Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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~309352 174/20
MET~OD AND CO.'~POSITION
FOR REDUCING SERUM CHOLESTEROL
_ P E C I F I C A T I O N_ _ _ _ _ _ _ _ _ _
BACKGROUND OF ~HE INVENTION
Field of the Invention
The present invention is directed to orally
administrable pharmaceutical compositions and methods for
reducing serum cholesterol. More particularly, the present
invention is directed to a method for reducing serum cholesterol
levels in humans by the oral administration of a pharmaceutical
composition containing an effective quantity of guar gum, or
other gel-forming fiber, in combination with calcium carbonate or
other mineral carbonates. The addition of mineral carbonates to
the gel-forming fiber produces enhanced dispersion of the fiber
and improves the speed of hydration in the acid environment of
the stomach. The formulation according to the present invention
results in significant total serum cholesterol (TC) and low-
density lipoprotein (LDL) reductions when administered to humans
19 according to the recommended dosage regimen.
Objects of the Present Invention
It is a principal object of the present invention to
provide novel pharmaceutical compositions for oral administra-
tion, which compositions are effective in reducing serum
cholesterol levels. Additionally, it is a further object o~ the
present invention to provide a pharmaceutical dosage formulation
27 ..hiCn contains ingredients which faci~itate more complete
~309352
dis~r~ on o~ active ingr~ie~ts in the stomach, ~acilitatirg
.ore r~?id hydration of gel-orming fibers which are then r,ore
bio-availa~le for reduction of serum cholesterol levels. It is a
further object o~ the present invention to provide a highly
dispersible, non-prescription, gel-forming fiber dietary additive
which lowers serum total cholesterol (TC) levels and low density
lipoprotein (LDL) levels. Lastly, it is an additional object of
the present invention to provide a palatable dosage form con-
taining a gel-orming fiber and mineral carbonate for the
reduction of serum cholesterol levels in humans.
SUMMARY OF THE INVENTION
Generally stated, the present invention accomplishes the
above-described objectives by providing a method and pharma-
ceutical composition for the reduc.ion of serum cholesterol
levels comprising ingestion of a composition containing an
effective quantity of gel-forming fiber and a mineral carbonate
to assist in the dispersion and hydration of the gel-forming
fiber. The composition can be administered to hyper-
cholesterolemic patients or to individuals desiring to reduce
their serum total cholesterol (TC) or low density lipoproteins
(LDL) irrespective of a diagnosis of hypercholesterolemia. Doses
of 15 grams/day of the subject composition were administered to
patients with elevated serum cholesterol lev~ls. Significant
reductions in total serum cholesterol (TC) and low density
27 lipoproteins (LDL) were reported.
1309352
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_ _ _ _ _ _ _ _
In a broad aspect, the method of the present invention
is based upon the surprising discovery that when a gel-for.ir.g
fiber, such as for e~ample, guar gum, is combined with a mineral
carbonate, such as for exa~ple, calcium carbonate, dispersion o~
the fiber in the gastrointestinal fluids is enhanced and the
fiber is hydrated more rapidly and completely. As a result, the
dietary fiber is more bioavailable and capable of rendering its
cholesterol-reducing effects.
Despite the encouraging recent decline in coronary heart
disease (CHD), it remains the number one cause of death in the
United States (Kannel, W.B., Thom, T.J., "Declining Cardio-
vascular Mortality", Circulation 70:331-336 (1984)). Coronary
heart disease is responsible for over 550,000 deaths in the
United States per year. It is responsible for more deaths than
all forms of cancer combined. It has been reported that there
are more than 5.4 million Americans with symptomatic coronary
heart disease and a large number of bthers with undiagnosed
coronary disease. Over 680,000 hospitalizations resulting from
myocardial infarction occur each year in the U.S. The direct
health costs associated with these figures are estimated at $8
billion with total economic costs estimated at more than $60
billion (National Institutes of Health Consensus Development
Conference On r owering Blood Cholesterol To Prevent Disease,
J~A: 253, No. 14, 2080 (19853) (hereinafter, NIH Consensus
Conference).
