Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITION CONTAINING STATINS AND CALCIUM FOR
IMPROVED CARDIOVASCULAR HEALTH
Field of the Invention
The present invention relates generally to a dietary supplement, and more
particularly, to an oral supplement.
Background of the Invention
Cardiovascular disease (CVD) is generally recognized to be the primary
killer of men and Women in developed countries globally. The cost of these
premature deaths is great both to the individuals and their families and to
the health
care system of the country as a whole. The risk factors for cardiovascular
disease are
well-recognized and include: higher than average serum cholesterol, elevated
levels
of LDL; a low level of HDL in proportion to the LDL level; higher than average
serum triglycerides; higher levels of lipid oxidation products creating
plaques and
streaks which cause blockages of coronary arteries. Another CVD risk factor,
high
blood pressure is also a risk factor for strokes.
Research has shown that reduction in these rislc factors also reduces the risk
of cardiovascular disease and its many costs. [See A. Bendich, R.J.
Deckelbaum,
eds. Preventive Nutrition' The Comprehensive Guide for Health Professionals.
Totowa, NJ: Humana Press (2000); for example, K.C. Hayes. "Dietary Fat and
Coronary Heart Disease. "]
"Statins" are cholesterol-lowing drugs, which worlc by blocking an enzyme
the liver needs for cholesterol production. There are at least a half dozen
statins
available on the market, from a number of different manufacturers. These
statins
vary somewhat in their potency and ability to lower LDL cholesterol.
Dietary supplements are well known and recent research has uncovered a
number of therapeutic uses therefor. For example, vitamin E is the major lipid-
soluble antioxidant in the human body [L. Mosca, et al., "Antioxidant nutrient
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supplementation reduces the susceptibility of low density lipoprotein to
oxidation in
patients with coronary artery disease," J Am Coll Cardiol, 30:392-9 (1997)].
Vitamin C is another well-lcnown anti-oxidant. See A. Bendich, L. Langseth,
"The
health effects of vitamin C supplementation: A Review" J. Am. Coll. Nutr.
14:124-
36 (1995), [published errata appear in J Am Coll Nutr Jun:l4(3):218 (1995) and
Aug:l4(4):398 (1995)]. A variety of benefits have been described in connection
with omega-3 fatty acids [W.E. Connor and S.L. Conner, "N-3 Fatty Acids from
Fish and Plants: Primary and Secondary Prevention of Cardiovascular Disease",
in:
A. Bendich and R.J. Declcelbaum, eds. Preventive Nutrition]. Similarly,
benefits of
dietary supplementation with folic acid, vitamin B6 and vitamin B12 have been
described [S.A. Beresford and C.J. Boushey, "Homocyst(e)ine, Folic Acid and
Cardiovascular Disease Risk", In: in: A. Bendich and R.J. Deckelbaum, eds.
Preventive Nutrition]. Calcium status has also been found to be inversely
associated
with blood pressure. High blood pressure is another important risk factor for
cardiovascular disease [D. A. McCarron and M.E. Reusser, "Finding consensus in
the dietary calcium-blood pressure debate," J. Am. Coll Nutr., 18:3985-4055
(1999)].
There have been dietary compositions described in the past which contain
specific vitamins or other supplements, either alone or in a variety of
combinations.
Many dietary supplements have been described in the art, but their efficacy in
preventing cardiovascular disease remains inadequate. As a result, in the
field of
CVD prevention, there is no single prior art composition which reduces the
variety
of risk factors associated with this pervasive disease and which has wide
spread
applicability to the population in developed countries.
Summary of the Invention
In one aspect, the present invention provides a novel composition, which
may be incorporated into an orally administered dietary supplement for the
reduction
of risk factors associated with CVD. The composition of the invention
represents a
unique combination of one or more statins with active dietary factors
(essential
nutrients and non-essential food components) that have never before been
developed
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into a single supplement. This combination is surprisingly effective in the
treatment
of a variety of risk factors which have been linked to heaa.-t attaclcs,
particularly
reduction of overall serum cholesterol levels, reductions in high blood
pressure,
increase in the HDL:LDL ratio, reduction of triglycerides and homocysteine
levels,
and prevention of lipid oxidation and the formation of plaques and strealcs.
