Note: Descriptions are shown in the official language in which they were submitted.
[001] SUSTAINED RELEASE CANNABINOID FORMULATIONS
[002] RELATED APPLICATIONS
[003] This application is a continuation-in-part (CIP) of United States
application
serial no. 15/717,026 filed 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 number 62/551,924, filed on August 30, 2017. The
aforementioned applications are explicitly incorporated herein by
reference in their entirety for all purposes.
[004] FIELD OF THE INVENTION
[005] 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.
[006] BACKGROUND OF THE INVENTION
[007] 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/
Tetrahydrocannabinol accessed 5/25/2015. All or any of these
cannabinoids can be used in the present invention.
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. .
. r
[008] 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.
[009] 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.
[0010] 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.
[0011] Dronabinol is the international nonproprietary name for a pure isomer
of
THC, (¨)-trans-A9-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).
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[0012] 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.
[0013] 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 Marinol. 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.
[0014] 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
identified 66 naturally occurring cannabinoids. The active ingredient in
Marinol, 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
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=
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.
[0015] 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.
[0016] 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
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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 Marino! 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.
[0017] 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.
[0018] As a result of Marinol's slow onset and poor bioavailablity, scientists
are
now in the process of developing a new formulation of pulmonary
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
CA 3005889 2018-05-23
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.
[0019] US 6,403,126 (incorporated herein by reference in its entirety)
discloses
methods of extracting and purifying cannabinoids from Cannabis using
organic solvent.
[0020] An analog of dronabinol, nabilone. is available commercially.
[0021] 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.
[0022] 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
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.
[0023] Pharmaceutical compositions comprising the cannabinoid active
pharmaceutical ingredient, crystalline trans-( )-A9-tetrahydrocannabinol,
and formulations thereof are disclosed in WO 2006133941. The invention
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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-( )-A9-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.
[0024] 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.
[0025] 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.
[0026] 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
advantageous to use because they avoid toxicity that is encountered with
psychoactive cannabinoids at high doses useful in the method of the
present invention.
[0027] US 8808734 discloses stable, fast-acting liposomal and micelle
formulations of cannabinoids or cannabinoid analogues.
[0028] US 6747058 discloses stable composition for inhalation therapy
comprising delta-9-tetrahydrocannabinol and semi-aqueous solvents.
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[0029] 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.
[0030] 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.
[0031] 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
8
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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
ineffective absorption, which is an important part of the high clinical
failure
rate due to poor pharmacokinetics. 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).
[0032] 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 Clin 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 Permeability BCS Class III BCS Class IV
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[0033] 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
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.)
[0034] For BCS Class ll 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).
[0035] 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.
[0036] 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.
[0037] Controlled Release Dosage Forms
[0038] Controlled-release formulations have been one of the major focuses in
pharmaceutical research and development.
CA 3005889 2018-05-23
[0039] 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.
[0040] Oral controlled release delivery systems should ideally be adaptable so
that release rates and profiles can be matched to physiological and
temporal requirements.
[0041] 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.
[0042] 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.
[0043] 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
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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.
[0044] 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.
[0045] 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.
[0046] 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 granules 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
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.
(J. 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
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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.
[0047] Another method of dealing with poorly soluble drugs is to employ
emulsions. Emulsions are formed by mixing two immiscible liquids (in the
case of drugs usually water and oil) stabilized by an emulsifying agent.
Self-emulsification is thought to take place when (as a result of) the
entropy change favoring dispersion is greater than the energy required to
increase the surface area of the dispersion. The free energy of the
emulsion is a function of the energy required to create a new surface
between the oil and water phases.