The NIH Consensus Conference panel has concluded that a
major cause of coronary artery disease is elevated serum
cholesterol. In evaluating whether there is a causal relation-
1309352
~ip bi't'~i~f~ 15~d c:~ol~sterol lrfe]s and c2ron-ry hr~t di~r2_r,
t~e p~nel agreed that while it is clear that an elevated blood
cholesterol level is not the only cause of coronary heart disease
"[t]he evidence supporting a causal relationship between
cholesterol levels and coronary heart disease comes from a wealth
of congruent results o~ genetic, experimental pathologic,
epidemiologic and intervention studies. These data establish
beyond any reasonable doubt the close relationship between
elevated blood cholesterol levels and coronary heart disease."
(~IH Consensus Conference, at page 2081.)
While multiple modifiable factors associated with the
development of clinical CHD have been identified, including
cigarette smoking, high blood pressure, obesity, sedentary life-
style, and elevated blood cholesterol, severe CHD can result from
high blood cholesterol levels in the absence of any other con-
tributory risk factors. (See, Dauber, T.R., The Framingham
Study, Cambridge, MA, Harvard University (1980) and Thelle, D.S.
et al., "The Tromso Heart Study: Methods and Main Results of the
Cross-Sectional Study." Acta. Med. Scand., 200:107-118 (1976)).
In fact, serum cholesterol concentrations may be one of
the most important factors and may play a central role in the
atherosclerotic process (Ross, R., Glomset, J., "The Pathogenesis
of Atherosclerosis", N. Engl. J. Med., 295:369-377, 420-425
.
~1976), and Henriksen, T. Mahoney, E.M. Steinberg, D.,
"Interactions of Plasma Lipoproteins With Endothelial Cells",
Ann. N.Y. Acad. Sci., 401:102-116 (1982)).
-
The lipids in plasma of major clinical importance arecholesterol and triglycerides. Cholesterol is always present as
a major ingredient in atherosclerotic plaque, along with fatty
acids esters of cholesterol, phosphatides, neutral fats and
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di~d~cch~le~erol. Cholest~rol i. not ~iscible with wat~r.
To carr~ it in the blood, it is combined or repac~:2ged with
protein. T~e cc~bination of cholesterol and protein is called a
lipoprotein. Very low-density lipopcoteins (VLDL or pre-beta-
lipoproteins), carry endogenously synthesized triglycerides,
which are removed by muscle, heart, adipose tissue, and other
sites. Major remnants of VLDL metabolism are low-density
lipoproteins (LDL or beta-lipoproteins). LDLs are catabolized at
cell membranes, but the major organ sites remain uncertain. It
is the LDLs which contain the greatest percentage of cholesterol.
These particles, when present in excess in the blood, are
deposited in the tissues and form a major part of the build-up in
the arterial wall to form atherosclerotic plaque which narrows
the channels of the coronary arteries which furnish the major
blood supply to the heart muscle. High density lipoproteins (HDL
or alpha-lipoproteins) contain phospholipids and cholesterol
complexed with apolipoproteins, the bulk of which differ from
those found in VLDLs and LDLs. It is the HDLs which contain the
greatest amount ~f protein and the smallest amount of cholesterol
and are believed to take cholesterol away from cells and trans-
port it back to the liver for processing or removal. In the
postabsorptive state, a total plasma cholesterol concentration of
200 mg/dl is distributed very roughly as follows: VLDL, 10; LDL,
120; and, HDL, 50. Most of the plasma triglycerides above about
sn mg/dl will be found in VLDLs.
