IMPROVED COMPLEXES AND COMPOSITIONS CONTAINING CURCUMIN
TECHNICAL FIELD
The present invention relates to improvements in and relating to the bioavailability of
curcumin, and methods of producing complexes and compositions providing improved
bioavailability of curcumin.
BACKGROUND ART
Curcumin is a compound present in the spice turmeric. Curcumin has been shown in
many studies to have pharmacologic effects such as antioxidant, anti-inflammatory,
antiproliferative and antiangiogenic activities. As such, curcumin represents a target to
fight diseases such as cancer, heart disease diabetes, Crohn’s disease and various
neurological diseases. For this reason, there has been significant research on curcumin
over the past 20-30 years.
A significant advantage of curcumin is its wide acceptance due to it being a natural
compound used for centuries as a spice in food such as curries. A further advantage is
that, even at high doses, there are little to no side effects. It is also relatively cheap to
source, and stores well at room temperature.
Despite these advantages, an overriding issue which has yet to be addressed is
curcumin’s well known problem of low bioavailability in animals. This is thought to be due
to a combination of factors including poor solubility and hence poor absorption, elimination
from the system and/or rapid metabolism.
In the past, this poor solubility has been overcome, at least in in vitro studies, by adding
carriers such as DMSO or Tween 80 which help to increase solubility of the curcumin.
However, addition of these carriers in a therapeutic medicament would not be suitable
reasons, primarily because carriers such as DMSO lead to a foul taste, it adds to the
manufacturing cost and process, and detracts from the advantage that curcumin is a
natural product (which consumers like).
Combining curcumin with an oil can improve the uptake of curcumin into the systemic
system. However, because the curcumin does not bind with the oil, the majority drops out
of suspension after mixing.
Agitating the curcumin and oil mixture vigorously can provide a slightly improved product
due to a small percentage being solubilised. Regardless of how vigorously the curcumin
and oil mixture is mixed, centrifuging the product will effectively precipitate most of the
curcumin from the oil.
In order to try to overcome the poor absorption/stability issue and to maximise from
curcumin’s beneficial effects, numerous approaches have been investigated over the past
few decades. These include preparation of liposomal or phospholipid structures,
nanoparticles, and structural analogues. Anand et al., Mol. Pharmaceutics, 2007, 4 (6),
807-818 provides a good review of these different approaches.
For example, describes a phospholipid complex with curcumin using
phospholipids from vegetable or synthetic origin. A molar ratio of curcumin to lipid of 1;2
or 1;4 was provided having about 16.9% curcumin in the resulting complex. However, the
resulting product was a viscous wax. This would make it substantially impossible to
encapsulate in soft gels, and hence the product would almost certainly be provided in a
tablet form. Although tablets are a suitable form for delivery of the complex, from the
manufacturing perspective, encapsulation can be a more attractive option particularly for
oil based formulations. Encapsulation in soft gels is only readily achievable if the resulting
complex solution is not too viscous. An alternative method is using hard gel capsules
whereby the paste is pumped into the gelatin capsules at slightly elevated temperatures.
A different avenue many research groups are exploring is combining curcumin with
adjuvants. Compounds like piperine, quercetin and / or Omega-3 polyunsaturated fatty
acids, such as docosahexaenoic acid (DHA) and/or eiscosapentaenoic acid (EPA) have
recently been shown to produce a synergistic therapeutic effect when used in combination
with curcumin, although the exact modes of action are still uncertain. These approaches
have also been outlined in Anand et al, 2007.
It is also thought that this synergy of curcumin is limited to a relatively small subset (about
8) of Omega 3 polyunsaturated fatty acids including DHA and EPA. For example,
Altenburg et al., BMC Cancer 2011, 11;149 describes the synergy of DHA and curcumin in
inhibiting numerous breast cancer cell lines.
In a further study, Swamy et al., Nutrition and Cancer 2008, 60: S1, 81-89 reported that a
ratio of about 2.5:1 (DHA to curcumin) showed the greatest effect on apoptosis in BxPC-3
cells, a form of pancreatic cancer cells.
Therefore, although there is reasonable information guiding the formulator to optimal
ratios of curcumin to adjuvants such as DHA, it can often be difficult to formulate a
composition retaining the desired ratios (which may differ depending on the exact
therapeutic effect desired), whilst also trying to accommodate for the issues around
instability, insolubility and poor absorption of curcumin, as well as other factors of the
composition such as preferred viscosity requirements.
