Note: Descriptions are shown in the official language in which they were submitted.
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SUSTAINED RELEASE CANNABINOID PELLETS
[001] RELATED APPLICATIONS
[002] This is a continuation-in-part of United States Patent Application No.
15/923,066 filed on March 16, 2018 and is a continuation-in-part of United
States Patent Application No. 15/717,026 filed on September 27, 2017
which claims priority from United States provisional patent applications:
serial numbers 62/400,216, filed on September 27, 2016; serial number
62/449,377, filed on January 23, 2017; and serial 62/551,924, filed on
August 30, 2017. The disclosures of all of the above applications are
incorporated herein by reference in their entirety.
[003] FIELD OF THE INVENTION
[004] The present invention relates to modified release pharmaceutical
compositions comprising one or more natural or synthetic cannabinoids,
one or more release modifying agent(s) and one or more pharmaceutically
acceptable excipient(s). More specifically, the invention relates to modified
release pharmaceutical compositions comprising cannabinoids and a
process for preparation thereof. The invention also relates to production of
large scale batches of modified release pharmaceutical compositions
comprising cannabinoids and a process for preparation thereof.
[001] BACKGROUND OF THE INVENTION
[002] Cannabinoids are a class of diverse chemical compounds that act on
cannabinoid receptors on cells that repress neurotransmitter release in the
brain. The most notable cannabinoid is the phytocannabinoid
tetrahydrocannabinol (THC), the primary psychoactive compound of
cannabis. Cannabidiol (CBD) is another major constituent of the plant.
There are at least 85 different cannabinoids isolated from cannabis,
exhibiting varied effects. From Wikipedia http://en.wikipedia.org/wiki/
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Tetrahydrocannabinol accessed 5/25/2015. All or any of these
cannabinoids can be used in the present invention.
[003] Synthetic cannabinoids encompass a variety of distinct chemical
classes:
the cannabinoids structurally related to THC, the cannabinoids not related
to THC, such as (cannabimimetics) including the aminoalkylindoles, 1,5-
diarylpyrazoles, quinolines, and arylsulfonamides, and eicosanoids related
to the endocannabinoids. All or any of these cannabinoids can be used in
the present invention.
[004] Delta-9-Tetrahydrocannabinol (dronabinol) is a naturally occurring
compound and is the primary active ingredient in marijuana. Marijuana is
dried hemp plant Cannabis Sativa. The leaves and stems of the plant
contain cannabinoid compounds (including dronabinol). Dronabinol has
been approved by the Food and Drug Administration for the control of
nausea and vomiting associated with chemotherapy and for appetite
stimulation of patients suffering from wasting syndrome. Synthetic
dronabinol is a recognized pharmaceutically active ingredient, but natural
botanical sources of cannabis rather than synthetic THC are also known in
the art. All or any of these cannabinoids can be used in the present
invention.
[005] Dronabinol is a light yellow resinous oil that is sticky at room
temperature
and hardens upon refrigeration. Dronabinol is insoluble in water and is
formulated in sesame oil. It has a pKa of 10.6 and an octanol-water
partition coefficient: 6,000:1 at pH 7. After oral administration, dronabinol
has an onset of action of approximately 0.5 to 1 hours and peak effect at 2
to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but
the appetite stimulant effect of dronabinol may continue for 24 hours or
longer after administration.
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[006] Dronabinol is the international nonproprietary name for a pure isomer
of
THC, (¨)-trans-Y-tetrahydrocannabinol, which is the main isomer, and the
principal psychoactive constituent, found in cannabis. Synthesized
dronabinol is marketed as Marino! (a registered trademark of Solvay
Pharmaceuticals).
[007] Marinol is manufactured as a gelatin capsule containing synthetic
delta-9-
tetrahydrocannabinol (THC) in sesame oil. It is taken orally and is
available in 2.5mg, 5mg and/or 10mg dosages. Marinol is prescribed for
the treatment of cachexia in patients with AIDS and for the treatment of
nausea and vomiting associated with cancer chemotherapy in patients
who have failed to respond adequately to conventional antiemetic
treatments. Like other oils provided in gelatin dosage forms there is an
urgent need for solid (powder and tablet) dosage forms of this drug as
provided in the instant invention.
[008] Despite FDA approval, it is almost universally accepted that medical
marijuana has many benefits over Marinol and that by prohibiting the
possession and use of natural cannabis and its cannabinoids, patients are
unnecessarily restricted to use a synthetic substitute that lacks much of
the therapeutic efficacy of natural cannabis. Sativex, is considered an
improvement over Marino!. Sativex is an oral cannabis spray consisting of
natural cannabinoid extracts, has greater bioavailability and is faster
acting than oral synthetic THC. Of course oral sprays have numerous
problems as a dosage form and Saitvex has not been widely adopted as a
replacement for medical marijuana. Why Marinol Is Not As Good As Real
Marijuana Posted by Johnny Green on March 5, 2012 - see
http://www.theweedblog.com/why-marinol-is-not-as-good-as-real-
marijuana/ accessed 9 18 2016. Incorporated by reference in its entirety.
[009] Marinol lacks several of the therapeutic compounds available in
natural
cannabis. Chemical compounds in cannabis, known as cannabinoids, are
responsible for its numerous therapeutic benefits. Scientists have
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identified 66 naturally occurring cannabinoids. The active ingredient in
Marino!, synthetic delta-9-tetrahyrdocannabinol (THC), is an analogue of
one such compound, THC. However, several other cannabinoids available
in cannabis ¨ in addition to naturally occurring terpenoids (oils) and
flavonoids (phenols) ¨ have also been clinically demonstrated to possess
therapeutic utility. Many patients favor natural cannabis to Marinol
because it includes these other therapeutically active cannabinoids. Why
Marinol Is Not As Good As Real Marijuana Posted by Johnny Green on
March 5, 2012 - see http://www.theweedblog.com/why-marinol-is-not-as-
good-as-real-marijuana/ accessed 9 18 2016.
