Note: Descriptions are shown in the official language in which they were submitted.
CA 022~1972 1998- lo- 1~
WO 97/38694 PCTIUS97/06127
~ TITLE OF THE INVENTION
COMBINATION THERAPY FOR ~EDUClNG THE RISKS
ASSOCIATED WITH CARDIOVASCULAR DISEASE
5 BACKGROUND OF THE INVENTION
The instant invention involves a combination therapy
comprising the administration of a 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase inhibitor (or HMG-CoA RI) and
folic acid or a pharmaceutically acceptable salt or ester thereof for
10 preventing, halting or slowing the progression of atherosclerotic
cardiovascular diseases and related conditions and disease events.
There is increasing evidence that high blood levels of
homocysteine are associated with an increased risk of coronary heart
disease (CHD) and stroke. The mechanism of the association is
15 unknown, but it is well established that folic acid (a B complex vitamin)
lowers plasma homocysteine by increasing its catabolism.
lt has been clear for several decades that elevated blood
cholesterol is a major risk factor for coronary heart disease, and many
studies have shown that the risk of CHD events can be reduced by lipid-
20 lowering therapy. Prior to 1987, the lipid-lowering armamentarium
was limited essentially to a low saturated fat and cholesterol diet, the
bile acid sequestrants (cholestyramine and colestipol), nicotinic acid
(niacin), the fibrates and probucol. Unfortunately, all of these
treatments have limited efficacy or tolerability, or both. Substantial
25 reductions in LDL (low density lipoprotein) cholesterol accompanied by
increases in HDL (high density lipoprotein) cholesterol could be
achieved by the combination of a lipid-lowering diet and a bile acid
sequestrant, with or without the addition of nicotinic acid. However,
this therapy is not easy to administer or tolerate and was therefore often
30 unsuccessful except in specialist lipid clinics. The fibrates produce a
moderate reduction in LDL cholesterol accompanied by increased HDL
cholesterol and a substantial reduction in triglycerides, and because they
are well tolerated these drugs have been more widely used. Probucol
produces only a small reduction in LDL cholesterol and also reduces
CA 022~1972 1998- lo- l~
WO 97/38694 PCT/US97/06127
HDL cholesterol, which, because of the strong inverse relationship
between HDL cholesterol }evel and CHD risk, is generally considered
undesirable. With the introduction of lovastatin, the first inhibitor of
HMG-CoA reductase to become available for prescription in 1987, for
5 the first time physicians were able to obtain large reductions in plasma
cholesterol with very few adverse effects.
Recent studies have unequivocally demonstrated that
lovastatin, simvastatin and pravastatin, all members of the HMG-CoA
reductase inhibitor class, slow the progression of atherosclerotic lesions
10 in the coronary and carotid arteries. Simvastatin and pravastatin have
also been shown to reduce the risk of coronary heart disease events, and
in the case of simvastatin a highly significant reduction in the risk of
coronary death and total mortality has been shown by the Scandinavian
Simvastatin Survival Study. This study also provided some evidence for
15 a reduction in cerebrovascular events.
Despite the substantial reduction in the risk of coronary
morbidity and mortality achieved by simvastatin, the risk is still
substantial in the treated patients. For example, in the Scandinavian
Simvastatin Survival Study, the 42% reduction in the risk of coronary
20 death still left 5% of the treated patients to die of their disease over the
course of this 5 year study. Further reduction of risk is clearly needed.
The use of folic acid to reduce the risk of cardiovascular
disease by reducing homocysteine levels is attractive as this therapy is
believed to be almost risk-free (folic acid is a vitamin) and relatively
25 inexpensive. In addition, as the dose of folic acid required to reduce
homocysteine is small (typically 1-5 mg daily) and, like HMG-CoA
reductase inhibitors, may be given once daily, the active agents can be
readily combined in a single tablet, capsule or other dosage form having
the same or similar size as the inhibitor of HMG-CoA reductase alone.
30 This would provide patient convenience, an important consideration
CA 022~1972 1998-10-1~
WO 97/38694 PCTIUS97/06127
especially in patients who already have coronary heart disease, as such
patients generally have several different drugs to take.