Therefore, despite certain advances, there is still significant need to improve on the
bioavailability and therapeutic effect of curcumin, the ability to increase loading of
curcumin, the stability of resulting compositions, as well as the ease/cost of manufacturing
the medicament in a convenient dosage form.
It is an object of the present invention to address one or more of the foregoing problems
or at least to provide the public with a useful choice.
All references, including any patents or patent applications cited in this specification are
hereby incorporated by reference. No admission is made that any reference constitutes
prior art. The discussion of the references states what their authors assert, and the
applicants reserve the right to challenge the accuracy and pertinency of the cited
documents. It will be clearly understood that, although a number of prior art publications
are referred to herein, this reference does not constitute an admission that any of these
documents form part of the common general knowledge in the art, in New Zealand or in
any other country.
Throughout this specification, the word "comprise", or variations thereof such as
"comprises" or "comprising", will be understood to imply the inclusion of a stated element,
integer or step, or group of elements integers or steps, but not the exclusion of any other
element, integer or step, or group of elements, integers or steps.
Further aspects and advantages of the present invention will become apparent from the
ensuing description which is given by way of example only.
DISCLOSURE OF THE INVENTION
According to a first aspect of the present invention there is provided a complex including a
phospholipid and curcumin,
characterised in that some or all of the phospholipid is a marine phospholipid.
According to a further aspect of the present invention there is provided a composition
including a complex with a phospholipid and curcumin,
characterised in that some or all of the phospholipid in the complex is a marine
phospholipid.
According to a further aspect of the present invention there is provided a method of
preparing a complex or composition substantially as herein described above
the method including the steps of:
a) forming a first solution by dissolving a quantity of curcumin in a solvent;
b) forming a further solution by adding slowly to the first solution a suitable quantity of
marine phospholipid
c) processing the further solution to form the complex
d) separating the complex from the solvent by distillation.
According to a further aspect of the present invention there is provided a method of
treatment using the composition substantially as herein described above, wherein the
composition is used to treat or prevent, or at least provide complementary treatment or
prevention, to one of the following conditions:
cancer,
heart disease,
diabetes,
Crohn’s disease, and
various neurological diseases.
The present invention surprisingly and advantageously benefits from the clever use of
marine based organisms that have a high content of phospholipids and are naturally
enriched with polyunsaturated fatty acids such as DHA and EPA. In brief, the present
invention:
- allows formation of a stable complex using marine phospholipids, and by forming a
stable complex, prevents separation of the components (therefore the present
invention helps to improve effective absorption of the curcumin)
- provides a high level of phospholipids, and by default a high level of
polyunsaturated fatty acids such as DHA and EPA (inherently present as in the
tails of the marine phospholipids). This increased level of fatty acids therefore
helps to achieve a desired molar ratio of curcumin to fatty acids, which in turn is
beneficial to provide the synergistic effect seen between these fatty acids with
curcumin.
Throughout this specification the term marine phospholipid should be taken as meaning
any phospholipid which is sourced from sea-based organisms such as fish and shellfish
wherein the phospholipid or phospholipids contains at least one type of polyunsaturated
fatty acid, and most preferably either DHA and/or EPA.
Some specific examples of such marine phospholipids are from marine oils include mussel
oil, krill oil, salmon oil, squid oil and so forth. Another example of marine oils may be the oil
from roe, again perhaps from fish or shellfish.
As also highlighted in other documents such as EP 1871399, marine phospholipids
(typically sourced from marine oils) that are also rich in these polyunsaturated fatty acids
include algae, phytoplankton and other plant based organisms. These marine
phospholipid sources are clearly encompassed by the present invention.
Marine oils such as these exemplified above beneficially have relatively high phospholipid
content. Therefore these may be beneficially used for the present invention to help
achieve a preferred molar ratio of curcumin to phospholipids and fatty acids, as discussed
further below. By using marine oils such as those exemplified above, the complex also
beneficially provides the synergistic therapeutic effect offered by the Omega -3 fatty acids
such as DHA or EPA with the curcumin present in the marine oil sourced lipids.
