U.S. patent application number 16/560342 was filed with the patent office on 2020-03-12 for cannabis sativa derived formulation for transmucosal and transdermal delivery.
This patent application is currently assigned to NuVessl, Inc.. The applicant listed for this patent is NuVessl, Inc.. Invention is credited to Deborah Duffey, Tanya Rhodes.
Application Number | 20200078427 16/560342 |
Document ID | / |
Family ID | 69719352 |
Filed Date | 2020-03-12 |
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United States Patent
Application |
20200078427 |
Kind Code |
A1 |
Rhodes; Tanya ; et
al. |
March 12, 2020 |
Cannabis Sativa Derived Formulation for Transmucosal and
Transdermal Delivery
Abstract
A Cannabis sativa-derived formulation for transmucosal and
transdermal delivery is disclosed comprising Cannabis
sativa-derived compounds nanoencapsulated in phospholipid-based
vesicles. A method of encapsulating cannabis-derived compounds in
nanosized phospholipid vesicles is also disclosed. Cannabis
sativa-derived extracts have enhanced bioavailability when
encapsulated in nanosized phospholipid vesicles prior to
administration to a subject as compared to non-encapsulated
cannabinoids. Also disclosed herein are methods of transmucosal and
transdermal administration of the formulation having phospholipid
vesicles with nanoencapsulated Cannabis sativa-derived
substances.
Inventors: |
Rhodes; Tanya; (Largo,
FL) ; Duffey; Deborah; (Safety Harbor, FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NuVessl, Inc. |
Calgary |
|
CA |
|
|
Assignee: |
NuVessl, Inc.
Calgary
CA
|
Family ID: |
69719352 |
Appl. No.: |
16/560342 |
Filed: |
September 4, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62727996 |
Sep 6, 2018 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 36/185 20130101; A61K 31/352 20130101; A61K 9/006 20130101;
A61K 9/51 20130101; A61K 9/127 20130101; A61K 9/1075 20130101; A61K
31/05 20130101; A61K 31/353 20130101; A61K 47/10 20130101; A61K
9/06 20130101; A61K 9/7023 20130101; A61K 47/24 20130101; A61K
47/44 20130101 |
International
Class: |
A61K 36/185 20060101
A61K036/185; A61K 31/352 20060101 A61K031/352; A61K 9/107 20060101
A61K009/107; A61K 47/10 20060101 A61K047/10; A61K 47/44 20060101
A61K047/44 |
Claims
1. A composition comprising: one or more Cannabis sativa-derived
substances nanoencapsulated in phospholipid vesicles having
phospholipids, ethanol and water, wherein phosphatidylcholine
comprises at least 50% by weight of the phospholipids in the
phospholipid vesicles; said Cannabis sativa-derived substances
being selected from cannabidiol (CBD), tetrahydrocannabinol (THC),
Cannabis sativa-derived terpenes, Cannabis sativa-derived
flavonoids, a whole plant extract of Cannabis sativa, and
combinations thereof.
2. The composition of claim 1, wherein the concentration of
Cannabis sativa-derived substance encapsulated in the phospholipid
vesicles is from 0.01% to 1.0% w/w.
3. The composition of claim 1, wherein the phospholipid vesicles
having the encapsulated Cannabis sativa-derived substance are sized
from 25 nm to 200 nm.
4. The composition of claim 1, wherein the Cannabis sativa-derived
substance is cannabidiol (CBD).
5. The composition of claim 1, wherein the Cannabis sativa-derived
substance is tetrahydrocannabinol (THC).
6. The composition of claim 1, wherein the Cannabis sativa-derived
substance is a combination of cannabidiol (CBD) and
tetrahydrocannabinol (THC).
7. The composition of claim 1, wherein the Cannabis sativa-derived
substance is a whole plant extract of Cannabis sativa.
8. The composition of claim 1, wherein the composition is
formulated for transmucosal or transdermal administration.
9. A composition comprising one or more Cannabis sativa-derived
substances nanoencapsulated in phospholipid vesicles sized from 25
nm to 200 nm, said phospholipid vesicles comprising phospholipids,
ethanol and water; said Cannabis sativa-derived substances being
selected from cannabidiol (CBD), tetrahydrocannabinol (THC),
Cannabis sativa-derived terpenes, Cannabis sativa-derived
flavonoids, a whole plant extract of Cannabis sativa, and
combinations thereof.
10. The composition of claim 9, wherein the concentration of
Cannabis sativa-derived substance encapsulated in the phospholipid
vesicles is from 0.01% to 1.0% w/w.
11. The composition of claim 9, wherein the phospholipids in the
phospholipid vesicles have at least 50% phosphatidylcholine by
weight.
12. The composition of claim 9, wherein the Cannabis sativa-derived
substance is cannabidiol (CBD).
13. The composition of claim 9, wherein the Cannabis sativa-derived
substance is tetrahydrocannabinol (THC).
14. The composition of claim 9, wherein the Cannabis sativa-derived
substance is a combination of cannabidiol (CBD) and
tetrahydrocannabinol (THC).
15. The composition of claim 9, wherein the Cannabis sativa-derived
substance is a whole plant extract of Cannabis sativa.
16. The composition of claim 9, wherein said phospholipid vesicles
with the nanoencapsulated Cannabis sativa-derived substance are
administered to the oral cavity of a subject for transmucosal
uptake of the Cannabis sativa-derived substance.
17. A composition comprising one or more Cannabis sativa-derived
substance nanoencapsulated in phospholipid vesicles sized from 25
nm to 200 nm, said Cannabis sativa-derived substance concentration
is from 0.01% to 1.0% w/w, and said phospholipid vesicles
comprising phospholipids, ethanol and water.
18. The composition of claim 17, wherein the Cannabis
sativa-derived substance is selected from cannabidiol (CBD),
tetrahydrocannabinol (THC), Cannabis sativa-derived terpenes,
Cannabis sativa-derived flavonoids, a whole plant extract of
Cannabis sativa, and combinations thereof.
19. The composition of claim 17, wherein the phospholipids in the
phospholipid vesicles have at least 50% phosphatidylcholine by
weight.
20. The composition of claim 17, wherein the Cannabis
sativa-derived substance is cannabidiol (CBD).
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/727,996 filed Sep. 6, 2018, which is
incorporated by reference into this utility patent application.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
TECHNICAL FIELD OF INVENTION
[0003] The present invention relates to encapsulation of
cannabinoid compounds, compositions and uses thereof.
BACKGROUND OF THE INVENTION
[0004] During most of the 20th century, the United States Food and
Drug Administration ("FDA") questioned the safety of cannabis due
to its potential for abuse, as well as the adverse cardiovascular,
reproductive and pulmonary effects associated with inhalation of
any type of smoke. In 1999, the Office of National Drug Control
funded a study by the Institute of Medicine to evaluate medicinal
uses of cannabis. The outcome of this 1999 study was a
recommendation to test alternative cannabinoid delivery systems for
medicinal use (other than inhalation of cannabis smoke).
[0005] Since then, a number of pharmaceutical companies have
analyzed the whole plant extract (and cannabidiol (CBD) and
tetrahydrocannabinol (THC)) for possible medicinal uses. Some of
these extracts have been approved in Canada for neuropathic pain in
multiple sclerosis and as an analgesic for cancer pain. It is
currently in phase III trials in the US for a cancer pain
indication.
