TECHNICAL FIELD
This invention relates to pharmaceutical formulations for treating patients at elevated
cardiovascular risk, and more particularly relates to dosage forms that combine a cholesterol-
lowering agent (HMG CoA reductase inhibitors), peroxisome proliferator activator (Fibric acid
derivatives), and Aspirin.
BACKGROUND AND PRIORART
Many individuals are at an elevated risk of suffering serious to life-threatening cardiovascular
events, such as myocardial infarction (heart attack), cardiac arrest, congestive heart failure,
stroke, peripheral vascular disease, and/or claudication. The risk factors are cigarette smoking,
diabetes, hypercholesterolemia (high serum cholesterol), hypertension, angina, systemic lupus
erythematosus, prior heart attacks or strokes, hemodialysis, hyperhomocysteine levels, obesity,
sedentary lifestyle, receiving an organ transplant, and others. There is a need for a safe and
convenient pharmaceutical formulation that would effectively reduce the risk of incurring a
cardiovascular event in individuals who have these risk factors.
US. 5,622,985, disclose that inhibitors of HMG CoA reductase (cholesterol-lowering drugs),
particularly pravastatin, when used alone or with an angiotensin converting enzyme (ACE)
inhibitor, decrease the risk of a second heart attack in a patient who has a substantially normal
cholesterol level. The combination with an ACE inhibitor is optional, and no mention is made of
combining HMG CoA reductase inhibitors with other inhibitors of the renin-angiotensin system
or with aspirin. In addition, the prevention of cardiovascular events other than second heart
attacks is not considered.
US.5,140,012, disclose the use of pravastatin alone, or in combination with an ACE inhibitor, to
prevent the onset of restenosis following angioplasty. HMG CoA reductase inhibitors other than
pravastatin are not considered, and no mention is made of combining HMG CoA reductase
inhibitors with other inhibitors of the renin-angiotensin system or with aspirin. The prevention of
cardiovascular disorders other than restenosis following angioplasty is not considered.
US. 5,461,039 and US 5,593,971 disclose the use of a cholesterol-lowering drug, alone or in
combination with an ACE inhibitor, to inhibit hypertension in a normotensive individual who has
insulin resistance. No mention is made of combining cholesterol-lowering drugs with inhibitors of
the renin-angiotensin system other than ACE inhibitors or with aspirin. In addition, the disclosed
2

methods are limited to normotensive individuals who are insulin resistant, and no mention is
made of directly preventing cardiovascular events.
Eisman et al., in U.S. Statutory Invention Registration No. H1286, disclose a method for treating
peripheral atherosclerotic disease and/or intermittent claudication by use of one or more
cholesterol-lowering drugs by themselves or together with an ACE inhibitor, or by use of an ACE
inhibitor alone. No mention is made of combining cholesterol-lowering drugs with inhibitors of
the renin-angiotensin system other than ACE inhibitors or with aspirin.
US 6,235,311 discloses pharmaceutical compositions that contain a statin (HMG CoA reductase
inhibitor) plus aspirin, optionally containing vitamins B.sub.6, B.sub.12, or folic acid, and
methods of their use for: lowering serum cholesterol; preventing, inhibiting, or treating
atherosclerosis; or reducing the risk of or treating a cardiovascular event or disease, coronary
artery disease, or cerebrovascular disease. No mention is made regarding use of Peroxisome
proliferator activator
US 6,248,729, disclose a method for preventing a cerebral infarction by administering to a
patient a combination of an ADP-receptor blocking antiplatelet drug, an antihypertensive agent
(such as an angiotensin II antagonist, an ACE inhibitor, or an ACE/NEP inhibitor), and
optionally, a cholesterol-lowering drug and/or aspirin. Pharmaceutical compositions comprising
combinations of these agents are also disclosed.
WO 01/15674, disclose the use of an inhibitor of the renin-angiotensin system, optionally
together with another antihypertensive drug, a cholesterol-lowering drug, a diuretic, or aspirin, in
the prevention of cardiovascular events. Also disclosed is a combination product for this
purpose containing an inhibitor of the renin-angiotensin system and a cholesterol-lowering
agent.
US 2005/032878 discloses the use of peroxisome proliferator activated compound, an
effective amount of at least one HMG-CoA reductase inhibitor compound of the statin
family, and at least one polyglycolized glyceride for the treatment of method of treating
hyperlipidemia or hypercholesterolemia. There is no literature mentioned in the prior art
which discloses combination of cholesterol-lowering agent (HMG CoA reductase
inhibitors), peroxisome proliferator activator (Fibric acid derivatives), and Aspirin.
3

