Note: Descriptions are shown in the official language in which they were submitted.
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
A METHOD OF PRODUCING A PROCESSED KAVA PRODUCT
HAVING AN ALTERED KAVALACTONE DISTRIBUTION AND PROCESSED
KAVA PRODUCTS PRODUCED USING THE SAME
CROSS-REFERENCE TO RELATED APPLICATIONS:
This application is claims priority under 35 U.S.C. ~ 119 to U.S. Provisional
Patent
Application Serial No. 60/326,928 entitled "Methods For Processing Kava Root
(Piper
Methysticum) And Kava-Derived Products Generated By These Methods Having
Controllable
Kavalactone Ratios", filed on October 3, 2001, and U.S. Provisional
Application Serial No.
60/369,889 entitled "Dry Flowable Kava Extract Powder And Fast-Dissolve Kava
Extract
Composition For Oral Delivery", filed on April 3, 2002. The entire contents of
both of these
applications are hereby expressly incorporated by reference.
FIELD OF THE INVENTION(S):
This invention is related to methods for processing kava to produce a kava
extract with
particular kavalactone concentration profile, a processed kava product, such
as a dry flowable
kava extract powder, and the use of such a powder in a rapid-dissolve tablet
for oral delivery.
BACKGROUND:
Kava plants, a type of pepper plant also known as Piper methysticum, are
generally found
in Polynesia, Melanesia, and Micronesia. The kava plant contains high
concentrations of
kavalactones (sometimes referred to as kavapyrones), including kavain,
methysticin, yangonin,
dihydromethysticin, desmethoxyyangonin, and dihydrokavain, and has been used
as an herbal
medicine. The prized part of the kava plant is the root system because it
contains the highest
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
concentrations of the active kavalactones. Kavalactones are also found in
other parts of the
plant. General information about kava plants can be found in Vincent Lebot, et
al., "Kava The
Pacific Elixir, The Definitive Guide to its Ethnobotany. History, and
Chemistry", Inner
Traditions Intl. Ltd. (March 1997).
After a kava plant is harvested, the root is conventionally processed to
generate a
consumable product. In conventional and historical methods, the root is dried
and ground to a
powder. This powder contains not only the kavalactones but also plant oils,
resins, and other
substances. The powder can be mixed with water to form a beverage. The
resinous ground dried
root can also be packaged into capsules or other forms of delivery.
The effects of ingesting kava root extract will vary from person to person.
Common
effects include a state of relaxation and a reduction in muscle tenseness.
Kava root has also been
used to help sufferers of insomnia. It can also produce a mild state of
euphoria. The ratios of the
various kavalactones in the consumed product has a large impact on the effect
experienced by
the user.
There are a large number of different kava cultivars, each of which has
differing ratios of
the different kavalactones. Through historical knowledge and experimentation,
various kava
cultivars have been classified according to their effect, such as "daily" or
"one-day", "custom",
"two-day", "medicinal", and "no drink". "Daily" kava cultivars are generally
consumed daily
and have relatively short-term effects. "Custom" kava cultivars tend to be
used for ritual and
ceremonial purposes. "Two-day" kava cultivars tend to have pronounced
physiological effects
and are known as "two day" because the drinker is usually affected for two
days. "Medicinal"
kava cultivars are specific for the treatment of ailments like rheumatism. "No
Drink" kava
2
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
cultivars are not recommended for consumption because they tend to induce
nausea and other
undesirable effects.
More recently, there have been concerns associating kava with occurrences of
liver
damage, although these reports are primarily anecdotal. Studies done in the
1970s and 1980s
have found that "two day" kava cultivars have particularly high concentrations
of methysticin
and dihydromethysticin. These kavalactones contain a methylenedioxyphenyl
functional group
which, when activated through metabolic activity, forms intermediary compounds
that can
inactivate multiple P450 enzymes. There are some suggestions that inhibition
of P450 enzymes
can interfere with the metabolism of many pharmaceuticals. The solution
proposed in the prior
art is the development of new kava cultivars with reduced amounts of
methysticin and
dihydromethysticin and increased kavain content.
One of the most highly prized kava cultivars is a one-day cultivar that grows
in Vanuatu.
Relative to other cultivars, this cultivar is naturally low in methysticin and
dihydromethysticin
and has a proportionally higher concentration of kavain. However, this
cultivar is not widely
grown or available and most commercially available cultivars have increased
levels of
methysticin and dihydromethysticin and lower concentrations of kavain.
Although breeding of
new cultivars that can be widely grown and which have lower concentrations of
methysticin and
dihydromethysticin and increased concentrations of kavain is possible, this
can be a time
consuming process and is not assured of success. In addition, the kavalactones
suspected of
producing toxic effects when consumed by humans are also toxic to various
insects and
microorganisms, such as fungi. Thus, the hardiest cultivars are generally
those which are least
suitable for human consumption.
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
In a kava extraction process, the rate at which various kavalactone components
are
extracted varies according to the extraction solvent and extraction conditions
used. However,
kava root extracts are conventionally sold based upon total kavalactone
content. Thus, the focus
of conventional commercial extraction techniques has been to extract as much
of the kavalactone
content from the root source as possible and knowledge regarding different
rates of extraction for
different kavalactones is used to adjust the extraction process or select
appropriate extraction
steps to provide for the greatest total kavalactone extraction.
Various extraction techniques have been used to process kava root. Such
techniques
include the use of supercritical carbon dioxide (C02) extraction, fluorocarbon
extraction, and the
use of various other organic and non-organic solvents to remove the
kavalactones from the dried
root. The resulting bulk extract is in the form of a paste.
Supercritical CO2 processes have been found to extract the largest quantity of
kavalactones from the root and thus conventional practice has been to focus on
the use of
supercritical COz to extract all of the kavalactones from the root in the
production of kava
extracts. As will be appreciated, bulk extracts of substantially all of the
kavalactones in the root
will generally contain kavalactones in the same or nearly the same proportions
as present in the
source root. Because of the differing effects produced by variations in the
kavalactone ratios of
different cultivars, producers of such kava products are limited to specific
kava cultivars as
source materials in order to produce a kava product that produces a desired
effect.
To the extent that the distribution profile of the various kavalactones in the
extract have
been of concern, conventional practice is to use additional processing steps,
such as high
pressure liquid chromatography (HPLC), to extract individual kavalactones. For
example, HPLC
and other chromatographic techniques, such as "flash" chromatography, have
been used to
4
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
process bulk kava extracts to isolate individual kavalactones. This process is
cumbersome to
implement and requires the use of machinery that is bulky and expensive to
operate. Methods for
extracting and purifying kava, including supercritical COz extraction and
chromatography, are
discussed in PCT publication WO 00/72861 to Martin et al. entitled
"Pharmaceutical
Preparations of Bioactive Substances Extracted from Natural Sources."
It would be advantageous and is an object of the present invention to provide
a method of
processing kava to provide an extract of kava as a paste, powder, or in other
forms, and which
allows the kavalactone profile to be altered during processing so as to have
reduced levels of
methysticin and dihydromethysticin and increased levels of kavain and
dihydrokavain. It would
be additionally advantageous if such techniques allowed the production of a
processed kava
product that had a kavalactone profile similar to (or improved upon) that of
the most preferred
"one-day" cultivars from Vanuatu by using a kava feedstock from a less desired
cultivar. There
would be yet a further advantage if such an altered-profile kava product could
be produced using
a minimal number of processing steps and without requiring additional
processing, such as via
chromatography, to isolate each individual kavalactone from the extract and
then recombine the
isolated kavalactones as appropriate.
There has been widespread use of bulk kava paste extracts as dietary
supplements, e.g.,
mixed in drinks or packaged in capsules. Because kava paste is not always well
suited for
processing into consumable form or for distribution, e.g., as a dietary
supplement, it would also
be advantageous to produce a dry flowable kava powder. The powder can be
distributed as is or
further processed, e.g., to produce kava tablets.
