U.S. patent application number 12/649383 was filed with the patent office on 2010-04-29 for pharmaceutical composition comprising a reduced concentration of cholesterol.
This patent application is currently assigned to Pronova BioPharma Norge. Invention is credited to Sverre Sondbo, Olav Thorstad.
Application Number | 20100104657 12/649383 |
Document ID | / |
Family ID | 30117183 |
Filed Date | 2010-04-29 |
United States Patent
Application |
20100104657 |
Kind Code |
A1 |
Sondbo; Sverre ; et
al. |
April 29, 2010 |
PHARMACEUTICAL COMPOSITION COMPRISING A REDUCED CONCENTRATION OF
CHOLESTEROL
Abstract
The invention relates to a process for decreasing the amount of
cholesterol in a mixture comprising a marine oil, the marine oil
containing the cholesterol, which process comprises the steps of
adding a volatile working fluid to the mixture, where the volatile
working fluid comprises at least one of a fatty acid ester, a fatty
acid amide and a hydrocarbon, and subjecting the mixture with the
added volatile working fluid to at least one stripping processing
step, in which an amount of cholesterol present in the marine oil
in free form is separated from the mixture together with the
volatile working fluid. The present invention also relates to a
volatile cholesterol decreasing working fluid and a health
supplement and a pharmaceutical, based on a marine oil, prepared
according to the process mentioned above.
Inventors: |
Sondbo; Sverre; (Sandefjord,
NO) ; Thorstad; Olav; (Porsgrunn, NO) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER;LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Assignee: |
Pronova BioPharma Norge
|
Family ID: |
30117183 |
Appl. No.: |
12/649383 |
Filed: |
December 30, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10520897 |
Jul 25, 2005 |
7678930 |
|
|
PCT/IB03/02776 |
Jul 11, 2003 |
|
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|
12649383 |
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Current U.S.
Class: |
424/523 |
Current CPC
Class: |
A23V 2002/00 20130101;
Y02A 40/818 20180101; C11B 3/14 20130101; A61P 9/12 20180101; C11C
3/10 20130101; C11B 3/006 20130101; F16D 55/24 20130101; A61P 3/06
20180101; A61P 25/28 20180101; C11B 3/12 20130101; A23K 20/158
20160501; A23V 2200/3262 20130101; A61P 9/00 20180101; A61P 9/10
20180101; A61P 13/12 20180101; A23L 33/115 20160801; A61P 29/00
20180101; A23D 9/00 20130101; A23K 50/80 20160501; F16D 2055/0008
20130101; A23V 2002/00 20130101; A23V 2200/3262 20130101 |
Class at
Publication: |
424/523 |
International
Class: |
A61K 35/60 20060101
A61K035/60; A61P 9/10 20060101 A61P009/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 11, 2002 |
SE |
0202188-9 |
Apr 8, 2003 |
IB |
PCT/IB2003/002827 |
Claims
1-24. (canceled)
25. A pharmaceutical composition comprising a
lowered-cholesterol-content marine oil, the marine oil comprising
eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and
cholesterol in free form, wherein the pharmaceutical composition is
not a health supplement and the amount of cholesterol in the marine
oil is reduced by: a) adding a volatile working fluid to the marine
oil, wherein the volatile working fluid comprises at least one
fluid chosen from fatty acid esters, fatty acid amides, and
hydrocarbons; and b) subjecting the mixture of marine oil and
volatile working fluid from step (a) to at least one stripping
processing step, wherein an amount of the cholesterol present in
the marine oil in free form is separated from the mixture together
with the volatile working fluid.
26. The composition according to claim 25, wherein the marine oil
comprises at least one fatty acid chosen from saturated fatty acids
in the form of triglycerides and unsaturated fatty acids in the
form of triglycerides, and wherein the marine oil is obtained from
fish, shellfish, sea mammals, or any combination thereof.
27. The composition according to claim 26, wherein the marine oil
is fish oil.
28. The composition according to claim 25, wherein the amount of
cholesterol in free form in the marine oil is less than 3 mg/g.
29. The composition according to claim 25, wherein the amount of
cholesterol in free form in the marine oil is less than 1.4
mg/g.
30. The composition according to claim 25, wherein the amount of
cholesterol in free form ranges from 0.2 mg/g to 1.4 mg/g.
31. The composition according to claim 25, wherein the amount of
cholesterol in free form ranges from 1.4 mg/g to 3 mg/g.
32. The composition according to claim 31, wherein the marine oil
is fish oil.
33. The composition according to claim 25, wherein the marine oil
further comprises cholesterol in bound form, and wherein the at
least one stripping processing step of step (b) is followed by: c)
subjecting the stripped marine oil to at least one
trans-esterification reaction with a C1-C6 alcohol under
substantially anhydrous conditions, and d) subjecting the
transesterified marine oil from step (c) to at least one
distillation process that yields a distillate marine oil fraction
and a residue marine oil fraction, wherein the distillate marine
oil fraction has concentrations of both free and bound cholesterol
lower than in the residue fraction.
34. The composition according to claim 33, wherein the marine oil
is fish oil.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a process for decreasing the
amount of cholesterol in a mixture comprising a marine oil,
containing the cholesterol. The present invention also relates to a
volatile cholesterol decreasing working fluid, a health supplement
and a pharmaceutical, prepared according to the process mentioned
above.