[0048] When an emulsion is formed surface area expansion is created between
the two phases. The emulsion is stabilized by the surfactant molecules
that form a film around the internal phase droplet. In emulsion formation,
the excess surface free energy is dependent on the droplet size and the
interfacial tension. If the emulsion is not stabilized using surfactants, the
two phases will separate reducing the interfacial tension and the free
energy. [Journal of Pharmacy and Alternative Medicine ISSN 2222-4807
(Online) Vol 1, 2012 Basics of Self Micro Emulsifying Drug Delivery
System Barkat Ali Khan*1, Satar Bakhsh1, Haroon Khan2, Tariq
Mahmood3, Akhtar Rasul]. Barkat
[0049] Self-emulsifying drug delivery systems ("SEDDS") including self-micro-
emulsifying drug delivery systems ("SMDDS") are mixtures of natural or
synthetic oils, solid or liquid surfactants, or alternatively, one or more
hydrophilic solvents and co-solvents/surfactants that have the ability to
form oil-in-water emulsions upon mild agitation followed by dilution in
aqueous media, such as GI fluids. The digestive motility of the stomach
and the intestine provides the agitation necessary for self-emulsification.
13
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,
[0050] To date, there are still numerous limitations to SEDDS and SMEDDS, for
example, they require high surfactant concentrations in formulations
(approximately 30-60%) which may irritate the gastrointestinal tract. They
include chemically unstable drugs that tend to precipitate, and the volatile
co-solvents in the self-micro emulsifying formulations are known to
migrate into the shells of soft or hard gelatin capsules, resulting in the
precipitation of the lipophilic drugs. In one example, the SMEDDS showed
around 50% degradation after only 30 days (AAPS PharmSciTech. 2009
June; 10(2): 482-487. SMEDDS of Glyburide: Formulation, In Vitro
Evaluation, and Stability Studies. Yogeshwar G. Bachhav and Vandana B.
Patravale). Further, these systems are hard to develop and tend to be
expensive. Such systems have only been useful for immediate release
dosage forms, useful, extended release dosage forms have not been
regularly achieved.
[0051] SMEDDS generally must be given as a liquid and so oral formulations are
often formulated as soft gels, for example: Neoral and Sandimmune;
Norvir; Fortase; and Convulex. The present invention represents a
considerable advance over such formulations.
[0052] Water insoluble polymers can be used in extended drug release
formulations. These include methacrylate- or acrylate-based polymers with
low permeability.
[0053] Hydrophilic functional groups such as trimethylaminoethyl methacrylate
can improve permeability and swellability in water thus altering release
behaviors.
[0054] 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
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www.thepharmajournal.com. THE PHARMA INNOVATION Vol. 1 No. 7
2012 www.thepharmajournal.com Page 1116 Osmotic-Controlled
Release Oral Delivery System: An Advanced Oral Delivery Form. Nitika
Ahuja, Vikash Kumar, Permender Rathee.
[0055] The instant invention solves these problems and provides for
cannabinoid
sustained release dosage forms in a technically and economically efficient
and surprising manner.
[0056] In general, the most desirable oral dosage form is a tablet, and it
would be
advantageous if a cannabinoid containing tablet could be made available
which does not suffer from the problems of expense and the need for
smoking or "edible" dosage forms. None of the documents described
above enable modified release cannabinoid tablets. There is a need for
new cheap and stable dosage formulations, especially tablets, comprising
an effective dose of cannabinoids or derivatives thereof. There is also a
need for a stable cannabinoid powder.
[0057] Another aspect the invention provides a pharmaceutical or nutraceutical
composition in the form of a tablet for oral administration comprising
cannabinoid wherein said tablet is preferably formed from a
pharmaceutically or even nutraceutically acceptable powder.
[0058] 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
ingredients and all other similar delivery methods whether approved or
unapproved.
[0059] Viewed from another aspect the invention provides a pharmaceutical or
nutraceutical tablet as hereinbefore described for use in the treatment or
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prophylaxis of all of the disorders that medical marijuana and drabinol is
used for at the present time.
[0060] 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.
[0061] DETAILED DESCRIPTION OF THE INVENTION
[0062] Extending drug release ("sustained 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.
[0063] 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.
[0064] The sustained release formulations of cannabinoids of the present
invention represent a significant improvement over existing formulations
and delivery methods of cannabinoids.
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CA 3005889 2018-05-23
[0065] The present invention involves a novel granulation method for
formulating
cannabinoids in a matrix and subsequently into tablets.