It should be appreciated that it is possible that the phospholipids are first extracted from
the marine oil (for instance through acetone precipitation) and then subsequently bound to
the curcumin to form the complex. During the extraction process, a waxy substance may
result after the above acetone precipitation of the phospholipids, which may then be
thinned down with a diluent before being complexed, or bound, with the curcumin.
Throughout this specification the term complex should be generally understood to be the
binding together, through some form of chemical interaction or forces, of at least one part
of the phospholipid and at least one curcumin compound. Without wishing to be bound by
theory, the inventor envisages that the binding occurs through binding of the curcumin to
the choline head group of the phospholipid so as to form a complex.
Alternatively the phospholipids may be obtained by adding several volumes of chilled
ethanol to a suitable oil such as krill oil in which case the phosphatidylcholine (a preferred
type of phospholipid as discussed further below) will become solubilised in the supernatant
and can be drawn off and obtained in that manner.
Preferably, the composition includes marine oil. This is a preferred option because it is
possible many of the components of the marine oil may be improving the therapeutic
effectiveness or stability of curcumin. For example, mussel oil has about 91 different
types of fatty acids.
Despite this synergy between the fatty acids DHA and/or EPA with curcumin being known
for considerable time, no one in the industry has yet arrived at the present invention of
actually bonding the curcumin to a marine derived phospholipid(s) to form acomplex.
Up until now, researchers have only been demonstrating a combination of DHA/Omega 3
with curcumin, but have never thought to actually form the complex by bonding the
curcumin with the marine phospholipids which are rich in such components, thereby
achieving two beneficial effects with a single component (namely benefiting from the
synergy between the fatty acids and curcumin, and also using the marine phospholipids to
form the complex.
On the other hand, researchers have primarily turned to using vegetable oil such as
soyabean lecithin oil to bond the curcumin to the relevant phospholipid headgroups It is
thought that soy phospholipids have been the mainstay for this curcumin complexing
because they are known to be highly absorbed in humans, and do not show any chronic
effects on animals in vivo, even at high dosages. Also the high amounts of
polyunsaturated fatty acids like linoleic acid present in soyabean oil has made it an
attractive option for reducing the risk of diseases like heart disease. Yet, a major
disadvantage is that there is no reported synergy with shorter chain fatty acids in
vegetable oils (like linoleic acid) and curcumin.
Throughout this specification the term phospholipid should be taken as meaning any type
of lipid that includes a hydrophobic tail and hydrophilic head. Phospholipids, in context of
this invention, are used to form micelles whereby the choline group (if using
phosphatidylcholine) head binds with the curcumin, while the phosphatidyl portion
envelops the bound part.
Preferably, the marine oil contains greater than 20% w/w phospholipid. Marine oils such
as salmon oil, mussel oil, krill oil and squid oil are all known to have phospholipid contents
above 20%. One particularly preferred marine oil with high levels of phospholipid is
mussel oil, with levels up to 65% w/w phospholipid.
Most preferably, the marine oil contains approximately 40% w/w phospholipid.
More preferably, the phospholipid is selected from the group consisting of
phosphatidylcholine (PC), phosphatidic acid (PA), phosphatidylethanolamine (PE),
phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylinositiol phosphate (PIP),
phosphatidylinositiol biphosphate (PIP2), and phosphatidylinositiol triphosphate (PIP3).
Most preferably, at least a portion of the phospholipid in the complex is
phosphatidylcholine (PC).
This is because PC accounts for at least 50% of the outer membrane of all the trillions of
cells in the human body. It is possible that the choice of PC as the marine phospholipid, in
light of their prevalence in the cells of the human body, may help to improve absorption of
the curcumin and fatty acids into cells where they can perform their therapeutic roles and
synergy.
However, potentially any one or combination of phospholipids could be used with the
present invention.
Again, good examples of marine oils that have both PC and PI include mussel oil, krill oil
and salmon oil.
Alternatively, the phospholipid is selected from the broad class of phosphosphingolipids.
In this alternative embodiment, the phospholipid is selected from the group consisting of
ceramide phosphorylcholine or ceramide phosphorylethanolamine (Sphingomyelin, SPH or
Cer-PE respectively) and ceramide phospholipid.
Throughout this specification the term curcumin should be taken as meaning any
curcuminoid. A curcuminoid may simply be curcumin as shown in the structure below, or
may be a derivative of curcumin with varied chemical groups which provide improved
stability or other pharmacokinetic properties of the compound.