BACKGROUND OF THE INVENTION
[0002] It is known that cholesterol is an important steroid found
in the lipids (fats) in the bloodstream and in all body's cells in
mammals. Cholesterol is used to form cell membranes, some hormones
and other needed tissues. A mammal will get cholesterol in two
ways; the body produces some of it, and the rest comes from
products that the mammal consumes, such as meats, poultry, fish,
eggs, butter, cheese and whole milk. Food from plants like fruits,
vegetables and cereals do not include cholesterol.
[0003] Cholesterol and other fats can't dissolve in the blood. They
have to be transported to and from the cells by special carriers
called lipoproteins, named on basis of their density. Low-density
lipoprotein, or LDL, transport cholesterol from the liver to
peripheral tissues and LDL transported cholesterol is known as the
"bad" cholesterol, because too much LDL cholesterol can clog the
arteries to the heart and increase the risk of heart attack.
High-density lipoprotein, or HDL, transport cholesterol back to the
liver where surplus cholesterol is disposed of by the liver as bile
acids. HDL transported cholesterol is known as the "good"
cholesterol and high levels of HDL may reduce cholesterol deposits
in arteries. For an organism to remain healthy, there has to be an
intricate balance between the biosynthesis of cholesterol and its
utilization, so that arterial deposition is kept at a minimum.
[0004] In e.g. marine oils, cholesterol is stored as "free"
respectively as "bound" cholesterol. In the bound form, cholesterol
is esterified on the OH-group by a fatty acid.
##STR00001##
Structural Formula of Cholesterol
[0005] The commercially important polyunsaturated fatty acids in
marine oils, such as fish oil, are preferably EPA (eicosapentaenoic
acid, C20:5), DHA (docosahexaenoic acid, C22:6). The full
nomenclature of these acids according to the IUPAC system is: EPA
cis-5,8,11,14,17-eicosapentaenoic acid, DHA
cis-4,7,10,13,16,19-docosahexaenoic acid. For many purposes it is
necessary that the marine oils should be refined in order to
increase the content of EPA and/or DHA to suitable levels, or to
reduce the concentrations of, or even eliminate, certain other
substances which occur naturally in the raw oil, e.g.
cholesterol.
[0006] The fatty acids EPA and DHA are also proving increasingly
valuable in the pharmaceutical and food supplement industries in
particular. It is also very important for fish oils and other
temperature sensitive oils (i.e. oils that contains long chain
polyunsaturated fatty acids) to keep the load of the temperature as
low as possible. Concerning the amount of cholesterol in the oils,
it is specially a problem in fish oils and milk fat.
[0007] Further, as the link between high serum cholesterol levels
and heart disease has become increasingly apparent,
cholesterol-free and cholesterol-reduced food products have become
more attractive to consumers, and food products that have no or
reduced cholesterol are gaining popularity as well as an increasing
share of the market. Consequently, removal or reduction of
cholesterol in high cholesterol foods has the potential to
substantially increase marketability and value.
[0008] The removal or reduction of cholesterol in marine oils is
not a trivial matter. Several different techniques to accomplish
this task have been developed, each with varying levels of success.
The content of cholesterol in marine oils will become a much more
important parameter for the process industry in the future.
[0009] Some methods of treating a fish oil is known from the prior
art. Such methods include conventional vacuum steam distillation of
fish oils at high temperatures which creates undesirable side
reactions, decreases the content of EPA and DHA in the oil and the
resulting product has a poor flavour stability and poor resistance
to oxidation.
SUMMARY OF THE INVENTION
[0010] One object of the invention is to offer an effective process
for decreasing the amount of cholesterol in a mixture comprising a
marine oil, containing the cholesterol, preferably by decreasing
and separating the amount of cholesterol present in free form.
[0011] According to a first aspect of the invention, this and other
objects are achieved with a process for decreasing the amount of
cholesterol in a mixture comprising a marine oil, the marine oil
containing the cholesterol, which process comprises the steps of
adding a volatile working fluid to the mixture, where the volatile
working fluid comprises at least one of a fatty acid ester, a fatty
acid amide and a hydrocarbon, and subjecting the mixture with the
added volatile working fluid to at least one stripping processing
step, in which an amount of cholesterol in the marine oil is
separated from the mixture together with the volatile working
fluid. Most preferably, the amount of cholesterol present in the
marine oil that is separated from the mixture together with the
volatile working fluid is constituted by cholesterol in free form.
Herein, "an amount" is interpreted to include decreasing of an
amount up to almost 100% of cholesterol present in free form, i.e.
a substantial removal of cholesterol in free form from a marine fat
or oil composition, at low mixture flow rates. The content of bound
cholesterol is less affected by the stripping process according to
the invention, since cholesterol in bound form has a higher boiling
point compared to the working fluid according to the invention.
[0012] The use of a volatile working fluid, where the volatile
working fluid comprises at least one of a fatty acid ester, a fatty
acid amide and a hydrocarbon, or any combination thereof, in a
stripping process (or processing step) for decreasing the amount of
cholesterol present in a marine oil in free form has a number of
advantages.