[0010] Cannabidol (CBD) is a non-psychoactive cannabinoid that has been
clinically demonstrated to have analgesic, antispasmodic, anxiolytic,
antipsychotic, antinausea, and anti-rheumatoid arthritic properties. Clinical
studies have shown CBD to possess anti-convulsant properties,
particularly in the treatment of epilepsy. Natural extracts of CBD, when
administered in combination with THC, significantly reduce pain, spasticity
and other symptoms in multiple sclerosis (MS) patients unresponsive to
standard treatment medications. CBD has been shown to be
neuroprotective against glutamate neurotoxicity (i.e. stroke), cerebral
infarction (localized cell death in the brain), and ethanol-induced
neurotoxicity, with CBD being more protective against glutamate
neurotoxicity than either ascorbate (vitamin C) or alpha-tocopherol
(vitamin E). Clinical trials have also shown CBD to possess anti-tumoral
properties,inhibiting the growth of glioma (brain tumor) cells in a dose
dependent manner and selectively inducing apoptosis (programmed cell
death) in malignant cells Why Marinol Is Not As Good As Real Marijuana
Posted by Johnny Green on March 5, 2012 - see
http://www.theweedblog.com/why-marinol-is-not-as-good-as-real-
marijuana/ accessed 9 18 2016. Dosage formulations of CBD and other
natural cannabinoids can also be formulated into solid dosage forms
according to the present invention.
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[0011] Additional cannabinoids possessing clinically demonstrated therapeutic
properties include: cannabinol (anticonvulsant and anti-inflammatory
activity); cannabichromine (anti-inflammatory and antidepressant activity);
and cannabigerol (anti-tumoral and analgesic activity). Natural cannabis'
essential oil components (terpenoids) exhibit anti-inflammatory properties
and its flavonoids possess antioxidant activity. Emerging clinical evidence
indicates that cannabinoids may slow disease progression in certain
autoimmune and neurologic diseases, including multiple sclerosis (MS),
Amyotrophic Lateral Sclerosis (Lou Gehrig's disease) and Huntington's
Disease. Why Marinol Is Not As Good As Real Marijuana Posted by
Johnny Green on March 5, 2012 - see http://www.theweedblog.com/why-
marinol-is-not-as-good-as-real-marijuana/ accessed 9 18 2016. Dosage
formulations of these cannabinoids can be formulated into solid dosage
forms according to the present invention.
[0012] Oral ingestion of Marinol avoids the potential risks of smoking,
however
because of synthetic THC's poor bioavailability, only 5-20 percent of an
oral dose ever reaches the bloodstream and the drug may not achieve
peak effect until four hours after dosing. National Academy of Sciences,
Institute of Medicine. 1999. Marijuana and Medicine: Assessing the
Science Base. p. 203; L. Growing et al. 1998. Therapeutic use of
cannabis: clarifying the debate. Drug and Alcohol Review. Moreover,
because Marinol is metabolized slowly, its therapeutic and psychoactive
effects may be unpredictable and vary considerably, both from one person
to another, and in the same person from one episode of use to another. S.
Calhoun et al. 1998. Abuse potential of dronabinol. Journal of
Psychoactive Drugs. 30: 187-196; J. Morgan and L. Zimmer, Marijuana
Myths, Marijuana Facts: A Review of the Scientific Evidence, p. 19. Thus
there is a need for improved bioavailability dosage forms of natural and
synthetic cannabinoids.
[0013] As a result of Marinol's slow onset and poor bioavailablity, scientists
are
now in the process of developing a new formulation of pulmonary
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dronabinol, delivered with a pressurized metered dose inhaler. Medical
News Today. "New synthetic delta-9-THC Inhaler offers safe, rapid
delivery, Phase I study." April 17, 2005. Unlike oral synthetic THC, it's
possible that pulmonary Marinol "could offer an alternative for patients
when a fast onset of action is desirable." Sativex, an oral cannabis spray
consisting of natural cannabinoid extracts, has greater bioavailability and
is faster acting than oral synthetic THC. Clinical trials comparing its
bioavailability and time of peak onset compared to vaporized cannabis
have not been performed, though anecdotal reports indicate that
vaporized cannabis and its cannabinoids likely possess greater
bioavailability and are faster acting than the Sativex spray. Thus there is a
need for improved bioavailability, simple, inexpensive solid dosage forms
of natural and synthetic cannabinoids.
[0014] US 6,403,126 (incorporated herein by reference in its entirety)
discloses
methods of extracting and purifying cannabinoids from Cannabis using
organic solvent.
[0015] An analog of dronabinol, nabilone. is available commercially.
[0016] US 20120231083 discloses a sustained release medicament which results
in delivery of a therapeutic level of one or more cannabinoids during a
clinically relevant therapeutic window. The therapeutic window is a longer
window than provided by an immediate release medicament such as
Marinol containing an equivalent amount of the cannabinoid. Oral
administration of the present compositions provides therapeutic dosing
while maintaining safe, side effect sparing, levels of a cannabinoid. The
present invention also provides methods of treating cannabinoid-sensitive
disorders.
[0017] US 20060257463 discloses a method of transmucosally delivering a
cannabinoid to a subject in need of such treatment comprising the steps
of: administering to the subject a transmucosal preparation containing the
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cannabinoid wherein said transmucosal preparation is made by
incorporating an effective amount of the cannabinoid via hot-melt
extrusion technology, hot-melt molding, admixing or a solvent cast
technique into a film matrix or a reservoir containing the cannabinoid, and
attaching said transmucosal preparation to the mucosa of the subject.
[0018] Pharmaceutical compositions comprising the cannabinoid active
pharmaceutical ingredient, crystalline trans-( )-.6,9-tetrahydrocannabinol,
and formulations thereof are disclosed in WO 2006133941. The invention
also relates to methods for treating or preventing a condition such as pain
comprising administering to a patient in need thereof an effective amount
of crystalline trans-( )-1i9-tetrahydrocannabinol. In specific embodiments,
the crystalline trans-( )-A9-tetrahydrocannabinol administered according
to the methods for treating or preventing a condition such as pain can
have a purity of at least about 98% based on the total weight of
cannabinoids.
[0019] US 20140100269 Al discloses oral cannabinoid formulations, including an
aqueous-based oral dronabinol solution, that are stable at room or
refrigerated temperatures and may possess improved in vivo absorption
profiles with faster onset and lower inter-subject variability.
[0020] US 8632825 discloses the use of a combination of cannabinoids,
particularly tetrahydrocannabinol (THC) and cannabidiol (CBD), in the
manufacture of a medicament for use in the treatment of cancer.
[0021] US 6630507 discloses that cannabinoids have antioxidant properties.