[0066] The benefits of the invention include maintaining cannabinoids in a
soluble, hydrophilic state in contact with body fluids.
[0067] 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 tablets and powders of
cannabinoid formulations using a novel combination of silica gel,
hydrogenated lecithin, glyceryl behenate, peg-6 (or -8) caprylic/capric
glycerides, hydroxypropylmethylcellulose, microcrystalline cellulose,
colloidal silicon dioxide, and hydroxypropylcellulose.
[00681 Cannabinoid Extract Resin
[0069] 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 granules and
tablets may be desirable in specific situations.
10070] Cyclodextrins
[0071] Cyclodextrins (sometimes called cycloamyloses) are a family of
compounds made up of sugar molecules bound together in a ring (cyclic
oligosaccharides).
[0072] 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.
17
CA 3005889 2018-05-23
[0073] Cyclodextrins are composed of 5 or more a-D-glucopyranoside units
linked 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.
[0074] All of these cyclodextrins can be employed in the present invention.
[0075] 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.
[0076] 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.
[0077] 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-
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
18
CA 3005889 2018-05-23
can form complexes with stable substances, like trichlorfon (an
organophosphorus insecticide) or sewage sludge, enhancing their
decomposition.
[0078] 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.
[0079] 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.
[0080] 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.
19
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,
,
[0081] 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.
[0082] P-cyclodextrins are the main ingredient in P&G's product Febreze which
claims that the p-cyclodextrins "trap" odor causing compounds, thereby
reducing the odor.
[0083] The cavity of the 7-membered p-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 flurbiprofen with cyclodextrins in aqueous solution and
in solid state, Acta Pharm. Suec. 20:11-20.].
[0084] Alkylation of p-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
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.
[0085] 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.
CA 3005889 2018-05-23
Jugoslay. 24:13-200.], was found to undergo delayed decomposition when
it was solubilized by hydroxyethyI-I3-cyclodextrin. Both of the above factors
have important implications for the absorption of the EHA and DPA
contained in omega 3 oils.
[0086] 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.
[0087] 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-
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.
[0088] 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.
[0089] Lecithin also extends shelf life by stabilizing emulsions, and it also
reduces "stickiness" and is often used as a "releasing agent."
[0090] Chemically, glyceryl behenate is a mixture of various esters of behenic
acid and glycerol (glycerides). The mixture predominately contains the
21
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,
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 nanoparticles such as
solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC).
Handbook of pharmaceutical excipient, 5th edition.
[0091] 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 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
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.
[0092] 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
the monolithic tablets of the instant invention, 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.
[0093] Hydrophilic polymers like HPMC 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
22
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diffusion and erosion. Such release mechanisms can apply to systems
where drug is dispersed in or coated with polymer.
[0094] Microcrystalline cellulose is derived from refined wood pulp and is
used in
the present invention as an anti-caking agent and emulsifier.
[0095] Microcrystalline cellulose (MCC) is pure partially depolymerized
cellulose
synthesized from a-cellulose precursor. The MCC can be synthesized by
different processes such as reactive extrusion, enzyme mediated, steam
explosion and acid hydrolysis. The later process can be done using
mineral acids such as H2SO4, HCl and HBr as well as ionic liquids. The
role of these reagents is usually to destroy the amorphous regions
remaining in the crystalline domains. The degree of polymerization is
typically less than 400. The MCC particles with size lower than 5 pm not
be more than 10%. The MCC is a valuable additive in pharmaceutical,
food, cosmetic and other industries. Different properties of MCC are
measured to qualify its suitability to such utilization, namely particle size,
density, compressibility index, angle of repose, powder porosity, hydration
swelling capacity, moisture sorption capacity, moisture content,
crystallinity index, crystallite size and mechanical properties such as
hardness and tensile strength. https://en.wikipedia.org/wiki/
Microcrystalline cellulose. Accessed September 16, 2016.