[0013] An advantage of using a volatile working fluid in a
stripping process is that the cholesterol present in free form can
more easily be stripped off together with the volatile working
fluid. Preferably, this is possible as long as the volatile working
fluid is essentially equally or less volatile than the cholesterol
that shall be removed from the oil mixture. The stripped
cholesterol present in free form and the volatile working fluid
will be found in the distillate. When the volatile working fluid
have the mentioned property, in combination with beneficial
stripping process conditions, it is possible to separate, or strip
off, almost all cholesterol present in a marine oil in free form
more effectively. The effect of adding a volatile working fluid to
a marine oil mixture before stripping is larger and also more
commercial useful, compared to a general process for decreasing
cholesterol in an oil mixture, at higher flow rates. Herein, "high
flow rates" is interpreted to include mixture flow rate in the
interval of 80-150 kg/hm.sup.2. Under the process conditions
mentioned above, the use of a volatile working fluid open up for a
much better utilization of the capacity of the process equipment
and a more rapid stripping process.
[0014] Further, according to the present stripping process it is
also possible to decrease an effective amount of cholesterol
present in a marine oil in free form at lower temperatures,
preferably at a temperature in the interval of 150-220.degree. C.,
compared to the techniques known from the prior art. It is
especially important to keep the temperature as low as possible
during processing of marine oils, such as fish oils, and other
temperature accommodating oils (i.e. oils comprising long chains of
polyunsaturated fatty acids). This is not so critical for oils not
included above. In addition, the volatile working fluid according
to the invention allows cholesterol present in free form to be
stripped off by e.g. molecular distillation even from oils of lower
quality, i.e. oil for feed purposes.
[0015] In a preferred embodiment of the present invention the
volatile working fluid is an organic solvent or solvent mixture
with a volatility comparable to the cholesterol in free form. The
volatile working fluid of the present invention is at least one of
a fatty acid ester, a fatty acid amide, and a hydrocarbon, also
including any combinations thereof.
[0016] In another preferred embodiment the volatile working fluid
comprises at least one fatty acid ester composed of C10-C22 fatty
acids and C1-C4 alcohols, or a combination of two or more fatty
acid ester each composed of C10-C22 fatty acids and C1-C4 alcohols.
Preferably, the volatile working fluid is at least one of amides
composed of C10-C22 fatty acids and C1-C4 amines, C10-C22 free
fatty acids, and hydrocarbons with a total number of carbon atoms
from 10 to 40. Most preferably, the volatile working fluid is a
mixture of fatty acids from marine oils, e.g. fish body oil and/or
fish liver oil, and/or ethyl or methyl esters of such marine fatty
acids.
[0017] In another embodiment of the invention a volatile working
fluid may be produced by subjecting fats or oils from an available
source, for instance fats or oils obtained from at least one of
animal, microbial or vegetable origin, to an inter-esterification
process, in which process the triglycerides in the fats or oils are
converted into esters of aliphatic alcohols. Additionally, a
bio-diesel and/or a mineral oil can be used as a volatile working
fluid. In the case when the volatile working fluid is a biodiesel,
it can be produced by a process, which is in common use for
production of engine fuels (biodiesel), and therefore also known by
a man skilled in the art, which process comprises mixing the fat or
oil with a suitable amount of aliphatic alcohol, adding a suitable
catalyst and heating the mixture for a period of time. Similar
esters of aliphatic alcohols may also be produced by a
high-temperature catalytic direct esterification process reacting a
free fatty acid mixture with the appropriate aliphatic alcohol. The
fatty acid ester mixture produced in this manner may be used as a
volatile working fluid as it is, but normally the conversion to
esters of aliphatic alcohols is not complete, the conversion
process preferably leaving some un-reacted non-volatile glycerides
in the mixture. Further, some fats or oils may also contain certain
amounts of non-volatile, non-glyceride components (e.g. polymers).
Such non-volatile components will be transferred to, and mixed with
the final product, which product is low in cholesterol, when the
fatty acid ester mixture is used as working fluid. A working fluid
produced in this manner should therefore be subjected to a
distillation, preferably a molecular and/or short path
distillation, in at least one step, which distillation process
generates a distillate more suitable to be used as a new volatile
working fluid.
[0018] In addition, the volatile working fluid according to the
invention allows cholesterol to be stripped off by e.g. molecular
distillation even from oils of lower quality.
[0019] In another preferred embodiment of the process, at least one
of a fatty acid ester and a fatty acid amide constituting said
volatile working fluid is obtained from at least one of a
vegetable, microbial and animal fat or oil, being edible or for use
in cosmetics. Preferably, the animal fat or oil is a marine oil,
e.g. a fish oil or an oil from other marine organism e.g. sea
mammals. It is also possible that the fatty acid esters mentioned
above can e.g. be a byproduct from distillation of an ethyl ester
mixture prepared by ethylation of preferably a fish oil. In the
process industry trade with intermediates is increasing and opens
up for an extra financial income.
[0020] In fish oils cholesterol is typically present in
concentrations of 5-10 mg/g, but higher concentrations have been
observed. In this case 2-4 mg/g is typically bound cholesterol and
3-6 mg/g is free cholesterol. Free cholesterol can be effectively
removed by adding a volatile working fluid prior to at least one of
the stripping processes according to the invention.