SUMMARY OF THE INVENTION
The instant invention involves a novel combination therapy
comprised of a therapeutically effective amount of an HMG-CoA
reductase inhibitor in combination with folic acid or a pharmaceutically
acceptable salt or ester thereof.
One object of the instant invention is to a-lmini.ster the
10 above-described combination therapy to people who do not yet show
clinical signs of atherosclerosis, but who are at risk of developing
atherosclerosis and associated diseases. Clinical manifestations of
atherosclerosis include atherosclerotic cardiovascular disease such as
coronary heart disease (al,so known as ischemic heart disease),
1~ cerebrovascular disease, and peripheral vessel disease. Toward this end,
the instant invention provides methods for preventing or reducing the
risk of developing atherosclerotic cardiovascular disease, coronary heart
disease, cerebrovascular disease and peripheral vessel disease, and
preventing or reducing the risk of occurrence, or recurrence where the
20 potential exists, of a coronary heart disease event, a cerebrovascular
event, and/or intermittent claudication, by a~lmini.~tering the above-
described combination therapy to said at-risk persons.
A second object of the instant invention is to provide the
above-described combination therapy to people who have clinical signs
of atherosclerosis. Toward this end, the instant invention provides
methods for halting or slowing the progression of atherosclerotic
cardiovascular disease, coronary heart disease, ischemic heart disease,
cerebrovascular disease and peripheral vessel disease, and preventing or
reducing the risk of occurrence, or recurrence where the potential
exists, of a coronary heart disease event, a cerebrovascular event, and/or
intermittent claudication, by administering the above-described
combination therapy to said persons who have clinically manifest
atherosclerotic disease.
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WO 97/38694 PCT/US97106127
A third object of the instant invention involves the above-
described methods further comprising the a-lministration of one or
more additional active agents, for example, a bile acid sequestrant,
cholesterol absorption inhibitor, squalene synthase i~hibitor, and/or
5 niacin, either in separate or combined dosage formulations. A fourth
object is to provide pharmaceutical compositions which can be used in
the above-described methods. Additional objects will be evident from
the following detailed description.
10 DETAILED DESCRIPTION OF THE INVENTION
The instant invention provides methods for preventing or
reducing the risk of developing atherosclerosis, as well as for halting or
slowing the progression of atherosclerotic disease once it has become
clinically evident, comprising the ~-lmini~tration of a therapeutically
15 effective amount of an HMG-CoA RI in combination with folic acid or a
pharmaceutically acceptable salt or ester thereof to a person who is at
risk of developing atherosclerosis or who already has atherosclerotic
disease.
Atherosclerosis encompasses vascular diseases and
20 conditions that are recognized and understood by physicians practicing
in the relevant fields of medicine. Atherosclerotic cardiovascular
disease, coronary heart disease (also known as coronary artery disease
or ischemic heart disease), cerebrovascular disease and peripheral vessel
disease are all clinical manifestations of atherosclerosis and are
25 therefore encompassed by the terms "atherosclerosis" and
"atherosclerotic disease."
The combination comprised of an HMG-CoA RI and folic
acid or folate may be ~lministered to prevent or reduce the risk of
occurrence, or recurrence where the potential exists, of a coronary
30 heart disease event, a cerebrovascular event, and/or intermittent
claudication. Coronary heart disease events are intended to include
CHD death, myocardial infarction (i.e., a heart attack), and coronary
revascularization procedure~. Cerebrovascular events are intended to
include ischemic or hemorrhagic stroke (also known as cerebrovascular
CA 022~1972 1998-10-1~
WO 97/38694 PCT/US97/06127
accidents) and transient ischemic attacks. Intelmittent claudication is a
clinical manifestation of peripheral vessel disease. The term
"atherosclerotic disease event" as used herein is intended to encompasses
coronary heart disease events, cerebrovascular events, and intermittent
5 claudication. It is intended that persons who have previously
experienced one or more non-fatal atherosclerotic disease event are
those for whom the potential for recurrence of such an event exists.
Accordingly, the instant invention also provides a method
for preventing or reducing the risk of occurrence, or recurrence where
10 the potential exists, of an atherosclerotic disease event comprising the
administration of a therapeutically effective amount of an HMG-CoA
reductase inhibitor in combination with folic acid or folate to a person
at risk of developing atherosclerotic disease. The instant combination
therapy can also be ~lmini~tered to a person who already has
15 atherosclerotic disease for preventing or reducing the risk of
occurrence, or recurrence where the potential exists, of an
atherosclerotic disease event.
