previous work, the ethosomal carrier has been
found to be very efficient at enhancing dermal and
transdermal delivery of various drugs [9,10]. In this
study, we designed and characterized CBD etho-
somes. The transdermal delivery of the cannabinoid
from these systems was investigated, and its pharma-
codynamic effect was assessed in a carrageenan-
induced acute inflammation model.
2. Materials and methods
2.1. Materials
CBD and THC were obtained from Prof. R.
Mechoulam’s laboratory. Soybean phosphatidylcho-
line (Phospholipon 90, PL-90) was a gift from
Natterman Phospholipid (Germany) and contained
93 F3% phosphatidylcholine. Phosphotungstic acid
(PTA) and type II carrageenan were purchased from
Sigma (USA), ethanol (EtOH) from Frutarom
(Israel), xylazine (ChanazineR2%) from Chantelle
(Ireland) and ketamine (KetasetRveterinary 10%)
from Fort Dodge (USA). Acetonitrile (ACN, J.T.
Baker, Holland), methanol (MeOH, Sigma) and
water (DDW, J.T. Baker, Holland) were all HPLC-
grade.
2.2. Methods
2.2.1. Preparation of CBD ethosomes
The name ‘‘CBD ethosomes’’ in this work refers to
ethosomal delivery systems containing 3% w/w CBD
and 40% w/w EtOH in a carbomer gel. The systems
were prepared at room temperature as previously
described [9].
2.2.2. Physical characterization of CBD ethosomes
2.2.2.1. CBD/PL-90 eutectic mixture visualized by
confocal laser scanning microscopy (CLSM). The
eutectic mixtures were prepared using the solvent
method and the fusion/melting method previously
described [11,12]. For comparison CBD and PL-
90 underwent the same melting and dissolving
separately.
The eutectic mixtures are transparent and light
microscopy is not sensitive enough to detect any
particles within them. For this reason, we chose the
much more powerful confocal microscope, which
enabled the visualization of all the samples.
Samples of PL-90, CBD crystals and their eutec-
tic mixture were examined utilizing a Zeiss LSM
410 CLSM System (Zeiss, Germany), connected to
Zeiss Axiovert 135 M inverted microscope and
equipped with a 25 mV air-cooled argon laser.
Images were taken with 20 /0.4 Plan-Neofluar lens
(Zeiss). Image processing was performed using
Zeiss LSM software package and Adobe Photoshop
programs.
2.2.2.2. Thermal analysis of ethosomal CBD by
differential scanning calorimetry (DSC). The tran-
sition temperature (T
m
) of ethosomal phospholipid
and CBD, pure and mixed together, was measured by
DSC, using a Mettler DSC 30, connected to a
computer with a Mettler Toledo Star Software Sys-
tem. PL-90, CBD or their mixture was pre-weighed
in an aluminum sample pan for DSC (aluminum
crucibles 40 Al with pin, ME-27331, Mettler Toledo,
Germany) [12]. The crucible was sealed, punctured
and placed in the DSC apparatus. The thermal
analysis was performed in the temperature range of
M. Lodzki et al. / Journal of Controlled Release 93 (2003) 377–387378
20 100 jC at a heating rate of 10 jC/min. Each
measurement was performed in triplicate, on different
samples.
2.2.2.3. Visualization of CBD ethosomes by trans-
mission electron microscopy (TEM). Ethosomal sys-
tems were visualized by TEM using a Philips TEM CM
12 electron microscope (Eindhoven, The Netherlands),
with an accelerating voltage of 100 kV. Samples were
negatively stained on a carbon-coated copper grid with
a 1% aqueous solution of PTA. The specimen was
viewed under the microscope at 10 30 K fold
enlargements [9,10].
2.2.3. CBD skin permeation and organ distribution
measured in vivo
All the animals used in this study were treated
according to the institutional guidelines. Six male
CD1 nude mice 8 9 weeks old (Harlan Olac, Israel)
were anesthetized by injection of xylazine and ket-
amine mixture. Hill Top or NexCare Patches contain-
ing CBD ethosomes were applied to the abdomen and
hip areas of each mouse and fixed for 24 h, during
which the mice were free in their cages and supplied
with food and water ad libitum. At the end of the
experiment, the mice were sacrificed and the follow-
ing tissues were excised: abdominal and hip skin;
abdominal and hip muscles, beneath the application
site; pancreas and liver.