OBJECTIVE OF THE INVENTION
Accordingly, it is a primary object of the invention to provide a pharmaceutical composition that
overcomes the limitations of the above-described formulations and dosage forms.
One object of this invention is to provide a combination of cholesterol-lowering agent (HMG CoA
reductase inhibitors), peroxisome proliferator activator (Fibric acid derivatives), and Aspirin,
optionally contains vitamin B.sub.6, vitamin B.sub.12, and folic acid.
Another object of the invention to provide a once-daily orally administrable pharmaceutical
composition for treating a patient at elevated cardiovascular risk, the composition comprising a
single dosage form containing a combination of therapeutically effective unit dosages of a HMG
CoA reductase inhibitors, Fibric acid derivatives, aspirin, and optionally one or more of vitamin
B.sub.6, vitamin B.sub.12, and folic acid, and at least one of the active agents is present in a
dosage unit within the dosage form that physically separates it from the other active agents.
Another object of the invention to provide an orally administrable solid dosage form wherein at
least two of the active agents are present in dosage units that physically separate them from the
other active agents and from each other.
Another object of the invention is to provide an orally administrable solid dosage form wherein at
least one of the active agents is present in a controlled release dosage unit, i.e., a sustained
release and/or delayed release dosage unit.
Another object of the invention is to provide such compositions wherein the cholesterol-lowering
agent is an HMG CoA reductase inhibitor, Aspirin and Fibric acid derivatives (PPAR agonist
agent), selected from the group consisting of fenofibrate, ciprofibrate, clofibrate, gemfibrozil,
bezafibrate and combinations thereof. Especially, the PPAR.alpha. agent is fenofibrate.
Additional objects, advantages and novel features of the invention will be set forth in part in the
description which follows, and in part will become apparent to those skilled in the art upon
examination of the following, or may be learned by practice of the invention.
The present invention provides a once-daily oral dosage form comprising a combination of a
therapeutically effective unit dose of a cholesterol-lowering agent, a therapeutically effective unit
4

dose of Fibric acid derivatives, and a therapeutically effective unit dose of aspirin, optionally
further combined with at least one vitamin B substance, wherein at least one of the active
agents is present in a dosage unit within the dosage form that physically separates it from the
other active agents. Preferably, at least two of the active agents are present in dosage units that
physically separate them from the other active agents and from each other, and still more
preferably, at least one of the active agents is present in a controlled release dosage unit, i.e., a
sustained release and/or delayed release dosage unit.
The invention also provides a method for treating a patient at elevated cardiovascular risk by
administering the dosage form on a daily basis.
The afforementioned dosage form provides a safe and effective method for reducing the risk of
cardiovascular events in these patients, by providing a single oral dosage form containing the
aforementioned combination of active agents, which is conveniently administered once per day,
wherein any detrimental interaction between active agents is minimized or eliminated. Such a
simple regime has a high degree of patient compliance, leading to substantially improved
efficacy.
In a preferred embodiment, the dosage form of the invention comprises: about 5 mg to
about120 mg, preferably about25 mg to about90 mg, of an HMG CoA reductase inhibitor
selected from the group consisting of atorvastatin, fluvastatin, Rosuvastatin, Pitvastatin,
lovastatin, pravastatin, and simvastatin; aboutl mg to about160 mg, preferably about 10 mg to
about 150 mg, of an peroxisome proliferator activator agent selected from the group consisting
of fenofibrate, ciprofibrate, clofibrate, gemfibrozil, and bezafibrate; about20 mg to about600 mg,
preferably about20 mg to aboutl50 mg, of aspirin; and, optionally contains Vitamin B and folic
acid.
DETAILED DESCRIPTION OF THE INVENTION
Before describing the present invention in detail, it is to be understood that this invention is not
limited to specific dosage forms, carriers, or the like, as such may vary. It is also to be
understood that the terminology used herein is for the purpose of describing particular
embodiments only, and is not intended to be limiting.
It must be noted that as used in this specification and the appended claims, the singular forms
"a," "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus,
5

for example, reference to "an active agent" or "a pharmacologically active agent" includes a
single active agent as well as two or more different active agents in combination, reference to "a
carrier" includes mixtures of two or more carriers as well as a single carrier, and the like.
In describing and claiming the present invention, the following terminology will be used in
accordance with the definitions set out below.
The terms "active agent," "pharmacologically active agent" and "drug" are used interchangeably
herein to refer to a chemical compound that induces a desired pharmacological, physiological
effect. The primary active agents herein are cholesterol-lowering agents, peroxisome proliferator
activator agent (Fibric acid derivatives), and aspirin; other active agents may include vitamin
B.sub.6, vitamin B.sub.12, and folate. The terms also encompass pharmaceutical^ acceptable,
pharmacologically active derivatives of those active agents specifically mentioned herein,
including, but not limited to, salts, esters, amides, prodrugs, active metabolites, analogs, and the
like. When the terms "active agent," "pharmacologically active agent" and "drug" are used, then,
or when an active agent such as an HMG CoA reductase inhibitor is specifically identified, it is
to be understood that applicants intend to include the active agent per se as well as
pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs,
metabolites, analogs, etc.
"Therapeutically effective amount" means that the amount of active agent, which halts or
reduces the progress of the condition being treated or which otherwise completely or partly
cures or acts palliatively on the condition. A person skilled in the art can easily determine such
an amount by routine experimentation and with an undue burden.
"Optional" or "optionally" means that the subsequently described circumstance may or may not
occur, so that the description includes instances where the circumstance occurs and instances
where it does not.
The terms "cholesterol-lowering agent" and "cholesterol-lowering drug" as used herein refer to a
pharmacologically active, pharmaceutically acceptable agent that, when administered to a
human subject who has hypercholesterolemia, has the effect of beneficially modifying serum
cholesterol levels. More particularly, the cholesterol-lowering agent lowers serum low density
lipoprotein (LDL) cholesterol levels, or inhibits oxidation of LDL cholesterol, whereas high
density lipoprotein (HDL) serum cholesterol levels may be lowered, remain the same, or be
6