When consumed, kava is typically swallowed. The kavalactones then pass through
the
stomach and intestines as they are absorbed into the bloodstream. It can take
a relatively long
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
time for the body to process kava and the effect of the ingested kavalactones
can then be further
diminished as the compounds are processed by the liver. It would therefore
also be
advantageous to deliver kava in the form of a rapid-dissolve tablet which
would permit the
kavalactones to be absorbed orally.
SUMMARY OF THE INVENTION(S):
These and other objectives are met by use of the present methods of processing
kava to
produce a kava product, such as a paste, resin, oil, or a powder suitable for
use in a fast dissolve
tablet and other applications, and which as a kavalactone profile that is
altered from the profile of
the kava feedstock. The present methodologies also allow the distribution of
kavalactones to be
altered or adjusted to achieve a particular kavalactone profile wherein the
effectiveness of the
kava can be enhanced or the negative. effects reduced. Various other novel
kava extract
compositions are also presented.
Preferably, a two stage process is used. First, the kavalactones are extracted
from the
kava root material to form a kava paste. Preferably, the paste is generated
using liquid COZ
extraction techniques. However, under some conditions, supercritical COZ
extraction techniques
can be used. During processing, an initial pressurization / depressurization
step can also be
included to increase the rate at which the kavalactones can be extracted from
the rootstock. The
output of the first processing step is a viscous paste, oil, and/or resin.
The paste can then be subjected to a second or further refinement stages, if
desired, to
further purify the kavalactones and produce a highly refined paste extract.
Preferably, the
parameters of the second processing stage (and possibly the first stage as
well) are selected to
alter the kavalactone distribution in the raw material in order to achieve a
predetermined
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
distribution and concentration of the various kavalactones without the need of
chromatography
or other techniques conventionally used to extract individual kavalactones.
Advantageously, the use of the extraction techniques according to the various
embodiments of the invention thus allows high quality kavalactone having a
desired profile, such
as reduced levels of methysticin and dihydromethysticin and increased levels
of kavain and
dihydrokavain, to be easily and economically produced from a kava feedstock,
such as dried
ground root, which has an undesired kavalactone profile. In a particular
example, an undesired
kava stock, such as a "two-day" or "no-drink" cultivar, can be processed to
produce a kava
extract having a kavalactone distribution profile which is comparable to the
most desired "one-
day" Vanuatu cultivar.
For example, processing of kava using COZ at pressures of 1100 psi or greater
and at a
temperature greater than 31°C places the COZ in a supercritical state
and will extract on the order
of 80% to 100% of the kavalactones in the source. However, the extraction rate
of the various
kavalactones are fairly similar and the resulting extract will have a
kavalactone profile that is
similar to, if not identical to, that of the feedstock. (However, with careful
control over the
extraction parameters, subtle changes in the kavalactone profile can be made
using supercritical
COZ extraction.)
In contrast, it has been found that processing the kava feedstock using liquid
COZ at
pressures of between about 1100 psi to about 1800 psi and temperatures between
about 0°C and
about 25°C produces preferential extraction wherein methysticin and
dihydromethysticin are
extracted at a considerably slower rate than other kavalactones. It has been
further found that
processing at between about 1100 to about 1500 psi at temperatures between
about 5°C and
7
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
about 10°C also produces an increased relative concentrations of kavain
and dyhydrokavain
relative to other kavalactones in the extract.
Through use of the present techniques, kava extracts can be produced having a
kavalactone profile that is unlike those found in nature and the profile can
be tailored to meet
particular design considerations. Preferably, the kava product has kavalactone
properties that
have been selected to be low in the combined weight percentage of methysticin
(M) and
dihydromethysticin (DHM), low in the combined weight percentage of desmethoxy
yangonin
(DMY) and yangonin (Y), and high in the combined weight percentage of kavain
(K) and
dihydrokavain (DHK). The preferred kava product can be characterized according
to one or
more of the following attributes: (a) a combined weight percentage of the six
major kavalactones
methysticin (M), dihydromethysticin (DHM), yangonin (Y), desmethoxyyangonin
(DMY),
kavain (K), and dihydrokavain (DHK) of between about 20% to a maximum of about
90%; (b) a
combined weight percentage of M and DHM between about 5-15% to about 29%; (c)
a ratio of
Y to DMY by weight, expressed as the logarithmic function 10*LOG10(Y/DMY) in
dB units,
from about -1 to about 2; (d) a ratio of DHK to K by weight, expressed as the
logarithmic
function 10*LOG10(DHK/K) in dB units, from about-4 to about 1; (e) a combined
weight
percentage of Y and DMY between about 5% to about 20-25%, and (f) a combined
weight
percentage of flavokavain A and flavokavain B of between about 0.3% to about
3%.
Once a suitable kava paste, resin, or oil, is provided, it can then processed
for various
uses. For direct ingestion, for example, a paste can be sweetened and
flavored. In addition or
alternatively, the paste can be mixed with other dietary supplements, such as
the very sweet
tasting herb Stevia, or other herbal or non-herbal ingredients.
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
A kava paste can also be further processed to prepare a high quality dry
flowable powder
which can be used, for example, to produce an ingestible kava tablet. In a
first embodiment, a
kava paste is combined with a carrier, such as maltodextrin, dextrose, or
starches and mixed with
a suitable solvent, such as ethyl alcohol or water. The mixture is then spray
dried to produce a
powder having grains comprised of kava extract and the carrier. In a second
embodiment, an
emulsion of kava paste is formed in water or ethyl alcohol using, e.g.,
magnesium carbonate,
magnesium carbonate + silica (at up to about 2% by weight), whey protein,
maltodextrin,
carboxymethylcellulose and/or other suitable materials. The emulsion is then
dried and
powdered. In a third embodiment, the extract is processed with supercritical
COZ and a carrier,
such as maltodextrin, dextrose, or starches and then subjected to a rapid
decompression of the
supercritical fluid. As the fluid evaporates, the extract and kava are
deposited as micro-sized
particles.
The resulting powder, preferably having a preselected ratio of kavalactones,
can then be
formed into a tablet that, when placed in the mouth, dissolves rapidly over a
period of between
about 5 to about 180 seconds and preferably in about 15 to about 60 seconds. A
tableting
powder can be formed by combining between about 25% to about 60% by weight of
the
powdered kava extract with between about 30% to about 60% by weight of a dry
water-soluble
absorbent such as magnesium carbonate, or a diluent, such as lactose. Other
dry tablet additives,
such as one or more of a sweetener, flavoring and/or coloring agents, a
binder, such as acacia or
gum arabic, a lubricant, a disintegrant, and a buffer, can also be added to
the tableting powder.
Preferably, the dry ingredients are screened to a particle size of between
about 80 to about 100
mesh.
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
To form the tablets, the tableting powder is then wet with a solvent, such as
alcohol or
water, until it achieves a doughy consistency. The paste is then molded or
pressed into tablets
which are dried and packaged. The tablets can be of any suitable size, shape,
and weight.
Preferably, the tablets are formed into disks or wafers having a diameter of
between about 1/8
and about '/2 inch, a thickness of between about 0.08 and about 0.2 inch, arid
a weight of between
about 50 mg to about 1000 mg. The tablets are preferably homogeneous. However,
they can
also be formed of regions of kava extract composition separated by non-kava
extract regions in
periodic or non-periodic sequences as may be desired.
BRIEF DESCRIPTION OF THE DRAWINGS:
The following detailed description of the preferred embodiments) will be
better
understood with reference to the following figures in which:
Fig. 1 is a plot of total kavalactone weight percentages measured in the
lateral roots for
five usage classes of Vanuatu kava cultivars: Daily, Custom, Two-day,
Medicinal and No Drink;
Fig. 2 is a plot of Methysticin + dihydromethysticin weight percentages
measured in the
lateral roots for five usage classes of Vanuatu kava cultivars;
Fig. 3 is a plot of average dihydrokavain + kavain vs. yangonin +
desmethoxyyangonin
kavalactone concentration ratios measured in the lateral roots for various
kava cultivars and
extracts; and
Figs. 4-7 show plots of relative kavalactone concentrations for different kava
cultivars
and show changes in the kavalactone profile introduced during processing
according to the
present invention.