In one particular embodiment, the composition of this invention comprises
the following components: statins; vitamin E; vitamin C; docasahexanoic acid
"DHA"; folic acid; vitamin B6 and vitamin B12, and calcium. In combination,
each
of these components, which independently reduce one or more of the risk
factors for
CVD, work synergistically to reduce the risk of CVD more effectively than any
of
these components taken alone. Additionally, all of the components have wide
safety
margins, therefore it is expected that the combination of all of these active
components will require a lower concentration of each component alone, and
therefore, enhance the safety of the combination of these dietary factors.
In another aspect, the invention provides a pharmaceutical and/ or dietary
composition containing the formulation described above in admixture with
pharmaceutically acceptable base, and optionally containing other known agents
including, but not limited to stabilizer agents, preservatives and
emulsifiers. The
compositions, according to this invention may be presented in different
embodiments, including but not limited to tablets, powders, chews, bars, and
shakes
or similar formulations.
In a further aspect of this invention, a method is provided for preparing the
novel dietary compositions described herein and incorporating the same into
orally
administrated pharmaceutical compositions.
In yet a further aspect, this invention provides a process for treating
individuals to reduce the risk factors for CVD comprising orally administering
a
pharmaceutical composition as described above.
Other aspects and advantages of the present invention will become apparent
from the following detailed description thereof.
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Detailed Description of the Invention
The present invention provides novel compositions comprised of
combinations of selected mixtures of one or more statins with active dietary
factors,
including certain vitamins and other components, which are surprisingly
effective in
their ability to reduce the risk factors of CVD and promote improved
cardiovascular
health. The oral administration of these compositions acts to reduce serum
cholesterol levels and blood pressure, increase HDL levels in proportion to
LDL
levels, to protect lipids from oxidation thereby preventing the formation of
plaques
and streaks which block coronary arteries, and to lower both triglyceride
levels and
homocysteine levels. In addition, it is believed that oral administration of
the
compositions of this invention acts to reduce the risk of stroke, as well as
heart
attack, in human adults.
The orally-administered compositions of this invention include those dietary
admixtures in wluch the formulations are swallowed in any acceptable form.
Conventional forms fox this purpose include but are not limited to liquids,
tablets,
effervescent tablets, pills, powders, chews, bars, wafers or premixed shakes.
See
Remingtton's Practice of Pharmacy, 1 l~' Edition, (1956).
The novel compositions of the present invention are comprised of the
following vitamins and dietary factors, which in combination provide a
surprising
result in reducing the risk factors of CVD. The combination of dietary factors
and
vitamins work synergistically to improve cardiovascular health to a great
degree than
expected. The essential components of the compositions are a statin or a
combination of statins, docosahexaenoic acid "DHA", vitamin E, vitamin C,
folic
acid, vitamin B6, vitamin B12, and calcium.
Statins are a class of cholesterol-lowering drugs. In one desirable
embodiment, the statin selected for the composition of the invention is
simvastatin
[available commercially from Merck as ZocorTM]. However, other statins
including,
without limitation, lovastatin [available commercially as MevacorTM from
Merck],
fluvastatin [available commerically from Novartis as LescoITM], pravastatin
[available commercially from Bristol-Meyers Squibb as PravachoITM],
atorvastatin
[available commercially from Parke-Davis/Pfizer as LipitorTM], and
cerivastatin
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[available commercially from Bayer as BaycolTM], may be used. Advantageously,
the statins are included in the composition to assist in the reduction of
serum
cholesterol levels. Used alone, simvastatin has been shown to reduce LDL
cholesterol levels by about 38% and total cholesterol by about 28% in
individuals
with moderately elevated or high serum cholesterol and triglyceride levels. In
suitable embodiment, the composition of the invention contains about 1 mg to
about
30 mg simvastatin, and preferably, 10 mg to 20 mg. However, other statins may
be
readily utilized; mixtures of statins may also be utilized. Suitably, the
concentration
of the selected statin(s) may be within the range of about 1 ~,g to about 120
mg, and
more preferably, about 10 ~.g to about 60 mg, and most preferably, about 1000
~g to
about 30 mg of the selected statin, per dose. A review article on New
Guidelines
for Managing Hypercholesterolemia may be found in the McI~enney, J., J. Amer.