Extraction of CBD from muscles and internal
organs was carried out as follows: Tissues were
collected from all mice and homogenized with a
2:1 v/v mixture of MeOH and chloroform. ACN
was added to the vial with vigorous vortex shaking.
The de-proteinized homogenate underwent double
centrifugation (3200 rpm, 10 min each). The result-
ing supernatant was vaporized under vacuum and
constant shaking, reconstituted with ACN, vortex-
mixed and vaporized again under vacuum and con-
stant shaking. The residue underwent reconstitution
with EtOH, vortex-mixing and centrifugation (3200
rpm, 10 min) and the resulting supernatant was
vaporized under vacuum and constant shaking. The
resulting residue was reconstituted with 400 Al EtOH
under vigorous shaking overnight. CBD was also
extracted from the abdominal skins, each in a sepa-
rate vial and hip skins, coupled-up, using ethanolic
extraction.
2.2.4. Determination of CBD plasma concentrations
following transdermal delivery from ethosomes
A total of 30 ICR mice (20 g, male, Harlan Olac)
were used for this experiment. The abdominal area
was shaved 13 20 h prior to the application. At
indicated time points (2, 4.5, 9, 13, 25, 37.5, 49.5,
and 73 h prior to bleeding time) three mice were
anesthetized with ether and 200 mg of CBD etho-
somes were applied to the abdominal area. The
formulation was covered with a Hill-Top patch and
fixed. The area of the skin exposed to the formulation
was 2.54 cm
2
. During the application period, the mice
were free in their cages and were supplied food and
water ad libitum, excluding the last 12 h prior to the
bleeding, during which they were fasted with free
access to water. Immediately after the bleeding the
mice were sacrificed by cervical dislocation.
At the end of the experiment, the mice were bled
by orbital sinus and the blood samples were placed in
EDTA 5-ml test tubes. Plasma (250– 500 Al/mouse)
was obtained by centrifugation (10,000 rpm, 15 min,
25 jC). Each plasma sample was spiked with 50 Alof
internal standard solution (THC 60 Ag/ml in MeOH),
vortex and left for 5 min to equilibrate. Three addi-
tional mice served as blank control and three others
for recovery calculations. These six mice were not
treated prior to their bleeding. The blank control
samples were treated as mentioned above, except for
the addition of the internal standard. The recovery
samples were similarly treated with the addition of 30
Al100Ag/ml CBD solution in MeOH and the addition
of the internal standard. All plasma samples under-
went extraction and clean-up as previously described
[13]. One hundred microliters of the extract were
analyzed by HPLC.
All peak areas (except for the recovery samples)
were normalized to a plasma volume of 300 Al. The
blank plasma served as background noise. For each
plasma sample, the average area (n= 3) of the back-
ground noise peak at CBD’s retention time was
deduced from CBD’s peak area. From the resulting
area, the concentration was calculated using the li-
near regression equation of CBD’s calibration curve
(R
2
= 0.9996). Each concentration was divided by the
recovery rate of THC in the specific sample to yield
CBD’s actual plasma concentration.
The actual dose of CBD penetrating the skin after
12 and 73 h application was calculated by HPLC
M. Lodzki et al. / Journal of Controlled Release 93 (2003) 377–387 379
quantification of the amount of CBD left in the patch
and on the skin of six male ICR mice, and deducing
that amount from the 6 mg of CBD applied to every
mouse.
2.2.5. Evaluation of the anti-inflammatory effect of
transdermal CBD
The anti-inflammatory effect of transdermal etho-
somal CBD was measured using carrageenan-induced
Fig. 1. CLSM images of PL-90 and eutectic combination of PL-90 with CBD (20a/0.4 lens, Zoom 1): (A) PL-90 dissolved in methanol and
evaporated; (B) PL-90, melted and cooled; (C) mixture of CBD and PL-90 prepared using methanol; (D) mixture of CBD and PL-90 prepared
using the fusion method.
M. Lodzki et al. / Journal of Controlled Release 93 (2003) 377–387380
aseptic paw edema [14] in male ICR mice. This model
was found suitable for the assessment of anti-inflam-
matory and anti-hyperalgesic drugs [15].