Persons to be treated with the instant combination therapy
include those at risk of developing atherosclerotic disease and of having
20 an atherosclerotic disease event. Standard atherosclerotic disease risk
factors are known to the average physician practicing in the relevant
fields of medicine. Such known risk factors include but are not limited
to hypertension, smoking, diabetes, low levels of high density
lipoprotein (HDL) cholesterol, and a family history of atherosclerotic
25 cardiovascular disease. Published guidelines for determining those who
are at risk of developing atherosclerotic disease can be found in:
National Cholesterol Education Program, Second report of the Expert
Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel 11), National Institute of
30 Health, National Heart Lung and Blood Institute, NIH Publication No.
93-3095, September 1993; abbreviated version: Expert Panel on
Detection, Evaluation, and Treatment of ~igh Blood Cholesterol in
Adults, Summary of the second report of the national cholesterol
education program (NCEP) Expert Panel on Detection, Evaluation. and
CA 02251972 1998-lO-l~
W O 97138694 PCT~US97/06127
Treatment of ~igh Blo~ld Cholesterol in Adults (Adult Treatment Panel
II), JAMA, 1993, 269, pp. 3015-23. People who are identified as
having one or more of the above-noted risk factors are intended to be
included in the group of people considered at risk for developing
5 atherosclerotic disease. People identified as having one or more of the
above-noted risk factors, as well as people who already have
atherosclerosis, are intended to be included within the group of people
considered to be at risk for having an atherosclerotic disease event.
A compound which inhibits HMG-CoA reductase is used in
10 combination with folic acid or folate to practice the instant invention.
Examples of HMG-CoA reductase inhibitors that may be used include
but are not limited to lovastatin (MEVACOR(~)), simvastatin
(ZOCOR~)), pravastatin (PRAVACHOL(~)), fluvastatin (LESCO~
atorvastatin and rivastatin (also known as cerivastatin). The structural
1~ formulas of these and additional HMG-CoA reductase inhibitors that
may be used in the instant methods are described at page 87 of M.
Yalpani, "Cholesterol Lowering Drugs", Chemist)y & Indllstry, pp. 85-
89 (5 February 1996). The term HMG-CoA reductase inhibitor is
intended to include all pharmaceutically acceptable salt and ester forms
20 of compounds which have HMG-CoA reductase inhibitory activity, and
therefor the use of such salts and esters is included within the scope of
this invention.
Compounds which have inhibitory activity for HMG-CoA
reductase can be readily identified by using assays well-known in the
25 art. For example, see the assays described or cited in U.S. Patent
4,231,938 at col. 6, and WO 84/02131 at pp. 30-33. Preferably, the
HMG-CoA RI is selected from lovastatin and simvastatin.
Folic acid or a pharmaceutically acceptable salt or ester
thereof is administered in combination with the HMG-CoA reductase
30 inhibitor. Pharmaceutically acceptable salts of folic acid are well known
to those skilled in the art and include, for example, the sodium salt and
the methylglucamine salt. The acid moiety also lends itself to the
preparation of pharmaceutically acceptable esters, and such esters are
likewise included in the scope of the invention. The term "folate" is
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WO 97/38694 PCT/US97/06127
used herein to refer to the pharmaceutically acceptable salts and esters
of folic acid.
Herein, the term "ph~ ceutically acceptable salts" shall
mean non-toxic salts of the compounds employed in this invention which
5 are generally prepared by reacting the free acid with a suitable organic
or inorganic base.
Ester derivatives of the described compounds may act as
prodrugs which, when absorbed into the bloodstream of a warm-
blooded ~nim~l, may cleave in such a manner as to release the drug
10 form and permit the drug to afford improved therapeutic efficacy.
The instant method involves the ~dmini.~tration of an HMG-
CoA reductase inhibitor in combination with folic acid or a folate. This
combination therapy includes administration of a single pharmaceutical
dosage formulation which contains both the HMG-CoA reductase
15 inhibitor and the folic acid or folate, as well as a~lministration of each
active agent in its own separate pharrnaceutical dosage formulation.