[0021] In another embodiment of the process according to the
invention, the marine oil containing saturated and unsaturated
fatty acids in the form of triglycerides, and the marine oil is
obtained from fish and/or sea mammals. Marine oils that contains no
or reduced amounts of cholesterol present in free form are gaining
popularity as well as an increasing share of the market.
[0022] It is important to note that the invention is not limited to
procedures were the working fluid is prepared from the same origin
as the oil that is being purified.
[0023] In a preferred embodiment of the invention, the ratio of
(volatile working fluid):(marine oil) is about 1:100 to 15:100. In
a more preferred embodiment the ratio of (volatile working
fluid):(marine oil) is about 3:100 to 8:100.
[0024] In a preferred embodiment of the invention, said stripping
process step is carried out at temperatures in the interval of
120-270.degree. C.
[0025] In a most preferred embodiment, the stripping processing
step is carried out at temperatures in the interval of
150-220.degree. C. By adding a volatile working fluid to the marine
oil mixture at this temperatures the invention surprisingly shows
that even termolabile polyunsaturated oils can be treated with good
effect, without causing degradation of the quality of the oil.
[0026] In another preferred embodiment, the stripping processing
step is carried out at a pressure below 1 mbar.
[0027] In further preferred embodiment, the stripping processing
step is at least one of a thin-film evaporation process, a
molecular distillation or a short-path distillation, or any
combination thereof. If at least one stripping process step is a
thin-film evaporation the process is also carried out at mixture
flow rates in the intervall of 30-150 kg/hm.sup.2, most preferably
in the range of 80-150 kg/hm.sup.2. The effect of adding a volatile
working fluid to a marine oil mixture before stripping is larger
and also more commercial useful, compared to a general process for
decreasing cholesterol present in a marine fat or oil in free form
at higher flow rates.
[0028] By using a stripping process, e.g. a distillation method,
for decreasing the amount of cholesterol present in a marine oil in
free form, the marine oil mixture comprising a volatile working
fluid, it is possible to carry out the stripping processes at lower
temperatures, which spare the oil and is at the same time
favourable to the end oil product.
[0029] Another embodiment of the present invention is a stripping
process wherein a working fluid is added to a mixture comprising a
marine oil, containing cholesterol, prior to a thin-film
evaporation process, and the volatile working fluid comprises at
least one of a fatty acid ethyl ester and a fatty acid methyl ester
(or any combinations thereof), and subjecting the mixture with the
added working fluid to a thin-film evaporation step, in which an
amount of cholesterol present in free form in the marine oil is
separated from the mixture together with the volatile working
fluid.
[0030] In a preferred embodiment according to the invention the
stripping process is carried out by a molecular distillation in the
following intervals; mixture flow rates in the interval of 30-150
kg/hm.sup.2, temperatures in the interval of 120-270.degree. C. and
a pressure below 1 mbar.
[0031] In a most preferred embodiment of the invention the
molecular distillation is carried out at temperatures in the
interval of 150-220.degree. C. and at a pressure below 0,05 mbar,
or by a thin-film process, which process is carried out at 80-150
kg/hm.sup.2 or at flow rates in the range of 800-1600 kg/h at a
heated thin film area of 11 m.sup.2; 73-146 kg/hm.sup.2. Please
note, that the present invention can also be carried out in one or
more subsequent stripping processing steps.
[0032] In another preferred embodiment of the present invention, a
volatile cholesterol decreasing working fluid, for use in
decreasing an amount of cholesterol present in a marine oil in free
form, the volatile working fluid is comprising at least one of a
fatty acid ester, a fatty acid amide and a hydrocarbon, with
essentially equally or less volatility compared to the cholesterol
that is to be separated from the marine oil, or any combination
thereof.
[0033] Preferably, the volatile cholesterol decreasing working
fluid is generated as a fractionation product. Additionally, the
volatile cholesterol decreasing working fluid is a by-product, such
as a distillation fraction, from a regular process for production
of ethyl and/or methyl ester concentrates. This by-product
according to the invention can be used in a new process preferably
for fat or oil being edible or for use in cosmetics. More
preferably, the volatile cholesterol decreasing working fluid, for
use in decreasing an amount of cholesterol present in a marine fat
or oil, can be a by-product (a distillate fraction) from a regular
process for production of ethyl ester concentrates, wherein a
mixture comprising an edible or a non-edible fat or oil, preferably
a fish oil, is subjected to an ethylating process and preferably a
two-step molecular distillation. In the two-step molecular
distillation process a mixture consisting of many fatty acids on
ethyl ester form is separated from each other in; a volatile (light
fraction), a heavy (residuum fraction) and a product fraction. The
volatile fraction from the first distillation is distilled once
more and the volatile fraction from the second distillation process
is then at least composed of the volatile working fluid, preferably
a fatty acid ethyl ester fraction. This fraction consists of at
least one of C14 and C16 fatty acids and at least one of the C18
fatty acids from the fat or oil, and is therefore also compatible
with the edible or non-edible oil. The fraction can be redistilled
one or more times if that is deemed to be suitable. This prepared
working fluid can then be used as a working fluid in a new process
for decreasing the amount of cholesterol present in a marine oil in
free form, wherein the edible or non-edible fats or oils and the
marine oil are of the same or different types.