This
property makes cannabinoids useful in the treatment and prophylaxis of
wide variety of oxidation associated diseases, such as ischemic, age-
related, inflammatory and autoimmune diseases. The cannabinoids are
found to have particular application as neuroprotectants, for example in
limiting neurological damage following ischemic insults, such as stroke
and trauma, or in the treatment of neurodegenerative diseases, such as
Alzheimer's disease, Parkinson's disease and HIV dementia.
Nonpsychoactive cannabinoids, such as cannabidoil, are particularly
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advantageous to use because they avoid toxicity that is encountered with
psychoactive cannabinoids at high doses useful in the method of the
present invention.
[0022] US 8808734 discloses stable, fast-acting liposomal and micelle
formulations of cannabinoids or cannabinoid analogues.
[0023] US 6747058 discloses stable composition for inhalation therapy
comprising delta-9-tetrahydrocannabinol and semi-aqueous solvents.
[0024] DOSAGE AND ADMINISTRATION OF DRONABINOL FROM FDA
DOCUMENT NDA 18-651/S-021; 500012 Rev Sep 2004:
= Appetite Stimulation: Initially, 2.5 mg Dronabinol Capsules should
be administered orally twice daily (b.i.d.), before lunch and supper.
For patients unable to tolerate this 5 mg/day dosage, the dosage
can be reduced to 2.5 mg/day, administered as a single dose in the
evening or at bedtime. If clinically indicated and in the absence of
significant adverse effects, the dosage may be gradually increased
to a maximum of 20 mg/day, administered in divided oral doses.
Caution should be exercised in escalating the dosage because of
the increased frequency of dose-related adverse experiences at
higher dosages.
= Antiemetic: Best administered at an initial dose of 5 mg/m2, given 1
to 3 hours prior to the administration of chemotherapy, then every 2
to 4 hours after chemotherapy is given, for a total of 4 to 6
doses/day. Should the 5 mg/m2 dose prove to be ineffective, and in
the absence of significant side effects, the dose may be escalated
by 2.5 mg/m2 increments to a maximum of 15 mg/m2 per dose.
Caution should be exercised in dose escalation, however, as the
incidence of disturbing psychiatric symptoms increases significantly
at maximum dose.
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[0025] Despite all of the work on cannabinoids and dronabinol, there is a need
in
the art for simple, inexpensive, improved dosage forms that have an
improved profile with faster onset, extended release profiles and lower
inter-subject variability than currently available cannabinoid products.
[0026] Sticking is one of the most common problems of tablet making. It occurs
when granules attach and stick to the faces of the punches instead of
locking together to create a uniform tablet. Products with granules that are
sensitive to compression¨ "sticky granules" ¨ can form excellent tablets.
But they are also prone to sticking to the punch faces and the problem
worsens over the course of the production run because granules that are
sensitive to compression will readily compact as they flow through the
hopper and into the feed frame. The particles of the present invention
solve this problem for cannabinoid formulations of resins, extracts and
isolates.
[0027] Picking is a specific type of sticking in which particles stick within
the
letters and logos that are embossed or debossed on the faces of the
compression tooling. Regardless whether it's sticking or picking, the result
is a defective tablet. The particles of the present invention solve this
problem for cannabinoid formulations of resins, extracts and isolates and
allow for efficient encapsulation and tableting.
[0028] In the 1970s and 1980s there were almost no marketed drugs with less
than 10 pg/ml solubility (10-100 pg/ml was considered low) (Solid
Dispersions: New Approaches and Technologies in Oral Drug Delivery,
Controlled Release Society; Rutgers, NJ 02 June 2009 Craig A. McKelvey
Merck & Co., Inc. hereinafter "McKelvey"). Now it is estimated that more
than 60% of Active Pharmaceutical Ingredients (API) in development have
poor bioavailability due to low aqueous solubility (WO 2013040187 citing
Manufacturing chemist, March 2010, 24-25). At least partially as a result
of advances in combinatorial chemistry and molecular screening methods
for identifying potential drug candidates, an increasing number of insoluble
drugs are being identified. Poor solubility of lead compounds results in
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ineffective absorption, which is an important part of the high clinical
failure
rate due to poor pharnnacokinetics. Drugs with very low aqueous solubility
usually have sizeable within and between subject pharmacokinetic
variability making study design and the conduct of Phase I studies very
challenging, the assessment of dose¨response and exposure response
relationships difficult, and resulting in difficult dose determination. Water
insoluble drugs usually have high propensity for drug interactions at the
absorption level, such as food interactions, and interactions with
gastrointestinal "GI" prokinetic agents, especially if these drugs also have
narrow therapeutic windows. There is an on-going need in the art for
better formulation technologies for poorly soluble drugs (Jain et al. Asian J
Pharm Clin Res, Vol 5, Suppl 4, 2012, 15-19).
[0029] The Biopharmaceutical Classification System (BCS) is a framework for
classifying a drug substance on the basis of its equilibrium aqueous
solubility and intestinal permeability. (Jain et al. Asian J Pharm Olin Res,
Vol 5, Suppl 4,2012, 15-19 hereinafter "Jain") When combined with the in
vitro dissolution characteristics of a drug product, the BCS takes into
account three major factors: solubility, intestinal permeability and
dissolution rate. These factors govern the rate and extent of oral drug
absorption for immediate release solid oral dosage forms. The BCS
defines four classes of drug substances based on their solubility and
permeability characteristics.
High Solubility Low Solubility
High Permeability BCS Class I BCS Class II
Low Permiability BCS Class III BCS Class IV
[0030] A drug substance is considered highly soluble when the highest dose
strength is soluble in 250 ml water over a pH range of 1 to 7.5. A drug is
considered highly permeable when the extent of absorption in humans is
determined to be 90% of an administered dose, based on the mass
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balance or in comparison to an intravenous dose (drug and metabolite). A
drug product is considered to dissolve rapidly when 85% of the labeled
amount of substance dissolves within 30 minutes, using USP apparatus I
or II in a volume of 900 ml buffer solution. (Gothoskar A.V.
Biopharmaceutical classification of drugs. Pharm Rev. 2005; 3:1.)
[0031] For BCS Class II drugs that have low bioavailability resulting from
poor
solubility and the inability to dissolve rapidly the selection of formulation
is
often a major hurdle preventing the development of a successful oral drug
product. Certain technologies have recently been developed to aid in the
formulation of these drugs including: salt formation, size reduction, co-
solvency, pH manipulation, surfactant and micelle use, inclusion
complexes, lipid formulations, and solid dispersions. Jain et al. Asian J
Pharm Clin Res, Vol 5, Suppl 4, 2012, 15-19).