[0006] Many studies are underway looking at the individual
components of CBD and THC as well as the many specific isolates, to
better define the mechanisms of action with respect to the
different receptors in the body. According to the United States
National Institute of Health ("NIH") there are more than 60
systematic reviews discussing the safety, toxicology, potency, and
therapeutic potential of cannabinoids. Preclinical trials over the
past four decades have found that the cannabinoids show promise as
an anti-inflammatory, neuroprotectant, analgesic, anti-tumoral
agent and anti-psychotic. Cannabidiol has also been found to be
effective for control of seizures associated with certain types of
epilepsy. Certain cannabinoids, like CBD, have been well-studied
and are well tolerated and safe in humans, even at high doses over
a period of time.
[0007] Cannabis sativa has over 483 known compounds, over 60 of
which are classified as cannabinoids, many of which have mental and
physical effects, including tetrahydrocannabinol (THC) and
cannabidiol (CBD). Cannabidiol (CBD) is one of the most prevalent
chemical compounds in the cannabis plant. Among the other
cannabis-derived compounds are a variety of terpenes. These
terpenes are oils secreted from the plant which give the plant its
characteristic odor. Terpenes produce physical effects similar to
those seen with CBD.
[0008] Hemp is a variety of the Cannabis sativa plant species that
is grown specifically for the industrial uses of its derived
products. Although cannabis used as a drug and hemp for industrial
use both derive from the species Cannabis sativa and contain
tetrahydrocannabinol (THC), the strains are distinct and have
unique phytochemical compositions and uses. Hemp has lower
concentrations of THC and higher concentrations of cannabidiol
(CBD), which decreases or eliminates its psychoactive effects. The
higher concentrations of cannabidiol and lower concentrations of
THC make hemp an ideal source for extraction of CBD.
[0009] THC is the primary compound associated with cannabis
psychoactive effects, while CBD does not appear to have
psychoactive effects. Unlike THC, CBD is non-psychoactive, but
still has an effect on the body. The THC portion of the plant is
the psychoactive ingredient and therefore progressing the use of
medical CBD alone is viewed as viable.
[0010] When considering the medical use of a Cannabidiol (CBD)
substance, the bioavailability of the CBD substance is the degree
and rate at which the CBD is absorbed into the body or is made
available at the site of physiological activity. This degree and
rate of absorption is an essential determining factor as to the
efficacy of the drug. There has been very little comparable testing
done on the bioavailability of CBD through the different modes of
administration in humans, and it is critical to gain an
understanding of the pharmacokinetics of CBD to ensure that it is
controlled and understood for each route of administration and any
specific indications.
[0011] Even though oral administration of CBD has shown anecdotal
positive effects, the bioavailability of oral CBD administrated
substances appears to be very low (.about.6%-15%) due to the "first
pass" metabolism." There is also been shown to be a great variation
from individual to individual in the absorption rates for oral CBD
administrated substances, with the effects generally lasting
between 5-8 hours resulting in a lower re-medication rate.
Sublingual (under the tongue) and buccal (cheek or gums) have shown
similar bioavailability results to oral administration. While
sublingual or buccal is not as fast acting as smoking/vaporizing,
it is considered a much safer option than smoking.
[0012] Studies have shown oromucosal bioavailability to be
approximately 35% bioavailability. With the exception of
intravenous (IV) application, smoking and vaporizing shows the
highest bioavailability in the shortest amount of time and as such
becomes the target standard to achieve by a different route of
administration (2%-56% with average around 40%); however, the
length of time CBD remains in the body via this route is only
around 3 hours. Smoking and vaporizing has historically been the
route of administration for experienced users, but is not
considered the most acceptable route of administration due to
exposure to the adverse health consequences of inhaling smoke in
the lungs. These adverse health impacts that arise with smoking and
vaporizing make it an unhealthy choice for the administration of a
CDB substance.
[0013] Recent studies have suggested a clear role for CBD as a
medical therapy for many disorders; however, the route of
administration severely impacts the bioavailability of the CBD, and
in all acceptable cases the bioavailability remains low. A route of
administration that is safe and controlled, that reaches the
bloodstream as quickly as smoking, has the highest peak value, and
remains in the bloodstream for the longest time is needed.
SUMMARY OF THE INVENTION
[0014] Disclosed herein is a composition comprising one or more
Cannabis sativa-derived substances nanoencapsulated in phospholipid
vesicles having phospholipids, ethanol and water.
Phosphatidylcholine comprises at least 50% by weight of the
phospholipids in the phospholipid vesicles. The Cannabis
sativa-derived substances for encapsulation may be selected from
cannabidiol (CBD), tetrahydrocannabinol (THC), Cannabis
sativa-derived terpenes, Cannabis sativa-derived flavonoids, a
whole plant extract of Cannabis sativa, and combinations
thereof.
[0015] The disclosed composition has a concentration of Cannabis
sativa-derived substance encapsulated in the phospholipid vesicles
from 0.01% to 1.0% w/w. The phospholipid vesicles having the
encapsulated Cannabis sativa-derived substance are sized from 25 nm
to 200 nm. The encapsulated Cannabis sativa-derived substances may
be a combination of cannabidiol (CBD) and tetrahydrocannabinol
(THC). The Cannabis sativa-derived substances for encapsulation may
be selected from cannabidiol (CBD), tetrahydrocannabinol (THC),
Cannabis sativa-derived terpenes, Cannabis sativa-derived
flavonoids, a whole plant extract of Cannabis sativa, and
combinations thereof.
[0016] The disclosed composition has one or more Cannabis
sativa-derived substances nanoencapsulated in phospholipid vesicles
formulated for transmucosal or transdermal administration. The
composition may be administered to the oral cavity of a subject for
transmucosal uptake of the Cannabis sativa-derived substance. The
Cannabis sativa-derived substances for encapsulation are selected
from cannabidiol (CBD), tetrahydrocannabinol (THC), Cannabis
sativa-derived terpenes, Cannabis sativa-derived flavonoids, a
whole plant extract of Cannabis sativa, and combinations
thereof.
[0017] The present invention is a composition formulated from a
Cannabis sativa-derived substance for transmucosal and transdermal
delivery using encapsulation in phospholipid carriers. Cannabis
sativa-derived substances for encapsulation are selected from
cannabidiol (CBD), tetrahydrocannabinol (THC), Cannabis
sativa-derived terpenes, Cannabis sativa-derived flavonoids, a
whole plant extract of Cannabis sativa, and combinations thereof.
The Cannabis sativa-derived substance may be cannabidiol (CBD). The
Cannabis sativa-derived substance may be tetrahydrocannabinol
(THC). The Cannabis sativa-derived substance may be a combination
of cannabidiol (CBD) and tetrahydrocannabinol (THC). The Cannabis
sativa-derived substance may be a whole plant extract of Cannabis
sativa.
[0018] The composition formulated for transmucosal or transdermal
delivery of Cannabis sativa derived substances in the present
invention is formulated to be encapsulated in a phospholipid
delivery system. For the present invention, one or more Cannabis
sativa-derived substance is nanoencapsulated in phospholipid
vesicles having phospholipids, ethanol and water. The phospholipid
vesicles having the encapsulated Cannabis sativa-derived substance
are sized from 25 nm to 200 nm. Phosphatidylcholine comprises at
least 50% by weight of the phospholipids in the phospholipid
vesicles. The concentration range of Cannabis sativa-derived
substance encapsulated in the phospholipid vesicles is from 0.01%
to 1.0% w/w.