[0034] In another preferred embodiment of the invention the
volatile working fluid comprises at least one of an ester and/or an
amide composed of shorter fatty acids and longer alcohols or
amines, or any combination thereof.
[0035] In a preferred embodiment of the invention, the volatile
cholesterol decreasing working fluid, for use in decreasing an
amount of cholesterol present in a marine oil, is preferably a
fatty acid ester (e.g. fatty acid ethyl ester or fatty acid methyl
ester) or a fatty acid amide obtained from at least one of
vegetable, microbial and animal fat or oil, or any combination
thereof. Preferably, said animal fat or oil is a marine oil, for
instance a fish oil and/or an oil from sea mammals.
[0036] In another embodiment of the invention, a volatile
cholesterol decreasing working fluid according to the present
invention, is used in a process for decreasing the amount of
cholesterol in a mixture comprising a marine oil, the marine oil
containing the cholesterol, in which process the volatile working
fluid is added to the mixture and then the mixture is subjected to
at least one stripping processing step, preferably a thin-film
evaporation process, a molecular distillation or a short-path
distillation or any combination thereof, and in which process an
amount of cholesterol present in the marine oil in free form is
separated from the oil mixture
[0037] In a more preferred embodiment, the volatile cholesterol
decreasing working fluid is a by-product, such as a distillate
fraction, from a regular process for production of ethyl and/or
methyl ester concentrates.
[0038] In another preferred embodiment a health supplement, or a
pharmaceutical containing oil (end) products with a decreased
amount of cholesterol, preferably strongly limited amounts of
cholesterol present in free form, prepared according to at least
one of the previously mentioned processes is disclosed. For the
pharmaceutical and food supplement industries, marine oils often is
processed in order to increase the content of EPA and/or DHA to
suitable levels and the removal or reduction of cholesterol have
the potential to substantially increase marketability and value.
Therefore, the present invention also discloses a health supplement
and a pharmaceutical respectively, containing at least a marine
oil, such as fish oil, which marine oil is prepared according to
the previously mentioned process, in order to decrease the total
amount of cholesterol present in the marine oil. It shall be noted
that the invented process may also be used for marine oils which
has not been processed in order to increase the content of EPA
and/or DHA to suitable levels.
[0039] In another embodiment of the invention the pharmaceutical
and/or health supplement is preferably intended for treating
cardiovascular diseases (CVD) and inflammatory diseases, but they
also have positive effects on other CVD risk factors such as the
plasma lipid profile, hypertension and vascular inflammation. In
more preferred embodiment of the invention the pharmaceutical
and/or health supplement comprises at least one of EPA/DHA
triglycerides/ethyl esters and is intended for a range of potential
therapeutic applications including; treatment of
hypertriglyceridaemia, secondary prevention of myocardial
infarction, prevention of atherosclerosis, treatment of
hypertension, mental disorders and/or kidney disease and to improve
children's learning ability.
[0040] Preferably, the pharmaceutical and/or health supplement
prepared according to at least one of the previously mentioned
processes is based on fish oil.
[0041] Further, the present invention also disclose a marine oil
product, prepared according to at least one of the previously
mentioned processes. Preferably, the marine oil product is based on
fish oil or a fish oil composition.
[0042] In another preferred embodiment the stripping process is
followed by a trans-esterification process. Preferably, the
stripping processing step is followed by the steps of; subjecting
the stripped marine oil mixture to at least one
trans-esterification reaction with a C.sub.1-C.sub.6 alcohol under
substantially anhydrous conditions, and in the presence of a
suitable catalyst (a chemical catalyst or an enzyme) to convert the
fatty acids present as triglycerides in the marine oil mixture into
esters of the corresponding alcohol, and thereafter subjecting the
product obtained in the step above to at least one or more
distillations, preferably one or more molecular distillations.
[0043] After the trans-esterification reaction some glycerides and
most of the bound cholesterol will remain unreacted. Both the
unreacted glycerides and the bound (esterified) cholesterol will
have higher boiling points than the valuable esters of
polyunsaturated fatty acids, and will therefore be concentrated in
the residue (waste) fraction. Thereby a substantial reduction in
bound cholesterol can be obtained in the distillate (product)
fraction.
[0044] By combining the steps of first stripping the cholesterol in
free form from the marine oil triglycerides using a volatile
working fluid, followed by catalysed esterification of the marine
oil with a C.sub.1-C.sub.6 alcohol under substantially anhydrous
conditions, and thereafter distillation under conditions suitable
to enrich the bound cholesterol in the residium (waste) fraction, a
fatty acid ester product with a significant reduction in both free
and bound cholesterol can be produced. More preferably, said
C.sub.1-C.sub.6 alcohol is ethanol.