Where separate dosage formulations are used, the HMG-CoA reductase
inhibitor and the folic acid or folate can be administered at essentially
the same time, i.e., concurrently, or at separately staggered times, i.e,
20 sequentially. It is preferred that the HMG-CoA reductase inhibitor and
the folic acid or folate be co-administered concurrently on a once-a-day
dosing schedule. A single dosage formulation comprised of both an
HMG-CoA reductase inhibitor and the folic acid or folate is preferred.
A single dosage forrnulation will provide convenience for the patient,
25 which is an important consideration especially for patients who already
have coronary heart disease and may be in need of multiple medications.
The term "therapeutically effective amount" is intended to
mean that amount of a drug or pharmaceutical agent that will elicit the
biological or medical response of a tissue, a system, animal or human
30 that is being sought by a researcher, veterinarian, medical doctor or
other clinician. The dosage regimen utilizing an HMG-CoA RI in
combination with folic acid or folate is selected in accordance with a
variety of factors including type, species, age, weight, sex and medical
condition of the patient; the severity of the condition to be treated; the
CA 022~l972 l998- lo-l~
WO 97138694 PCT/US97/06127
route of ~rlmini~tration; the renal and hepatic function of the patient;
and the particular compound or salt or ester thereof employed. A
consideration of these factors is well within the purview of the
ordinarily skilled clinician for the purpose of determining the
5 therapeutically effective dosage amounts to be given to a person in need
of the instant combination therapy. Dosage information for HMG-CoA
RI's and for folic acid is well known in the art, since several HMG-CoA
RI's and nutritional supplements containing folic acid are marketed in
the U.S.
In particular, the daily dosage amounts of the HMG-CoA
reductase inhibitor are intended to be the same or similar to those
amounts which are employed for anti-hypercholesterolemic treatment
and which are described in the Physicians' Desk Reference (PDR). For
example, see the 50th Ed. of the PDR, 1996 (Medical Economics Co); in
15 particular, see at page 216 the heading "Hypolipidemics," sub-heading
"HMG-CoA Reductase Inhibitors," and the reference pages cited therein.
Preferably, the oral dosage amount of HMG-CoA RI is from about 1 to
200 mg/day, and more preferably from about 5 to 160 mg/day.
However, dosage amounts will vary depending on the potency of the
20 specific HMG-CoA reductase inhibitor used as well as other factors as
noted above. An HMG-CoA Rl which has sufficiently greater potency
may be given in sub-milligram daily dosages.
As examples, the daily dosage amount for simvastatin may
be selected from ~ mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg; for
25 lovastatin, 10 mg, 20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20
mg, 40 mg and 80 mg; and for pravastatin sodium, 10 mg, 20 mg, and
40 mg.
The therapeutically effective amount of folic acid to be
used in the instant method is intended to be a dosage amount
30 sufficient to reduce the plasma level of homocysteine below the pre-
treatment plasma level of homocysteine in the person receiving the
combination therapy. Examples of dosage amounts of folic acid are
described in the PDR. For exampleg see at page 119 of the 1996
PDR the heading "Folic Acid" and the reference pages cited therein.
. . . , _
CA 022~1972 1998- lo- 1~
WO 97/38694 PCT/US97/0612i
For example, the daily dosage amount of folic acid or folate
employed in the instant combination therapy can be from about 0.1
to 20 mg/day. In particular, the dosage is from about 0.1 to 10
mg/day, more particularly from about 0.1 to 5 mg/day, and most
5 particularly from about 1 to 5 mg/day, based on the free acid weight.
For example, the daily dosage amount of folic acid or folate may be
selected from 1 mg, 2 mg and 5 mg, based on the free acid weight.