[0019] For transmucosal administration, the phospholipid vesicles
with the nanoencapsulated Cannabis sativa-derived substance are
administered to the oral cavity of a subject for transmucosal
uptake of the Cannabis sativa-derived substance. Transmucosal
delivery can be via liquids such as drops, sprays, aerosols or
shots, gels, pastes, lozenges, gums, gummy candies, hard candies,
orally dissolving strips, tablets, swish and swallow preparations,
or other form suitable for contact to oral mucosa. For transdermal
administration, the phospholipid vesicles with the nanoencapsulated
Cannabis sativa-derived substance are applied to the epidermis of a
subject for transdermal uptake of the Cannabis sativa-derived
substance. Transdermal delivery can be via a topically applied
preparation, such as a cream, lotion, ointment, wax, topically
applied spray, gel, balm, transdermal patch or other transdermal
application means.
BRIEF DESCRIPTION OF THE FIGURES
[0020] FIG. 1 is a graph showing a comparison of serum levels of
encapsulated vs. non-encapsulated CBD against historical data.
DETAILED DESCRIPTION
[0021] Disclosed herein is a composition comprising Cannabis
sativa-derived substances encapsulated in a phospholipid delivery
system. The Cannabis sativa-derived substances for encapsulation
are selected from cannabidiol (CBD), tetrahydrocannabinol (THC),
Cannabis sativa-derived terpenes, Cannabis sativa-derived
flavonoids, a whole plant extract of Cannabis sativa, and
combinations thereof.
[0022] Cannabis sativa-derived substances for encapsulation may be
cannabidiol (CBD), tetrahydrocannabinol (THC), or cannabidiol (CBD)
and tetrahydrocannabinol (THC). The Cannabis sativa-derived
substances can be derived from all varieties of Cannabis sativa,
including hemp. Cannabis varieties used for hemp production are one
preferred source of CBD because of a high concentration of CBD with
a low concentration of THC in materials from those plants.
[0023] Cannabis-derived compounds can be extracted from plant parts
of Cannabis sativa, either from marijuana grade Cannabis or from
industrial grade hemp. There are numerous Cannabis-derived
compounds with the most prevalent being cannabinoids, such as
cannabidiol (CBD) and tetrahydrocannabinol (THC), terpenes and
flavonoids. CBD and THC are the best known of the cannabis-derived
compounds and both have been studied for medical applications.
[0024] The cannabis-derived compounds are extracted from plant
parts of Cannabis sativa. For use in the claimed invention,
cannabis-derived compounds can be extracted from Cannabis plants
having 0.3% tetrahydrocannabinol (THC) or less in the leaves and
flowering heads (industrial hemp), from Cannabis plants having more
than 0.3% tetrahydrocannabinol (THC) in the leaves and flowering
heads, from the whole cannabis plant, or any combination
thereof.
[0025] The cannabis-derived compounds can be extracted from the
Cannabis plant parts using solvents such as butane, propane or
ethanol, or by using a super-critical CO.sub.2 extraction process.
CBD can be derived from cannabis or hemp plant parts by extraction
processes, including organic solvent extraction using one or more
organic solvent, including, but not limited to, butane, propane and
alcohols, with ethanol the preferred alcohol. Solvent-free CBD can
be derived from cannabis or hemp plant parts by a super-critical
CO.sub.2 extraction process. CBD extracts useful for the claimed
invention are in a liquid, oil or crystalline form.
[0026] Solvent directed processes, such as butane or propane
extraction, must be purged of residual solvent prior to use.
Ethanol is often used as an extraction solvent because the ethanol
does not require purging to remove the ethanol, as do butane or
propane. The composition of the extracts will vary based on the
type of solvent used, with solvents such as butane and propane
extracting only lipid soluble compounds, while alcohols extract
both lipid and water soluble compounds. Extracts produced by
solvent extraction typically have an oily or waxy consistency and
may require additional processing to remove impurities.
[0027] Supercritical CO.sub.2 extraction uses phase changes in
carbon dioxide, utilizing temperature and pressure, to produce an
extract having a high purity that does not require purging to
remove solvent residues. Because CO.sub.2 does not leave residues
in the extracted materials, the super-critical CO.sub.2 extraction
process yields an extract with greater than 99% purity that is free
of solvent residues. Extracts produced by CO.sub.2 extraction are a
white needle-like crystalline powder.
[0028] THC can also be extracted from cannabis or hemp plant parts
by extraction using an organic solvent, such as butane, propane or
ethanol, or by the super-critical CO.sub.2 extraction process.
Additionally, solvents such as polyethylene glycol 400 (PEG 400),
glycerin, or oelic acid can be used instead of or in addition to
the butane, propane and ethanol solvent processes. Oils are the
most commonly available form for THC extracts.
[0029] Terpenes and flavonoids are cannabis-derived compounds that
can also be extracted from cannabis plant parts using butane,
propane, ethanol or CO.sub.2 extraction processes. Terpenes are
aromatic compounds and flavonoids are phytonutrients, and these
cannabis-derived compounds can be used as isolates or in
combination with the CBD and/or THC cannabinoids. Terpenes and
flavonoids work synergistically with cannabinoids to produce
variations in benefits and side effects associated with the
cannabinoids.
[0030] Cannabinoids other than CBD and THC can be derived from
Cannabis sativa and may also be used in the disclosed invention.
Most of the other cannabinoids are non-psychoactive or mildly
psychoactive, and many have physiological effects similar to the
effects seen for CBD. These other cannabinoids may work
synergistically to enhance the effects of CBD and THC.
[0031] Additional cannabinoids that may be used in the disclosed
invention include, but are not limited to: Cannabigerol CBG),
Cannabidiolic Acid CBDA), Tetrahydrocannabinolic Acid (THCA),
Cannabinol (CBN), Cannabichromene (CBC), Cannabicyclol (CBL),
Cannabivarin (CBV), Tetrahydrocannabivarin (THCV), Cannabidivarin
(CBDV), Cannabichromevarin (CBCV), Cannabigerovarin (CBGV),
Cannabigerol monomethyl ether (CBGM), Cannabielsoin (CBE),
Cannabicitran (CBT), and combinations thereof. Whole plant extracts
of Cannabis sativa may also be used in the disclosed invention.
[0032] CBD and THC extracts can be used in combination in the
nanosized phospholipid vesicle composition. CBD and THC are
extracted from cannabis plants as separate isolates, either as oils
or crystals, and then combinations of these extracts can be
encapsulated in the phospholipid vesicles. Whole plant cannabis
extracts can also be encapsulated in the nanosized phospholipid
vesicles. Whole plant cannabis extract is an oily or waxy material
that is soluble in lipids and alcohols. Whole plant extracts will
vary in the amount of cannabinoids in the extract depending on
whether the extract is prepared from marijuana-grade cannabis or
industrial-grade hemp. Both types of whole plant extracts will have
cannabinoids, terpenes and flavonoids, with the primary difference
being the concentrations of CBD and THC in the final extract.
[0033] Nano-encapsulated CBD has a greater bioavailability than the
equivalent, non-encapsulated form of a CBD substance, thus reducing
the need for frequent re-medication, while providing a greater
bioavailability, greater active duration and a greater ease of use
resulting in increased compliance. That is, one way to enhance the
bioavailability of CBD and other cannabinoids is to use
nano-encapsulation of the CBD formulation using phospholipid
vesicles.