There is no absolute definition of hyperlipidemia. For
biologic variables, upper limits such as the upper five or ten
percent of the distribution within the population are often used,
but for plasma cholesterol, these statistical limits are too high
to be used clinically. Correlations between the cholesterol
13093~;2
conc~t.~tio-5 ir ;-,l 9 r~en in ~;orth ,~meric~ 2r,d inci~nc~ o
pre ature isc~ ic h~art disease indic~t~ that an increasin~ ris'~
can be detected ~hen the cholesterol is highe~ than 220 mg/dl, a
val~e close to the mean for men from 40 to 49 years of age in
this population. E~trapolation o~ similar data from other
populations suggests that a cholesterol level at birth averages
60 mg/dl. Within one month the average has risen to about 120
mg/dl and by the first year to 175 mg/dl. A second rise begins
in the third decade and continues to about age fifty in men and
somewhat later in women. In other populations this cholesterol
rise in adulthood is far less prominent. It is therefore not to
be considered necessarily physiologic. The age-related increases
in cholesterol are associated mainly with the rise in LDL concen-
trations, the increases in triglycerides with a rise in VLDL.
HDL concentrations in women average about 20% higher than in
men. Estrogen tends to raise and androgens tend to lower HDL
levels. The average serum cholesterol level for middle-aged
adults in the U.S. is 215 mg/dl. The U.S. Health and Nutrition
Examination Survey (1971-1974) indicates that the prevalence rate
of a serum cholesterol level in excess of 260 mg/dl in the
American male work force between the ages of 45 and 55 years is
approximately 30~. (U.S. Department of Health and Human
Services: Cardiovascular Primer for the Workplace, NIH
Publication No. 81-2210, 75 (January, 1981)).
Evidence tha-t actively decreasing LDL content in men
with hypercholesterolemia results in a lower incidence of
cardiovascular events has been greatly strengthened by the
results of the Coronary Primary Prevention Trial-Lipid Research
Clinic (LRC). ~his seven-year, randomized double blind trial
conducted with 3,806 men convincingly demonstrated a significant
1309352
re~ction o~ myoc2rdi21 infarction (~I) and sudden cardiac de2th
in the group that achieved LDL reduction by means of a mGderate
diet in com~ination with cholestyramine, a bile acid-sequestering
resin. This investigation further demonstrated that a 2~%
reduction in total plasma cholesterol (TC~ concentration results
in a 49% reduction in the frequency of myocardial infarction and
sudden cardiac death. (Lipid Research Clincs Program: The Lipid
Research Clinics Coronary Primary Prevention Trial Results: I.
Reduction in Incidence of Coronary Heart Disease, and II. The
Relationship of Reduction in Incidence of Coronary Heart Disease
to Cholesterol Lowering, JAMA, 251: 351-374 (1984)).
Accordingly, every 1% reduction in total cholesterol (TC) levels
results in an approximately 2% reduction in risk of myocardial
infarction.
The classic approach to cholesterol management has been
to employ a two-stage treatment. In the first stage, non-
pharmaceutical methods, such as low-fat diets, exercise, weight
loss and alteration of environmental factors are employed. The
second stage involves administration of medications which alter
lipid metabolism. The hygienic methods employed in stage one are
often fraught with significant problems. A common difficulty
with this hygienic aspect of the classic approach is the effort
required on the part of the subject to achieve a substantial
reduction in plasma LDL's. Frequently, patient-initiation is
resisted and long-term compliance may suffer as patients find it
difficult to exercise, modify life-long dietary habits and reduce
body weight. Often as a result of inadequate patient compliance
with hygienic methods above, pharmacologic medications are
employed in part as a result of the relative ease of use and
ra~id results. ~owever, the pharmacologic methods suffer from
1309352
'; i ~, . l ~ i C . . . ~ ;"~ 5 ~ . D~ }~ r~ t ~. 2'1
U~CC,.~ ,, 2.,~ can ir, sc e patients b~ c~ite se;ere. Eu~ r -e,
fre~uer~tl~ 2n individual is placed on a multiple drug resi,en
which ca~ result in significant drug interactions.