The curcumin may be isolated from a natural source such as turmeric, or it may be
synthetically prepared through a range of techniques.
Most preferably, demethoxycurcumin is used. In Cuomo et al, J. Nat. Prod. 2011, 74 664-
669, it was shown that phospholipid formulation increased the absorption of
demethoxylated curcuminoids much more than that of curcumin, therefore making it
particularly applicable for use in the current invention. A further commonly used alternative
curcumin is bisdemethoxycurcumin.
However, any other form of curcumin, either known currently or developed in future, may
be used as part of the present invention without departing from the scope thereof.
Preferably, the complex includes above 1% w/w curcumin.
Preferably, the complex includes between 1 to 5540 % w/w curcumin.
As discussed previously, a higher concentration and loading of curcumin is one strategy to
improve the ultimate aim of greater absorption of curcumin into the body.
More preferably, the complex includes approximately between 2-8% w/w curcumin. It
would certainly be possible to increase the level of curcumin beyond 8% within the
complex of the present invention. This is discussed further in the specification.
Preferred example of molar ratios in the complex
Preferably, the molar ratio of the curcumin to phospholipids in the complex is in the range
of about 1:1 to 1:20.
Preferably, the molar ratio of the curcumin to phospholipids in the complex is in the range
of about 1.1 to 1:5.
As discussed previously with reference to Altenburg and Swamy, there are reports to
show that the most preferred molar ratio which provides the most effect synergy for the
cancer cell lines studied was about 2.5 to 1 (DHA to curcumin). However it is clear a
higher ratio upwards of 20:1 (DHA and/or other fatty acids such as EPA to curcumin) also
show synergy, but to a lesser degree. It quite possible that depending on the particular
therapeutic use (for example, the type of cancer cells to be targeted), the molar ratio that
provides a heightened synergy could vary.
Such preferred ratios are beneficial as they are seen to effectively work with the trial
examples performed by the inventor and are well documented to provide suitable
complexing of curcumin with the phospholipid. For example, provides
shows in Example 4 that up to 16% w/w curcumin could be achieved in a stable complex
when the ratio of curcumin to phospholipid is as high as 1:4. Obviously, one could achieve
a stable complex if the amount of phospholipid is increased in this ratio.
An example of how a particularly preferred 1:10 ratio of curcumin to phospholipids is
provided below.
Mussel oil has approximately 65% w/w phospholipids, and also contains about 24% w/w
EPA, 13% DHA and about 4-5% of six other Omega 3 acids, totalling about 41-42%
Omega 3 polyunsaturated fatty acids which are predominantly bound to the phospholipids.
Therefore, if one were to add 4 kg of curcumin to 100 kg (approximately 100 L) of mussel
oil, a ratio of approximately 1:16 (curcumin to phospholipid) may be achieved in the
resulting complex, and provide about a 40 g/L (or 4% w/w) curcumin in the complex.
Research shows that there can be a therapeutic effect of curcumin in the body (suggested
by in vitro trials) with a molar ratio of curcumin to phospholipids of only 10 uM.
Preferably, the complex includes an amount of lecithin.
This may be to help achieve/and or maintain a preferred molar ratio of curcumin to
phospholipids (although this may vary), and also help avoid the problem with an increased
viscosity which may happen as a result of the fatty acids from the marine phospholipids.
This is a particularly preferred concept for the encapsulation of a lower viscosity oil based
liquid containing the complex of the present invention.
Throughout this specification the term lecithin should be taken as meaning any mixture of
substances from animal or plant tissue which includes phospholipids together with other
components such as phosphoric acid, choline, fatty acids, glycerol, glycolipids, and/or
triglycerides. The term lecithin throughout this specification should similarly be understood
that it is a different substance to the marine phospholipid of the present invention and may
or may not provides a source of phospholipids but is devoid of longer chain Omega-3 fatty
acids such as DHA and EPA, i.e. carbon chains of 20 or above.
One scenario is that the amount of curcumin may be increased in the complex and
composition supported by the phospholipids from the lecithin and from the marine oil
phospholipids. As a result, it allows the molar ratio of the curcumin to fatty acids (from the
marine oil phospholipids) to be increased within the complex, because the amount
polyunsaturated fatty acids is not increased in the complex. Not only does this allow the
formulator to increase the molar ratio of curcumin to fatty acids if so desired, but it also
avoids the deleterious increase in viscosity attributed to the fatty acids. The molar ratio
must always refer to phospholipids, the fatty acids are there purely as the extension (tails)
of the phosphatidylcholine.