[0034] Phospholipid vesicles are very similar to structures that
the body naturally produces with phospholipid vesicles being tiny
hollow spheres that have the ability to carry both water soluble
and fat soluble compounds through the body and cell membranes.
Encapsulating cannabinoids in this manner would allow the
cannabinoids to enter the bloodstream at a much greater
bioavailability than a non-encapsulated form of the same
therapeutic compounds. Phospholipid nano-encapsulation has shown
promise in enhancing the speed of absorption as well as overall
bioavailability of Cannabis sativa-derived substances.
[0035] A single dose of CBD in its nano-encapsulated form (using
transdermal and sublingual administration methods) will reach the
bloodstream faster, have a higher peak availability, and remain in
the bloodstream longer, than its non-encapsulated counterpart.
Nano-encapsulation technology is safe and has been for used
successfully for topical drug delivery and oral nutritional
delivery in human subjects. The nano-encapsulation technique
enhances the bioavailability, uptake, and sustainability of the
cannabinoids in the body.
[0036] Multiple routes of administration have been used for
Cannabis sativa-derived substances with transmucosal and
transdermal routes preferred for cannabinoids nanoencapsulated in
phospholipid vesicles. A CBD amount of .about.10 mg is generally
considered a "starting dose" by the medical community, with amounts
typically going up to 300 mg daily for specific disease states.
Cannabis sativa-derived substances which are nanoencapsulated in
phospholipid vesicles can be administered in dosages ranging from 1
mg to 300 mg per day in single or divided doses. Optionally,
dosages range from 10 mg to 100 mg per day in single or divided
doses.
[0037] Disclosed herein is a composition comprising one or more
Cannabis sativa-derived substance nanoencapsulated in phospholipid
vesicles having phospholipids, ethanol and water. The phospholipid
vesicles having the encapsulated Cannabis sativa-derived substance
are sized from 25 nm to 200 nm. Phosphatidylcholine comprises at
least 50% by weight of the phospholipids in the phospholipid
vesicles. The concentration range of Cannabis sativa-derived
substance encapsulated in the phospholipid vesicles is from 0.01%
to 1.0% w/w.
[0038] Cannabis-derived extracts have enhanced bioavailability when
encapsulated in nanosized phospholipid vesicles prior to
administration to a subject as compared to non-encapsulated
cannabinoids. Also disclosed herein is a method of using the
composition having nano-encapsulated cannabis-derived compounds to
administer the cannabis-derived active compounds to a subject in
need of treatment. Cannabis-derived substances encapsulated in
nanosized phospholipid vesicles can be advantageously administered
through transmucosal and transdermal routes.
[0039] A delivery option comprising encapsulating one or more
cannabis-derived compounds as passenger molecules in a potentiated
nanolipidic process capable of delivering the cannabis-derived
compound to a subject is disclosed. The route of delivery can be
oral transmucosal (including sublingual and buccal) or
transdermal.
[0040] Disclosed herein is a composition formulated for
transmucosal delivery of Cannabis sativa derived substances
encapsulated in a phospholipid delivery system. Cannabis
sativa-derived substances for encapsulation are selected from
cannabidiol (CBD), tetrahydrocannabinol (THC), Cannabis
sativa-derived terpenes, Cannabis sativa-derived flavonoids, a
whole plant extract of Cannabis sativa, and combinations thereof.
Oral delivery can be via a transmucosal preparation, a
sublingual/buccal preparation, or a preparation administered to the
oral cavity. Transmucosal preparations can be liquids such as
drops, sprays, aerosols or shots, gels, pastes, lozenges, gums,
gummy candies, hard candies, orally dissolving strips, tablets,
swish and swallow preparations, or other form suitable for contact
to oral mucosa. The preparation may be applied to the mucosa under
the tongue (sublingual), inside the cheeks (buccal), or placed
inside the oral cavity.
[0041] Also disclosed herein is a composition formulated for
transdermal delivery of Cannabis sativa derived substances
encapsulated in a phospholipid delivery system. Cannabis
sativa-derived substances for encapsulation are selected from
cannabidiol (CBD), tetrahydrocannabinol (THC), Cannabis
sativa-derived terpenes, Cannabis sativa-derived flavonoids, a
whole plant extract of Cannabis sativa, and combinations thereof.
For transdermal administration, the phospholipid vesicles with the
nanoencapsulated Cannabis sativa-derived substance are applied to
the epidermis of a subject for transdermal uptake of the Cannabis
sativa-derived substance. Transdermal delivery can be via a
topically applied preparation, such as a cream, lotion, ointment,
wax, topically applied spray, gel, balm, transdermal patch or other
transdermal application means.
[0042] Disclosed is a method of nano-encapsulating a Cannabis
sativa-derived substance including the steps of preparing a
cannabis stock by dissolving a Cannabis sativa-derived substance in
an ethanolic stock having phospholipids, ethanol and water;
diluting the cannabis stock with a quantity of ethanol; combining
the diluted cannabis stock with a quantity of purified water having
a pH of 6-8; and mixing the diluted cannabis stock/water
combination vigorously to encapsulate the Cannabis sativa derived
substance in one or more phospholipid vesicle.
[0043] Cannabis sativa-derived substances for the disclosed
encapsulation method are selected from cannabidiol (CBD),
tetrahydrocannabinol (THC), Cannabis sativa-derived terpenes,
Cannabis sativa-derived flavonoids, a whole plant extract of
Cannabis sativa, and combinations thereof. The Cannabis
sativa-derived substance may be cannabidiol (CBD). The Cannabis
sativa-derived substance may be tetrahydrocannabinol (THC). The
Cannabis sativa-derived substance may be a combination of
cannabidiol (CBD) and tetrahydrocannabinol (THC). The Cannabis
sativa-derived substance may be a whole plant extract of Cannabis
sativa.
[0044] The ethanolic stock in the disclosed nano-encapsulation
method has 75-89% ethanol, 10-20% phospholipids and 1-5% water
(w/w). In the present method, phosphatidylcholine (PC) is at least
50% of the phospholipid total in the ethanolic stock. In the
present method, the phospholipid vesicles with nanoencapsulated
Cannabis sativa-derived substance are sized from 25 nm to 200 nm.
In the present method, the cannabis stock has a concentration range
from 1 part Cannabis sativa-derived substance to 10 parts ethanolic
stock up to 10 parts Cannabis sativa-derived substance to 1 part
ethanolic stock (w/w). In the present method, the quantity of
ethanol combined with the cannabis stock is at a ratio of 1:1 to
1:10 parts of cannabis stock to ethanol (by volume). In the present
method, the quantity of water combined with the diluted cannabis
stock is at a ratio from 1:5 to 1:25 parts of diluted cannabis
stock to water (by volume).
[0045] Disclosed is a method of preparing lipid vesicles
nanoencapsulating Cannabis sativa derived substances comprising the
steps of preparing a plurality of non-spherical phospholipid
vesicles having nanoencapsulated cannabidiol (CBD) derived from
Cannabis sativa by dissolving CBD in an ethanolic stock having
75-89% ethanol, 10-20% phospholipids and 1-5% water (w/w), diluting
the CBD-ethanol stock with a quantity of ethanol, and mixing the
diluted CBD-ethanol stock combination to incorporate the CBD in
said plurality of non-spherical phospholipid vesicles, said
vesicles sized less than 10 nm; adding a quantity of purified water
having a pH of 6-8 to the plurality of non-spherical phospholipid
vesicles; and mixing said plurality of non-spherical phospholipid
vesicles vigorously with said quantity of water to encapsulate the
CBD in spherical phospholipid vesicles sized from 25 nm to 200 nm.