[0045] In another preferred embodiment of the invention the
volatile working fluid comprises at least one of an ester, amides
and/or esters composed of longer fatty acids and shorter alcohols
or amines, or any combination thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0046] The advantages and details of the present invention will
become apparent from the following description when taken in
conjugation with the accompanying drawings, in which;
[0047] FIG. 1 is a schematic flow chart of one embodiment
illustrating a method for decreasing the amount of cholesterol in a
marine oil, by adding a volatile working fluid prior to a molecular
distillation.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0048] A number of preferred embodiments of the process for
decreasing the amount of cholesterol in a mixture comprising a
volatile working fluid and a marine oil, containing the
cholesterol, will be disclosed below.
[0049] A first embodiment of a process for decreasing the amount of
cholesterol in a marine oil by adding a volatile working fluid
prior to a molecular distillation is presented in FIG. 1. The
starting marine oil in the first embodiment of the invention is a
fish oil whether freshly refined, reverted or mixtures thereof
characterized by an initial or native cholesterol level. The exact
amount of cholesterol varies depending upon such factors as fish
species, seasonality, geographical catch location and the like.
[0050] As used herein the term molecular distillation is a
distillation process performed at high vacuum and preferably low
temperature (above 120.degree. C.). Herein, the condensation and
evaporation surfaces are within a short distance from each other,
so as to cause the least damage to the oil composition.
[0051] The molecular distillation plant (1) illustrated in FIG. 1,
comprises a mixer (2), a pre-heater (3), a degasser (4), a
distillation unit (5) and a vacuum pump (6). In accordance with
this embodiment, a volatile working fluid comprising an ethyl ester
fraction (6% relative to the oil) is added to a fish oil mixture
and blended in a mixer (2). The fish oil mixture is then optionally
passed through a means for controlling the oil feed rate, such as
an ordinary throttling valve. The fish oil mixture is then
preheated with a heating means (3) such as a plate heat exchanger
to provide a preheated fish oil mixture. The mixture is then passed
through a degassing step (4) and admitted into the short path
evaporator (5), a tube (7) including the condensation (8) and
evaporation (9) surface. The fish oil mixture to be concentrated is
picked up as it enters the tube (7a) by rotating blades (not
shown). The blades extend nearly to the bottom of the tube and
mounted so that there is a clearance of about 1,3 mm between their
tips and the inner surface of the tube. In addition, the blades are
driven by an external motor. The fish oil mixture is thrown against
the tube wall and is immediately spread into a thin film and is
forced quickly down (A) the evaporation surface. The film flows
down by gravity, and as it falls the light and heavy fractions are
separated because of differences in boiling point.
[0052] Heated walls and high vacuum strips off the volatile working
fluid together with the cholesterol, i.e. the more volatile
components (distillate) is derived to the closely positioned
internal condenser (8), the less volatile components (residue)
continues down the cylinder. The resulting fraction, the stripped
fish oil mixture containing at least the fatty acids EPA and DHA is
separated and exit through an individual discharge outlet (10).
[0053] In a second embodiment a falling film evaporator is used. In
falling film evaporators liquid and vapours flow downwards in
parallel flow. The liquid to be concentrated, herein the fish oil
mixture, is preheated to boiling temperature. The oil mixture
enters the heating tubes via a distribution device in the head of
the evaporator, flows downward at boiling temperature, and is
partially evaporated. This gravity-induced downward movement is
increasingly augmented by the co-current vapour flow. Falling film
evaporators can be operated with low temperature differences
between the heating media and the boiling liquid, and they also
have short product contact times, typically just a few seconds per
pass.
[0054] In a third embodiment of the invention the process is
carried out by a short path distillation, which includes the use of
a short path evaporator that integrates the features and advantages
of thin film or wiped film evaporators but adds internal condensing
for applications. Short path evaporators are widely used in fine
and specialty chemicals for thermal separation of intermediates,
concentration of high value products, and molecular distillation
under fine vacuum conditions. Their key features make them uniquely
suitable for gentle evaporation and concentration of heat sensitive
products at low pressures and temperatures.
[0055] In a fourth embodiment of the invention the stripping
process is followed by the steps of subjecting the stripped marine
oil mixture to at least one trans-esterification reaction with a
C.sub.1-C.sub.6 alcohol under substantially anhydrous conditions
and thereafter subjecting the product obtained in the step above to
at least one or more distillations, preferably one or more
molecular distillations. The key step in all trans-esterification
reactions is the reaction between an ester mixture, composed of
fatty acids bound to an alcohol A, and an alcohol B where the
reaction products are an ester mixture, composed of the same fatty
acids bound to alcolhol B, and alcohol A as shown in this general
formula:
##STR00002##
[0056] The reaction is preferably catalysed and the reaction is an
equilibrium and the yield of the expected fatty acid ester is to a
large extent controlled by the concentration of the alcohols.
Herein, for instance the stripping process is followed by a
catalysed trans-esterification of marine oil triglycerides. The
separation of the ethyl ester fraction from the fraction containing
the unreacted glycerides and bound cholesterol is suitably carried
out by at least one of a molecular distillation technique, whereby
the less volatile residual mixture can be readily removed from the
relatively volatile ethyl esters.
[0057] It should be understood that many modifications of the above
embodiments of the invention are possible within the scope of the
invention such as the latter is defined in the appended claims. It
will be apparent for one skilled in the art that various changes
and modifications, i.e. other combinations of temperatures,
pressures, and flow rates during the stripping process can be made
therein without departing from the spirit and scope thereof.