Preferably, the ratio of lecithin to marine oil in the composition is between 1:3 to 3:1. Most
preferably, the ratio of lecithin to marine oil in the composition is approximately 2:1.
In a preferred embodiment, the lecithin is a vegetable lecithin oil. For example, the
vegetable lecithin oil may be soybean lecithin oil or sunflower lecithin oil which are
considered by the inventor to be particularly applicable to the present invention. This is
because both sunflower lecithin oil and soyabean lecithin oil provide choline as a health
supplement for brain function. However, other sources of lecithin are also within the
scope of the present invention.
The inventor foresees that the lecithin is best provided in a liquid form opposed to a
powdered form to avoid disadvantageously and unnecessarily increasing the viscosity.
Preferably, the composition includes a diluent.
The inventor foresees that the amount of phospholipid provided by the marine oil and
lecithin is sufficient to support a stable complex with a concentration of curcumin up to 5%
w/w and potentially higher as documented in . Yet, at these higher
concentrations of curcumin above about 5% w/w, even with lecithin added to the
composition in place of portion of the marine oil phospholipids, the viscosity of the
complex may increase beyond what is practical to encapsulate in soft gels
Preferably, additional components may be incorporated into the composition. These
components do not necessarily bind to the complex but may help to improve stability, or
for instance, may be added as adjuvants to improve the therapeutic effect of the
composition.
Preferably, the composition includes quercetin which can bond with and form a complex
with phospholipids.
Preferably, the composition includes piperine.
Both quercetin and piperine are known to be valuable adjuvants to curcumin, for example
to increase absorption or potency of the curcumin for an improved therapeutic effect.
Preferably, some or all of the adjuvants are simultaneously complexed with the
phospholipids. As discussed below, the quercetin and piperine are preferably added
together with the curcumin prior to dissolving in the solvent, and prior to the addition of the
phospholipids sourced from the marine oil. In this way, the quercetin is able to be
complexed with the phospholipids in the same manner as the curcumin.
Method of manufacture
According to a further aspect of the present invention there is provided a method of
preparing a composition substantially as herein described above
the method including the steps of:
a) dissolving a quantity of curcumin in a solvent (preferably warm) to form a first
solution, placing said solution under vacuum and 40- 50 degrees centigrade until
gentle refluxing.
b) mixing slowly to above solution a quantity of the marine phospholipid to form a
second solution;
c) processing the second solution to form the complex; and
d) separating the complex from the solvent, preferably by vacuum distillation.
The solvent(s) used in the present invention may vary depending upon the type or amount
of curcumin used, and the type or amount of phospholipid and/or other components
intended for the composition or complex. Therefore the exact composition of the solvent
should not be seen as being limiting.
Preferred embodiments in which the first constituent is a natural plant or animal based
extract may utilise one or more solvents from the following list, it should be appreciated
however that this list is not exhaustive and therefore should not be seen as being limiting.
Hexane
Benzene
Toluene
Diethyl ether
Chloroform
Acetic acid
Butanol
Isopropanol
Propanol
Ethanol
Methanol
Formic acid
Dimethyl Sulfoxide,
Acetone.
Preferably, the solvent is a Protic solvent. Throughout this specification, the term Protic
solvent should be taken as meaning any solvent that has a hydrogen atom bound to an
oxygen (i.e. a hydroxyl group) or a nitrogen (i.e. an amine group). From the list above,
protic solvents include acetic acid, butanol, isopropanol, ethanol, methanol and formic
acid.
Most preferably, the solvent is ethanol.
Preferably step a) includes mixing approximately 40-50 parts volume of solvent to about 1
part curcumin.
This ratio helps to ensure the curcumin is properly dissolved and prevents precipitation
during the mixing process. The process may also be aided by performing the dissolving
step at warmer temperatures.
Solvents such as ethanol may be advantageous as utilise food grade quality ethanol is
commercially available for processing techniques such as this.
The step of processing the second solution to form the complex may be achieved through
numerous ways. There are many known techniques to form micellar complexes using
phospholipids and a drug or compound, for example as documented in .