A non-cannabis substance may optionally be dissolved in the
quantity of water prior to combining with the diluted cannabis
stock.
[0046] Disclosed is a method of preparing lipid vesicles
nanoencapsulating Cannabis sativa derived substances comprising the
steps of preparing a first plurality of non-spherical phospholipid
vesicles having nanoencapsulated cannabidiol (CBD) derived from
Cannabis sativa by dissolving CBD in an ethanolic stock having
75-89% ethanol, 10-20% phospholipids and 1-5% water (w/w), diluting
the CBD-ethanol stock with a quantity of ethanol, and mixing the
diluted CBD-ethanol stock combination to incorporate the CBD in
said first plurality of non-spherical phospholipid vesicles, said
vesicles sized less than 10 nm; preparing a second plurality of
non-spherical phospholipid vesicles nanoencapsulating a non-CBD
Cannabis sativa derived substance by dissolving the non-CBD
Cannabis sativa derived substance in an ethanolic stock having
75-89% ethanol, 10-20% phospholipids and 1-5% water (w/w), diluting
the non-CBD cannabis-ethanol stock with a quantity of ethanol, and
mixing the diluted non-CBD cannabis-ethanol stock combination to
incorporate the non-CBD Cannabis sativa in said second plurality of
non-spherical phospholipid vesicles, said vesicles sized less than
10 nm; combining said first plurality of non-spherical phospholipid
vesicles with said second plurality of non-spherical phospholipid
vesicles; adding a quantity of purified water having a pH of 6-8 to
the combined first and second plurality of non-spherical
phospholipid vesicles; and mixing said combined first and second
plurality of non-spherical phospholipid vesicles vigorously with
said quantity of water to encapsulate the CBD and non-CBD Cannabis
sativa derived substances in spherical phospholipid vesicles sized
from 25 nm to 200 nm. A non-cannabis substance may dissolved in the
quantity of water prior to combining with the diluted cannabis
stock.
[0047] A method for administration of a Cannabis sativa-derived
substance comprising the steps of: providing a preparation having
one or more Cannabis sativa-derived substance, nanoencapsulated in
one or more phospholipid vesicles having phospholipids, ethanol,
and water, and having a Cannabis sativa-derived substance
concentration of 0.01% to 1.0% w/w; and administering a quantity of
the preparation having 1 mg to 100 mg of Cannabis sativa-derived
substance to a subject in need of treatment. The Cannabis
sativa-derived substance is selected from cannabidiol (CBD),
tetrahydrocannabinol (THC), Cannabis sativa-derived terpenes,
Cannabis sativa-derived flavonoids, a whole plant extract of
Cannabis sativa, and combinations thereof. The Cannabis
sativa-derived substance may be cannabidiol (CBD),
tetrahydrocannabinol (THC) or a combination of cannabidiol (CBD)
and tetrahydrocannabinol (THC).
[0048] In the disclosed method, the preparation having one or more
Cannabis sativa-derived substance nanoencapsulated in one or more
phospholipid vesicles may be applied to an oral mucosa area of the
subject and the preparation is kept in contact with the oral mucosa
for 1 minute to 10 minutes or the preparation having one or more
Cannabis sativa-derived substance nanoencapsulated in one or more
phospholipid vesicles may be applied to an epidermal area of the
subject and the preparation is kept in contact with the epidermal
area for 1 minute to 24 hours. Transmucosal preparations can be
liquids such as drops, sprays, aerosols or shots, gels, pastes,
lozenges, gums, gummy candies, hard candies, orally dissolving
strips, tablets, swish and swallow preparations, or other form
suitable for contact to oral mucosa. The preparation may be applied
to the mucosa under the tongue (sublingual), inside the cheeks
(buccal), or placed inside the oral cavity. Transdermal delivery
can be via a topically applied preparation, such as a cream,
lotion, ointment, wax, topically applied spray, gel, balm,
transdermal patch or other transdermal application means
[0049] A method is disclosed for intraoral transmucosal
administration of a Cannabis sativa-derived substance comprising
the steps of: providing a preparation having one or more Cannabis
sativa-derived substance selected from cannabidiol (CBD),
tetrahydrocannabinol (THC), Cannabis sativa-derived terpenes,
Cannabis sativa-derived flavonoids, a whole plant extract of
Cannabis sativa, and combinations thereof, nanoencapsulated in one
or more phospholipid vesicles, said one or more phospholipid
vesicle having phospholipids, ethanol and water; applying a
quantity of the preparation having from 1 mg to 100 mg to the
subject's oral mucosa; and allowing the preparation to remain in
contact with the mucosa for a period of time ranging from 1 minute
to 10 minutes or may be kept in contact for 1 minute to 5 minutes.
The preparation may be applied to intraoral mucosa, including
sublingual and buccal mucosa. The preparation of nanosized
phospholipid vesicles has a Cannabis sativa-derived substance
concentration of 0.01% to 1.0% w/w, the phospholipid vesicles with
nanoencapsulated Cannabis sativa-derived substance are sized from
25 nm to 200 nm, and phosphatidylcholine (PC) is at least 50% of
the phospholipid total in the phospholipid vesicles.
[0050] A method for transdermal administration of a Cannabis
sativa-derived substance comprising the steps of: providing a
preparation of a Cannabis sativa-derived substance
nano-encapsulated in one or more phospholipid vesicle having
phospholipids, ethanol and water; applying a quantity of the
preparation having from 1 mg to 100 mg to an area of the subject's
epidermis; and allowing the preparation to remain in contact the
epidermis for a period of time ranging from 1 minute to 24 hours.
The Cannabis sativa-derived substance applied to the epidermis may
be cannabidiol (CBD), tetrahydrocannabinol (THC), or a combination
of cannabidiol (CBD) and tetrahydrocannabinol (THC). The
preparation is applied via a cream, lotion, ointment, wax, gel,
balm, spray or transdermal patch.
[0051] To prepare the nanoencapsulated cannabinoids, the
cannabis-derived extracts are first dissolved in an ethanolic stock
comprising ethanol, phospholipids and water. Phospholipids are
combined with ethanol and stirred at ambient room temperature until
dissolved. Optionally, the ethanol used in the ethanolic stock is
dehydrated 190 proof ethanol. A small quantity of water having a pH
of 6-8 is added to the ethanol/phospholipid mixture and stirred
until an optically clear ethanolic stock is formed. The ratio of
the components in the ethanolic stock has a range of 75-89%
ethanol, 10-20% phospholipids and 1-5% water, with a preferred
ratio of 80% ethanol/17.75% phospholipids/2.25% water (w/w).
Optionally, the phospholipids are derived from soy lecithin. The
phospholipids are selected from phosphatidylcholine (PC),
phosphatidylethanolamine (PE), phosphatidic acid (PA) and
phosphatidylinositol (PI), and mixtures thereof. Optionally,
phosphatidylcholine (PC) comprises at least 50% by weight of the
phospholipid mixture. Optionally, phosphatidylcholine comprises 65%
of the phospholipid total.