EXAMPLES
[0058] The invention will now be illustrated by means of the
following non-limiting example. This example is set forth merely
for illustrative purposes and many other variations of the process
may be used. The example below summarize some results from
different purification of fish oils by molecular distillation.
EXAMPLE 1
A Stripping Process for Decreasing the Amount of Cholesterol
Present in a Fish Oil Mixture in Free form with Respectively
without Using a Volatile Working Fluid
[0059] This example shows an industrial scale process for
decreasing the amount of cholesterol in a refined fish oil mixture
in free form, with and without adding a volatile working fluid to
the fish oil mixture, and subjecting the mixture to a molecular
distillation process.
[0060] Herein, an Anchovy oil from Peru, with a fatty acid
composition of 18% EPA and 12% DHA was used. The oil contains about
9 mg cholesterol/g fish oil, of which 6 mg/g was constituted by
cholesterol present in free form and about 3 mg/g in bound form. In
tests 1 and 3 a volatile working fluid constituted by a fatty acid
ethyl ester mixture, 6% ethyl ester relative to the fish oil,
i.e.
[0061] the ratio of (volatile working fluid):(fish oil) about
6:100, was added to the fish oil mixture before subjecting the
mixture to a molecular distillation process. All tests below were
carried out at mixture flow rates of 900 or 400 kg/h in a molecular
distillation unit with an evaporation surface of 11 m.sup.2. Test 1
and 2 were carried out at a temperature of 210.degree. C. and at a
mixture flow rate of 900 kg/h. Test 3 and 4 were carried out at a
lower temperature, 205.degree. C., and at a lower flow rate, 400
kg/h. The amount of cholesterol present in the fish oil mixture in
free form was analysed by a method based on standard high
performance liquid chromatographic analyses.
TABLE-US-00001 TABLE 1 Amounts of cholesterol present in a fish oil
in free form after molecular distillation Flow rate % added Free
cholesterol Test Temp. (.degree. C.) (kg/h) ethyl ester (mg/g) 1
210 900 6 1.4 2 210 900 0 2.4 3 205 400 6 0.2 4 205 400 0 0.4
[0062] The results in the table above illustrates that it is
possible to decrease (to separate) an amount of free cholesterol in
a marine oil more effective by adding a volatile working fluid to a
marine oil composition and thereafter subjecting the fish oil
composition to a stripping processing step according to the
invention. It is important to note that the effect by adding a
volatile working fluid to a marine oil composition, before
subjecting at least one stripping processing step, is better, and
more interesting, when the stripping process is carried out at
higher mixture flow rates, preferably flow rate in the interval of
80-150 kg/hm.sup.2. Under these conditions, the use of a volatile
working fluid opens up for a much better utilization of the
capacity of the process equipment and a more rapid stripping
process.
[0063] Another advantage by using a volatile working fluid
according to the invention is that the stripping effect is
satisfactory at low temperatures [temperatures in the interval of
120-220.degree. C.] for marine oils. Namely, for marine oils, such
as fish oils, and other temperature accommodating oils (oils
comprising long chains of polyunsaturated fatty acids) it is
important to keep the temperature load during the processes as low
as possible. But, this is less important for other oils not
mentioned above.
[0064] Further, the effect of adding a volatile working fluid,
compared with no adding of the same, is less noticeable in the case
when the stripping process is carried out at low mixture flow rates
[i.e. flow rates <30 kg/hm.sup.2]. But on the other hand, it is
not known commercially interesting to carry out a stripping process
using low feed rates and relatively high temperatures because the
stripping process will take too long to finish. Additionally, today
it is a problem for the marine oil industry to find effective and
rapid techniques that are able to decrease the amount of
cholesterol in marine oils at higher flow rates.
[0065] The tests above also show that the amount of free
cholesterol is reduced from about 6 mg/g to about 1,4 mg/g by
adding a volatile working fluid to a fish oil mixture prior to a
molecular distillation process, which process being carried out at
a temperature of 210.degree. C. and at a mixture flow rate of 900
kg/h pr. Here, the amount of cholesterol in free form is decreased
with about 75-80%.
[0066] When the stripping process is carried out at 900 kg/h the
amount of free cholesterol is reduced further compared to the
stripping process where no ethyl ester (working fluid) has been
added, at the same flow rate. Note that the content of bound
cholesterol is less affected by the stripping process according to
the invention. Additionally, the use of very high temperatures,
i.e. temperatures above 270.degree. C., isn't of interest. Such
temperatures will cause damage to the oil. Too high temperatures
also can be harmful for the production equipment.
[0067] Further, the amount (%) of addition of ethyl ester is also
of importance. Addition of at least 4% ethyl ester or an ethyl
ester fraction has also generated good results. Preferably, the
ratio of (volatile working fluid):(marine oil) is about 1:100 to
15:100 and more preferably, the ratio of (volatile working
fluid):(marine oil) is about 3:100 to 8:100.
[0068] While the invention has been described in detail and with
reference to specific embodiments thereof, it will be apparent for
one skilled in the art that various change and modifications can be
made therein without departing from the spirit and scope
thereof.