Additional active agents may be combined with the
HMG-CoA RI and folic acid or folate in a single dosage formulation,
10 or may be ~-lministered to the patient in a separate dosage
formulation, which allows for concurrent or sequential
administration. One or more additional active agents may be
administered with the HMG-CoA RI and folic acid or folate. The
additional active agent or agents can be cholesterol lowering
15 compounds. Examples of additional active agents which may be
employed include HMG-CoA synthase inhibitors; squalene epoxidase
inhibitors; squalene synthetase inhibitors (also known as squalene
synth~se inhibitors), acyl-coenzyme A: cholesterol acyltransferase
(ACAT) inhibitors; probucol; niacin; fibrates such as clofibrate,
20 fenofibrate, and gemfibrizol; cholesterol absorption inhibitors; bile
acid sequestrants; LDL (low density lipoprotein) receptor inducers;
vitamin B6 (also known as pyridoxine) and the pharmaceutically
acceptable salts thereof such as the HCI salt; vitamin B12 (also known
as cyanocobalamin); aspirin; beta-blockers; and anti-oxidant vitamins
25 such as vitamin C and E and beta carotene.
Examples of HMG-CoA synthase inhibitors include: the
beta-lactone derivatives disclosed in U.S. Patent No. 4,806,564,
4,816,477, 4,847,271, and 4,751,237; the beta lactam derivatives
disclosed in U.S. 4,983,597 and the substituted oxacyclopropane
30 analogues disclosed in European Patent Publication EP O 411 703.
The squalene synthetase inhibitors suitable for use herein include, but
are not limited to, those disclosed by Biller et al., J. Med. Chem.,
1988 Vol. 31, No. 10, pp. 1869- 1871, including isoprenoid
(phosphinylmethyl)-phosphonates such as those of the formula
. . . .. . . ...
CA 02251972 1998- lO- 15
WO 97/386g4 PCT/US97/06127
- 10 -
O O O O
Il 11 _ 11 11
R1-P-CH2-P-O Rl-P-CF2-P-O-
O O O ~
11
wherein R1 is:
a
b
c ~1
d ~\ 6 ~
including the triacids thereof, triesters thereof and tripotassium and
trisodium salts thereof as well as other squalene synthetase inhibitors
5 disclosed in pending U.S. Patent No. 4,871,721 and 4,924,024 and in
Biller et al ., J. Med .Chem., 1988, Vol. 31, No. 10, pp. 1869 to 1871.
In addition, other squalene synthetase inhibitors suitable
for use herein include the terpenoid pyrophosphates disclosed by P.
Ortiz de Montellano et al., J. Med. Chem., 1977, 20, 243-249, the
10 farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-
PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc.
1976, 98, 1291-1293, phosphinylphosphonate reported by McClard,
R. W. et al., J.A.C.S., 1987, 109, 5544 and cyclopropanes reported
by Capson, T.L., PhD dissertation, June, 1987, Dept. Med. Chem. U.
CA 022~l972 l998- lO- l~
WO 97/38694 PCT/US97/06127
- 11 -
of Utah, Abstract, Table of Contents, pp. 16, 17, 40-43, 48-51,
Sllmm~ry.
Further, the benzodiazepine squalene synthase inhibitors
described in EP O 567 026 to Takeda Chemical Industries, and the
5 quinuclidinyl squalene synthase inhibitors described in PCT
publications WO 94/03451, WO 93/09115, WO 93/21183, WO
93/21184, WO 93/24486, and U.S. 5,135,935, may be co-
~lministered with the HMG-CoA RI plus folic acid or folate
combination of the present invention. In addition, the zaragozic acid
10 type squalene synthase inhibitors as described in U.S. Patents
5,284,758; 5,283,256; 5,262,435; 5,260,332; 5,264,593; 5,260,215;
5,258,401; 5,254,727; 5,256,689; 5,132,320; 5,278,067, and PCT
Publications WO 92/12156; WO 92/12157; WO 92/12158; WO
92/12159; WO 92/12160; WO 93/18040; WO 93/18039; WO
15 93/07151; and European Patent Publications EP O 512 865, EP O
568 946; EP O 524,677 and EP O 450 812, as well as the acyclic
tricarboxylic acid compounds of U.S. patent 5,254,727, may be
employed.
Illustrative examples of squalene epoxidase inhibitors
20 are disclosed in European Patent Publication EP O 318 860 and in
Japanese Patent Publication JO2 169-571A. LDL-receptor gene
inducer molecules are disclosed in U.S. Patent No. 5,182,298s.