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
DESCRIPTION OF THE PREFERRED EMBODIMENT(S):
To better appreciate the utility of the present invention, it is useful to
present data
describing the differences between the total and relative amounts of various
kavalactones in a
variety of kava cultivars. The HPLC measurements for kava cultivars are taken
from V. Lebot's
and J. Levsque's paper in Allertonia (1989) entitled, "On The Origin And
Distribution Of Kava
(piper methysticum forst. F., piperaceae): A Phytochemical Approach". Lebot's
and Levesque's
procedure for the extraction and analysis of total kavalactone weight
percentages and
kavalactone concentration spectra for kava cultivars consisted of the
following steps: First,
select only the lateral roots of a kava plant that reached the age of two
years. Next, dry lateral
roots in an oven at 60-80°C for eight hours, and then grind the roots
into powder. Then, perform
a six hour Soxhlet extraction of powdered root using chloroform as the
solvent. Finally, analyze
the chloroform extract using HPLC.
Note that Lebot and Levesque used only the lateral roots to measure the
kavalactone
concentration spectrum for a given kava cultivar. This is important because
different parts of the
kava plant (e.g., rhizome, stem, leaves) have different kavalactone
concentration spectra, as well
as different total kavalactone weight percentages. Total kavalactone weight
percentage is
highest in the lateral roots, and decreases towards the aerial parts of the
plant (pg. 67, Lebot,
Merlin, Lindstrom, Kava-The Pacific Elixir, 1997). Lebot (1988) found in
Vanuatu kava
cultivars that when the total kavalactone weight percentage was about 15% in
the lateral roots, it
dropped to about 10% and 5% in the rhizome and basal stem, respectively.
Lebot, et al (1997)
on pp. 74-75 report that K and DMY are the dominant kavalactones in the
rhizome, whereas
DHK and DHM tend to be the kavalactones with the highest concentrations in the
leaves. In
summary, the kavalactone concentration spectrum and total kavalactone weight
percentage for a
11
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
given kava cultivar can be determined by a number of factors, which include
age of the plant,
method of extraction, as well as the part of the plant.
66 of the 67 Vanuatu cultivars identified in Table 2 in Lebot and Levesque
(1989) were
analyzed (33 Daily, 11 Custom, 14 Two-day, 4 Medicinal, and 4 No Drink
cultivars). Also
analyzed were 26 of the 27 Fijian kava cultivars from Table 6 in Lebot and
Levesque (1989).
Lebot and Levesque did not classify these cultivars according to the system
described above.
HPLC was used to determine the total kavalactone weight percentages and
kavalactone
concentration spectra for the various samples.
Figure 1 presents a plot of the total kavalactone weight percentages measured
by Lebot
and Levesque (1989) in the lateral roots for the five usage classes of Vanuatu
kava cultivars:
Daily (D), Custom (C), Two-day (T), Medicinal (M), and No Drink (N). As will
be appreciated,
the total kavalactone weight percentage does not uniquely identify the type of
kava cultivar, e.g.,
there are several D, C, T and M kava cultivars with total kavalactone weight
percentages in the
range of 11-12%. Figure 1 also shows that the selection of a kava cultivar
with a very low total
kavalactone percentage does not mean that it has the least effect because the
class of No Drink
kava cultivars has the lowest average total kavalactone concentration.
Accordingly, kava
cultivars that have high concentrations of desirable kavalactones may also
contain high
concentrations of undesirable kavalactones, making these cultivars unsuitable
for use in
producing consumable kava products without first altering the profile of the
kavalactones.
Figure 2 is a bar graph plotting number of Vanuatu kava cultivars vs. the
combined
M+DHM weight percentage measured by Lebot and Levesque (1989) in the lateral
roots for the
D, C, T, M and N classes of kava cultivars described for Figure 1. Table 1
below summarizes
the M%+DHM% averages for the five usage classes:
12
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
TABLE 1
Average Weight Percentage
of Methysticin and
Dihydromethysticin
in Lateral Roots for
the Five Usage Classes
of
Vanuatu Kava cultivars
Kava Cultivar Usage Avera a M%+DHM%
Class
Daily 25 ~ 4%
Custom 33 ~ 9%
Two-day 39 t 6%
Medicinal 33 t 13%
No Drink ~ 57 t 10%
Figure 2 and Table 1 indicate that the frequency of use for a kava cultivar is
proportional
to the M%+DHM%, with the Daily kavas having the lowest average of 25 t 4%, the
Two-day
kavas are 14% higher at 39 f 6%, and the No Drink kavas have the highest
M%+DHM% at 57 t
10%. Thus, the higher the M%+DHM% for a Vanuatu kava cultivar, the less
frequent its use.
Moreover, M%+DHM% has been found to be proportional to the degree of induced
nausea, which could help explain why frequency of use drops with increasing
M%+DHM%. In
particular, Lebot, et al (1997) report on pg. 78 that DHM is a major component
of Two-day (or
tudei) kavas that frequently produce nausea. According to the work of the
Meyer group in
Freiburg, the M and DHM kavalactones are absorbed the slowest in the
gastrointestinal tract.
The strong anticonvulsive and muscle relaxant action of M and DHM (see Meyer
group work)
combined with the fact that M and DHM remain for longer periods of time in the
gastrointestinal
tract are consistent with the induction of nausea resulting from kava
preparations containing high
percentages of M and DHM.
The relationships between M%+DHM% and Vanuatu kava cultivar usage presented in
Figure 2 and table 1 above are important steps in classifying Vanuatu kava
cultivars, and can
also be used to classify other kava preparations and products. However, this
classification does
not help with distinguishing the neuroactive effects of the different kava
cultivars. In order to
13
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
better distinguish the neuroactive effects of kava products, a two-dimensional
logarithmic
coordinate system is presented which maps the concentrations of the
neuroactive kavalactones
that cross the blood-brain barrier the fastest: K, DHK, Y and DMY. The Y/DMY
ratio defines
the "X-axis" for this coordinate system and the DHK/K ratio defines the "Y-
axis". The
logarithmic nature of the coordinate system comes from the fact that the DHK/K
and Y/DMY
concentration ratios are in dB's, which means 10*LOG~o(DHK/K) and
10*LOG~o(Y/DMY). A
point centered on the origin (0,0) signifies that the DHK/K and Y/DMY ratios
are both 1.
Positive values reflect ratios greater than l, and negative values correspond
to ratios less than 1.
Figure 3 is a map of average DHK/K vs. Y/DMY concentration ratios (in dB) for
1)
lateral roots of the five different usage classes of Vanuatu kava cultivars,
2) lateral roots of 26
Fijian kava cultivars, 3) Alden Botanica's Essence of Kava (or EoK) extract of
Vanuatu kava,
and 4) Schwabe's Laitan kava extract. The DHK/K vs. YLDMY map in Figure 3 is
effective in
separating the five classes of Vanuatu kava cultivars, the Fijian kava
cultivars, EoK, and Laitan.
The average for the Fijian kavas falls in the fourth quadrant (DHK < 1 and
Y/DMY > 1), in
contrast to the averages for the D, C, M, and T Vanuatu kava cultivars in the
first quadrant (DHK
> 1 and Y/DMY > 1), and the average for the N Vanuatu kava cultivars in the
second quadrant
(DHK > 1 and Y/DMY < 1). Although EoK is made from Vanuatu kava, the
composition is
about 20% lateral roots and 80% rhizome. The high percentage of rhizome in EoK
could explain
why its DHK/K ratio is less than 1 because K tends to dominate in the rhizome.