[0032] According to the "Intra-Agency Agreement Between the Eunice Kennedy
Shriver National Institute of Child Health and Human Development
(NICHD) and the U.S. Food and Drug Administration (FDA) Oral
Formulations Platform¨Report 1" dronabinol is a class 2 or class 4 drug
with low solubility and unknown permeability. Thus it may be formulated in
the same manner as a class 2 drug.
[0033] Absorption and distribution: Dronabinol capsules are almost completely
absorbed (90 to 95%) after single oral doses. Due to the combined effects
of first pass hepatic metabolism only 10 to 20% of the administered dose
reaches the systemic circulation. FDA document NDA 18-651/S-021.
[0034] Controlled Release Dosage Forms
[0035] Controlled-release formulations have been one of the major focuses in
pharmaceutical research and development.
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[0036] The advantages of controlled release products are well known in the
pharmaceutical field. Sustained release drug formulations may be useful
to reduce the frequency of drug administration (especially in the case of
drugs with short compound half lives), improve patient compliance, reduce
drug toxicity (local or systemic associated with high peak exposure),
reduce drug level fluctuation in blood, stabilize medical condition with
more uniform drug levels, reduce drug accumulation with chronic therapy,
improve bioavailability of some drugs because of spatial control, and
reduce total drug usage when compared with immediate release drugs.
[0037] Oral controlled release delivery systems should ideally be adaptable so
that release rates and profiles can be matched to physiological and
temporal requirements.
[0038] Mechanical devices aside, interaction between a drug and a polymeric
material often forms the basis of controlled oral drug delivery. A polymer at
certain concentrations in a solution imposes pathways for drug diffusion.
Polymers that dissolve in or otherwise hydrate in aqueous media can alter
the drug diffusion process in a time-dependent manner. For example, a
commonly used material, hydroxypropyl methylcellulose (HPMC), which is
water soluble, behaves as a swellable absorptive polymer in the limited
volumes of aqueous media in the gastrointestinal tract. Drug dispersed in
this polymer, as in monolithic tablets, diffuses through the viscous
hydrated polymer at a rate dependent on the movement kinetics of the
polymer chains. The faster these relax, the faster the diffusion rate.
[0039] Development of dosage form depends on chemical nature of the drug and
polymers, the matrix structure, swelling, diffusion, erosion, the release
mechanism and the in vivo environment.
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[0040] Hydrophilic polymers like HPMC may also control drug release by erosion
mechanisms. After consumption of the dosage form, the GI tract fluid
encounters the dosage unit, causing the polymer to hydrate and swell.
Weakened mechanical properties in the swollen state may cause the
hydrated polymer to break away from the prime particle (compact or
pellet). Drug release may therefore be controlled by a combination of
diffusion and erosion. Such release mechanisms can apply to systems
where drug is dispersed in or coated with polymer.
[0041] Extended release dosage forms of class 2 drugs often require expensive,
difficult, and proprietary osmotic delivery systems such as Alza's Oros TM
and Duros TM technologies. (See US 4612008; US 4327725; 4,765,989;
and 4,783,337). Other technologies have been developed to exploit
diffusion, erosion, and other physicochemical mechanisms and provide
drug and disease-specific release profiles. Examples also include the
release from a ContramidTM tablet controlled by the degree of crosslinking
of high amylase starch.
[0042] Different hydrogels have been described for use in controlled release
medicines, most of which are semi-synthetic or of natural origin. A few
contain both synthetic and non-synthetic material. However, many of the
systems require special process and production equipment, and in
addition some of these systems are susceptible to variable drug release.
[0043] In another modified release approach, a solid dispersion comprising API
with two different polymers is employed. JP Patent Application No. 2004-
67606 discloses a tablet comprising fine pellets obtained by spraying a
solution containing itraconazole, which is a poorly soluble drug, a water-
soluble polymer and an enteric polymer, on a mixed powder of an
excipient and a disintegrator, granulating and drying. Karel Six et al. (J.
Pharm. Sci. 93, 124-131, 2004) discloses a solid dispersion composition
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of Itraconazole, a class II drug, Eudragit E100 and copovidone. The use of
a combination of fast- and slow- dissolving polymers in solid dispersions
compositions has resulted in increased physical stability and improved
dissolution properties of itraconazole. In another approach, Hirasawa et al.
(/. Pharm. Soc. of Japan, 124(1), 19-23, 2004; Chem. Pharm. Bull. 52(2)
244-247, 2004; JP Patent Application No. 2001335483 A) disclose a solid
dispersion comprising Nilvadipine (NIL)/ Crospovidone (cl-PVP)/
Methylcellulose (MC). US Patent Publication No. 20070248681 discloses
a granule of a solid dispersion of a poorly soluble drug, a water-soluble
polymer, an excipient and a disintegrator, wherein the content of the
water-soluble polymer is 1 to 10% by weight and the content of the
disintegrator is 15 to 50% by weight. A method for producing a tablet of a
solid dispersion is also disclosed.
[0044] Water insoluble polymers can be used in extended drug release
formulations. These include methacrylate- or acrylate-based polymers with
low permeability.
[0045] Hydrophilic functional groups such as trimethylaminoethyl methacrylate
can improve permeability and swellability in water thus altering release
behaviors.
[0046] Various drug candidates such as diltiazem hcl, carbamazepine,
metoprolol, oxprenolol, nifedipine, glipizide have been formulated as
osmotic delivery systems. Problems with such osmotic delivery systems
include the need for special equipment for making an orifice in the system;
residence time of the system in the body varies with the gastric motility
and food intake; such systems may cause irritation or ulcer due to release
of saturated solutions of drug. Vol. 1 No. 7 2012. Online Available at
www.thepharmajournal.com. THE PHARMA INNOVATION Vol. 1 No. 7
2012 www.thepharmajournal.com Pagel 116 Osmotic-Controlled
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Release Oral Delivery System: An Advanced Oral Delivery Form. Nitika
Ahuja, Vikash Kumar, Permender Rathee.
[0047] The instant invention solves the problems associated with formulation
cannabinoid drugs and provides for cannabinoid sustained release dosage
forms in a technically and economically efficient and surprising manner.