Examples of bile acid sequestrants which may be
employed in the present method include cholestyramine, colestipol,
25 and poly[methyl-(3-trimethylaminopropyl)imino-trimethylene
dihalide] and those disclosed in W095/34585 to Geltex
Pharmaceuticals, Inc. and EP 0 622 078 assigned to Hisamitsu
Pharmaceutical Co., Inc.
Examples of cholesterol absorption inhibitors which
30 may be employed in the present method include those described in
WO 95/18143 and WO 95/18144 both assigned to Pfizer Inc., and
WO 94/17038, WO 95/08532 and WO 93/02048 each assigned to
Schering Corp.
CA 022Ctl972 l998- lO- lC
WO 97/38694 PCT/US97/06127
The additional active agents described above which may be
employed along with the HMG-CoA RI and folic acid or folate
combination therapy can be used, for example, in amounts as indicated
in the PDR or in amounts a~ indicated in the reference disclosures, as
appropriate.
Pharmaceutical formulations for both HMG-CoA RI's and
for folic acid or folates are well-known to those skilled in the art, as
evidenced by the information provided in the 1996 PDR. Methods for
preparing various ph~ ceutical compositions comprising the
combination of an HMG-CoA RI and folic acid or folate are likewise
well known to those skilled in the art. For example, see Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.
For example, the active agent.s employed in the instant
combination therapy can be administered in such oral forms as tablets,
capsules (each of which includes sustained release or timed release
formulations), pills, powders, granules, elixirs, tinctures, suspensions,
syrups, and emulsions. The instant invention includes the use of both
oral rapid-release and time-controlled release pharmaceutical
formulations. Oral formulations are preferred.
In the methods of the present invention, the HMG-CoA RI
and the folic acid or folate may be formulated together with or without
an additional active agent, and are typically administered in admixture
with suitable pharmaceutical diluents, excipients or carriers (collectively
referred to herein as "carrier" materials) suitably selected with respect
to the intended form of administration, that is, oral tablets, capsules,
elixirs, syrups and the like, and consistent with conventional
pharmaceutical practices.
For instance, for oral a(lmini~tration in the form of a tablet
or capsule, the active drug component can be combined with a non-
toxic, pharmaceutically acceptable, inert carrier such as lactose, starch,
sucrose, glucose, modified sugars, modified starches, methyl cellulose
and its derivatives, dicalcium phosphate, calcium sulfate, mannitol,
sorbitol and other reducing and non-reducing sugars, magnesium
stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium
CA 022~1972 1998- lo- l~
WO 97/38694 PCT/US97/06127
stearate and the like. For oral ~lmini~tration in liquid form, the drug
components can be combined with non-toxic, pharmaceutically
acceptable inert carrier such as ethanol, glycerol, water and the like.
Moreover, when desired or necessary, suitable binders, lubricants,
5 disintegrating agents and coloring and flavoring agents can also be
incorporated into the mixture. Stabilizing agents such as antioxidants
(BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also be
added to stabilize the dosage forms. Other suitable components include
gelatin, sweeteners, natural and synthetic gums such as acacia,
10 tragacanth or alginates, carboxymethylcellulose, polyethylene glycol,
waxes and the like.
Although the active agents of the present method may be
ninistered in divided doses, for example two or three times daily, a
single daily dose of each of the HMG-CoA RI and the folic acid or folate
15 is preferred, with a single daily dose of both agents in a single
pharmaceutical composition being most preferred.
As such, a therapeutically effective amount of an HMG-
CoA Rl and folic acid or a pharmaceutically acceptable salt or ester
thereof can be used together for the preparation of a medicament useful
20 for preventing or reducing the risk of developing atherosclerotic
disease, halting or slowing the progression of atherosclerotic disease
once it has become clinically manifest, and preventing or reducing the
risk of occurrence, or recurrence where the potential exists, of an
atherosclerotic disease event. For example, the medicament may be
25 comprised of folic acid or folate in combination with about 1 mg to 200
mg of an HMG-CoA RI, or more particularly about 5 mg to 160 mg of
the HMG-CoA RI. More specific amounts of HMG-CoA RI which may
be used in the medicament preparation include 1 mg, 5 mg, 10 mg, 20
mg, 40 mg, 80 mg, and 160 mg, as well as sub-milligram amounts of
30 HMG-CoA RI's which have sufficient potency at such levels. As a
further example, the medicament may be comprised of an HMG-CoA RI
in combination with about 0.1 to 20 mg of folic acid or folate. In
particular, the amount of folic acid or folate used in the preparation of
the medicament may be from about 0.1 to 10 mg, or more particularly
CA 022~1972 1998- lo- 1~
WO 97/38694 PCT/US97/06127
- 14 -
from about 0.1 to 5 mg, and most particularly from about 1 to 5 mg,
based on the free acid weight. For example, the medicament may be
comprised of 1 mg, 2 mg or 5 mg of folic acid or folate, based on the
free acid weight.