increased. Preferably, the cholesterol-lowering agent brings the serum levels of LDL cholesterol
and HDL cholesterol (and, more preferably, triglyceride levels) to normal or nearly normal levels.
The term peroxisome proliferator activator agent or Fibric acid derivatives as used herein refers
to a pharmacologically active, pharmaceutically acceptable agent that, when administered to
human subject with hyperlipidemia lowers the level of triglyceride rich lipoprotein , such as
VLDL, variable effects on LDL, moderately raise HDL levels.
By "pharmaceutically acceptable," such as in the recitation of a "pharmaceutically acceptable
carrier," or a "pharmaceutically acceptable acid addition salt," is meant herein a material that is
not biologically or otherwise undesirable, i.e., the material may be incorporated into a
pharmaceutical composition administered to a patient without causing any undesirable
biological effects or interacting in a deleterious manner with any of the other components of the
composition in which it is contained. "Pharmacologically active" (or simply "active"), as in a
"pharmacologically active" derivative or metabolite, refers to a derivative or metabolite having
the same type of pharmacological activity as the parent compound and about equivalent in
degree. When the term "pharmaceutically acceptable" is used to refer to a derivative (e.g., a
salt) of an active agent, it is to be understood that the compound is pharmacologically active as
well, i.e., therapeutically effective to reduce elevated cardiovascular risk.
"Carriers" or "vehicles" as used herein refer to conventional pharmaceutically
acceptable carrier materials suitable for drug administration, and include any such
materials known in the art that are nontoxic and do not interact with other components of
a pharmaceutical composition or drug delivery system in a deleterious manner.
The term "modified-release" encompasses extended-release , sustained release.delayed-
release, controlled release and the like.
The term "controlled release" is intended to refer to any drug-containing formulation in which
release of the drug is not immediate, i.e., with a "controlled release" formulation, oral
administration does not result in immediate release of the drug into an absorption pool. The
term is used interchangeably with "nonimmediate release" as defined in Remington: The
Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company,
1995).
The term "sustained release" is used in its conventional sense to refer to a drug formulation that
provides for gradual release of drug over an extended period of time, and that preferably,
7

although not necessarily, results in substantially constant blood levels of drug over an extended
time period.
The term "delayed release" is used in its conventional sense to refer to a drug formulation in
which there is a time delay provided between oral administration of a drug dosage form and the
release of the drug therefrom. "Delayed release" may or may not involve gradual release of drug
over an extended period of time, and thus may or may not be "sustained release." The preferred
"controlled release" formulations herein are "delayed release," and particularly preferred
"delayed release" formulations are enterically coated compositions.
"Enteric coating" or "enterically coated" as used herein relates to the presence of polymeric
materials in a drug formulation that result in an increase in the drug's resistance to disintegration
in the stomach. Typically, the polymeric material is present as a coating surrounding a drug-
containing core, but the polymeric material may also be present in admixture with the drug itself
within a coated formulation.
By an "effective" amount or a "therapeutically effective amount" of a drug or pharmacologically
active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the
desired effect. In the combination therapy of the present invention, an "effective amount" of one
component of the combination is the amount of that compound that is effective to provide the
desired effect when used in combination with the other components of the combination. The
amount that is "effective" will vary from subject to subject, depending on the age and general
condition of the individual, the particular active agent or agents, and the like. Thus, it is not
always possible to specify an exact "effective amount." However, an appropriate "effective"
amount in any individual case may be determined by one of ordinary skill in the art using routine
experimentation
The terms "treating" and "treatment" as used herein refer to reduction in severity and/or
frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the
occurrence of symptoms and/or their underlying cause, and improvement or remediation of
damage. Thus, for example, "treating" a patient involves prevention of a particular disorder or
adverse physiological event in a susceptible individual as well as treatment of a clinically
symptomatic individual.
8