The
M%+DHM% for EoK is 21%, which is characteristic of a Vanuatu Daily kava. The
lateral root
and rhizome compositions in Laitan are not known, and so it is difficult to
suggest a reason for
its DHK/K vs. Y/DMY mapping. However, its M%+DHM% of 34% is closer to the
average
M%+DHM% for Vanuatu Custom, Medicinal and/or Two-day kava cultivars and the
average for
14
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
Fijian kava cultivars. The high M%+DHM% of Laitan relative to that for EoK
implies that
Laitan will have a more muscle relaxing effect and a higher probability of
inducing nausea.
As will be appreciated, there are many kava cultivars that contain kavalactone
distributions which are not well suited for consumption. In order to generate
a kava product,
such as a paste or a dry flowable powder for use in fast dissolve tablet and
other applications,
raw kava root is processed to produce a kava paste, oil or resin (collectively
referred to herein as
"paste") that contains the kavalactones in the desired proportions, such as a
distribution profile
that corresponds to the most preferred Vanuatu one day cultivars. The paste
can then be further
processed, e.g., to produce a refined paste and/or a flowable powder.
Preferred techniques are
discussed below. These products generally can be referred to as a processed
kava products.
As an initial step, the kava itselfmust be harvested, dried, and ground to
size. The active
kavalactones are most prevalent in the lateral roots of the plant. Various
different cultivars are
conventionally used, including but not limited to Isa, Mahakea, Moi, Papa
Eleele, Borogu,
Ahine, Kelai, Palisi, Puna Green, Hanakapiai, Hiwa, Spotted Hiwa, Nene, SIG,
Apu Awa, Alia,
Melomelo, and Pia. Each cultivar has a typical concentration of the various
kavalactones
resulting in different effects from ingesting the root or a root extract. The
harvested roots are
preferably dried to a moisture content of between 3% and 10%, most preferably
around 5%, and
then ground to a particle size suitable for subsequent processing. A typical
particle size is
between about 60 mesh to about 300 mesh, which correlates to about 250p to
about SOp,
respectively, and preferably to between about 100p and about 75~.
The powdered kava root is then processed to produce a kava paste using
techniques
described below. In a preferred technique, the kava is processed using COz in
the liquid phase,
but supercritical phase COZ extraction can be used. A solvent modifier, such
as ethyl alcohol or
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
refrigerant chemicals, can be added. Preferably, prior to the primary
extraction steps, the
feedstock is initially processed by subjecting it to a high pressure carbon
dioxide environment
followed by a rapid decompression. This compression-decompression process
advantageously
results in a substantially higher kavalactone yield than achieved without the
decompression step.
The paste can then be further processed to produce a flowable powder. Although
a paste
made according to the present invention is preferably used, kava pastes
produced using various
alternative techniques can alternatively be used. Such methods include those
disclosed in
Published PCT Application WO 00/72861 to Martin et al. entitled
"Pharmaceutical Preparations
of Bioactive Substances Extracted from Natural Sources" and in U.S. Patent
5,512,285 to Wilde
entitled "Fragrance Extraction," the entire contents of which are both
expressly incorporated by
reference.
In a specific implementation of the method for producing the kava paste, the
powdered
dried root is placed in a stainless steel vessel and preprocessed by
pressurizing the vessel with
COZ to between about 1100 psi and about 4500 psi, preferably at least about
1800 psi, at a
temperature of between about 10° C and about 60° C, and
preferably between about 15° C and
about 20° C. It is not required that the pressures reach the critical
point of COZ ( 1100 psi and 31 °
C) during this stage. After the desired pressure is reached and held for a
period of time, ranging
from continuous flow to fill and hold, where the hold time can vary from
between about 5
minutes to about 60 minutes, the pressure in the extraction vessel is rapidly
and substantially
reduced, preferably to a level at or near one atmosphere. This preprocessing,
while not
necessary, allows for a higher efficiency of extraction in the subsequent
processing steps.
As noted above, various extraction steps can be used to prepare the refined
kava paste
from a starting material. The particular techniques and solvents used are
selected, to some
16
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
extent, based on the moisture content present in the feedstock and on user
preference. A specific
factor that should be considered is the relative concentrations of the various
kavalactones that is
desired in the final product. For example, it can be beneficial to
substantially reduce the amount
of particular kavalactones in the extract which may cause interaction with
various prescription
drugs or cause various negative effects, while retaining high relative
percentages of other
kavalactones.
After the preferred decompression processing step is performed, the root
contained within
the stainless steel vessel is then processed to produce the kava extract
paste. Various extraction
processes (with or without the decompressive preprocessing) can preferably be
used, with liquid
COz being the most preferred technique. The processes are preferably used in
the alternative but
two or more processes could be combined if desired. The processes are:
(1) COZ in the supercritical fluid phase.
(2) COZ in the liquid phase.
(3) COZ in the supercritical phase in combination with added ethyl alcohol as
a modifier
which is added in the range of 2% to 15%, and preferably between 2% and 10%
based on the
total mass.
(4) COZ in the liquid phase in combination with ethyl alcohol as a modifier
which is
added in the range of 2% to 15% and preferably between 2% and 10% based on the
total mass.
(5) Refrigerant chemicals such as hydrofluorocarbons (HFCs),
hydrochlorofluorocarbons
(HCFCs), and/or chlorofluorocarbons (CFCs) such as: HFC-23, HFC-32, HFC-125,
HFC-134a,
HFC-143a, HFC-152a, R-404a, R-407c, R-410a, HCFC-22, HCFC-123, HCFC-141b, HCFC-
142b, R-502, R-11, R-12, and R-113. A more complete listing of suitable
refrigerant chemicals is
17
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
in Table 2. These refrigerants are widely available from various chemical
manufacturers and
suppliers.
The selection of one extraction procedure over another depends on the
objectives of the
extraction, the kavalactone concentration profile of the raw starting material
and the desired
concentration profile of the extract end product. In order to extract the
largest quantity of
kavalactones in the aggregate, supercritical COZ extraction generally provides
the best results.
To alter or adjust the kavalactone profile, liquid COz extraction techniques
are more suitable.
However, a carefully controlled supercritical COz process may also be used. A
gaseous COZ
process may also be suitable under certain circumstances.
For example, if a starting kava feedstock has a kavalactone concentration
profile
(specified as weight percentages of the individual kavalavctones) that is
relatively low in
(K+DHK) and relatively high in both (M+DHM) and (DMY+Y), and a kava product is
desired
that is relatively high in (K+DHK) and relatively low in both (M+DHM) and
(DMY+y), then
the COZ extraction in the liquid phase becomes the preferred process. The
figures discussed
below illustrate how liquid COZ extraction transformed the kavalactone
concentration profile of
the starting materials. In summary, the above extraction procedures provide
maximum
flexibility in starting with any kava raw product to obtain and extract end
product with a specific
kavalactone concentration profile.
In a first embodiment of the process, COz is used in the supercritical phase
to perform the
extraction step. The pressure is held at a pressure and temperature regime
that between about
1100 psi and about 8000 psi and at a temperature between about 31 ° C
and about 80° C. During
the process the extractable material is collected within a stainless steel
collection vessel that
could be the same one as that used in the first "low pressure" extraction
step, and the
18
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
supercritical COZ can either be recycled for future use or vented into the
atmosphere. The
solvent-to-feed ratio increases as the pressure and temperature of the
supercritical COZ is
lowered. It has been found that when the material is processed at a pressure
of about 8000 psi
and a temperature of about 80° C, all extractable material is obtained
after a solvent-to-feed ratio
of 8 is achieved.
In a second, most preferred, embodiment, COZ in the liquid phase is used to
perform the
extraction step. Since the COz is in the liquid phase, the extraction
temperature can not exceed
about 31 ° C, however the pressure can rise to about 8000 psi.
Conversely, the pressure can be
maintained below about 1100 psi and the temperature can be varied from about
5° C up to about
70° C. During this process the extractable material is collected within
the stainless steel
collection vessel (which could be the same one as that used in a first "low
pressure" extraction
step). The liquid COz can either be recycled for future use or vented into the
atmosphere.