Ethosomal CBD patches were applied and fixed to
the abdominal area of six mice 19 h prior to the
carrageenan injection. The abdominal area was shaved
approximately 12 h prior to the application. The
patches were composed of 100 mg ethosomal CBD,
covered with Hill-Top patches. Six additional mice
comprised the control group and received no treat-
ment prior to the inflammation induction.
Twenty microliters of 3% type II carrageenan
solution in non-pyrogenic normal saline for injection
were injected (sub-plantar) into right hind paw of the
Fig. 2. DSC thermograms of: (A) PL-90; (B) CBD and (C) CBD and PL-90 mixture.
M. Lodzki et al. / Journal of Controlled Release 93 (2003) 377–387 381
12 mice. The left (control) hind paw was injected with
the same amount of non-pyrogenic normal saline for
injection. Thus, we achieved two controls—for each
mouse and for the entire treatment group. Paw thick-
ness was measured hourly for 4 h using JOCAL
calipers (Mitutoyo, Japan) calibrated in 0.01-mm
gradations [16]. During those 4 h, the mice were left
free in their cages and were supplied food and water
ad libitum.
Data processing assumed each mouse served as its
own control. From every measurement the paw thick-
ness at t
0
(immediately prior to injection) was de-
ducted to obtain the delta thickness. For every mouse,
delta thickness of saline-injected paw was deducted
from that of the carrageenan-injected paw (inflamed
paw) at all time points. For every time point, the mean
and standard deviation of these differences were
calculated.
2.2.6. CBD assays
CBD was quantified by a modified HPLC method
[13] and identified by GC/MS. HPLC separations
were carried out on a Merck-Hitachi D-7000 liquid
chromatography system using an RP-18 5 Am
25 0.46 cm column (YMC-Pack Pro). UV detection
was made at 220 nm with a mobile phase 7:1:2 ACN/
MeOH/water, all HPLC-grade, at a flow rate of 0.8
ml/min. CBD’s retention time under these conditions
was 11.7 min. The method was validated in terms of
specificity, linearity and reproducibility. The limit of
quantification was 200 ng/ml.
Tissue extracts, which gave no separate CBD peak
on the HPLC chromatogram, were analyzed by GC/
MS for verification of its presence. CBD was deriv-
atized into a diacetate for MS analysis. GC/MS
analysis was carried out on a Hewlett Packard model
HP5971 (GCD Plus, G1800 B) using a 30 m 0.25
mm column, which was heated at a rate of 30 jC/min
from 90 to 280 jC, where it was maintained for 15
min. The GC was operated under the following
conditions: manual splitless injection; injector temper-
ature of 250 jC and detector temperature of 280 jC;
helium as the carrier gas, with a flow rate of 0.7 ml/
min. The MS detector was operated under a TIC scan.
Under these conditions CBD diacetate peaks at 11.3
min, its fingerprint containing strong molecular ions at
231, 313, 355 and 397 m/z.
3. Results
3.1. Physical characterization of CBD ethosomal
system
CBD is a yellow resin or crystals [17]. CBD, both
melted and re-cooled or dissolved in MeOH and
Fig. 2 (continued).
M. Lodzki et al. / Journal of Controlled Release 93 (2003) 377–387382
evaporated, gave a solid yellow mass. PL-90 under-
going the same processes changed its consistency and
degree of firmness from an opaque solid wax to a
clear yellow liquid, with a texture seen on the confo-
cal microscope. Fig. 1 shows the CLSM images of the
melted and re-cooled PL-90 (Fig. 1A) and of PL-90
after dissolution in MeOH and evaporation (Fig. 1B).
Both the texture of the PL-90 and the CBD crystals
disappeared when they were mixed, and the resulting
mixture was a clear liquid, different from the two
solids comprising it. Moreover, the CLSM images of
CBD and PL-90 mixtures were entirely different:
these mixtures were transparent and the resulting
image was one of a clear surface embedded with
small (6 8 Am) particles (Fig. 1C and D). It is quite
possible that these particles are dust or very small
CBD crystals.
Fig. 2 shows DSC thermograms of pure PL-90,
pure CBD and a mixture of CBD/PL-90 at a molar
ratio of 1:2. The thermograms clearly show the
disappearance of the transition peak of the CBD as
compared to the pure substance. It can also be seen
that the pretransition peak, which characterizes the
phosphatidylcholine and represents its liquid-crystal-
line state, is greatly reduced in the presence of CBD.