The term "elevated cardiovascular risk" as used herein refers to an increased risk of incurring a
cardiovascular event, peripheral vascular disease, coronary heart disease, restenosis, or
atherosclerosis in an individual, such risk being due to disorders, diseases, genetic factors,
behaviors, diets, or other conditions or factors. The conditions or factors that lead to elevated
cardiovascular risk include, without limitation: systemic lupus erythematosus, current or prior
cigarette smoking, diabetes, hemodialysis, receiving an organ transplant, manifest coronary
artery disease, history of myocardial infarction, history of transient ischemic attacks or stroke,
history of peripheral vascular disease, angina, hypertension, hypercholesterolemia, obesity,
atherosclerosis, kidney disease, Chlamydia infection, Bartonella infection, and obstructive
pulmonary disease.
The term "cardiovascular event" as used herein refers to a disorder or disease of the
cardiovascular system having a rather sudden onset; it can also refer to a rather sudden
worsening of such a disorder or disease. Examples of cardiovascular events include, without
limitation: cardiac arrest, myocardial infarction, ischemia, stroke, worsening of angina, and
congestive heart failure.
A. Cholesterol-Lowering Agents
This invention relates to any cholesterol-lowering agent or combination of such agents.
Preferred cholesterol-lowering agents are HMG CoA reductase inhibitors, bile acid
sequestrants, probucol, and fibric acid agents. Particularly preferred are HMG CoA reductase
inhibitors, especially atorvastatin, cerivistatin, fluindostatin, fluvastatin, lovastatin,pitvastatin,
lovastatin, mevastatin, pravastatin, simvastatin, and velostatin; the most preferred agents are
atorvastatin and pravastatin, particularly atorvastatin. Brief descriptions of some of the classes
of cholesterol-lowering agents that may be used in this invention follow.
HMG CoA reductase inhibitors: The members of this class of compounds inhibit 3-hydroxy-3-
methylglutaryl coenzyme A (HMG CoA) reductase. This enzyme catalyzes the conversion of
HMG CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of
cholesterol. Examples of HMG CoA reductase inhibitors that may be used include but are not
limited to lovastatin (MEVACOR.TM.; see U.S. Pat. No. 4,231,938), simvastatin (ZOCOR.TM.;
see U.S. Pat. No. 4,444,784), pravastatin (PRAVACHOLTM.; see U.S. Pat. No. 4,346,227),
fluvastatin (LESCOL.TM.; see U.S. Pat. No. 5,354,772), atorvastatin (LIPITOR.TM.; see U.S.
Pat. No. 5,273,995), cerivastatin (also called rivastatin; see U.S. Pat. No. 5,177,080),
9

mevastatin (see U.S. Pat. No. 3,883140), fluindostatin (Sandoz XU-62-320), velostatin (also
called synvinolin; see U.S. Pat. Nos. 4,448,784 and 4,450,171), and compounds related to
these as described in the cited references. All pharmaceutically acceptable HMG CoA
reductase inhibitors are included in this invention.. The term "HMG CoA reductase inhibitor" is
intended to include all pharmaceutically acceptable salt, ester, and lactone forms of compounds
that have HMG CoA reductase inhibitory activity, and therefore the use of such salt, ester, and
lactone forms is included within the scope of this invention.
HMG CoA reductase inhibitors are particularly preferred cholesterol-lowering agents herein,
insofar as they tend to exhibit fewer undesirable side effects than other cholesterol-lowering
agents, are more desirable in terms of safety and tolerance issues, do not need to be titrated,
and exhibit one or more beneficial effects in addition to lowering cholesterol, e.g., a reduction in
bone loss.
B. Peroxisome proliferator activator agent or Fibric acid derivatives: These compounds, also
known as "fibrates," lower triglyceride levels, raise high density lipoprotein (HDL) levels, and
have variable effects on LDL cholesterol levels in the blood. Examples of fibric acid derivatives
that may be used in this invention include, without limitation, bezafibrate (Bezalip.TM.),
beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, etofibrate, fenofibrate (Lipidil.TM.
Lipidil Micro.TM.), gemfibrozil (Lopid.TM.), nicofibrate, pirifibrate, ronifibrate, simfibrate, and
theofibrate.
C. Aspirin /NSAID
Aspirin (acetylsalicylic acid), when administered in low daily doses over a long term to patients
at risk for cardiovascular events, is well established to prevent myocardial infarction and strokes
due to thrombosis. Second heart attacks, strokes, and cardiovascular deaths are reduced by at
least 25% through the daily administration of low doses (about80 mg) of aspirin.
A number of mechanisms are likely responsible for the cardiovascular protective activity of
aspirin, but its antithrombotic, anti-platelet aggregating activities are probably highly significant
in this regard. Aspirin irreversibly acetylates the enzyme cyclooxygenase, rendering it
nonfunctional. Cyclooxygenase is essential to the synthesis of (among other compounds)
prostaglandins, many of which are proinflammatory; thromboxane A.sub.2, which is synthesized
by platelets to promote platelet aggregation and ultimately thrombosis (blood clotting); and
10