Yet without forming the complex, the curcumin and phospholipid are unstable and will
separate quickly. This is not only a problem for shelf-life stability, but it also lowers the
bioavailability of the curcumin as noted in the background art. To improve absorption,
techniques including forming complexes help to keep the curcumin bound to the
phospholipids for improved absorption in the body.
Preferably, step c) includes separation by way of evaporation.
Preferably, step c) includes heating the second solution to raise the temperature of the
second solution to greater than the boiling point of the solvent, but less than the remaining
components in the second solution.
Preferably, step c) includes heating the second solution in a pressure vessel.
Most preferably, the second solution is heated at below atmospheric pressure. This
reduces the boiling point of the solvent and fluid and allowing efficient evaporation at lower
temperatures. For example, the method may be performed under vacuum.
In some embodiments the pressure in the pressure vessel may be reduced sufficiently to
facilitate evaporation of the solvent at room temperature.
In some embodiments the pressure in the pressure vessel may be raised to increase the
boiling point of the solvent and fluid.
In a particularly preferred embodiment of the method of manufacture, the method includes
the steps of:
a) dissolving a quantity of curcumin in ethanol to form a first solution;
b) mixing the first solution with a quantity of a marine phospholipids to form a second
solution, and
c) boiling off the ethanol from the second solution to result in a complex formed
between the phospholipid and curcumin.
In some preferred embodiments the step of boiling may be performed at atmospheric
pressure or above, whereby the further solution is heated in order to exceed the boiling
point of the ethanol.
In preferred embodiments the ethanol that is boiled off is condensed and recovered.
In some preferred embodiments the step of boiling may be performed by reducing the
pressure in a vessel containing the further solution, the reduced pressure lowering the
effective boiling point of the ethanol.
Reducing the temperature of evaporation by applying a vacuum is advantageous as it
reduces the chance of the oil becoming rancid. Oils are sensitive to heat, light and
exposure to oxygen. The use of a vacuum reduces both the contribution of heat and of
oxygen to the degeneration of the oil.
Preferably, step c) includes applying a slow vacuum at around 40-50°C for 1 – 2 hours
and then a full vacuum until all the ethanol is boiled off.
In some embodiments a combination of reduced pressure and heating of the further
solution may be employed to evaporate off the ethanol.
.In some embodiments the pressure may be increased, thereby increasing the boiling
point of the ethanol, thereby requiring a greater degree of heating to evaporate the
ethanol.
It will be appreciated that the rate of evaporation may be controlled by increasing and
decreasing the pressure within the pressure vessel in which the further solution is
contained.
In preferred embodiments the vacuum pressure in the pressure vessel is in the range of 1-
100 torr.
ADVANTAGES OF THE PRESENT INVENTION:
- Bonding the curcumin marine to a phospholipid improves bioavailability as the
curcumin is protected by the complex.
- Bonding the curcumin to the phospholipid prevents separation which is seen
when curcumin is simply added in combination with an oil (without complexing).
- Sourcing the phospholipid from a marine organism allows a preferred molar ratio of
curcumin to omega 3 in the complex to be achieved.
- Using a marine oil sourced phospholipid beneficially maintains the synergistic
effect seen between Omega 3 fatty acids with curcumin. Omega 3 fatty acids are
by default always present in marine phospholipids.
- There is good public acceptance and trust of marine oils used in therapeutic
compositions.
- The present invention also provides provision of a stable complex and ability to
achieve higher molar ratios of curcumin to fatty acids by increasing the
concentration. However, in such embodiments, the most preferred option would
be tabletting or use of hard gels due to the higher viscosity of the composition.
BRIEF DESCRIPTION OF DRAWINGS
Further aspects of the present invention will become apparent from the following
description which is given by way of example only and with reference to the accompanying
drawings in which:
Figure 1 is a flow diagram of one preferred method of preparing a composition in
accordance with the present invention, and
BEST MODES FOR CARRYING OUT THE INVENTION
Figure 1 is a flow diagram illustrating the overall stages of producing a particularly
preferred composition in accordance with the present invention. Box 1 of Figure 1 depicts
the stage of combining of the various components such as curcumin, ethanol, marine
phospholipids . It will be appreciated that combination may be performed in any order
without departing from the scope of the invention; however the preferred option is adding
the phospholipid to the curcumin and ethanol.