Pharm. Assn, July/August (2001), Vol. 41, No. 4, pages 596-607.
The composition of the invention further includes vitamin E, which may be
in any suitable form. Natural vitamin E can be isolated from vegetable oils,
including corn, cottonseed, rapeseed, peanut, sunflower and soybean oil, or
obtained
from a variety of commercial sources. Natural vitamin E may be in the form d-
alpha-tocopherol (RRR-alpha-tocopherol), or the acetate [d-alpha-tocopheryl
acetate
(RRR-alpha-tocopheryl acetate)] or succinate salt thereof [d-alpha-tocopheryl
acid
succinate (RRR-alpha-tocopheryl acid succinate)], or may be in the form of
natural
mixed tocopherols [d-alpha-, d-beta-, d-gamma and d-delta-tocopherol].
Alternatively, synthetic vitamin E may be produced from petrochemicals in the
form
of dl-alpha-tocopherol ( all-rac-alpha-tocopherol), or the acetate [dl-alpha-
tocopheryl acetate, (all-rac-alpha-tocopheryl acetate)] or succinate salt
thereof [dl-
alpha-tocopheiyl acid succinate (all-rac-alpha-tocopheryl acid succinate), or
mixtures thereof. Where reference is made herein to vitamin E, any of the
natural or
synthetic forms of the vitamin may be used, or combinations thereof. In the
formulation of the invention, Vitamin E prevents the blockage of coronary
arteries
and other vessels within the body that result when oxidized lipids are
permitted to
form [S.B. Kritchevsky et al, "Dietary antioxidants and carotid artery wall
thickness", The ARIC Study. Atherosclerosis Risk in Communities Study,
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Circulation, 92:2142-50 (1995)]. Thus, vitamin E is a useful as an antioxidant
[Jeng et al, Am. J. Clin. Nutr., 64:960-5 (1996); F.M. Steinberg and A. Chait,
Am. J.
Clin. Nutr., 68:319-27 (1998), [publ. erratum appears in Am J Clin Nutr.,
Jun:69(6):1293 (1999)]. Thus, vitamin E clearly is an important component in
the
formulation of the composition designed for the prevention of CVD. In one
embodiment, the composition of the invention contains about 50 IU to about 800
ILJ
of vitamin E, and most preferably, about 100 IU.
Vitamin C is another component of the composition of the invention.
Vitamin C is an anti-oxidant that works synergistically with Vitamin E to
protect
cellular components from oxidative damage leading to cardiovascular disease.
Vitamin C optimizes the effects of Vitamin E to reduce the oxidation of
lipids.
Further, Vitamin C taken alone has been linked with a decreased risk of CVD as
well as CVD mortality, possibly because of the reduction in systolic and
diastolic
blood pressure seen in those individuals taking large does of the vitamin
[S.J. Duffy
et al, "Treatment of hypertension with ascorbic acid", Lancet, 354:2048-9
(1999); P.
Weber et al, "Vitamin C and human health - a review of recent data relevant to
human requirements", Int. J. Vitam. Nutr. Res., 66:19-30 (1996)). In one
suitable
embodiment, vitamin C is in the form of ascorbate or ascorbic acid, and is
present in
an amount of about 60 mg to about 1000 mg, or about 100 to about 500 mg.
The present invention further includes an omega-3 fatty acid which is known
to cause reduction in triglycerides and increase in HDL levels. Most
preferably, this
omega-3 fatty acid is in the form of docasahexaenoic acid "DHA", which may be
extracted from algae using known methods or purchased commercially. DHA is the
longest omega-3 fatty acid and is known to be important in the functioning of
every
cell membrane in the body. It is found in especially high concentration in the
human
brain and retina. DHA has also been seen to reduce the risk of ventricular
arrhythmia that can result in sudden death. In one desirable embodiment, the
composition of the invention contains about 125 mg to about 500 mg, and
preferably
about 230 to about 250 mg DHA. Alternatively, another omega-3 oil may be
included in the composition of the invention.