prostacyclins, which have anti-platelet aggregating properties. Cyclooxygenases are
synthesized in endothelial cells and not in platelets. Low doses of aspirin neutralize
cyclooxygenase selectively in the platelets, while allowing continued cyclooxygenase and
prostacyclin synthesis in the endothelial cells. The net effect is to reduce inflammation and
platelet aggregation, and thus thrombosis, in the blood vessels.
While aspirin is most preferred for use in this invention, other salicylates, including magnesium
salicylate, and other anti-platelet aggregating agents, such as anagrelide, dipyridamole,
clopidogrel, and ticlopidine, may also be used herein. Other cyclooxygenase inhibitors, including
other nonsteroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen, sulindac, sulindac
sulfide, sulindac sulfone, flurbiprofen, indomethacin, naproxen, meclafenamic acid, and
piroxicam, may also be used in this invention.
D. Vitamin B Compounds
Elevated serum levels of homocysteine, an amino acid not found in proteins, is highly correlated
with atherosclerosis, heart disease, stroke, and peripheral vascular disease. Many studies have
shown that orally administered supplements of vitamin B.sub.6 (also called pyridoxine), vitamin
B.sub.12 (also called cyanocobalamin), and folic acid (or folates) can lower homocysteine levels
and reduce the incidence of atherosclerosis, myocardial infarction, and stroke. Folic acid and
folates appear particularly potent in this regard. In the practice of this invention, folinic acid or
folates may be used instead of folic acid, though folic acid is preferred. Folates that may be
used include 5-methyl tetrahydrofolic acid (5MeTHF), tetrahydrofolic acid (THF), and 5-formyl
tetrahydrofolic acid
E. Derivatives
Any of the active agents may be administered in the form of a salt, ester, amide, prodrug, active
metabolite, analog, or the like, provided that the salt, ester, amide, prodrug, active metabolite, or
analog is pharmaceutically acceptable and pharmacologically active in the present context.
Salts, esters, amides, prodrugs, metabolites, analogs, and other derivatives of the active agents
may be prepared using standard procedures known to those skilled in the art of synthetic
organic chemistry.
Other derivatives and analogs of the active agents may be prepared using standard techniques
known to those skilled in the art of synthetic organic chemistry, or may be deduced by reference
11

to the pertinent literature. In addition, chiral active agents may be in isomerically pure form, or
they may be administered as a racemic mixture of isomers.
When two or more active agents are combined in a single pharmaceutical dosage form,
possible interactions among the active agents, and among the active agents and the excipients,
must be considered. Such consideration is well within the purview of those skilled in the art of
pharmaceutical formulation. For example, aspirin is acidic and may react with basic compounds
or alkali esters in such a way as to cause hydrolysis of the aspirin and/or degradation of the
other compounds. Aspirin may, for example, react with acid labile compounds such as
pravastatin or atorvastatin to degrade them. The present composition thus encompasses
pharmaceutical compositions wherein two or more of the active agents are separated from each
other within the pharmaceutical dosage form, by, for example, separating potentially interacting
compounds from each other within the pharmaceutical dosage form, as in separate flat layers of
a tablet (e.g., a bilayer or trilayer tablet), concentric layers, coated beads or granules (which
may be incorporated into a compressed tablet or into a capsule), and/or by using buffers . It will
also be appreciated by those in the art that such dosage forms, wherein two or more active
agents are physically separated from the other active agents, can be manufactured so that
different active agents will have different release profiles, e.g., if one active agent is formulated
with an enteric coating, another active agent is formulated in a sustained release matrix, and the
like. Alternatively, non-reactive pharmaceutically active derivatives of one or more of the
potentially interacting compounds may be used, such as using a neutral salicylate instead of
aspirin.
The invention provides pharmaceutical dosage forms that contain two or more multiple dosage
units that are physically segregated from each other, wherein the various dosage units may
have different release profiles. For example, one or more dosage units may provide immediate
release of an active agent (e.g., within about an hour following oral ingestion), one or more
dosage units may provide sustained release of an active agent (such that the active agent
therein is gradually released over an extended time period), and one or more dosage units may
provide delayed release of an active agent, wherein release following the initial "delay" may or
may not be sustained release. Drug release may be made "pulsatile" in that two or more drug
doses are released at spaced apart intervals of time.
In one embodiment, the dosage forms are closed and preferably sealed capsules housing at
12

least two drug-containing dosage units wherein each dosage unit within the capsule may or may
not provide a different drug release profile. Control of the delayed release dosage unit(s) is
accomplished by a controlled release polymer coating on the dosage unit, or by incorporation of
the active agent in a controlled release polymer matrix. Each dosage unit may comprise a
compressed or molded tablet, wherein each tablet within the capsule provides a different drug
release profile. Alternatively, each dosage unit in the capsule may comprise a plurality of drug-
containing beads, granules or particles. As is known in the art, drug-containing "beads" refer to
beads made with drug and one or more excipients or polymers. Drug-containing beads can be
produced by applying drug to an inert support, e.g., inert sugar beads coated with drug or by
creating a "core" comprising both drug and one or more excipients. As is also known, drug-
containing "granules" and "particles" comprise drug particles that may or may not include one or
more additional excipients or polymers. In contrast to drug-containing beads, granules and
particles do not contain an inert support. Granules generally comprise drug particles and require
further processing. Generally, particles are smaller than granules, and are not further
processed. Although beads, granules and particles may be formulated to provide immediate
release, beads and granules are generally employed to provide delayed release.
In another embodiment, the individual dosage units are compacted in a single tablet, and may
represent integral but discrete segments thereof (e.g., layers) or be present in an admixture.
Layered tablets, with each layer containing a different active agent and/or providing a different
release profile, provide several manufacturing advantages. Such tablets may be made in single
step compression, thereby eliminating the operations of methods necessary for preparing
coated core dosage forms. Layered tablets additionally eliminate the concomitant steps of in-
process and quality controls for manufacturing two or more different tablets. Further, layers
containing only excipients can be interspersed between layers that contain active agents, to
prevent possible interactions between or among the active agents. With tablets containing
different dosage units in admixture, drug-containing beads, granules or particles with different
drug release profiles (e.g., immediate and delayed release profiles), and/or drug-containing
beads, granules or particles containing different active agents, can be compressed together into
a single tablet using conventional tableting means. In the admixture, there is a random
possibility of the different active agents coming into contact with each other. However, protective
and/or delayed release coatings provided on the granules or other dosage units provide a
physical barrier, thereby minimizing direct physical contact between the active agents.
13