The above-described medicament may also be prepared
with one or more additional active agents such as an HMG-CoA synthase
inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor,
an ACAT inhibitor, probucol, niacin, a fibrate, a cholesterol absorption
inhibitor, a bile acid sequesterant, an LDL receptor inducer, vitamin B6
10 and the pharmaceutically acceptable salts thereof, vitamin B12, aspirin.
beta-blockers. vitamin C. vitamin E and beta carotene.
An example of an oral dosage formulation comprising
both an HMG-CoA RI and folic acid which is suitable for use in
practicing the instant method invention is as follows:
Ingredient Amount
simvastatin l - 200 mg.
folic acid or folic acid equivalent 0.05 - 20 mg.
diluent
binder
disintegrant ~ excipients qs. 200 - 400 mg.
lubricant
More specific examples of oral dosage formulations are
as follows.
CA 022~1972 1998- lO- l~
PCT/US97/06127
WO 97t38694
- 15 -
EXAMPLE 1
In~redient Amount
Simvastatin 5.0 mg
BHA 0.02mg
Ascorbic acid 2.50 mg
Citric acid 1.25 mg
Microcrystalline cellulose 5.0 mg
Pregel starch 10.0 mg
Magnesium stearate 0.5 mg
Lactose 74.73 mg
Folic acid 1.0 mg
All the ingredients except magnesium stearate are blended
together in a suitable mixer. The powder mixture is then granulated
with adequate ~uantities of granulating solvent(s). The wet granulated
mass is dried in a suitable dryer. The dried granulation is sized through
a suitable screen. The sized granulation is mixed with magnesium
20 stearate before tableting. The tablets may be coated if deemed
necessary. Additional ingredients that may be added to the above
include suitable color and mixtures of colors.
EXAMPLE 2
In,~redient Amount
Simvastatin 5.0 mg
BHA 0.04 mg
Citric acid 2.5 mg
Microcrystalline cellulose 10.0 mg
Pregel starch 20.0 mg
Magnesium stearate 1.0 mg
Lactose 148.46 mg
Folic acid 5.0 mg
Hydrolized gelatin 8.0 mg
The process of manufacture is essentially the same as in
Example l, above
CA 022~1972 1998-10-1~
PCT/US97/06127
WO 9~/38694
- 16 -
EXAMPLE 3
In~redient Amount
Simvastatin 80.0 mg
BHA 0.16 mg
Ascorbic acid 20.0 mg
Citric acid 10.0 mg
Microcrystalline cellulose 40.0 mg
Pregel starch 80.0 mg
Lactose SS0.0 mg
Folic acid 10.0 mg
Colorant 5.0 mg
Magnesium stearate 4.8 mg
The process of manufacture is essentially the same as in
Example 1, above.
While the invention has been described and illustrated
with reference to certain particular embodiments thereof, those
20 skilled in the art will appreciate that various changes, modifications
and substitutions can be made therein without departing from the
spirit and scope of the invention. For example, effective dosages
other than the particular dosages as set forth herein above may be
applicable as a consequence of variations in the responsiveness of the
25 m~mm~l being treated for any of the indications for the active agents
used in the instant invention as indicated above. Likewise, the
specific pharmacological responses observed may vary according to
and depending upon the particular active compound selected or
whether there are present pharmaceutical carriers, as well as the type
30 of formulation and mode of administration employed, and such
expected variations or differences in the results are contemplated in
accordance with the objects and practices of the present invention. It
is intended, therefore, that the invention be defined by the scope of
the claims which follow and that such claims be interpreted as
35 broadly as is reasonable.