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Folic acid (or a pharmaceutically acceptable salt thereof), vitamin B6 and
vitamin B 12 are all involved in normal amino acid metabolism. Specifically,
these
vitamins have been known to significantly reduce elevated homocysteine levels
that
have been linlced to an increased risk of CVD, as well as stroke, peripheral
vascular
disease and dementia. Most suitably, the composition of the invention contains
about 400 ~g to about 1000 ~,g folic acid (or folate); about 2 mg to about 50
mg
vitamin B6, preferably about 10 to 25 mg vitamin B6; and about 6 ~.g to about
1 mg
vitamin B 12.
Calcium has been associated with reducing systolic and diastolic blood
pressure. The composition of this invention contains about 200 to about 100 mg
of
elemental calcium, which may be in the form of pharmaceutically acceptable
salt
thereof. In one desirable embodiment, calcium is present in the composition of
the
form of calcium carbonate.
Optionally, the active components discussed above may be admixed with
other active ingredients. Preferably, however, these components are the only
active
ingredients in the composition of the invention.
One particularly desirable embodiment of the composition of the invention is
provided in Example 1 below. However, the invention is not limited by this
formulation, or by the ranges provided herein, which are intended for guidance
only.
One of skill in the art can readily select other ranges, depending upon the
delivery
form (e.g., effervescent tablet vs. tablet), the age, and condition of the
patient, among
other factors.
A composition of the formulation of the invention may be used orally to treat
and/or prevent risk factors of CVD and stroke, including reduction of high
blood
pressure and overall serum cholesterol.
While not wishing to be bound by theory, the inventors believe that the
compositions work by acting at different sites and aspects of cardiovascular
disease.
High cholesterol, high LDL, elevated triglycerides, high blood pressure, low
HDL,
high homocysteine levels and oxidized lipids are all attacked by one or more
of the
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dietary factors present in the oral formulation and act synergistically to
reduce the
risk factors of CVD. By affecting CVD risk factors at several sites and by
different
mechanisms of action, there is an enhancement of the effects of the supplement
that
is greater than the additive effect of the dietary factors. The dietary
supplement
contains active ingredients that are safe, efficacious and cost-effective in
lowering
CVD risk factors.
The compositions of the present invention axe preferably presented for
administration to humans and animals in unit dosage forms, such as tablets,
capsules, pills, powders, granules, and oral solutions or suspensions and the
like,
containing suitable quantities of an active ingredient. For oral
administration either
solid or fluid unit dosage forms can be prepared.
Powders are prepared quite simply by comminuting the active ingredients)
to a suitably fine size and mixing with a similarly comminuted diluent. The
diluent
can be an edible carbohydrate material such as lactose or starch.
Advantageously, a
sweetening agent or sugar is present as well as a flavoring oil. Additional
pharmaceutically acceptable binders, lubricants, colouring agents, and
sweeteners,
well known in the art may be added as necessary.
Capsules are produced by preparing a powder mixture as hereinbefore
described and filling into formed gelatin sheaths. Advantageously, as an
adjuvant to
the filling operation, a lubricant such as a talc, magnesium stearate, and the
like is
added to the powder mixture before the filling operation.
Soft gelatin capsules are prepared by machine encapsulation of a slurry of
active ingredients with an acceptable vegetable oil, light liquid petrolatum
or other
inert oil or triglyceride.
Tablets, chews and bars axe made by preparing a powder mixture, granulating
or slugging, adding a lubricant and pressing into tablets, chews, or bars. The
powder
mixture is prepared by mixing an active ingredient, suitably comminuted, with
a
diluent or base such as staxch, lactose, kaolin, dicalcium phosphate and the
like. The
powder mixture can be granulated by wetting with a binder such as corn syrup,
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gelatin solution, methylcellulose solution or acacia mucilage and forcing
through a
screen. As an alternative to granulating, the powder mixture can be slugged,
e.g.,
run through the tablet, bar or chew, machine and the resulting imperfectly
formed
tablets brolcen into pieces (slugs). The slugs can be lubricated to prevent
sticking to
the shape-forming dies by means of the addition of stearic acid, a stearic
salt, talc or
mineral oil. The lubricated mixture is then compressed into tablets, chews or
bars,
as desired. Optionally, a tablet can be provided with a protective coating
consisting
of a sealing coat or enteric coat of shellac, a coating of sugar and
methylcellulose
and polish coating of carnauba wax. Advantageously, chews and bars may be
mixing with a variety of flavorings, sweetening agents, or the like.