[0048] In general, it would be advantageous if a cannabinoid containing
capsule
could be made available which does not suffer from the problems of
expense and the need for smoking or "edible" dosage forms and for which
the release profile can be controlled and optimized. None of the
documents described above enable controlled release cannabinoid
capsules or powders. There is a need for new cheap and stable dosage
formulations, especially capsules, comprising an effective dose of
cannabinoids or derivatives thereof. There is also a need for a stable
cannabinoid powder and tablets.
[0049] Another aspect the invention provides a pharmaceutical or nutraceutical
composition in the form of a capsules for oral administration comprising
cannabinoid wherein said capsule is preferably formed from
pharmaceutically or even nutraceutically acceptable pellets which provide
controlled release profiles.
[0050] By "nutraceutical" is meant a composition that provides medical or
health
benefits, including the prevention and treatment of disease. Dietary
supplements and natural health products are examples of nutraceuticals.
In many places natural cannabinoids are considered nutraceuticals. Within
the context of this invention it is understood that the term "drug" is used
generically to include prescription and non-prescription pharmaceutical
products as well as nutraceuticals including dietary supplements, natural
health products, medicinal foods, drinks, candy bars with active
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ingredients and all other similar delivery methods whether approved or
unapproved.
[0051] Viewed from another aspect the invention provides a pharmaceutical or
nutraceutical capsule as hereinbefore described for use in the treatment or
prophylaxis of all of the disorders that medical marijuana and drabinol is
used for at the present time.
[0052] As used herein, the term "drug" includes not only pharmaceuticals but
also
natural medicines, alternative medicines, and dietary supplements and
generally refers to all forms of cannabinoids.
[0053] DETAILED DESCRIPTION OF THE INVENTION
[0054] Extending drug release ("sustained release" or "controlled release")
from a
dosage form can prolong its action and attenuate peak plasma levels,
thereby obviating concentration-related side effects or optimize efficacy by
matching systemic presence with other time-related effects. Sustained
release drug forms can be achieved by embedding the drug in a matrix
that prevents immediate release and delivers excipient at a desired rate
consistent with absorption or disposition requirements. A wide variety of
materials can be used to design the most appropriate release profile and
provide a viable and consistent mode of manufacture. The present
invention approaches this problem systematically and solves it in a unique
way using particles of a very precise size and composition.
[0055] The present invention involves the use of cannabinoid particles that
have
been formulated to provide controlled release of the cannabinoid extract or
isolate. The particles can be encapsulated, tableted, or provided in a
powder-sachet dosage form. These particles are typically in the form of
pellets or granules. Preferably, the diameter of the pellets ranges from
about 0.05 to about 0.5 mm. Preferably, the average diameter of the
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particles ranges from 0.07 to 0.3 mm. Diameters referred to throughout
the specification are average diameters. Although it is preferred that all
particles are within the recited ranges, it is acceptable for minor or trace
amounts of undersize or oversize particles to be present.
[0056] Surprisingly, it was found that cannabinoid containing particles of
specific
formulations and sizes minimize the sticking phenomena encountered
during tablet compression or encapsulation. In one of its aspects, the
present invention relates to a unit dosage form comprising a plurality of
pellets having a diameter in the range of from 0.05 to .5 mm wherein each
particle comprises a can nabinoid resin, extract or isolate, and at least one
pharmaceutically acceptable excipient.
[0057] Such particles according to the present invention are stable and can be
filled on fast running encapsulation machines without presenting the
sticking and picking phenomena
[0058] Tablets and gelatin capsules of cannabinoids cannot easily be
formulated
from powder mix or by conventional wet granulation procedure due to
picking and sticking phenomena during tablet compression or
encapsulation. Thus, there was a need for extracts and isolates containing
products and dosage forms which would be stable against moisture and
heat during production and storage. Surprisingly, it was found that
granules according to the present invention substantially between 0.05mm
and 0.5 mm in size are substantially easier to formulate into tablets and to
encapsulate.
[0059] Prior to the methods and formulations of the present invention, tablets
and
hard gelatin capsules of CBDs and THC cannot easily be formulated from
powder mix or by conventional wet granulation procedures due to picking
and sticking phenomena during tablet compression or encapsulation.
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Thus, there was a need for extract containing products and dosage forms
which would be stable against moisture and heat during production and
storage.
[0060] Surprisingly, it was found that particles according to the present
invention
do not feature the sticking and picking phenomena and exhibit
encapsulation and tabletting properties.
[0061] As discussed above, BCS Class II drugs present immense challenges for
oral delivery, let alone attempts at zero order pharmacokinetics. In
particular embodiments, the dosage form may provide a zero order
release from about 1 hour to about 24 hrs after administration. In certain
embodiments, the dosage form releases more than about 90% of the
active agent in less than about 24 hrs. In particular embodiments, the
dosage form may provide a zero order rate of release for at least a portion
of the delivery period. In other embodiments, the dosage form may
provide an ascending rate of release for at least a portion of the delivery
period. In yet other embodiments, the dosage form may provide a fast
initial rate of release followed by a slower rate of release and an
ascending rate of release of the remaining active agent.
[0062] The sustained release formulations of cannabinoids of the present
invention represent a significant improvement over existing formulations
and delivery methods of cannabinoids.
[0063] The present invention involves a novel granulation method for
formulating
cannabinoids into a pellet matrix and subsequently into capsules.
[0064] The benefits of the invention include maintaining cannabinoids in a
soluble, hydrophilic state in contact with body fluids.
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[0065] The present invention provides a deceptively simple formulation
solution
to the problem of formulating modified release versions of cannabinoids
involving a few simple ingredients combined in an extremely inventive and
unique way. The present invention provides capsules and powders of
cannabinoid formulations using a novel combination of silica gel,
hydrogenated lecithin, glyceryl behenate, peg-8 caprylic/capric glycerides,
hydroxypropylmethylcellulose, microcrystalline cellulose, colloidal silicon
dioxide, and hydroxypropylcellulose.
[0066] Cannabinoid Extract Resin
[0067] The cannabinoid extracts of the present invention can be extracted and
formulated to provide a number of sustained release combinations useful
in the present invention. Of particular interest are 100 percent THC
tablets, 100% CBD tablets, 10:1 THC/CBD, 1:10 THC/CBD, and 50:50
THC/CBD although other variations of sustained release Pellets and
tablets may be desirable in specific situations.
[0068] Cyclodextrins
[0069] Cyclodextrins (sometimes called cycloamyloses) are a family of
compounds made up of sugar molecules bound together in a ring (cyclic
oligosaccharides).