In still another embodiment, a dosage form of the invention may comprises a coated core-type
delivery system wherein an outer layer is comprised of one active agent, one or more
intermediate layers are optionally present each containing one or more additional active agents,
and an internal core contains still another active agent, or is comprised of an inert material.
Each layer and/or the core may also provide different release profiles.
As will be appreciated by those skilled in the art and as described in the pertinent texts and
literature, a number of methods are available for preparing drug-containing tablets, beads,
granules or particles that provide a variety of drug release profiles. Such methods include, but
are not limited to, the following: coating a drug or drug-containing composition with an
appropriate coating material, typically although not necessarily a incorporating a polymeric
material; increasing drug particle size; placing the drug within a matrix; and forming complexes
of the drug with a suitable complexing agent.
Delayed Release Dosage Units and Enteric Coatings: Solid dosage forms, whether tablets,
capsules, caplets, or particulates, may, if desired, be coated so as to provide for delayed
release. Dosage forms with delayed release coatings may be manufactured using standard
coating procedures and equipment. Such procedures are known to those skilled in the art..
Delayed release coating compositions comprise a polymeric material, e.g., cellulose butyrate
phthalate, cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinyl acetate
phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl
methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose
succinate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate,
polymers and copolymers formed from acrylic acid, methacrylic acid, and/or esters thereof.
The delayed release dosage units in any of the embodiments of the invention can be prepared,
for example, by coating a drug or a drug-containing composition with a selected coating
material. The drug-containing composition may be, e.g., a tablet for incorporation into a capsule,
a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing
beads, particles or granules, for incorporation into either a tablet or capsule. Preferred coating
materials are comprised of bioerodible, gradually hydrolyzable, gradually water-soluble, and/or
enzymatically degradable polymers, and preferred delayed release coatings are comprised of
enteric coating materials.
14

An enteric coating also prevents exposure of an active agent to the epithelial and mucosal
tissue of the buccal cavity, pharynx, esophagus, and stomach, and to the enzymes associated
with these tissues.
The "coating weight", or relative amount of coating material per dosage unit, generally dictates
the time interval between ingestion and drug release. The preferred coating weights for
particular coating materials may be readily determined by those skilled in the art by evaluating
individual release profiles for tablets, beads and granules prepared with different quantities of
various coating materials. Generally, however, coating weights of about5 wt. % to 50 wt. % are
appropriate.
Suitable enteric polymers include, but are not limited to, polymerized gelatin, cellulose butyrate
phthalate, cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinyl acetate
phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT),
hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl
methylcellulose succinate, carboxymethyl ethylcellulose (CMEC), hydroxypropyl methylcellulose
acetate succinate (HPMCAS), shellac, zein, and acrylic acid polymers and copolymers,
preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl
methacrylate, ethyl methacrylate, and/or other vinyl monomers. Preferred enteric polymers are
acrylic acid and methacrylic acid polymers and copolymers, particularly those that are
commercially available under the tradenames Eudragit.RTM. L and Eudragit.RTM. S, in which
the ratio of free carboxyl to ester groups is about1:1 and 1:2, respectively, and wherein each
copolymer has a (weight average) molecular weight of aboutl 35,000 Da.
The coating can, and usually does, contain a plasticizer to prevent the formation of pores and
cracks that would permit the penetration of the gastric fluids. Suitable plasticizers include, but
are not limited to, triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate
(Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate,
acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate.
The coating can also contain other coating excipients such as detackifiers, antifoaming agents,
lubricants (e.g., magnesium stearate), and stabilizers (e.g., hydroxypropylcellulose, acids and
bases) to solubilize or disperse the coating material, and to improve coating performance and
the coated product.
15