In a particular example of liquid COZ extraction and fractionation, COz at a
pressure
between about 1100 and about 1800 psi is used at a temperature of between
about 5° C and about
20° C. The low temperature during extraction is controlled via a
recirculating chiller plumbed to
jacketed extractors, and the pressure within the extraction vessel is
controlled via a back pressure
regulator. Because of preferential absorption, and as discussed more fully
below with respect to
Figs. 4-7, the kavalactone profile of the dissolved kava can be substantially
different from the
profile of the source kava.
The extract-laden fluid emanating from the extractor is then collected. A
single
collection vessel can be used or the fluid can be sequentially processed using
multiple collecting
vessels to allow for further refinement of the kava extract. In a particular
example, the liquid is
first heated, e.g., by using a heat exchanger, to a temperature between about
30° C and about 37°
19
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
C. The vessel into which the fluid is deposited is also maintained at the same
temperature. A
valve, such as a back pressure regulator situated just upstream of the
collection vessel, can be
used to allow the fluid to flow into the vessel at the set pressure. An
additional back pressure
regulator situated at the outlet of the first collection vessel can be used to
maintain the first
collection vessel at a pressure lower than that of the incoming fluid.
Maintaining the first collection vessel at a pressure of between about 1000 to
about 1200
psi introduces a 100 psi to 800 psi pressure drop in the collection vessel
relative to the fluid
entering the collection vessel. The increase in temperature and decrease in
pressure creates
conditions that are not conducive to keeping the kavalactones, and kavain and
dihydrokavain in
particular, in solution. As a result, the kavalactones precipitate out of
solution and can be
collected in the collection vessel.
A second and third collection vessel can be situated in series with the first
collection
vessel such that a generally constant pressure in the two vessels of between
about 1000 psi and
about 1200 psi is maintained. However the temperature of each collection
vessel increases so
that, for example, the second collection vessel is maintained at a temperature
above that of the
first collection vessel, such as between about 35° C and about
45° C, and the third collection
vessel is maintained at a temperature above that of the second collection
vessel, such as between
about 40° C and about 50° C.
In a third embodiment, COZ is used in the supercritical phase to perform the
second
extraction step with the addition of ethyl alcohol as a solvent modifier. The
conditions are
maintained identical to that described in (1) with the addition of ethyl
alcohol at about 2% to
about 15% and preferably between about 2% and about 10% of ethyl alcohol
content by total
mass. During the process the extractable material is collected within a
stainless steel collection
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
vessel which can be the same vessel as used in the first "low pressure"
preprocessing step, and
the supercritical COZ can either be recycled for future use or vented into the
atmosphere. In this
embodiment the extract will contain ethyl alcohol that can be removed in
subsequent processing
steps. The addition of ethyl alcohol increases the polarity of the solvent,
resulting in enhanced
extraction of the kavalactones with higher polarity, such as methysticin and
dihydromethysticin,
relative to the other kavalactones in the source material.
In a fourth embodiment, the conditions are generally the same as in the third
embodiment
but liquid COZ is used instead of supercritical CO2.
In a fifth embodiment, refrigerant chemicals, such as HFCs, HCFCs, and CFCs,
are used
in the liquid phase to perform the extraction step. A selection of suitable
HFCs, HCFCs, and
CFCs appears in Table 2. During the extraction, the refrigerant chemicals) are
maintained in the
liquid state and the pressure is kept below about 400 psi. Because of the
comparatively low
pressure, the extraction is varied primarily by temperature. Preferably, the
temperature is
maintained at between about 20° C and about 70° C and, in order
to ensure suitable control and
predictability, to within about ~ 0.1 ° C of a target temperature. The
refrigerant chemicals pass
through the stainless steel extraction vessel containing the powdered root
material and the
extract-laden liquid is deposited into a stainless steel collection vessel
(which can be the same
one as that used in the preprocessing step). The refrigerant chemical of
choice can be reclaimed
via collection of the refrigerant chemical in its vapor state and subsequent
pressurization into the
liquid state. This is, in effect, a distillation process that leaves behind
the root extract while
recovering the refrigerant chemical as a liquid. The refrigerant chemical can
then be re-cycled
through the same mass of powdered root to repeat the process until all
extractable material is
21
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
removed from the powdered root or, leveraging changes in temperature and
extraction solvent,
until the extract has a desired kavalactone concentration.
The above-discussed processing steps will produce a kava root extract as a
viscous oil,
resin, or paste. According to one aspect of the invention, the preferential
and/or differing rates of
extraction of the various kavalactones in the feedstock for different solvents
and extraction
methods can be leveraged to produce a final refined kava product that has a
relative kavalactone
concentration meeting predefined specifications, even when those
specifications may differ
considerably from the concentrations present in the input kava feedstock.
Multiple extraction steps can be performed. In addition, and although not
necessary,
extraction can also be performed during the compression-decompression
preprocessing step to
selectively alter various kavalactone concentrations.
According to a particular aspect of the invention, an improved paste extract
can be
produced by performing an additional extraction step comprising use of
supercritical COZ as a
mobile phase combined with an adsorbent material such as that used for solid-
phase extractions
(SPE) and/or diatomaceous earth. The bonded materials used as silica sorbents
include but are
not limited to: C18 (Octadecyl), C8 (Octyl), C2 (Ethyl), CH (Cyclohexyl), PH
(Phenyl), and CN
(End-capped Cyanopropyl). In operation, the extract paste material obtained by
the initial
processing, such as via the methods discussed above, is mixed with the SPE
bonded phase in a
ratio of about 5:1 to about 1:1 (SPE bonded phase to root extract) by mass to
produce a mixture
having a doughy consistency. The mixture is then placed in an extraction
vessel. Fractions can
then be collected over time by pressurizing the vessel to between about 1100
psi and about 8000
psi and a temperature between about 31 ° C and about 80° C. The
material that elutes from this
fractionation can be segregated from each other by using multiple stainless
steel collection
22
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
vessels. Each fraction will generally have a different percentage of
kavalactones, as well as a
unique distribution of kavalactones that is distinct from that seen in the
original root material.
Typically, the percentages of kavain and dihydrokavain are increased relative
to the other
kavalactones in the extract.
As will be appreciated, the time during which a solvent is allowed to flow
over the kava
feedstock can also effect the ratio of the final product since, for example,
even a solvent that
extracts a particular kavalactone slowly may eventually extract all of that
kavalactone if
sufficient time has passed. The particular amount of time to allow the solvent
to operate before
extraction of dissolved material from the solvent begins is dependent on the
kavalactone
distribution of the feedstock, the different rates at which the solvent
extracts each of the
kavalactones, and the desired kavalactone profile of the kava extract. Given
the information
presented herein, one of ordinary skill in the art, using only routine
experimentation can select an
appropriate time to terminate the extraction process.
The composition of a kava product can be described in a variety of ways. In
accordance
with the present invention, several parameters are defined which can be used
to describe the
composition of a kava extract:
1) Combined weight percentage of the six major alpha-pyrones: methysticin (M),
dihydromethysticin (DHM), yangonin (Y), desmethoxyyangonin (DMY), kavain (K),
and
dihydrokavain (DHK);
2) Combined weight percentage of M and DHM;
3) Combined weight percentage of DHK and K;
4) Combined weight percentage of Y and DMY;
S) Ratio of the weight percentages of Y and DMY, i.e., Y/DMY;
23
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
6) Ratio of the weight percentages of DHK and K, i.e., DHK/K;
7) Combined weight percentage of flavokavain A and flavokavain B.
The first property is a rough indicator of the potency of the extract, e.g.,
if the extract has
0% total kavalactones it has no potency, and if it has 100% total kavalactones
it is very potent.
Properties 2-6 combine to define whether the kava extract can be classified in
the "Daily" or
"non-daily" categories, such as "Two-Day" and "No Drink". Property 7 is an
indicator of the
amount of flavokavains in the extract, Flavokavains are flavanoids specific to
the kava plant.
Flavanoids in general are anti-oxidants.