[0070] Cyclodextrins are produced from starch by means of enzymatic
conversion. They are used in food [Szente, L., & Szejtli, J. (2004).
Cyclodextrins as food ingredients. Trends in Food Science & Technology,
15(3-4), 137-142], pharmaceutical, [Stella, V., & He, Q. (2008).
Cyclodextrins. Toxicologic Pathology, 36(1), 30-42] drug delivery, [Laza-
Knoerr, A. L., Gref, R., & Couvreur, P. (2010). Cyclodextrins for drug
delivery. Journal of Drug Targeting, 18(9), 645-656.] and chemical
industries, as well as agriculture and environmental engineering.
CA 3005885 2018-05-23
20
[0071] Cyclodextrins are composed of 5 or more a-D-glucopyranoside unitslinked
1->4, as in amylose (a fragment of starch). The 5-membered macrocycle
is not natural. Recently, the largest well-characterized cyclodextrin
contains 32 1,4-anhydroglucopyranoside units, while as a poorly
characterized mixture, at least 150-membered cyclic oligosaccharides are
also known. Typical cyclodextrins contain a number of glucose monomers
ranging from six to eight units in a ring, creating a cone shape:
= a (alpha)-cyclodextrin: 6-membered sugar ring molecule
= P (beta)-cyclodextrin: 7-membered sugar ring molecule
= y (gamma)-cyclodextrin: 8-membered sugar ring molecule
= a- and y-cyclodextrin are being used in the food industry.
[0072] All of these cyclodextrins can be employed in the present invention.
[0073] Cyclodextrins are able to form host-guest complexes with hydrophobic
molecules given the unique nature imparted by their structure. As a result,
these molecules have found a number of applications in a wide range of
fields.
[0074] Because cyclodextrins are hydrophobic inside and hydrophilic outside,
they can form complexes with hydrophobic compounds. Thus they can
enhance the solubility and bioavailability of such compounds. This is of
high interest for pharmaceutical as well as dietary supplement applications
in which hydrophobic compounds shall be delivered.
[0075] Cyclodextrins can solubilize hydrophobic drugs in pharmaceutical
applications, and crosslink to form polymers used for drug delivery. [Laza-
Knoerr, A. L., Gref, R., & Couvreur, P. (2010). Cyclodextrins for drug
delivery. Journal of Drug Targeting, 18(9), 645-656. One example is
Sugammadex, a modified y-cyclodextrin which reverses neuromuscular
blockade by binding the drug rocuronium. Other than the above-
CA 3005885 2018-05-23
21
mentioned pharmaceutical applications, cyclodextrins can be employed in
environmental protection: these molecules can effectively immobilise
inside their rings toxic compounds, like trichloroethane or heavy metals, or
can form complexes with stable substances, like trichlorfon (an
organophosphorus insecticide) or sewage sludge, enhancing their
decomposition.
[0076] Typical cyclodextrins are constituted by 6-8 glucopyranoside units, can
be
topologically represented as toroids with the larger and the smaller
openings of the toroid exposing to the solvent secondary and primary
hydroxyl groups respectively. Because of this arrangement, the interior of
the toroids is not hydrophobic, but considerably less hydrophilic than the
aqueous environment and thus able to host other hydrophobic molecules.
In contrast, the exterior is sufficiently hydrophilic to impart cyclodextrins
(or
their complexes) water solubility.
[0077] The formation of the inclusion compounds greatly modifies the physical
and chemical properties of the guest molecule, mostly in terms of water
solubility. This is the reason why cyclodextrins have attracted much
interest in many fields, especially pharmaceutical applications: because
inclusion compounds of cyclodextrins with hydrophobic molecules are able
to penetrate body tissues, these can be used to release biologically active
compounds under specific conditions. In most cases the mechanism of
controlled degradation of such complexes is based on pH change of water
solutions, leading to the loss of hydrogen or ionic bonds between the host
and the guest molecules. Alternative means for the disruption of the
complexes take advantage of heating or action of enzymes able to cleave
a-1,4 linkages between glucose monomers.
CA 3005885 2018-05-23
22
[0078] a-Cyclodextrin has been authorized for use as a dietary fiber in the
European Union since 2008. In 2013 the EU commission has verified a
health claim for alpha-cyclodextrin. The EU assessment report confirms
that consumption of alpha-cyclodextrin can reduce blood sugar peaks
following a high-starch meal. Weight loss supplements are marketed from
alpha-cyclodextrin which claim to bind to fat and be an alternative to other
anti-obesity medications.
[0079] Due to its surface-active properties, a-cyclodextrin can also be used
as
emulsifying fiber, for example in mayonnaise as well as a whipping aid, for
example in desserts and confectionary applications.
[0080] 13-cyclodextrins are the main ingredient in P&G's product Febreze which
claims that the 13-cyclodextrins "trap" odor causing compounds, thereby
reducing the odor.
[0081] The cavity of the 7-membered 13-cyclodextrin and 8-membered y-
cyclodextrin offer enough space even for comparatively large molecules,
and are able to form the most stable complexes (Uekama, K., et al.
(1983). Improvement of dissolution and absorption characteristics of
benzodiazepines bycyclodextrin complexation. Int. J. Pharm., 10:1-15;
Seo, H. et al. (1983) Enhancement of oral bioavailability of spironolactone
by p- and y-cyclodextrin complexations. Chem. Pharm. Bull., 31:286-291;
Otagiri, M. et al. (1983) Inclusion complex formations of the anti-
inflammatory drug flurbiprofenwith cyclodextrins in aqueous solution and
in solid state, Acta Pharm. Suec. 20:11-20.].
[0082] Alkylation of 13-cyclodextrin functions with different substituents
results in
derivatives having a drastically increased aqueous solubility, while also
preserving the complexing properties of the starting compound and
allowing for solubilization [Muller B, Brauns U. Solubilization of drugs by
CA 3005885 2018-05-23
23
modified P-cyclodextrins. Intl J Pharm 1985; 26: 77-88.] In addition,
studies have shown a stabilizing effect on aqueous solutions, in which
decomposition was delayed.
[0083] As mentioned above, the formation of inclusion compounds or "inclusion
complexes" modifies the physical and chemical properties of the guest
molecule, mostly in terms of water solubility, and allows hydrophobic
molecules to penetrate body tissues and release biologically active
compounds. Studies conducted on the use of indomethacin as a guest
molecule, which normally undergoes controlled degradation by hydrolytic
cleavage with a rate constant depending on the pH of the solution
[Krasowska, H. (1974) Kinetics of indomethacin hydrolysis. Acta. Pharm.