Fluid unit dosage forms for oral administration such as syrups, elixirs and
suspensions can be prepared wherein each teaspoonful of composition contains a
predetermined amount of active ingredient for administration. The water-
soluble
forms can be dissolved in an aqueous vehicle together with sugar, flavoring
agents
and preservatives to form a syrup. An elixir is prepared by using a
hydroalcoholic
vehicle with suitable sweeteners together with a flavoring agent. Suspensions
can be
prepared on the insoluble forms with a suitable vehicle with the aid of a
suspending
agent such as acacia, tragacanth, methylcellulose and the like.
In another embodiment, the invention provides a method of using the
composition to improve the health of the heart and to reduce risk factors
associated
with cardiovascular disease by delivering to an individual the composition of
the
invention. Thus, delivery of the composition of the invention, e.g., by oral
administration, is useful for preventing oxidation of low density lipoprotein
(LDL),
increasing high density lipoprotein (HDL), and for reducing total cholesterol.
Delivery of the composition of the invention is also useful for reducing
triglycerides
and reducing homocysteine.
Desirably, the compositions of the invention are formulated such that an
effective amount is delivered by two tablets (or other suitable formulation) a
day.
Suitably, these doses may be taken with meals, mixed into feed, or taken on an
empty stomach. Generally improvement is observed after two to eight weeks of
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daily use. Optionally, the compositions of the invention may be delivered
daily in a
suitable form (e.g., a chew or bar) for a limited period of time, e.g., six to
eight
weeks. Other suitable dosage regimens may be readily developed by one of skill
in
the art. Such dosage regimens are not a limitation of the invention: Several
factors
have been observed to interfere with the positive effects of dietary
supplementation
with the compositions of the invention, including smoking, eating a high fat
diet,
omitting dietary fibers or roughage from a daily diet and maintaining an
essentially
sedentary lifestyle.
The compositions of the present invention, in addition to their use in
treating
CVD in humans, may also be useful in treating non-human animals, particularly
mammals. For example, these dietary supplements may be useful for companion
animals such as dogs and cats, for cattle, horses, and pigs, among other
animals.
The following example which demonstrates the compositions of the
invention for illustrative purposes only and does not limit the scope of the
invention.
The compositions of this invention are anticipated to produce surprisingly
good
results in reducing a variety of risk factors associated with impaired
cardiovascular
conditions. As demonstrated in the following example, the compositions of the
invention have advantages over the prior art in safely lowering CVD risk
factors in a
cost effective mangier.
Example
In one exemplary embodiment, the components listed below were combined
into a tablet, using simple mixing procedures.
Table 1
Component Amount
Simvastatin 20 mg
DHA 125 mg
Vitamin E 50 ILT
Vitamin C 60 mg
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Folic Acid 400 ~g
Vitamin B6 20 mg
Vitamin B12 6 ~,g
Calcium 100 ~,g
The above ingredients all or in part can be:
1. Mixed dried (direct compression process-DCP) with well recognized
tableting aids) / filler(s), binding agent(s), disintegrant (s) and
lubricants) as
necessary or desired to form a blend that can be directly compressed into
tablets; or
2. Wet granulated (Wet Granulation Process-WGP) with well recognized
tableting aid(s)/filler(s), granulating agent(s), disintegrant (s) and
lubricants) as
necessary or desired to form a blend that it can be directly compressed into
tablets.
Numerous modifications of this invention are encompassed by the above
description and the scope of the following claims. For example, other suitable
optional ingredients may be employed in the composition of this invention
which are
obvious to one of skill in the art considering the present disclosure.
Similarly other
systemic disorders other than those described may be treated with the
compositions
of this invention. It should be understood therefore that various changes may
be
made in the products and processes herein described without significantly
affecting
the resultant formulations or their use in medical treatment. Various
modifications
in conditions of preparation such as time and temperature, or changes in
administrative procedure or dosages differing from those given herein as
illustrative
of the preferred embodiments of the invention, may be made without departure
from
the scope of the invention envisioned by the inventor.
All publications, including but not limited to patents and patent
applications,
cited in this specification are herein incorporated by reference as if each
individual
publication were specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
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