A most preferred kavalactone distribution for a kava extract, such as in a
kava paste or a
dry flowable power for use in oral delivery has a combination of the following
properties:
1 ) Total weight percentage of M + DHM + Y + DMY + DHK + K ranges from a
minimum
of about 20% to a maximum of about 90%;
2) Combined M+DHM weight percentage ranges from a minimum of about 15% or
lower to
a maximum of about 29%;
3) Combined weight percentage of DHK and K ranges from a minimum of about 50%
to a
maximum of about 70%-80%;
4) Combined weight percentage of Y and DMY ranges from a minimum of about 5%
to a
maximum of about 25%;
5) Ratio of Y weight percentage to DMY weight percentage, expressed as the
logarithmic
function 10*LOG~o(Y/DMY) in dB units, ranges from a minimum of about -1 to a
maximum of about 2;
24
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
6) Ratio of DHK weight percentage to K weight percentage, expressed as the
logarithmic
function 10*LOG~o(DHK/K) in dB units, ranges from a minimum of about-4 to a
maximum of about 1; and
7) Combined weight percentage of flavokavain A and flavokavain B ranges from a
minimum of about 0.3% to a maximum of about 3%.
The value of these properties for a sample of a processed kava product can be
determined
using conventional analytical techniques, such as HPLC-UV-S (High Performance
Liquid
Chromotography with Ultra-Violet detection (254 nm) and Chemical Standards),
or HPLC-
Electrospray-Mass Spectrometry.
Property 1 indicates that in order to have a potent product, such as a tablet,
it should have
a minimum of about 20% kavalactones by weight, and a maximum of about 90%
kavalactones
by weight. Property 7 indicates that the weight percentage of the flavokavains
should be about
0.3% to about 3%, which values are typical for unprocessed kava. However, in
conventional
processed kava extracts, the flavokavains tend to be removed, either
deliberately or due to
processing effects.
Properties 2-4 combine to define extracts with a kavalactone distribution
typical of a
"Daily" kava cultivar found in Vanuatu. Properties Attributes 2, 5 and 6 also
combine to define
extracts with a kavalactone distribution typical of a "Daily" kava cultivar
found in Vanuatu. The
range of properties 2-7 are taken from the values measured for "Daily" kava
cultivars found in
Vanuatu.
According to a preferred particular embodiment, a processed kava product
produced
according to the invention comprises less than about 15% of the combination of
methysticin and
dehyromethysticin, less than about 8% of the combination of yangonin and
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
desmethooxyyangonin, and greater than about 70% of the combination of kavain
and
dihydrokavain. A similar kavalactone composition comprises up to about 7%
methysticin, up to
about 5% dehyromethysticin, up to about 1 % yangonin, up to about 4%
desmoxyyangonin, and
greater than about 38% kavain.
In the extraction methods discussed above, the desired kavalactones were
extracted from
a source material, such as ground kava root or a pre-processed kava paste, and
the remainder
contained the undesirable materials. The opposite technique can also be used.
In particular, a
kava source material can be processed using a solvent that preferentially
extracts undesired
kavalactones, such as methysticin and dehyromethysticin, faster than other,
more desired
kavalactones. The material remaining in the extraction vessel would then be
collected and cold
have the desired altered kavalactone profile. It has been determined that the
extraction rate of
methysticin and dehyromethysticin increases with increasing polarity of the
extract and that
certain refrigerant solvents, such as R22, can extract these undesirable
kavalactones at a
sufficiently greater rate than remaining kavalactones to allow this
alternative refinement
technique to be used. The specific extraction environments, rates of
extraction, and solvent used
depends on the starting profile of the source material and the degree of
profile change desired.
Specific solvent and environmental attributes can be determined by those of
ordinary skill in the
art using no more than routine experimentation typical for adjusting a process
to account for,
e.g., variations in the attributes of starting materials that is to be
processed to produce an output
material that has specified attributes.
A kava paste extract, such as discussed above, can be processed to produce
consumable
items, for example, by mixing it in a food product or in a capsule, or
providing the paste itself for
use as a dietary supplement, with sweeteners and flavors added as appropriate.
However, a paste
26
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
extract of this type can be difficult to process because it does not flow well
and may therefore not
be well suited for processing by various types of high speed machinery.
According to a further aspect of the invention, the kava paste extract
discussed above (or
a kava paste produced using other techniques) can be further processed to
produce a dry,
flowable kava powder. The powder can be used as a dietary supplement that can
be added to
various edible products. The powder is also suited for use in a rapid dissolve
tablet.
According to a particular aspect of the invention, the kava extract powder is
produced to
have a kavalactone distribution that is particularly well suited for delivery
in the oral cavity of
human subjects, e.g., via a rapid dissolve tablet. Preferably, the desired
distribution properties
are achieved by adjusting the extraction process to take advantage of the
differing extraction
rates of the various kavalactones according to type of extraction method and
the operating
parameters used. Although this technique may not result in an extract that
contains substantially
all of the kavalactones from a sample (as is the goal of conventional
extraction processes), the
desired ratios can be achieved without having to perform extraction of
individual kavalactones,
e.g., through chromatography, and then a subsequent recombination of the
individual extracts.
In one embodiment of a method for producing the kava powder, the extract paste
is
mixed with a suitable solvent, such as ethyl alcohol or water, along with a
suitable food-grade
earner material, such as maltodextrin, dextrose, or starch and the mixture is
spray air-dried using
conventional techniques to produce a powder having grains of very small kava
extract particles
combined with the food-grade carrier material.
In a particular example, a kava extract paste, preferably about 60% to about
80% total
kavalactones by weight, is mixed with about twice its weight of a food-grade
carrier, such as
maltodextrin having with an average particle size of between about 100 to
about I50
27
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
micrometers and an ethyl alcohol solvent using a high shear mixer. Inert
earners, such as silica,
preferably having an average particle size on the order of about 1 to about 50
micrometers, can
be added to improve the flow of the mixture. Preferably, such additions are up
to about 2% by
weight of the mixture. The amount of ethyl alcohol used is preferably the
minimum needed to
form a solution with a viscosity appropriate for spray air-drying. Typical
amounts are in the
range of between about 5 to about 10 liters per kilogram of paste. The
solution of kava extract,
maltodextrin and ethyl alcohol is spray dried to generate a powder with an
average particle size
comparable to that of the starting carrier material and a kavalactone content
of about 20% to
about 35% by weight.
In a second embodiment, the kava extract paste and a food-grade carrier, such
as
magnesium carbonate, a whey protein, or maltodextrin, are dry mixed, followed
by mixing in a
high shear mixer containing a suitable solvent, such as ethyl alcohol or
water. The mixture is
then dried via freeze drying or refractive window drying. In a particular
example, kava extract
paste comprising on the order of about 60% to about 80% total kavalactones by
weight is
combined with about one and one-half times by weight of the paste of a food-
grade carrier, such
as magnesium carbonate, having an average particle size of about 20 to about
100 micrometers.
Inert carriers, such as silica, and preferably having an average particle size
of about 1 to about SO
micrometers can be added, preferably in an amount up to 2% by weight of the
mixture, to
improve the flow of the mixture. The magnesium carbonate and silica are then
dry mixed in a
high-speed mixer, similar to a food processor-type of mixer, operating at
100's of rpm. The kava
extract paste then is heated until it flows like a heavy oil. Preferably, it
is heated to at least
about 50°C. The heated kava paste/oil is then added to the magnesium
carbonate and silica
powder mixture that is being mixed in mixer.