Enterically coated dosage forms, whether enterically coated tablets, tablet segments, capsules,
granules, or beads, may be manufactured using standard enteric coating procedures and
equipment. For example, an enteric coating can be applied to a tablet, tablet segment, bead,
granule, caplet or capsule using a coating pan, an airless spray technique, fluidized bed coating
equipment, or the like. The coating thickness, as noted above, must be sufficient to ensure that
the oral dosage form remains intact until the desired site of delivery in the lower intestinal tract is
reached.
Alternatively, a delayed release dosage unit may be formulated by dispersing an active agent
within a matrix of a suitable material such as an enteric coating material or other delayed
release polymeric materials. Hydrophilic polymers and certain fatty compounds are particularly
useful for providing a delayed release matrix. Such hydrophilic polymers may be comprised of
polymers or copolymers of cellulose, cellulose ester, acrylic acid, methacrylic acid, methyl
acrylate, ethyl acrylate, and vinyl or enzymatically degradable polymers or copolymers as
described above. Fatty compounds for use as a matrix material include, but are not limited to,
waxes (e.g. carnauba wax) and glycerol tristearate. Once the active ingredient is mixed with the
matrix material, the mixture can be compressed into tablets.
The pharmaceutical composition of the present invention comprise of two or more active agent,
excipients and optionally coated with hydrophilic or hydrophobic polymers.
Pharmaceutically acceptable excipients include but are not limited to binders, diluents,
lubricants, glidants and surface-active agents.
The amount of additive employed will depend upon how much active agent is to be used. One
excipient can perform more than one function.
Binders include, but are not limited to, starches such as potato starch, wheat starch, corn
starch; microcrystalline cellulose; celluloses such as hydroxypropyl cellulose, hydroxyethyl
cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl
cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone,
syrup, polyethylene oxide, polyvinyl pyrrolidone and the like and mixtures thereof.
16

Fillers or diluents, which include, but are not limited to confectioner's sugar, compressible sugar,
dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol
talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic,
calcium sulphate, and the like can be used.
Lubricants may be selected from, but are not limited to, those conventionally known in the art
such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium
stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered
cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate,
colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the
art.
The pharmaceutical formulation according to the present invention include but is not limited to
tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets,
matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile
release tablets, timed release tablets), pellets, beads, granules, sustained release formulations,
capsules, microcapsules, tablets in capsules and microspheres, matrix formulations,
microencapsulation and powder/pellets/granules for suspension.
Matrix-type dosage form comprises an aminosalicylate active agent its salts or metabolites,
mixed with either water-soluble, e.g., hydrophilic polymers, or water-insoluble, e.g., hydrophobic
polymers. Generally, the properties of the polymer used in a modified-release dosage form will
affect the mechanism of release. For example, the release of the active agent from a dosage
form containing a hydrophilic polymer can proceed via both surface diffusion and/or erosion.
Mechanisms of release from pharmaceutical systems are well known to those skilled in the art.
Matrix-type systems can also be monolithic or multiunit, and can be coated with water-soluble
and/or water-insoluble polymeric membranes.
Matrix formulations of the present invention can be prepared by using, for example, direct
compression or wet granulation or any conventional method known in the prior art.. A functional
coating, as noted above, can then be applied in accordance with the invention. Additionally, a
17

barrier or sealant coat can be applied over a matrix tablet core prior to application of a functional
coating.
In a matrix-based dosage form in accordance with the present invention, the drug and/or pro-
drug or metabolites and optionally pharmaceutically acceptable excipient(s) are dispersed within
a polymeric matrix, which typically comprises one or more water-soluble polymers and/or one or
more water-insoluble polymers. The drug can be released from the dosage form by diffusion
and/or erosion
The formulations of the present invention can exist as multi-unit or single-unit formulations. The
term "multi-unit" as used herein means a plurality of discrete or aggregated particles, beads,
pellets, granules, tablets, or mixtures thereof, for example, without regard to their size, shape, or
morphology. Single-unit formulations include, for example, tablets, caplets, and pills.
Immediate Release Dosage Units: The immediate release dosage unit of the present dosage
forms-le., a tablet within a capsule, a plurality of drug-containing beads, granules or
particles, a layer within a multilayered tablet, or a layer or core of a coated core dosage form-
contains a therapeutically effective quantity of a particular active agent or mixture of active
agents, with conventional pharmaceutical excipients. The immediate release dosage units may
or may not be coated with a protective coating. A preferred method for preparing immediate
release tablets (e.g., as incorporated into a capsule) is by compressing a drug-containing
blend, e.g., blend of granules, prepared using a direct blend, wet-granulation or dry-
granulation process. Immediate release tablets may also be molded rather than compressed,
starting with a moist material containing a suitable water-soluble lubricant. However,
preferred tablets herein are manufactured using compression rather than molding. A
preferred method for forming an immediate release drug-containing blend is to mix drug
particles directly with one or more excipients such as diluents (or fillers), binders,
disintegrants, lubricants, glidants, colorants or the like. Beads containing the active agent in
immediate release form may also be prepared by any one of a number of conventional
techniques, typically starting from a fluid dispersion. For example, a typical method for
preparing drug-containing beads involves blending the active agent with conventional
pharmaceutical excipients such as microcrystalline cellulose, starch, polyvinylpyrrolidone,
methylcellulose, talc, metallic stearates, silicone dioxide, or the like. The admixture is used to
coat a bead core such as a sugar sphere (or so-called "non-pareil") having a size of about20
to 60 mesh.
An alternative procedure for preparing drug beads is by blending drug with one or more
pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose,
polyvinyl pyrrolidone, talc, magnesium stearate, a disintegrant, etc., extruding the blend,
spheronizing the extrudate, drying and optionally coating to form the immediate release beads.
18