As a result of the significant drawbacks associated with
pharm2cologic treatment of hypercholsterole~ia, an approach has
been suggested which would bridge the gap between non-
pharmaceutical methods and administration of pharmacologic agents
to reduce cholesterol. One such suggestion has been to admin-
ister cholesterol-reducing dietary additives such as gel-forming
plant fibers, to individuals desiring to reduce their cholesterol
levels (Superko, R.H., ~Decreasing Blood Cholesterol Levels With
a Dietary Additive: An Additional Approach to Diet and Drugs,"
Cardiovascular Reviews ~ Reports, 6: No. 11,1253 (November
1985)). One such plant fiber, guar gum is obtained from the
leguminous Guar plant (Cyamopsis Tetragonoloba) which grows to a
height of three to six feet. The Guar plant bears bean-like
pods, each of which contains six to nine small rounded seeds.
The guar seed is typically composed of 40-46~ germ, 38-45
endosperm and 14-16% husk. Guar gum is produced from the
endosperm of the guar seed. Chemically, guar gum is a galacto-
mannon storage polysaccharide composed of mannose and galactose
groups. It is commercially available from, for example, Henkel
Corporation as Supercol~ Guar Gum in a variety of powder
formulations with different granulations and terminal viscosi-
ties. Guar gum is used extensively in the food industry and is
recognized as safe by the Food and Drug Administration. Further-
more, guar gum has been shown to reduce serum cholesterol levels
in normal and hypercholesterolemic subjects. However, problems
such as poor dispersibility have been associated with oral dosage
1309352
for~ ch 25 t~let5 or c'?s~ 7~) GC p~lr~ g~r 5~.~ or
with c~h~r ~ bers such as psylliu.~ seed, pectin or oat.
Further..o-e, p.oble.~,s 2ssociated with its highly viscous nature
have been r~c-gnized and have hampered the long-term clinical
application of guar gum as a palatable cholesterol-reducing agent
(Khan, A.R. et al., ~Effect of Guar Gum on 2100d Lipids," The
~erican Journal of Clinical Nutrition, 34:2446-2449 (November,
1981)). Laboratory experiments on capsule formulations of pure
guar gum in gastric simulators which approximate the conditions
present in the stomach, indicate that as the capsule dissolves,
and hydration of the gum begins, only the powder around the
perimeter of the dosage hydrates or gels leaving an unhydrated
inner core of gum. This incomplete dispersion leaves perhaps as
much as 30~ to 40% of the guar fiber unhydrated.
The mechanism of action of guar gum as a plasma
cholesterol-reducing agent is unclear. However, the mode of
action appears to be associated wlth its viscosity. It has been
postulated that the viscous guar gum may coat the intestinal
mucosa and interfere with adsorption of lipids which may be
related to an increase in resistance of the unstirred water layer
and limit the intestinal bulk phase diffusion. (See, Modaky, S.,
"Effect of Dietary Pectin and Algin on Blood Cholesterol Level in
Growing Rats Fed on Cholesterol-Free Diet," Nutr. Metabol.,
15:290-294 (1973), Kay, R.M. et al., "Effect of Citrus Pectin on
Blood Lipids and Feca-l Steroid Excretion in Man," Am. J. Clin.
Nutr., 30:111-175 (1977).) One study found that the presence of
a polysaccharide gum in the fluid film surrounding the villi in
rat jejunum increases its viscosity and gives rise to a thicken-
ing of the rate-limiting unstirred layer in vitro (Johnson et
al., "Effect of Gel-Forming Gums on the Intestinal Unstirred
1309~352
L~r ~ 5~ n~s t in Vitro,~ G~t, 22.3~8-;~3 (~
O~h~r ~or~ Gn r2ts re~.~ealed an elevation of enzy~e acti~Jity in
the int~stire that ~ay be due to a slower rate o~ enzy~e deqrada-
tion. Hu~an evidence also suggests an in vitro inhibition of
pancreatic enzyme activity by dietary fibers. Trypsin, amylase,
lipase and phospholipidase activities were reduced in human
duodenal juice following exposure to various fibers including
guar (Isaksson, G. et al., "In Vitro Inhibition of Pancreatic
Enzyme Activities by Dietary Fiber," Diqestion, 24:54-59 (1982)).