Box 2 of Figure 1 depicts a mixing step in which the further solution is mixed in order to
evenly distribute the different components. It will be appreciated that this step could be
combined with the combination step of box 1 and/or the reflux/evaporation of step 3. The
mixing step 2 may be performed for a fixed period prior to reflux/evaporation step 3 so as
to ensure even mixing.
Box 3 of Figure 1 depicts a reflux/evaporation step. Reflux/evaporation may be achieved in
a number of ways, including:
boiling the mixed further solution at ambient pressure until the solvent has been
evaporated off;
boiling the mixed further solution at elevated temperatures at above ambient
pressure;
boiling the mixed further solution at reduced temperatures at below ambient
pressure.
The boiling point of the solvent may be substantially lower than that of other fluids in the
further fluid, as such the temperature/pressure may be controlled so that only the solvent
is boiled off.
The evaporation stage may be controlled either manually, or by way of a control system,
to control the rate of evaporation.
Typically the curcumin to be used will be initially as a powder. The powder can be
dissolved in the solvent and the resulting solution added to the at least one or more further
compounds. If the one or more further compounds include powdered compounds these
can also be dissolved in the solvent prior to combining with the other compounds. The
solvent may also be combined with a particularly viscous fluid in order to make the viscous
fluid more fluent.
In some embodiments a further step may be included which involves taking a sample of
fluid during the reflux/evaporation stage and centrifuging the sample to ascertain the
degree of bonding between at least the first constituent and at least one of the at least one
further constituents. It will be appreciated the in cases where bonding has not occurred
centrifuging results in sedimentation of the first constituent forming. Where strong bonding
has occurred little or no sedimentation is formed during centrifuging.
Examples
The invention is further described by way of reference to the following examples. These
examples should not however be construed as being limiting.
Example 1 – Method of manufacture
In this example, the amounts of each component added is based on a “by weight” amount
as illustrated in Example 2.
Step 1: In a vacuum tank, 40-50 parts of warm ethanol is mixed with an amount of
curcumin, quercetin and piperine.
Step 2: Mixing occurs under reflux and vacuum (less than 100 mBar) and at a
temperature of approximately 40-50°C until all the components are in suspension.
Step 3: An amount of mussel oil is slowly added to the solution formed by step 2.
Step 4: After 30 minutes of reflux, the mixture from step 3 is further mixed under a slow
vacuum at around 40-50°C for 1 – 2 hours and then a full vacuum until all the ethanol is
boiled off and collected in a evaporator leaving the curcumin bound to the phospholipid as
a complex.
Step 5 (optional): Lecithin may then be added to the final composition, if required.
Example 2 – Exemplary composition of the present invention
Component Relative amount
Demethoxycurcumin 3.76% w/w
Mussel oil 31.9% w/w
Vegetable oil lethicin 63.9% w/w
Piperine 0.04% w/w
Quercetin 0.2% w/w
Total Approx 100%
Example 3
To illustrate the effectiveness of forming the curcumin-phospholipid complex on stability,
the following study was done.
A control composition was produced by directly mixing 4% by weight curcumin powder
with 500ml of mussel oil with a blender. The mixture was vigorously mixed in the blender
for 20 minutes.
A comparable trial composition (4% curcumin) was then produced according to the
method outlined in example 1 (method of manufacture) and 2 (example composition) and
in accordance with the present invention.
The control and trial compositions were both placed in an IEC DPR6000 centrifuge and
subjected to 4500 rpm (5550 G) for 1 hour. The resulting precipitate was weighed for
each of the control mixtures.
The results showed that the control composition had only 0.3% by weight as soluble
curcumin. This correlates to known rates of between 0.2 to 0.5% w/w solubilisation of
curcumin. Oppositely, the trial composition did not produce any precipitate indicating that
the entire 4% w/w of curcumin had been bound to the mussel oil derived phospholipids .
Example 4:
The inventors compared a composition having just marine oil to a composition having both
marine oil and lecithin. The concentration of curcumin was kept at 4% w/w for both
compositions. It was found that the stability of the complex was not affected in the
composition having lecithin. This meant that convenient encapsulation techniques could
still be achieved for the lecithin-containing composition even when curcumin loading was
increased beyond 4% w/w.
Aspects of the present invention have been described by way of example only and it
should be appreciated that modifications and additions may be made thereto without
departing from the scope thereof.
WHAT I/WE