DEFINITIONS
[0069] As used herein the term marine oil also includes marine fat
and a fermented or refined product containing at least n-3
polyunsaturated fatty acids, predominately EPA and DHA from a raw
marine oil. Further, the marine oil is preferably oil from at least
one of fish, shellfish (crustaceans) and sea mammals, or any
combination thereof. Non limiting examples of fish oils are
Menhaden oil, Cod Liver oil, Herring oil, Capelin oil, Sardine oil,
Anchovy oil and Salmon oil. The fish oils mentioned above may be
recovered from fish organs, e.g. cod liver oil, as well as from the
meat of the fish, from the whole fish or from fish waste.
Additionally, the term "oil and fat" means fatty acids in at least
one of the triglyceride and phospholipid forms. Generally, if the
start material in the stripping process is a marine oil, the oil
may be any of raw or partially treated oil from fish or other
marine sources and which contains fatty acids, including
polyunsaturated fatty acids, in the form of triglycerides.
Typically, each triglyceride molecule in such a marine oil will
contain, more or less randomly, different fatty acid ester
moieties, be the saturated, monounsaturated or polyunsaturated, or
long chain or medium chain. Further, examples of vegetable oils or
fats are corn oil, palm oil, rapeseed oil, soybean oil, sunflower
oil and olive oil. Additionally, the marine fat or oil may be
pre-processed in one or several steps before constituting the start
material in the stripping process as described above.
[0070] As used herein the term edible means edible for humans
and/or animals. Additionally, as used herein the term "for use in
cosmetics" means an oil or a fat that can be used in products that
contributes to enhance humans appearance and/or health, e.g.
cosmetic and/or beauty care products. Further, a fat or an oil,
being edible or for use in cosmetics, according to the invention
can also be a blend of e.g. microbial oils, fish oils, vegetable
oils, or any combination thereof.
[0071] As used herein the term microbial oils also includes "single
cell oils" and blends, or mixtures, containing unmodified microbial
oils. Microbial oils and single cell oils are those oils naturally
produced by microorganisms during their lifespan.
[0072] As used herein the term working fluid is interpreted to
include a solvent, a solvent mixture, a composition and a fraction,
e.g. a fraction from a distillation process, that has a suitable
volatility, comprising at least one of esters composed of C10-C22
fatty acids and C1-C4 alcohols, amides composed of C10-C22 fatty
acids and C1-C4 amines, C10-C22 free fatty acids, mineral oil,
hydrocarbons and bio-diesel.
[0073] As used herein the term essentially equally or less volatile
is interpreted to include that the volatile working fluids having a
suitable volatility in relation to the volatility of the
cholesterol present in the marine oil in free form that is to be
stripped off from the marine mixture. Further, commonly this is the
case when the volatility of the working fluid is the same or lower
than the volatility of the cholesterol present in free form.
However, the term essentially equally or less volatile is also
intended to include the case when the volatile working fluid is
somewhat more volatile than the cholesterol in free form.
[0074] Further, as used herein the term stripping is interpreted to
include a general method for removing, separating, forcing or
flashing off gaseous compounds from a liquid stream. In addition,
the term "stripping processing step" preferable herein is related
to a method/process for decreasing the amount of cholesterol in a
marine oil or fat by one or more distilling or distillation
processes, e.g. short path distillations, thin-film distillations
(thin-film stripping or thin-film (steam) stripping), falling-film
distillations and molecular distillations, and evaporation
processes.
[0075] As used herein the term "together with", means that the
volatile working fluid will be stripped off together with, combined
with, or adhering the cholesterol, namely that the cholesterol will
accompany the working fluid.
[0076] As used herein the term health supplement is interpreted to
include food and food supplement to animals and/or humans,
fortification of food, dietary supplement, functional (and medical)
food and nutrient supplement.
[0077] As used herein the term "treating" means both treatment
having a curing or alleviating purpose and treatment having a
preventive purpose. The treatment can be made either acutely or
chronically. In addition, as used herein the term pharmaceutical
means pharmaceutical preparations and compositions, functional food
(foodstuff having an increased value) and medical food. A
pharmaceutical preparation according to the present invention may
also comprise other substances such as an inert vehicle or a
pharmaceutically acceptable adjuvance, carriers, preservatives
etc., which all are well-known to those skilled in the art.
[0078] As used herein the term "oils with a low quality" preferably
means that the oil contains high amounts of free fatty acids, that
makes them less useful for nutritional purposes and that
traditional alkaline refining in such oils is complicated and
costly. Additionally, as used herein, the term mineral oil is
interpreted to include mineral oil products such as e.g. fractions
from distillation processes and white spirit. As used herein
hydrocarbons is interpreted to include organic compounds, that are
relatively large molecules composed mainly of carbon and hydrogen.
They can also include nuclei of nitrogen, phosphorus, sulphur, and
chlorine, among others.
[0079] Further, the method according to the invention is also
applicable to a variety of sterols including cholesterol. Most of
these sterols can, when present on free form, be separated from a
marine oil by the described technique as long as the volatile
working fluid is essentially equally or less volatile than the
sterol in free form that is to be separated from the marine oil
mixture.
* * * * *