Additional possibilities for the gel forming fiber's
mechanism of action may include bile acid sequestration, fat
adsorption sites, facilitation of gallbladder emptying and
gastrointestinal motility. There has also been some speculation
that hypercholesterolemic activity may be related to diminished
caloric intake following administration of these types of
fibers. Vpon hydration, the fibers gel and provide a full
feeling in the stomach which may contribute to a reduction in
dietary intake and weight loss. These effects may contribute to
reduced blood sugar and cholesterol Ievels. However, work on
rats has suggested that bile salt 105s associated with steator-
rhea may be the mechanism by which pectin lowers the serum
cholesterol. Certain studies indicate that both guar gum and
pectin administration was also associated with greatly increased
fat loss in the stool. (Jenkins, D.J. et al., "Effect of Pectin,
Guar Gum, and ~heat Fibre on Serum-Cholesterol", The Lancet,
1116-1117, (May 17, 1975)).
In Superko, supra, at page 1257, a compilation of
clinical studies on the effects of guar gum on blood lipids in
humans was collected. The respective studies indicate that a
series of different formulations of guar gum such as granules,
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1309352
crispbread and capsules, were administered in various
dosages over treatment durations ranging from one week to
four months. The results indicated that total serum
cholesterol reduction ranged from a nonstatistically
significant 3.4~ up to as high as 16.6~.
Table I illustrates the significantly greater choles-
terol-reducing properties of one of the dosage forms
according to the present invention. 15 grams of guar gum
and calcium carbonate in a capsule formulation in a 5:1
ratio was administered in three divided doses of 5 grams at
mealtime to patients with elevated serum cholesterol
levels.
TABLE I
Total Percent Low Density (LDL) Percent
Patient cholesterol (TC) Reduction (TC~ Li~o~rotein (LDL~ Reduction
A.
Baseline 289mg/dl 165mg/dl
After 2 wks 204mg/dl29% 86mg/dl 48%
After 4 wks 209mg/dl28% 98mg/dl 41%
8.
Baseline 283r.lg/dl 208mg/dl
After 2 wks 220mg/dl22~ 157mg/dl 25
After 4 wks 206mg/dl27% 130mg/dl 38%
Taking into consideration the results of the Lipid
Research Clinic (LRC) Program, supra, which demonstrated a
49% reduction in the frequency of myocardial infarction and
sudden cardiac death with every 25~ reduction in total
plasma cholesterol, the significant reductions in choles-
terol reported in Table I are encouraging.
It is understood that compositions according to the
present invention may contain optional preservatives,
sweeteners or flavorants which may provide a more palatable
dosage form and assist in long-term patient compliance.
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1309352
th^~ry, it i; ~ la~d ttl~t t~e ~or~lati-,n according to the
present inJen-ion is more rapidly dispersed and t~ereby more
avail~ble for its cholesterol-reducing effects. It is postulated
that the formulat-on according to the method of the present
invention eYhibits a physical/chemical interaction whereby the
mineral carbonate ions interact with the gel which is formed when
the guar gum hydrates. Normally, with pure guar gum fiber, bile
acid anions diffuse through the gel. With the formulation
according to the present invention, the mineral ions, calcium,
magnesium and potassium, precipitate the bile acids entrapping,
entangling and enmeshing them. The liver then produces more bile
acids. Since the liver uses cholesterol to make bile acids, the
cholesterol pool becomes depleted, thereby lowering cholesterol
levels. Furthermore, ~he action of the mineral carbonate causes
release oE carbon dioxide in the stomach which facilitates the
rapid dispersion of the guar formulation thereby causing better,
more complete and more rapid hydration of the guar fiber. Addi-
tionally, the speed of hydration of the guar fiber is enhanced as
a result of the more rapid dispersion. The prior art problems of
incomplete hydration with an unhydrated inner core are avoided by
the composition according to the present invention.
The present invention may be embodied in other specific
forms without departing from the spirit or essential attributes
thereof and, accordingly, reference should be made to the
appended claims, rather than to the foregoing specification, as
26 indicating the scope of the invention.