Table 1 shows that DH values were greatly reduced
as compared to the pure substances, indicating that
much less energy was needed for the mixtures to
melt.
Fig. 3 represents TEM image of our ethosomal
system. As can be seen, the ethosomal composition is
a homogenous system of spherical vesicles, 300 –400
nm in diameter. The vesicles seem to be very mallea-
ble, as evident by their imperfect round shape. This
characteristic can be explained by the fluidizing effect
of ethanol [9] and CBD on phospholipid bilayers.
3.2. Skin permeation studies
In in vivo experiments, the application of ethoso-
mal CBD to the skin of nude mice resulted in a
significant accumulation of the drug in the skin.
After a 24-h application, a reservoir of CBD was
detected in hip skin (37.43 F13.58 Ag/cm
2
), abdom-
inal skin (110.07 F24.15 Ag/cm
2
) and abdominal
muscle (11.537 Ag CBD/g muscle). CBD was also
identified by GC/MS in the hip muscle, liver and
pancreas.
Table 1
Summary of the melting enthalpies obtained in DSC experiments
Sample Energy absorbed during melting (J/g)
PL-90 CBD Mixture
(PL-90 + CBD)
Pre-transition peak 10.67 1.08
Transition peak 1.64 67.33 1.01
Fig. 3. TEM visualization of CBD ethosomal systems.
M. Lodzki et al. / Journal of Controlled Release 93 (2003) 377–387 383
In further experiments, CBD plasma concentration
profile during 72-h system application to the 2.54-cm
2
abdominal area of ICR mice was evaluated. Fig. 4
represents the profile of CBD’s absorption from the
transdermal ethosomal system containing 6 mg of the
drug to the plasma. Steady-state (SS) levels were
reached at about 24 h and lasted at least until the
end of the experiment, at 72 h. CBD’s plasma con-
centration stabilized at a value of 0.67 Ag/ml.
The actual transdermal dose of CBD penetrating
the skin in vivo after 12 and 73 h of application was
calculated to be 1.37 F0.72 mg (22.83 F12% of the
Fig. 5. Anti-inflammatory effect of CBD transdermal patch, applied 19 h prior to the injection, is compared to no pretreatment:
D(mean FS.E.M.) between the thickness of carrageenan injected and saline injected paws of the same mouse at different time points post
injection. **p< 0.01; *p< 0.05.
Fig. 4. Kinetic profile of CBD’s delivery from transdermal ethosomal system to the plasma of 24 male ICR mice. Calculations are based on THC
recovery rate for each sample (mean FS.E.M.).
M. Lodzki et al. / Journal of Controlled Release 93 (2003) 377–387384
initial dose) and 2.60 F0.79 mg (43.33 F13.16% of
the initial dose), respectively. Considering the mice
weight to be around 30 g, CBD’s dose was 45.7 F
24.3 mg/kg body weight after 12 h and 86.7 F26.3
mg/kg after 72 h of application.
3.3. Anti-inflammatory effect of ethosomal CBD
Carrageenan-induced aseptic paw edema [14,15] in
male ICR mice, evaluated by measuring paw thick-
ness hourly for 4 h following the carrageenan injec-
tion, indicated that this model discriminates between
CBD treatment and control animal groups. Fig. 5
shows the pharmacodynamic profiles of the CBD
pretreatment group and the control group. For each
mouse, the thickness of saline-injected paw was
deduced from that of the carrageenan-injected paw
(inflamed paw) at all time points. Each mouse served
as its own control. For every time point, the mean
(n= 6) and standard deviation of these differences
were calculated. As can be seen from pharmacody-
namic profiles, the development of an edema caused
by carrageenan was prevented entirely only in the
CBD-pretreated group of mice. The delta in paw
thickness of CBD-pretreated mice was statistically
different from that of the non-pretreated mice starting
from 1 h post carrageenan injection and lasting until
the end of the inflammation course.
4. Discussion
Cannabinoids are lipid-soluble neutral compounds
with a very high membrane/aqueous solution-parti-
tioning coefficient. As such, they can penetrate into
lipid bilayer regions of synthetic and biological mem-
branes and cause perturbation of ordered phospholipid
regions [18]. The presence of the highly polar pheno-
lic group in the cannabinoid interacting with one or
more corresponding polar groups at the bilayer inter-
face is the pivotal event involved in membrane
perturbation [19].