[0096] Microcrystalline cellulose is a naturally occurring polymer, it is
composed
of glucose units connected by a 1-4 beta glycosidic bond. These linear
cellulose chains are bundled together as microfibril spiralled together in
the walls of plant cell. Each microfibril exhibits a high degree of three-
dimensional internal bonding resulting in a crystalline structure that is
insoluble in water and resistant to reagents. There are, however, relatively
weak segments of the microfibril with weaker internal bonding. These are
called amorphous regions. The crystalline region is isolated to produce
microcrystalline cellulose. https://en.wikipedia.org/wiki/ Microcrystalline
cellulose. Accessed September 16, 2016.
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=
[0097] Colloidal silicon dioxide or silicon dioxide is used in the instant
invention
as an anti-caking agent, adsorbent, disintegrant, and glidant to allow
powder to flow freely when tablets are processed.
[0098] Hydroxypropylcellulose (HPC) is an ether of cellulose in which some of
the
hydroxyl groups in the repeating glucose units have been
hydroxypropylated. In the instant invention it is used as a tablet binder and
emulsifier.
[0099] In each of the following examples cannabinoid isolates may be
advantageously substituted for cannabinoid resin.
[00100] 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.
[00101] 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.
[00102] 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.
[00103] 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.
[00104] In a preferable example of compositions of the instant invention, the
compositions use a cannabinoid isolate which is water soluble.
[00105] Examples
[00106] Example 1: Ingredients useful for 25 mg cannabinoid tablet (total
287.70mg) components
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CA 3005889 2018-05-23
[00107] Granules ¨ 229.0mg granules
beta-cyclodextrin 150.0mg
Sesame Oil 25.0mg
Cannabinoid Resin 25.0mg
Compritol 888 4.0mg
Soy Lecithin 2.5mg
Labrasol 22.5mg
[00108] Blend
Syloid XDP 3150 2.5mg
Klucel LF Pharm 5.0mg
ProSolv90 25.0mg
HPMC LVCR K100 12.5mg
[00109] Coating
Green Colour 5% 13.70mg
[00110] Example 2: Formulation Methods
[00111] 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;
5. slowly sprinkle the glyceryl behenate on to the resin,
cyclodextrin mixture obtained in step 3 and mix for about 15
minutes;
CA 3005889 2018-05-23
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 granules;
11. screen the granules through a 30 mesh;
12. screen each of the silica gel, hydroxypropylcellulose,
microcrystalline cellulose/colloidal silicon dioxide, and
hydroxypropylmethylcellulose together with through a 30 mesh;
13. add the resin granules and blend for about 10 minutes;
14. form tablets;
15. mix colour and water together for about 30 minutes;
16. preheat the coating machine to 70 C with the guns blowing air,
to stabilize the temperature; and
17. coat tablets to a 5% uniform coating.
[00112] Example 3: Branded ingredients useful for 25 mg cannabinoid tablet
components
Granules
beta-cyclodextrin 150.0mg
Sesame Oil 25.0mg
Cannabinoid Resin 25.0 mg
Compritol 888 4.0mg
Soy Lecithin 2.5mg
Labrasol 22.5mg
Blend
Syloid XDP 3150 2.5mg
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CA 3005889 2018-05-23
Klucel LF Pharm 5.0mg
ProSolv90 25.0mg
HPMC LVCR K100 12.5mg
Coating
Green Colour 5% 13.7mg
[00113] Example 4: Branded ingredients useful for 15.5 mg cannabinoid
tablet components
[00114] Granules
beta-cyclodextrin 150.0mg
Sesame Oil 25.0mg
Cannabinoid Resin 15.5mg
Compritol 888 4.0mg
Soy Lecithin 2.5mg
Labrasol 15.0mg
[00115] Blend
Syloid XDP 3150 2.5mg
Klucel LF Pharm 5.0mg
ProSolv90 25.0mg
HPMC LVCR K100 12.5mg
[001161 Coating
Green Colour 5% 12.85mg
[00117] Example 5: Ingredients useful for preparing larger scale 25 mg
cannabinoid tablets (total weight 323mg) components
[00118] Granules
Beta-cyclodextrin 1.5kg
Sesame Oil 0.250kg
27
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Cannabinoid Resin 0.250kg
Compritol 888 0.050kg
Soy Lecithin 0.050kg
Labrasol 0.230kg
[00119] Blend ¨ using 1.864kg of above
Syloid XDP 3150 0.040kg
Klucel LF Pharm 0.080kg
ProSolv90 0.400kg
HPMC LVCR K100 0.200kg
[00120] Coating
Green Colour 5%
[00121] Example 6: Formulation Methods
[00122] 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;
5. slowly sprinkle the glyceryl behenate (Cornp888) 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;
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CA 3005889 2018-05-23
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 granules;
Surprisingly, the amounts of glyceryl behenate and soy lecithin
are crucial to control, as too little will result in very long drying
times for the granules and a loss of efficiency.