[0052] A cannabis stock is prepared by combining the ethanolic
stock with one or more cannabis-derived extract and mixed at
ambient room temperature until the extract is completely dispersed
in the ethanolic stock. The ratio range of cannabis-derived extract
to ethanolic stock is from 1 part cannabis-derived extract to 20
parts ethanolic stock to 20 parts cannabis-derived extract to 1
part ethanolic stock. Optionally, the ratio range of
cannabis-derived extract to ethanolic stock is from 1 part
cannabis-derived extract to 10 parts ethanolic stock to 10 parts
cannabis-derived extract to 1 parts ethanolic stock. In one
embodiment, the ratio of cannabis-derived extract to ethanolic
stock is 1:1. Optionally, the ratio of cannabis-derived extract to
ethanolic stock is any ratio between 0.5 g:4.5 g and 4.5 g:0.5 g.
In one embodiment, the ratio of cannabis-derived extract to
ethanolic stock is 1:1. In another embodiment, the ratio of
cannabis-derived extract to ethanolic stock is 0.5 g:4.5 g. In
another embodiment, the ratio of cannabis-derived extract to
ethanolic stock is 4.5 g:0.5 g. Mixing of cannabis-derived extract
into the ethanolic stock may be with a vortex, a magnetic stir-bar,
an overhead mixer or a propeller type mixer.
[0053] Following preparation of the cannabis stock, a quantity of
ethanol is added to the cannabis stock and thoroughly mixed at room
temperature. Optionally, the additional quantity of ethanol is
mixed with the cannabis stock using a vortex, a magnetic stir bar,
or an overhead mixer. This dilution with ethanol can range from 1:1
to 1:100 by volume, with 1 to 100 parts of ethanol added to 1 part
of the cannabis stock, inclusive of any amount between 1 and 100
parts of ethanol being added to 1 part of the cannabis stock.
Optionally, the cannabis stock is combined with the ethanol at a
ratio of 1:25 by volume. Optionally, the cannabis stock is combined
with the ethanol at a ratio of 1:10 by volume. Optionally, the
ethanol is added to the cannabis stock with the ethanol at 1:5 by
volume. Optionally, the cannabis stock is combined with the ethanol
at a ratio of 1:2.5 by volume. Optionally, the cannabis stock is
combined with the ethanol at a ratio of 1:1 by volume. The
secondary addition of ethanol adjusts the size of the lipid
vesicles with the vesicle size decreasing as the amount of ethanol
added increases. Following the addition of the secondary quantity
of ethanol, the vesicles are less than 10 nm diameter and have not
attained a spherical shape.
[0054] A quantity of an aqueous solvent comprising distilled or
deionized water having a pH of 6-8 is added to the ethanol-diluted
cannabis stock and thoroughly mixed at ambient room temperature
until a uniform composition having an opalescent appearance is
achieved. Optionally, the aqueous solvent is mixed with the
ethanol-diluted cannabis stock using a vortex, a magnetic stir bar,
or an overhead mixer.
[0055] This addition of aqueous solvent can range from 1:1 to 1:100
by volume, with 1 to 100 parts of aqueous solvent added to 1 part
of the ethanol-diluted cannabis stock, inclusive of any amount
between 1 and 100 parts of aqueous solvent being added to the
ethanol-diluted cannabis stock. Optionally, the ratio is from 1:1
to 1:25 parts of ethanol-diluted cannabis stock to aqueous solvent.
Optionally, the ratio is from 1:5 to 1:25 parts of ethanol-diluted
cannabis stock to aqueous solvent. Optionally, the ratio is 1:9
parts of ethanol-diluted cannabis stock to aqueous solvent.
[0056] Secondary passenger substances can be dissolved in the
aqueous solvent prior to combining with ethanol-diluted cannabis
stock. Optionally, secondary passengers are water soluble
cannabis-derived extracts. Optionally, the secondary passengers are
non-cannabis substances. Non-cannabis substances are substances
that can be used advantageously to enhance the usability of the
nanosized phospholipid vesicles. Optionally, the substances enhance
usability of the nanosized phospholipid vesicles as flavoring
agents, masking agents, penetrating agents, augmenting agents,
synergistic agents, or other agents to improve application and
bioavailability of the encapsulated passenger.
[0057] Spherical nanosized phospholipid vesicles result in the
opalescent composition when the aqueous solvent is fully combined
with the ethanol-diluted cannabis stock. The opalescent composition
has spherical nanosized phospholipid vesicles that are sized from
25 nm to 200 nm in diameter. Optionally, the vesicles are sized
from 80 nm to 100 nm. Optionally, the vesicles are about 80 nm in
diameter.
[0058] Cannabinoid compounds incorporated in the ethanol-diluted
cannabis-derived extract/ethanolic stock have a concentration range
of 0.1%40% (w/w). Following 1:10 dilution with the aqueous solvent,
the nanosized phospholipid vesicles have a concentration of 0.01%
to 1.0% (w/w). Optionally, the concentration of cannabinoid
compounds incorporated in the ethanol-diluted cannabis-derived
extract/ethanolic stock is from 1% to 2%. Optionally, following
1:10 dilution with the aqueous solvent, the nanosized phospholipid
vesicles have a cannabinoid compound concentration from 0.1% to
0.2% (w/w).
[0059] A cannabis stock having CBD is prepared by combining a
crystalline CBD isolate having greater than 99% purity with
ethanolic stock at a concentration range of 0.1%40% (w/w) and mixed
at ambient room temperature until completely dissolved. The
cannabis stock is then combined with a quantity of ethanol, 1:1 to
1:100 (by volume) and stirred until the mixture is homogenous. The
ethanol-diluted cannabis stock is then combined with a quantity of
aqueous solvent, 1:1 to 1:100 (by volume) and mixed until a uniform
composition having an opalescent appearance is achieved. The
opalescent composition has nanosized spherical phospholipid
vesicles that are from 25 nm to 200 nm in diameter. Optionally, the
vesicles are sized from 80 nm to 100 nm. Optionally, the vesicles
are about 80 nm in diameter.
[0060] A cannabis stock having THC is prepared by combining THC oil
at a concentration range of 0.1%40% (w/w) with ethanolic stock and
mixed at ambient room temperature until completely dissolved. The
cannabis stock is then combined with a quantity of ethanol, 1:1 to
1:100 (by volume), and stirred until the mixture is homogenous. The
ethanol-diluted cannabis stock is combined with a quantity of
water, 1:1 to 1:100 (by volume), and mixed until a uniform
composition having an opalescent appearance is achieved. The
opalescent composition has nanosized spherical phospholipid
vesicles that are from 25 nm to 200 nm in diameter. Optionally, the
vesicles are sized from 80 nm to 100 nm. Optionally, the vesicles
are about 80 nm in diameter.
[0061] Combinations of CBD and THC, at a concentration range of
0.1%-10% (w/w) of combined cannabinoids, can be co-encapsulated in
the nanosized phospholipid vesicles such that a combination
composition results. A cannabis stock is prepared by adding CBD
and/or THC separately or together to the ethanolic stock and mixed
at ambient room temperature until completely dissolved. The CBD/THC
cannabis stock combination is then mixed with a quantity of
ethanol, 1:1 to 1:100 (by volume), and further mixed until
homogeneous. The ethanol-diluted cannabis stock is then combined
with a quantity of aqueous solvent, 1:1 to 1:100 (by volume), and
mixed until a uniform composition having an opalescent appearance
is achieved. The opalescent composition has nanosized spherical
phospholipid vesicles that are from 25 nm to 200 nm in diameter.