CLSM and DSC data show that interactions occur
between CBD and PL-90, suggesting the formation
of an eutectic mixture. CBD’s thermodynamic inter-
action with PL-90 caused a decrease in the heat of
transition of PL-90 and reduction of pre-transition
peak with almost no effect on the melting tempera-
ture. Previous work has shown that CBD and D
1
-
THC have a remarkable fluidizing effect on dipalmi-
toyl phosphatidylcholine liposomes [18]. CBD and
D
1
-THC affect the transition of phospholipids from
crystalline gel to liquid-crystalline state by reducing
both the melting temperature and the enthalpy of
melting of the phospholipid on DSC thermograms
[18 20].
As we have previously shown, eutectic systems
could increase transdermal permeation through en-
hancer-membrane as well as drug-enhancer interac-
tions [12]. This interaction may contribute to an
enhanced fluidity of ethosomes and further affect the
delivery of cannabinoid.
In vivo occluded application of CBD ethosomes to
the abdominal skin of CD1 nude mice resulted in
significant accumulation of the drug in the skin and in
the underlying muscle. Upon application of the etho-
somal system to the abdomen of ICR mice for 72 h,
the kinetic profile of CBD’s plasma concentration
shows that steady-state (SS) levels were reached at
about 24 h and lasted at least until the end of the
experiment.
In an earlier work performed in our laboratory on
D
6
-THC’s transdermal permeation, systems contain-
ing 32 mg D
6
-THC in a vehicle composed of 10% w/
w oleic acid in propylene glycol/ethanol/polyethylene
glycol/water were tested. In this work, the systems
were applied to the backs of hairless rats on an
occluded surface of 6.5 cm
2
for 48 h [21].This
permeation-enhancing combination was chosen after
it had been proven to have the best enhancement in a
series of in vitro and in vivo experiments with
different non-saturated fatty acids [22]. Steady-state
THC serum concentrations were reached after 17 h and
remained stable for about 14 h. C
max
was about 0.05
Ag/ml. Following the SS phase, the concentration
slowly declined with time, with relatively high levels
found in the serum until the end of the experiment
[21]. Despite the differences in the animal models, a
comparison between data obtained in experiments
with the two cannabinoids, which closely resemble
each other chemically, suggests that the ethosomes
enhance skin permeation to a much greater extent than
the permeation enhancing combination of oleic acid.
We did not conduct a blood/plasma partition study
of CBD. However, in the dog it was shown that there
is a low uptake of CBD by the blood cells. Stability
M. Lodzki et al. / Journal of Controlled Release 93 (2003) 377–387 385
tests carried out with CBD in dog blood showed that
CBD is stable in blood [5]. Furthermore, CBD, like
THC, is highly bound to serum proteins [23].
The anti-inflammatory effect of CBD ethosomal
systems was evaluated using carrageenan-induced
aseptic paw inflammation in male ICR mice. Carra-
geenan is a sulphated cell wall polysaccharide found
in certain red algae. Upon injection into mice paws,
carrageenan provokes a local, acute inflammatory
reaction, which is a suitable method for evaluating
anti-inflammatory agents [24]. Carrageenan elicits a
time-dependent increase in paw depth, which consists
of a significant increase after 1 h and a maximum
inflammation occurring at 4 h post injection [15,25].
More specifically, the time course of development of
this hind-limb edematous response consists of: (1) an
immediate (0 60 min post carrageenan injection)
response; (2) an appreciable non-phagocytic edema;
and (3) a late dual phagocytic inflammatory response.
Three phases compose the non-phagocytic immediate
response: the first component based on direct physical
damages at the injection site develops in the 0- to 2-
min interval; the second component, which develops
in the 2- to 10-min interval, is equally produced by
serotonin and arachidonic acid metabolites and is
therefore inhibited by pretreatment with arachidonate
cyclooxygenase inhibitors and antiserotonin agents;
the third component is unaffected by these drugs [26].
Considering what we know of carrageenan-in-
duced aseptic paw inflammation the reaction seen in
the non-pretreated mice was anticipated, even though
the timing of our inflammation was somewhat shorter
than previously reported in the literature. This differ-
ence may be attributed to the use of a different type of
carrageenan, since most reports do not specify the
type used.