Jugoslay. 24:13-200.], was found to undergo delayed decomposition when
it was solubilized by hydroxyethy1-13-cyclodextrin.
[0084] The silica gel is used herein as an adsorbant and solid carrier and
should
be selected for properties making it ideal for use with lipid formulations;
able to adsorb large amounts of oils with a resulting density and flowability
that is useful for maximum loading into tablets. It is also desirable that the
oil will release from the silica gel without the use of additional
surfactants.
[0085] Lecithin is a naturally occurring mixture of the diglycerides of
stearic,
palmitic, and oleic acids, linked to the choline ester of phosphoric acid,
commonly called phosphatidylcholine. Hydrogenated Lecithin is the
product of controlled hydrogenation of Lecithin. Bilayers of these
phospholipids in water may form liposomes, a spherical structure in which
the acyl chains are inside and not exposed to the aqueous phase. Lecithin
and Hydrogenated Lecithin are used in a large number of cosmetic
formulations as skin conditioning agents-miscellaneous and as surfactant-
emulsifying agents. Hydrogenated Lecithin is also used as a nonsurfactant
suspending agent. Lecithin is virtually nontoxic in acute oral studies, short-
CA 3005885 2018-05-23
24
term oral studies, and subchronic dermal studies in animals. Lecithin is not
a reproductive toxicant, nor is it mutagenic in several assays. Fiume Z. Int
J Toxicol. 2001;20 Suppl 1:21-45.
[0086] Soy lecithin one of the most widely used food additives on the market
today. It is used as an emulsifier. It helps to emulsify numerous foods,
even unlikely emulsions such as chocolate. In chocolate, lecithin stabilizes
the cocoa butter fat so it doesn't separate from the moisture, cocoa solids
and dairy.
[0087] Lecithin also extends shelf life by stabilizing emulsions, and it also
reduces "stickiness" and is often used as a "releasing agent."
[0088] Chemically, glyceryl behenate is a mixture of various esters of behenic
acid and glycerol (glycerides). One example is Campitrol 888. The mixture
predominately contains the diester glyceryl dibehenate. 21 C.F.R.
184.1328. Glyceryl behenate is a tablet and capsule lubricant and a lipidic
coating excipient. It has been used for the encapsulation of various drugs
such as retinoids. It has also been used as a matrix-forming agent for the
controlled release of water-soluble drugs and as a lubricant in oral solid
dosage formulations. It is also used widely as ingredient for preparation of
lipidic nano-particles such as solid lipid nanoparticles (SLN) and
nanostructured lipid carriers (NLC). Handbook of pharmaceutical
excipient, 5th edition.
[0089] Peg-8 caprylic/capric glycerides (Labrasol) is a polyethylene glycol
derivative of a mixture of mono-, di-, and triglycerides of caprylic and
capric acids with an average of 6 or 8 moles of ethylene oxide. It is used in
the present invention as an emulsifying agent. A preferred form is
caprylocaproyl macrogo1-8 glycerides, a non-ionic water dispersible
surfactant composed of polyethylene glycol (PEG) esters, a glyceride
CA 3005885 2018-05-23
25
fraction, and free PEG. This form is able to self-emulsify on contact with
aqueous media to form a fine micro-emulsion. It is a solubilizer and
wetting agent: its surfactive power improves the solubility and wettability of
active pharmaceutical ingredients in vitro and in vivo. See for example,
http://www.gattefosse.com.
[0090] The preparation of cannabinoid isolates can be completed by many well-
known methods. See US Patent No. 2304669A, Adams, Roger, D. C.
Pease, and J. H. Clark. "Isolation of cannabinol, cannabidiol and
quebrachitol from red oil of Minnesota wild hemp." Journal of the American
Chemical Society 62.8 (1940): 2194-2196, Ben-Shabat, Shimon, et al.
"New cannabidiol derivatives: synthesis, binding to cannabinoid receptor,
and evaluation of their antiinflammatory activity." Journal of medicinal
chemistry 49.3 (2006): 1113-1117., and Lago-Fernandez, Ana, et al. "New
Methods for the Synthesis of Cannabidiol Derivatives." Methods in
enzymology. Vol. 593. Academic Press, 2017. 237-257. for examples and
an overview of the preparation of cannabinoid isolates.
[0091] One advantage of cannabinoid isolates is the ability to isolate the
desired
cannabinoid for use in pharmaceutical compositions, such as those which
form the instant invention.
[0092] An advantage of using cannabinoid isolates instead of cannabinoid resin
is that cannabinoid isolates that are pure CBD, or nearly pure CBD, can
be formed. Cannabinoid isolates comprising 100% CBD, or nearly 100%
CBD, can be formed by a process which removes THC and other
cannabinoids from a plant extract, cannabinoid resin, or other cannabinoid
extract.
[0093] Therefore, cannabinoid isolates can be used in the instant invention to
form compositions which are high in CBDs. Cannabinoid isolates which
CA 3005885 2018-05-23
26
comprise 100% CBD, or nearly 100% CBD, can be utilized to prepare
100% CBD tablets, which are particularly of interest.
[0094] Another advantage of the use of Cannabinoid isolates in compositions of
the present invention is that a carrier oil, such as sesame oil, is not
required for formulation.
[0095] In each of the following examples cannabinoid isolates may be
advantageously substituted for cannabinoid resin.
[0096] The preparation of cannabinoid isolates can be completed by many well-
known methods. See US Patent No. 2304669A, Adams, Roger, D. C.
Pease, and J. H. Clark. "Isolation of cannabinol, cannabidiol and
quebrachitol from red oil of Minnesota wild hemp." Journal of the American
Chemical Society 62.8 (1940): 2194-2196, Ben-Shabat, Shimon, et al.
"New cannabidiol derivatives: synthesis, binding to cannabinoid receptor,
and evaluation of their anti-inflammatory activity." Journal of medicinal
chemistry 49.3 (2006): 1113-1117., and Lago-Fernandez, Ana, et al. "New
Methods for the Synthesis of Cannabidiol Derivatives." Methods in
enzymology. Vol. 593. Academic Press, 2017. 237-257. for examples and
an overview of the preparation of cannabinoid isolates.
[0097] One advantage of cannabinoid isolates is the ability to isolate the
desired
cannabinoid for use in pharmaceutical compositions, such as those which
form the instant invention.