Optionally, the vesicles are sized from 80 nm to 100 nm.
Optionally, the vesicles are about 80 nm in diameter.
[0062] Optionally, the CBD and THC are combined and encapsulated
together in a single addition to the ethanolic stock. Optionally,
the CBD and THC are encapsulated separately in the ethanolic stock
prior to the addition of the additional ethanol and the vesicles
having CBD are combined with the vesicles having THC after addition
of the additional ethanol to the individual preparations.
Optionally, the CBD and THC encapsulation vesicles are combined
prior to the addition of the aqueous solvent. Optionally, the CBD
and THC vesicles are combined after addition of the aqueous
solvent. The combining of the vesicles with two separately
encapsulated materials advantageously allows for tuning of the
ratios of the two compounds for specific applications as well as
allowing for the maximum concentration of each compound to be
individually encapsulated prior to combining.
[0063] In another embodiment, the THC is encapsulated as a
lipophilic passenger added to the ethanolic stock and mixed with
additional ethanol, and water-soluble CBD is added to the aqueous
solvent phase, then THC/ethanolic stock/ethanol is combined with
the CBD/aqueous solvent to form the final vesicles having both THC
and CBD encapsulated therein.
[0064] A whole plant cannabis stock can be prepared by combining
whole plant cannabis extracts at a concentration range of 0.1%40%
(w/w) with ethanolic stock and mixed at ambient room temperature
until completely dissolved. The whole plant cannabis stock is then
combined with a quantity of ethanol, 1:1 to 1:100 (by volume) and
mixed until homogenous. The ethanol-diluted cannabis stock is
combined with a quantity of aqueous solvent, 1:1 to 1:100, (by
volume) and mixed until a uniform composition having an opalescent
appearance is achieved. Optionally, the whole plant extract is a
pourable oil, a viscous oil, or a waxy oil. Optionally, the whole
plant extract is gently heated to liquefy the oils prior to
combining with the ethanolic stock. The opalescent composition has
nanosized spherical phospholipid vesicles that are from 25 nm to
200 nm in diameter. Optionally, the vesicles are sized from 80 nm
to 100 nm. Optionally, the vesicles are about 80 nm in
diameter.
[0065] Delivery options comprise encapsulating one or more
cannabis-derived compounds as passenger molecules in a potentiated
nanolipidic process capable of delivering the cannabis-derived
compound to a subject. Optionally, the route of delivery is oral,
via a transmucosal preparation, a sublingual preparation, a buccal
preparation, or an oral preparation. Optionally, the delivery route
is transdermal via a topically applied preparation, such as a
topically applied cream, lotion, ointment, wax, topically applied
spray, gel, balm, transdermal patch or other transdermal
application means.
[0066] Cannabis sativa-derived substances which are
nanoencapsulated in phospholipid vesicles can be administered in
dosages ranging from 1 mg to 300 mg per day in single or divided
doses or any dose between 1 mg and 300 mg per day. Optionally,
dosages range from 10 mg to 100 mg per day in single or divided
doses. Optionally, the dosages range from 1 mg to 20 mg per day in
a single or divided dose.
[0067] Nanoencapsulated cannabidiol (CBD) for transmucosal delivery
is disclosed. The nanoencapsulated lipid vesicles are formulated
for transmucosal delivery of the cannabis-derived compounds to the
mucosa of a subject. Optionally, the mucosa is oral, sublingual or
buccal mucosa.
[0068] A method of encapsulating cannabis-derived compounds for
transmucosal delivery is disclosed. The ethanolic stock for
preparing the encapsulated nanolipidic preparation is manipulated
by dilution with a non-aqueous solvent comprising ethanol and
further manipulated by dilution with an aqueous solvent comprising
water to achieve the desired transmucosal dose.
[0069] Disclosed herein is a formulation for transmucosal delivery
of Cannabis sativa derived substances in a phospholipid delivery
system. The substances can be derived from all varieties of
Cannabis sativa, including hemp. Cannabis varieties used for hemp
production are one preferred source of CBD because of a high
concentration of CBD with a low concentration of THC in materials
from those plants.
[0070] Cannabidiol can be extracted from hemp plant materials by a
supercritical carbon dioxide extraction process, wherein phase
changes induced in the CO.sub.2, utilizing temperature and
pressure, yield extracts free of toxic solvents. Other organic
solvents, such as ethanol, butane, and propane, can also be used to
extract Cannabis-derived substances, including cannabidiol (CBD),
tetrahydrocannabinol (THC), flavonoids and terpenes. The
transmucosal preparation is formulated for application to a subject
as oral transmucosal, buccal or sublingually-applied liquids (as
drops, sprays, aerosols or shots), gels, pastes, lozenges, gums,
gummy candies, hard candies, orally dissolving strips, tablets,
swish and swallow preparations or other transmucosal application
means. Optionally, flavoring or masking agents are added to the
preparation prior to administration. The preparation may be applied
to the mucosa under the tongue (sublingual), inside the cheeks
(buccal), or placed inside the oral cavity. Flavoring or masking
agents can be combined with the aqueous solvent used in preparing
the phospholipid vesicles.
[0071] Disclosed herein is a formulation for transdermal delivery
of Cannabis sativa derived substances in a phospholipid delivery
system. The substances can be derived from all varieties of
Cannabis sativa, including hemp. Cannabis varieties used for hemp
production are one preferred source of CBD because of a high
concentration of CBD with a low concentration of THC in materials
from those plants.
[0072] Cannabidiol can be extracted from hemp plant materials by a
supercritical carbon dioxide extraction process, wherein phase
changes induced in the CO.sub.2, utilizing temperature and
pressure, yield extracts free of toxic solvents. Other organic
solvents, such as ethanol, butane and propane can also be used to
extract Cannabis-derived substances, including cannabidiol (CBD),
tetrahydrocannabinol (THC), flavonoids and terpenes. The
transdermal preparation is formulated for application to skin as a
cream, lotion, ointment, wax, topically applied spray, gel, balm,
transdermal patch or other transdermal application means.
[0073] Single cannabinoid isolates, such as CBD and THC, can be
encapsulated in nanosized phospholipid vesicles for transmucosal or
transdermal delivery to a subject. Preparation of a composition of
cannabidiol for transmucosal administration is described.
[0074] CBD from the Cannabaceae family, preferably Cannabis sativa,
can be extracted from the Cannabis plant material by a
supercritical CO.sub.2 extraction process. Cannabidiol (CBD) is
procured in a crystalline form having greater than 99% purity.
Crystalline CBD useful for encapsulation is a fine white powder
having needlelike crystals. While the supercritical CO.sub.2
extraction process is preferred, ethanol and butane extractions are
also commonly used.
[0075] Crystalline CBD having greater than 99% purity is combined
with an ethanolic stock having phospholipids and water in an
ethanol base until uniformly distributed in the ethanolic stock.
Phospholipids used in the ethanolic stock are optionally derived
from lecithin. Phospholipids used in the ethanolic stock are
optionally derived from soy. When the cannabidiol is fully
incorporated into the ethanolic stock, additional ethanol is added
to the mixture. A quantity of water is then added to the mixture
resulting in discrete nano-sized lipid vesicles having CBD
encapsulated in a phospholipid vesicle. Optionally, flavoring or
masking agents are combined with the quantity of water before
mixing with the cannabidiol-phospholipid mixture.