28
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
The mixing of the kava paste/oil and the magnesium carbonate and silica is
continued
preferably until the particle sizes are in the range of between about 250
micrometers to about 1
mm. Between about two to ten liters of cold water (preferably at about
4°C) per kilogram of
paste is introduced into a high shear mixer. The mixture of kava extract
paste, magnesium
carbonate and silica is the introduced slowly or increments into the high
shear mixer while
mixing. An emulsifying agent, such as carboxymethylcellulose can also be added
to mixture if
needed. Sweetening agents can also be added at this stage if desired, such as
up to about 5% by
weight. Alternatively, extract of Stevia rebaudiana, a very sweet-tasting
dietary supplement, can
be added instead of, or in conjunction with, a specific sweetening agent. (For
simplicity, Stevia
will be referred to herein as a sweetening agent.) After mixing is completed,
the mixture is dried
using freeze-drying or refractive window drying. The resulting dry flowable
powder of kava
extract, magnesium carbonate, silica and optional emulsifying agent and
optional sweetener has
an average particle size comparable to that of the starting carrier material
and a kavalactone
content of about 20% to about 35% by weight.
According to another embodiment, kava extract paste that is on the order of
about 60% to
about 80% total kavalactones by weight is combined with approximately an equal
weight a food-
grade carrier, such as whey protein, preferably having an average particle
size of between about
200 to about 1000 micrometers. Inert carriers, such as silica preferably
having an average
particle size of between about 1 to about 50 micrometers, or
carboxymethylcellulose, preferably
having an average particle size of between about 10 to about 100 micrometers,
can be added to
improve the flow of the mixture. Preferably, this addition is no more than
about 2% by weight of
the mixture.
29
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
The whey protein and inert ingredient are then dry mixed in a food processor-
type of
mixer that operates at 100's of rpm. The kava extract paste is heated until it
flows like a heavy
oil. Preferably, it is heated to at least 50°C. The heated kava
paste/oil is then added to the whey
protein and inert carrier that is being mixed in the food processor-type
mixer. The mixing of the
kava paste/oil and the whey protein and inert carrier is continued until the
particle sizes are in the
range of about 250 micrometers to about 1 mm. Next, 2 to 10 liters cold water
(preferably about
4C) per kilogram of paste is introduced into a high shear mixer. The mixture
of kava extract
paste, whey protein and inert earner is preferably introduced slowly or in
incremental amounts
with the high shear mixer while mixing. Sweetening agents or other sweet-
tasting additives of
up to about 5% by weight, such as Stevia, can be added at this stage if
desired.
After mixing is completed, the mixture is dried using freeze-drying or
refractive window
drying. The resulting dry flowable powder of kava extract, whey protein, inert
earner and
optional sweetener has an average particle size of about I 50 to about 700
micrometers and a
kavalactone content of about 20% to about 35% by weight.
In a third embodiment, the kava extract paste is dissolved in a supercritical
fluid, which is
then adsorbed onto a suitable food-grade carrier, such as maltodextrin,
dextrose, or starch.
Preferably, supercritical COZ is used as the solvent. Specific examples
include starting with a
kava extract paste that is on the order of about 60% to about 80% total
kavalactones by weight
and adding from I to one one-half times the paste by weight of a food-grade
carrier, such as
maltodextrin, and having an average particle size of between about 100 to
about 150
micrometers. This mixture is placed into a chamber containing mixing paddles
and which can be
pressurized and heated. The chamber is pressurized with COZ to a pressure in
the range of
between about 1100 to about 8000 psi and set at a temperature in the range of
between about 20°
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
to about 100°C. The exact temperature and pressure is selected to place
the COz in a
supercritical fluid state.
Once the COz in the chamber is in the supercritical state, the kava extract
paste is
dissolved. The mixing paddles agitate the carrier powder so that it has
intimate contact with the
supercritical COz that contains the dissolved kava extract paste. The mixture
of supercritical
COz, dissolved kava extract paste and the earner powder is then vented through
an orifice in the
chamber so that it undergoes explosive decompression into a collection vessel
which is at a
pressure and temperature that does not support the supercritical state for the
COz. The COz is
thus dissipated. The resulting powder in the collection vessel is the carrier
powder impregnated
with the kava extract paste. The powder has an average particle size
comparable to that of the
starting carrier material and a kavalactone content of between about 20% to
about 40% by
weight. The resulting powder is dry and flowable. If needed, the flow
characteristics can be
improved by adding inert ingredients to the starting carrier powder, such as
silica at up to about
2% by weight as discussed above.
Once a dry kava powder is obtained, such as by the methods discussed herein,
it can be
distributed for use, e.g., as a dietary supplement or for other uses. In a
particular embodiment,
the powder is mixed with other ingredients to form a tableting composition of
powder which can
then be formed into tablets. In a particular embodiment, the tableting powder
is first wet with a
solvent comprising alcohol, alcohol and water, or other suitable solvents, in
an amount sufficient
to form a thick doughy consistency. Suitable alcohols include, but are not
limited to, ethyl
alcohol, isopropyl alcohol, denatured ethyl alcohol containing isopropyl
alcohol, acetone, and
denatured ethyl alcohol containing acetone. The resulting paste is then
pressed into a tablet
mold. An automated molding system, such as described in U.S. Patent No.
5,407,339 can be
31
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
used. The tablets are then removed from the mold and dried, preferably by air-
drying for at least
several hours at a temperature high enough to drive off the solvent used to
wet the tableting
powder mixture, typically between about 70° to about 85° F. The
tablets can then be packaged
for distribution.
A wide variety of tablet formulations can be made. Preferably, the tablet has
a
formulation that results in a rapid dissolution or disintegration in the oral
cavity. The tablet is
preferably of a homogeneous composition that dissolves or disintegrates
rapidly in the oral
cavity to release the kava extract content over a period of about 2 seconds or
less to about 60
seconds or more, preferably about 3 to about 45 seconds, and most preferably
between about S to
about 15 seconds.
Various rapid-dissolve tablet formulations known in the art can be used.
Representative
formulations are disclosed in U.S. Patent Nos. 5,464,632, 6,106,861, and
6,221,392, the entire
contents of which are expressly incorporated by reference herein. A
particularly preferred
tableting composition or powder contains about 10 % to about 60% by weight of
the kava extract
powder and about 30% to about 60% of a water-soluble diluent. Suitable
diluents include
lactose, dextrose, sucrose, mannitol, and other similar compositions. Lactose
is a preferred
diluent but mannitol adds a pleasant, cooling sensation and additional
sweetness in the mouth.
More than one diluent can be used. A sweetener can also be included,
preferably in an amount
of between about 3% to about 40% by weight depending on the desired sweetness.
Preferred
sweetening substances include sugar, saccharin, sodium cyclamate, aspartame,
and Stevia
extract, used singly or in combination, although other sweeteners could
alternatively be used.
Flavorings, such as mint, cinnamon, citrus (e.g., lemon or orange), can also
be included,
preferably in an amount between about 0.001 % to about 1 % by weight.
32
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
Typically, the kava extract added to the tablet has a golden color and it is
considered
unnecessary to include additional colorings. However, if a coloring is
desired, natural and/or
synthetic colors can be added, preferably in an amount of between about 0:5%
to about 2% by
weight.
Typically, this tableting composition will maintain its form without the use
of a binder.
However, if needed, various binders are suitable and can be added in an amount
of between
about S% to about 15% or as necessary. Preferred binders are acacia or gum
arabic. Alternative
binders include sodium alginate, extract of Irish moss, panwar gum, ghatti
gum, mucilage of
isapol husks, carboxymethylcellulose, hydroxyethylcellulose, methylcellulose,
polyvinylpyrrolidone, VEEGUM~ (available from R.T Vanderbilt Co., Inc. of
Norwalk, CT),
larch arabogalactan, gelatin, Kappa carrageenan, copolymers of malefic
anhydride with ethylene
or vinyl methyl ether.
A tablet according to this aspect of this invention typically does not require
a lubricant to
improve the flow of the powder for tablet manufacturing. However, if it is so
desired, preferred
lubricants include talc, magnesium stearate, calcium stearate, stearic acid,
hydrogenated
vegetable oils, and carbowax in amounts of between about 2% to about 10% by
weight.