11. screen the granules through a 30 mesh;
12. screen each of the silica gel, hydroxypropylcellulose,
microcrystalline cellulose/colloidal silicon dioxide, and
hydroxypropylmethylcellulose together with through a 30 mesh;
The amounts of hydroxypropyl methylcellulose and
microcrystalline cellulose are crucial in order to get tablets with
desirable dissolution profiles.
13. add the resin granules and blend for about 10 minutes;
14. form tablets;
15. mix colour and water together for about 30 minutes;
16. preheat the coating machine to 70 C with the guns blowing air,
to stabilize the temperature; and
17. coat tablets to a 5% uniform coating.
[00123] Example 7: Branded ingredients useful for 2.5 mg cannabinoid tablet
components
[00124] Granules
Beta-cyclodextrin 150.0mg
Sesame Oil 25.0mg
Cannabinoid Resin 2.5mg
Compritol 888 4.0mg
29
CA 3005889 2018-05-23
,
Soy Lecithin 2.5mg
Labrasol 15.0mg
[00125] Blend
Syloid XDP 3150 2.5mg
Klucel LF Pharm 5.0mg
ProSolv90 25.0mg
HPMC LVCR K100 12.5mg
[00126] Coating
Colour 5% 12.85mg
[00127]Example 8: Branded ingredients useful for 5 mg cannabinoid tablet
components
[00128] Granules
Beta-cyclodextrin 150.0mg
Sesame Oil 25.0mg
Cannabinoid Resin 5mg
Compritol 888 4.0mg
Soy Lecithin 2.5mg
Labrasol 15.0mg
[00129] Blend
Syloid XDP 3150 2.5mg
Klucel LF Pharm 5.0mg
ProSolv90 25.0mg
HPMC LVCR K100 12.5mg
[00130] Coating
Colour 5% 12.85mg
[00131] Example 9: Branded ingredients useful for 10 mg cannabinoid tablet
components
[00132] Granules
CA 3005889 2018-05-23
Beta-cyclodextrin 150.0mg
Sesame Oil 25.0mg
Cannabinoid Resin 10mg
Compritol 888 4.0mg
Soy Lecithin 2.5mg
Labrasol 15.0mg
[00133] Blend
Syloid XDP 3150 2.5mg
Klucel LF Pharm 5.0mg
ProSolv90 25.0mg
HPMC LVCR K100 12.5mg
[00134] Coating
Colour 5% 12.85mg
[00135] In each of the foregoing examples cannabinoid isolates may be
advantageously substituted for cannabinoid resin.
[00136] Example 10: Ingredients useful for preparing cannabinoid tablet
components using a cannabinoid isolate
[00137] Granules
Beta-cyclodextrin 0.3kg
Purified Water 0.945kg
Cannabinoid Isolate 0.070kg
Compritol 888 0.010kg
Soy Lecithin 0.020kg
Labrasol 0.046kg
[00138] Blend
Syloid XDP 3150 0.00826kg
Klucel LF Pharm 0.01652kg
ProSolv90 0.08260kg
HPMC LVCR K100 0.04130kg
[00139] Coating
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Colour As desired
[00140] 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.
[00141] As will be immediately apparent to the skilled artisan after reading
the
present disclosure, some of the steps may be carried out simultaneously
or in a different order, such variations form part of the present invention.
[00142] 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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