[0076] The CBD concentration in the combined stock ranges from 0.1%
to 10%. Optionally, the concentration range is from 1% to 5%.
Optionally, the concentration range is from 1.167% to 2.0%. The
encapsulated CBD concentration following 1:10 dilution with the
aqueous solvent ranges from 0.01% to 1.0%. Optionally, encapsulated
CBD concentration following 1:10 dilution with the aqueous solvent
ranges from 0.1% to 0.5%. Optionally, the encapsulated CBD
concentration following 1:10 dilution with the aqueous solvent
ranges from 0.167% to 0.2%.
[0077] Table 1 shows a representation of percentages of components
in a composition with encapsulated CBD.
TABLE-US-00001 TABLE 1 CBD Encapsulation Composition Code
Description INCI % w/w A DZ0060 Ethanolic Stock Alcohol, Lecithin,
Water 0.833 A CBD (hemp) Cannabidiol Cannabidiol 0.167 B DZ2330
Ethanol Alcohol 9.00 C DZ1370 Purified Water Water 90.00 100.00
[0078] Preparations of nanoencapsulated CBD were tested for
stability. Results are summarized in Table 2 below.
TABLE-US-00002 TABLE 2 Summary of CBD Encapsulation Studies for 1CB
CBD (.sup.~99%) Crystalline Stability Studies *Final CBD Fill Study
Name/ Vendor of .sup.~99% Product Concentration Day 0 Day 1 Day 2
Day 3 size and Start Date CBD Crystals Code (mg/g) (PSA) (PSA)
(PSA) (PSA) Batch Size Packaging Study 2 Isodiol 1CB .sup.~1.65
mg/g (N/A) (.sup.~170 nm) (N/A) (.sup.~167 nm) 5 grams of 5 g of
(25.degree. C.) (Lot#ISOB99109) CBD 1CB in a (Jun. 27, 2017)
produced 15 mL and filled Centrifuge into 1 Tube centrifuge tube
Study 2 1CB (N/A) (.sup.~185 nm) (N/A) (.sup.~178 nm) 5 grams of
(4.degree. C.) CBD (Jun. 27, 2017) produced and filled into 1
centrifuge tube Study 14B Isodiol ISO99 1CB .sup.~1.65 mg/g Day 0
Study: 1CB lasted up to 48 hrs 150 grams of .sup.~27 g of (Jan. 31,
2018) (Lot#010918) Day 7 Study: 1CB lasted up to 24 hrs CBD 1CB in
a Day 14 Study: 1CB lasted up to 48 hrs produced 1 oz Day 21 Study:
3 bottles of 1CB lasted up to and filled Cobalt Blue 48 hrs, the
other 3 bottles are still in solution into 6 Cobalt Glass Bottle 33
Days later Blue Bottles Day 35 Study: 1CB lasted up to 48 hrs Day
56 Study: currently in progress Combination Material Using a Whole
Plant Extract having .sup.~70% Cannabinoids Stability Study *Final
Concentration of Fill Study Name/ Product Cannabinoids Day 0 Day 1
Day 2 Day 3 size and Start Date Material Code (mg/g) (PSA) (PSA)
(PSA) (PSA) Batch Size Packaging Study 6 **Whole plant 1CB
.sup.~1.17 mg/g (113.1 nm) (104.6 nm) (67.9 nm) (91.4 nm) 5 grams 5
g of (Aug. 1, 2017) Combo Material produced 1CB in a and filled 15
mL into 1 Centrifuge centrifuge Tube tube Study 6B **Whole plant
1CB .sup.~1.17 mg/g (124.5 nm) (N/A) (N/A) (N/A) 5 grams 5 g of
(Aug. 4, 2017) Combo Material produced 1CB in a and filled 15 mL
into 1 Centrifuge centrifuge Tube tube *Final CBD Concentration
dependent on purity of cannabidiol.
[0079] Preparations were found to maintain stability from 24 hours
up to more than one month.
Example 1: Enhanced Serum Levels of Nano-Encapsulated Vs
Non-Encapsulated CBD
[0080] For transmucosal administration, CBD was encapsulated in a
nanosized phospholipid vesicle for the nanoencapsulated
preparation, and for comparison purposes, CBD was combined with an
olive oil carrier for a non-encapsulated control preparation. The
nanoencapsulation vesicles were prepared with a shelf-stable
ethanolic stock comprised of water, phospholipids and ethanol, or a
similar solvent. Lecithin was used as a source of the
phospholipids. The crystalline CBD for use as a control may be
dispersed in olive oil, coconut oil or other orally acceptable
oil.
[0081] Cannabinoids have a greatly increased bioavailability when
encapsulated in nanosized phospholipid vesicles as compared to
non-encapsulated cannabinoids. FIG. 1 shows a comparison of serum
levels achieved for oromucosal administration of cannabidiol
encapsulated in nanosized phospholipid vesicles and a control of
cannabidiol mixed in olive oil.
[0082] In the FIG. 1 graph, a comparison is shown of serum levels
in mg/L (104) of encapsulated (101) vs. non-encapsulated (102) CBD
against historical data (103) for CBD over time (105). Serum levels
from subjects who received transmucosal administration of
nano-encapsulated CBD (101) and serum levels from subjects who
received transmucosal administration of non-encapsulated CBD in
olive oil (102) were compared to historic expected results (103).
These historic results for oromucosal bioavailability were compiled
from multiple sources for plasma cannabinoid pharmacokinetics.
[0083] For the nano-encapsulated and non-encapsulated CBD
comparison, test subjects in both groups were administered 1.65 mg
CBD, sublingually, and blood samples were collected at regular time
intervals and tested for levels of CBD. The FIG. 1 graph shows the
serum level results obtained over the first four hours after
administration for the nano-encapsulated CBD (101) and the
non-encapsulated CBD (102).
[0084] For the historic expected results data (103), data was
compiled for concentrations of 5, 10 and 15 mg/L and serum levels
obtained showed less than one third of the CBD was found in the
serum at the peak concentration (C max):
5 mg CBD.fwdarw.1.2 microgram per liter (nanogram per mL) C max; 10
mg CBD.fwdarw.3.0 microgram per liter (nanogram per mL) C max; 15
mg CBD.fwdarw.3.7 microgram per liter (nanogram per mL) C max.
(Tmax=3.6-4.5 hours and AUC (0-10.5 hours=4.1-12.6).
[0085] Surprisingly, the serum levels for the nano-encapsulated CBD
(101) were not only higher than the historic results would have
predicted, they demonstrated a greatly increased bioavailability of
the encapsulated CBD over non-encapsulated CBD. The serum yield for
a dosing of 1.65 mg CBD.fwdarw.3.99 microgram per liter (nanogram
per mL) C 1 hour for the nanoencapsulated CBD. This demonstrates a
ten-fold increase in serum concentration of nano-encapsulated CBD
over the expected serum concentration of 0.4 microgram per liter as
based on historical data for oromucosal bioavailability of CBD.
[0086] The serum levels for non-encapsulated CBD were much lower
than expected. Based on the historical data, the expectation for
non-encapsulated CBD administered in olive oil would be: 1.65 mg
CBD.fwdarw.0.4 microgram per liter (nanogram per mL) C max.
However, the actual results for non-encapsulated CBD (102) was:
1.65 mg CBD.fwdarw.0.0 microgram per liter (nanogram per mL) C 1
hour indicating that CBD in olive oil was not absorbed.
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