Similarly, a disintegrant is not expected to be necessary to produce rapid
dissolve tablets
using the present tablet composition. However, a disintegrant can be included
to increase the
speed with which a resulting tablet dissolves in the mouth. If desired,
between about 0.5% to
about 1 % by weight of a disintegrant can be added. Preferred disintegrants
include starches,
clays, celluloses, algins, gums, crosslinked polymers (including
croscarmelose, crospovidone and
sodium starch glycolate), VEEGUM~ HV, agar, bentonite, natural sponge, canon
exchange
33
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
resins, aliginic acid, guar gum, citrus pulp, sodium lauryl sulphate in an
amount of about 0.5% to
about 1 % of the total mass of the tablet.
It is also generally considered unnecessary to buffer the tablet composition.
However, a
buffer may be beneficial in specific formulations. Preferred buffering agents
include mono- and
di-sodium phosphates and borates, basic magnesium carbonate and combinations
of magnesium
and aluminum hydroxide.
In a preferred implementation, the tableting powder is made by mixing in a dry
powdered
form the various components as described above, e.g., active ingredient (kava
extract), diluent,
sweetening additive, and flavoring, etc. An overage in the range of about 10%
to about 15 % of
the active extract of the active ingredient can be added to compensate for
losses during
subsequent tablet processing. The mixture is then sifted through a sieve with
a mesh size
preferably in the range of about 80 mesh to about 100 mesh to ensure a
generally uniform
composition of particles.
The tablet can be of any desired size, shape, weight, or consistency. The
total weight of
the kava extract in the form of a dry flowable powder in a single oral dosage
is typically in the
range of about 80 mg to about 600 mg. An important consideration is that the
tablet is intended
to dissolve in the mouth and should therefore not be of a shape that
encourages the tablet to be
swallowed. The larger the tablet, the less it is likely to be accidentally
swallowed, but the longer
it will take to dissolve or disintegrate. In a preferred form, the tablet is a
disk or wafer of about
1/8 inch to about 1/2 inch in diameter and about 0.2 inch to 0.08 inch in
thickness, and has a
weight of between about 160 mg to about 1,200 mg. In addition to disk, wafer
or coin shapes, the
tablet can be in the form of a cylinder, sphere, cube, or other shapes. For
example, the tablet can
be formed into the general shape of a kava plant leaf. Although the tablet is
preferably
34
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
homogeneous, the tablet may alternatively be comprised of regions of powdered
kava extract
composition separated by non-kava extract regions in periodic or non-periodic
sequences, which
can give the tablet a speckled appearance with different colors or shades of
colors associated
with the kava extract regions and the non-kava extract regions
An exemplary 250 mg tablet contains about 125.0 mg powdered kava extract,
about 12.5
mg extract of Stevia, about 35.5 mg carboxymethylcellulose, and about 77.0 mg
lactose. An
exemplary 350 mg tablet contains about 160.0 mg powdered kava extract, about
15.0 mg extract
of Stevia, about 15.0 mg acacia, and about 160.0 mg lactose. Other
formulations are also
possible.
Although the extraction techniques are discussed herein in terms of kava, it
should be
recognized that the disclosed techniques can be adapted for use in forming an
extract, in the form
of a dry flowable powder or another form and containing compositions extracted
from other
plant products, such as ginseng, cherry, lettuce, echinacea, mate, and areca.
In addition, while
the preferred rapid dissolved formulation is disclosed herein in the context
of kava extract, the
formulation can also be used to provide a rapid dissolve tablet containing
additional or other
active ingredients that can be provided in powder form, such as varieties of
ginseng, cherry,
lettuce, echinacea, mate, and areca.
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
EXAMPLES:
The following examples are illustrative of the nature of the present invention
and are not
to be regarded as limiting.
Example l:
This example describes the preparation of a kava extract having the properties
shown in
Figs. 1-4 (i.e., properties typical of a "Daily" kava cultivar from Vanuatu).
This process can be
varied as needed and in accordance with the profile of the source kava and the
desired kava
profile of the extract.
About 30 lbs. of chopped and ground lateral roots of kava are added to a 32
liter
extraction vessel. Pre-cooled liquid carbon dioxide (the pressurized liquid
carbon dioxide was
passed through a heat exchanger that was maintained at 0° C) was pumped
through the vessel at a
pressure of 1800 psi. The carbon dioxide expanded and flashed into a gas, thus
cooling the
lateral root to approximately 10° C. The resultant temperature
equilibrium of the effluent
flowing from the extraction vessel was between 5° C and 20° C.
Approximately 500 lbs. of liquid
carbon dioxide was passed through the lateral roots under pressure, but below
the supercritical
temperature. This extraction was high pressure liquid extraction. The extract
laden liquid carbon
dioxide was collected in a vessel that was at atmospheric pressure.
Figs. 1-4, respectively, are plots of (DHK%+K%) vs. (M%+DHM%), (DMY%+Y%) vs.
(M%DHM%), (DMY%+Y%) vs. (DHK%+K%), and 10*LOG,o(DHK/K) vs.
10*LOG~o(Y/DMY) for the appropriate values measured for "Daily", Two-Day" and
"No Drink"
kava cultivars from Vanuatu. The plots show the changes in the kavalactone
profile introduced
during processing according to the present invention. The plots show how the
kavalactone
36
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
profile of the processed product is shifted away from an undesirable profile
to a more desired
profile.
More generally, Figs. 1-4 show how a raw kava product with a kavalactone
distribution
that is not typical of the preferred "Daily" kava can be processed to yield an
extract with a
kavalactone distribution more typical of the "Daily" kava. Note that the
processing method
simultaneously changes all Properties 2-6, discussed above, as well as
increasing the total
kavalactone weight percentage. In an optional step, the extract laden liquid
carbon dioxide was
collected into a cascade of three different vessels that are maintained at
different temperatures
and under pressures so as to further altered the kavalactone profile of the
extract collected in
each vessel.
EXAMPLE 2:
A common kava feedstock was processed and passed through sequentially
connected
collection vessels containing different temperature and pressure environments
to produce
different extraction conditions. In particular, three vessels were used
containing liquid,
supercritcal and gaseous CO2, respectively. The profile of the kava extracts
at each stage of
processing compared with the profile of the source. The first collection
vessel was used for
liquid COZ extraction. The vessel was pressurized to 1150 psi and maintained
at 26.2°C. The
extraction was performed at 1200 psi and 7°C. The second collection
vessel was used for
supercritical COZ extraction. The vessel was pressurized to 1150 psi and
maintained at 33.5°C.
The third collector was used for gaseous COZ collection. The collection vessel
was pressurized
to 850 psi and maintained between 20°C and 30°C.
A comparison of the profile of the source feedstock and the profile of the
extracts is
shown in table 3, below:
37
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
TART.R ~
CHANGE IN KAVALACTONE
PROFILE (in percentages)
Kavalactone FeedstockProfile Profile Profile
in 1s' in 2 in 3'
extraction extractionextraction
vessel vessel vessel
Methysticin (M 19.7 13.9 4.8 2.6
Dih dromethysticin 10.2 10.4 13.0 8.7
(DHM)
Kavain (K 22.5 41.8 39.0 28.0
Dih drokavain (DHK 12.7 10.9 30.0 52.4
Yan onin (Y) 22.7 5.8 1.4 0.0
Desmethoxyyangonin 12.3 17.3 11.8 8.4
DMY)
There are three dramatic changes that have occurred. First, the combined M +
DHM content has
dropped from 29.9% to as low as 11.3%. Second, the combined K + DHK content
has increased
from 35.2% to as high as 80.4%. Third, the yangonin content has dropped from
22.7% to a non-
detected level, effectively 0.0%. As will be appreciated, a careful choice of
the temperature and
pressure for each collector will result in controlled and preferential
distributions of the
kavalactones.
CA 02462661 2004-04-02
WO 03/028662 PCT/US02/31771
C~
U
. r..,,
U
y
N
~
~
N N o
w
~N
M
~
N ~ N
. ,-~ _
w
t+ w U
~wo
N ~ 00
Ux
MU ~
~ w
w ~
i ,
UwwU
~~~w
U
U ~
U N N
r3: w w
U
xxxx
UUUU
~ N M ~