In the CBD-pretreated mice, the course of inflam-
mation was quite different. A difference was seen
between the saline and the carrageenan-injected paws
at all times during the experiment, indicating that the
inflammation was prevented by CBD. This effect is
further emphasized in Fig. 5, where it can be seen that
the paw thickness of CBD-pretreated mice is statisti-
cally different from that of the non-pretreated mice
starting from 1 h post carrageenan injection. Fig. 5
clearly shows that in the CBD-pretreated group of mice
the inflammation and edema induced by sub-plantar
injection of carrageenan were prevented altogether.
Tissue damage following carrageenan injection is
a complex phenomenon, involving many different
mediators and pathways to produce inflammatory
hyperalgesia (e.g., arachidonic acid metabolites, his-
tamine, 5-HT, bradykinin, neurokinins, cytokines,
NO, nerve growth factor (NGF), etc.) [1]. The trans-
dermal pretreatment with CBD might prevent the
inflammatory process by affecting the capacity of
macrophages to process antigens and IL-1; preventing
the arachidonic acid metabolism by inhibition of
cycloxygenase and lipoxygenase [27]; and inhibition
of NO production by peritoneal macrophages [1].
CBD is a compound with potentially broad ther-
apeutic applications, which possesses a potent anti-
inflammatory effect, several hundred times that of
aspirin [1]. Oral administration of CBD has a num-
ber of disadvantages. CBD has an extremely low
oral bioavailability (6% in humans), that results from
a high extraction ratio in the liver, possible instability
at gastric pH and incomplete absorption due to the
molecule’s high lipophilicity. By delivering CBD
through the skin, drawbacks associated with oral
delivery can be avoided. Transdermal drug adminis-
tration could also provide a means to obtain constant
systemic drug levels with no fluctuation in plasma
drug concentration. Moreover, it is known that
transdermal delivery systems are more comfortable
to the patients and therefore result in higher treat-
ment compliance. However, since CBD is a highly
lipophilic molecule [6], it accumulates within the
stratum corneum, with no permeation to deeper skin
layers [7].
Our results prove that ethosomal carrier efficiently
delivered CBD systemically to the inflamed organ and
enabled therapeutically anti-inflammatory levels at the
site. This study suggests that transdermal CBD may
be valuable in the treatment of chronic inflammatory
diseases.
Acknowledgements
Profs. E. Touitou and R. Mechoulam are
affiliated with David R. Bloom Center of Pharmacy
at the School Pharmacy, The Hebrew University of
Jerusalem.
This work was partially supported by the Szold
Fund, The Hebrew University of Jerusalem.
M. Lodzki et al. / Journal of Controlled Release 93 (2003) 377–387386
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Plasma levels of cannabidiol (CBD) were ascertained weekly in 14 Huntington's disease patients undergoing a double-blind, placebo-controlled, crossover trial of oral CBD (10 mg/kg/day=about 700 mg/day) for 6 weeks. The assay procedure involved trimethylsilyl (TMS) derivatization of CBD and the internal standard delta-6-tetrahydrocannabinol (THC), capillary column gas chromatography, ion trap mass spectroscopy in positive ion chemical ionization mode using isobutane, and calculations of CBD levels based on peak ion intensity of the 387 M+H peak of delta-6-THC-TMS and the 459 M+H peak of CBD-2TMS. The sensitivity of the assay was about 500 pg/ml, and the precision was about 10–15%. Mean plasma levels of CBD ranged from 5.9–11.2 ng/ml over the 6 weeks of CBD administration. CBD levels averaged 1.5 ng/ml one week after CBD was discontinued, and were virtually undetectable thereafter. The elimination half-life of CBD was estimated to be about 2–5 days, and there were no differences between genders for half-life or CBD levels. Additionally, no plasma delta-1-THC, the major psychoactive cannabinoid of marijuana, was detected in any subject.
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The interaction of hashish compounds, delta 1-tetrahydrocannabinol and cannabidiol, with dipalmitoyl phosphatidylcholine was investigated using differential scanning calorimetry. Both drugs affect the transition of dipalmitoyl phosphatidylcholine from the gel to liquid crystalline state, decreasing both the melting temperature and the enthalpy of melting. At a drug to dipalmitoyl phosphatidylcholine ratio of approx. 1:5, two peaks appear in the transition profile, suggesting a phase separation in the drug dipalmitoyl phosphatidylcholine mixture.