[0098] An advantage of using cannabinoid isolates instead of cannabinoid resin
is that cannabinoid isolates that are pure CBD, or nearly pure CBD, can
be formed. Cannabinoid isolates comprising 100% CBD, or nearly 100%
CBD, can be formed by a process which removes THC and other
CA 3005885 2018-05-23
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cannabinoids from a plant extract, cannabinoid resin, or other cannabinoid
extract.
[0099] Therefore, cannabinoid isolates can be used in the instant invention to
form compositions which are high in CBDs. Cannabinoid isolates which
comprise 100% CBD, or nearly 100% CBD, can be utilized to prepare
100% CBD tablets, which are particularly of interest.
[00100] Another advantage of the use of Cannabinoid isolates in compositions
of
the present invention is that a carrier oil, such as sesame oil, is not
required for formulation.
[00101] In a preferable example of compositions of the instant invention, the
compositions use a cannabinoid isolate which is water soluble.
[00102] Examples
[00103] Example 1: Ingredients and amounts useful for dosage units of 25
mg of cannabinoid pellets
[00104] Pellets ¨ 229.0mg of pellets
beta-cyclodextrin 150.0mg
Sesame Oil 25.0mg
Cannabinoid Resin 25.0mg
Compritol 888 4.0mg
Soy Lecithin 2.5mg
Labrasol 22.5mg
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[00105] Example 2: Pellet Formulation Methods
[00106] The pellet formulations according to the present example may be
prepared as follows:
1. mix cyclodextrin with water for approximately 2.5 hours to form
a slurry;
2. mix a cannabinoid resin and sesame oil together at a temp of
about 60 C until a uniform mixture is obtained;
3. add the uniform mixture or resin and oil to the cyclodextrin
slurry and mix for about 1 hour;
4. mix soy lecithin and water together at a temperature of about
60 C, until a uniform slurry mixture is obtained;
5. slowly sprinkle the glyceryl behenate on to the resin,
cyclodextrin mixture obtained in step 3 and mix for about 15
minutes;
6. slowly add the soy lecithin slurry to the mixture obtained in step
while increasing the mixer speed to achieve a uniform
mixture;
7. slowly add Labrasol to the mixture obtained in step 6 while
maintaining the uniform mixture;
8. continue mixing until a uniform mixture is obtained and being
careful to not over mix;
9. transfer the mixture to stainless steel (or other suitable) trays;
10. place in an oven and dry at about 70 C until the moisture
content is less than 2.0% to form Pellets; and
11. screen the dry mixture using mesh screens of 30 followed by a
mesh of 270 to obtain particles substantially between 0.05mm
and 0.5mm in size.
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[00107] Example 3: Branded ingredients useful for 25 mg of cannabinoid
pellets
Pellets
beta-cyclodextrin 150.0mg
Sesame Oil 25.0mg
Cannabinoid Resin 25.0 mg
Compritol 888 4.0mg
Soy Lecithin 2.5mg
Labrasol 22.5mg
[00108] Example 4: Ingredients useful for preparing larger scale cannabinoid
pellet
batches
Pellets ¨
beta-cyclodextrin 1.5kg
Sesame Oil 0.250kg
Cannabinoid Resin 0.250kg
Compritol 888 0.050kg
Soy Lecithin 0.050kg
Labrasol 0.230kg
[00109] Example 6: Pellet Formulation Methods
[00110] The formulation according to the present example may be prepared as
follows:
1. mix cyclodextrin with water for approximately 2.5 hours to form
a slurry;
2. mix a cannabinoid resin and sesame oil together at a temp of
about 60 C until a uniform mixture is obtained;
3. add the uniform mixture or resin and oil to the cyclodextrin
slurry and mix for about 1 hour;
4. mix soy lecithin and water together at a temperature of about
60 C, until a uniform slurry mixture is obtained;
CA 3005885 2018-05-23
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5. slowly sprinkle the glyceryl behenate (Comp888) on to the
resin, cyclodextrin mixture obtained in step 3 and mix for about
15 minutes;
6. slowly add the soy lecithin slurry to the mixture obtained in step
while increasing the mixer speed to achieve a uniform
mixture;
7. slowly add Labrasol to the mixture obtained in step 6 while
maintaining the uniform mixture;
8. continue mixing until a uniform mixture is obtained and being
careful to not over mix;
9. transfer the mixture to stainless steel (or other suitable) trays;
10. place in an oven and dry at about 70 C until the moisture
content is less than 2.0% to form Pellets; and
11. screen the dry mixture using mesh screens of 30 followed by a
mesh of 270 to obtain particles substantially between 0.05mm
and 0.5mm in size.
Surprising the amounts of glyceryl behenate and soy lecithin
are crucial to control as too little will result in very long drying
times for the pellets and a loss of efficiency.
[00111] Example 7: Ingredients useful for preparing can nabinoid pellets
using a cannabinoid isolate
Granules
Beta-cyclodextrin 0.3kg
Purified water 0.945kg
Cannabinoid Isolate 0.070kg
Compritol 888 0.010kg
Soy Lecithin 0.020kg
Labrasol 0.046kg
CA 3005885 2018-05-23
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[00112] In each of the foregoing examples cannabinoid isolates may be
advantages substituted for cannabinoid resin or extract.
[00113] A further aspect of the invention are pharmaceutical preparations or
compositions for oral administration, comprising the particles. They can be
simply filled in a PVC container from which the particles can be taken with
a dosing spoon. Other oral dosage forms are sachets in which the
particles are filled, alone or together with appropriate excipients, such as
skim milk powder, microcrystalline cellulose, sodium
carboxymethylcellulose and talc, to form a powder for reconstitution.
Another possibility is to embed the particle in a matrix excipient, for
example, microcrystalline cellulose, followed by compression to tablets,
particularly chewable tablets. The particle, can also be filled in capsules,
for example, hard gelatin capsules.
[00114] As will be immediately obvious, some of the steps may be carried out
simultaneously or in a different order, such variations are included in the
present invention.
[00115] All publications mentioned above are hereby specifically incorporated
herein by reference in full for the teachings for which they are cited. The
examples and claims of the present invention are not limiting. Having
read the present disclosure, those skilled in the art will readily recognize
that numerous modifications, substitutions and variations can be made to
the description without substantially deviating from the invention described
herein. Such modifications, substitutions and variations constitute part of
the invention described herein.
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