Sustained release dosage forms and dosage units: Sustained release formulations provide for
drug release over an extended time period, and may or may not be delayed release. Generally,
as will be appreciated by those of ordinary skill in the art, sustained release dosage units are
formulated by dispersing a drug within a matrix of a gradually bioerodible (hydrolyzable) material
such as an insoluble plastic, a hydrophilic polymer, or a fatty compound, or by coating a solid,
drug-containing dosage form with such a material. Insoluble plastic matrices may be comprised
of, for example, polyvinyl chloride or polyethylene.
Hydrophilic polymers useful for providing a sustained release coating or matrix cellulosic
polymers include, without limitation: cellulosic polymers such as hydroxypropyl cellulose,
hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose,
cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl
cellulose phthalate, hydroxypropylcellulose phthalate, cellulose hexahydrophthalate, cellulose
acetate hexahydrophthalate, and carboxymethylcellulose sodium; acrylic acid polymers and
copolymers, preferably formed from acrylic acid, methacrylic acid, acrylic acid alkyl esters,
methacrylic acid alkyl esters, and the like, e.g. copolymers of acrylic acid, methacrylic acid,
methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, particularly those
commercially available under the tradename Eudragit.RTM., with a terpolymer of ethyl acrylate,
methyl methacrylate and trimethylammonioethyl methacrylate chloride (sold under the
tradename Eudragit.RTM. RS) representing one preferred example; vinyl polymers and
copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate,
vinylacetate crotonic acid copolymer, ethylene-vinyl acetate copolymers, and polyvinyl
acetate/polyvinyl pyrrolidone mixtures; carbomers, i.e., hydroxylated vinylic polymers referred to
as "interpolymers," which are prepared by crosslinking a monoolefinic acrylic acid monomer with
a polyalkyl ether of sucrose (available under the tradename Carbopol.RTM. from the B. F.
Goodrich Chemical Company); zein; and shellac, ammoniated shellac, shellac-acetyl alcohol,
and shellac n-butyl stearate.
Fatty compounds for use as a sustained release matrix material or as a sustained release
coating material include, but are not limited to, waxes generally (e.g., camauba wax), glyceryl
tristearate, and hydrogenated oils such as hydrogenated vegetable oil, cottonseed oil, castor oil,
canola oil, palm oil, palm kernel oil and soybean oil.
19

Any of the dosage forms of the invention, and any of the dosage units contained therein, may
be coated with a protective coating. If a delayed release or sustained release coating is also
used, the protective coating is applied thereover. Suitable protective coating materials will be
known to those of ordinary skill in the art and are described in the pertinent texts, e.g.,
Remington's, supra. Generally, however, protective coatings are comprised of a material that
serves as a sealant encasing the individual dosage units, such that the different active agents
are physically isolated from each other within the dosage form. Coating materials suitable as
sealants are generally comprised of a resinous material such as shellac, zein, cellulose acetate
phthalate, polyvinyl acetate phthalate, or a shellac-polyvinylpyrrolidone combination. Sealant
coatings may also be applied to the outer surface of an entire dosage form, to strengthen a
tablet or capsule and improve product stability.
Pharmaceutical dosage forms of the invention can be coated by a wide variety of methods.
Suitable methods include compression coating, coating in a fluidized bed or a pan and hot melt
(extrusion) coating. Such methods are well known to those skilled in the art.
Tablets may be manufactured using standard tablet processing procedures and equipment. One
method for forming tablets is by direct compression of a powdered, crystalline, or granular
composition containing the active agent(s), alone or in combination with one or more carriers,
additives, or the like. As an alternative to direct compression, tablets can be prepared using wet-
granulation or dry-granulation processes. Tablets may also be molded rather than compressed,
starting with a moist or otherwise tractable material; however, compression and granulation
techniques are preferred.
In addition to the active agent(s), then, tablets prepared for oral administration using the method
of the invention will generally contain other materials such as binders, diluents, lubricants,
disintegrants, fillers, stabilizers, surfactants, coloring agents, and the like. Binders are used to
impart cohesive qualities to a tablet, and thus ensure that the tablet remains intact after
compression. Suitable binder materials include, but are not limited to, starch (including corn
starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and
lactose), polyethylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium
alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose,
hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and the
20

like), and Veegum. Diluents are typically necessary to increase bulk so that a practical size
tablet is ultimately provided. Suitable diluents include dicalcium phosphate, calcium sulfate,
lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Lubricants
are used to facilitate tablet manufacture; examples of suitable lubricants include, for example,
magnesium stearate, calcium stearate, and stearic acid. Stearates, if present, preferably
represent at no more than about2 wt. % of the drug-containing core. Disintegrants are used to
facilitate disintegration of the tablet, and are generally starches, clays, celluloses, algins, gums,
or crosslinked polymers. Fillers include, for example, materials such as silicon dioxide, titanium
dioxide, alumina, talc, kaolin, powdered cellulose, and microcrystalline cellulose, as well as
soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, and
sorbitol. Stabilizers are used to inhibit or retard drug decomposition reactions that include, by
way of example, oxidative reactions. Surfactants may be anionic, cationic, amphoteric, or
nonionic surface-active agents.
The dosage form may also be a capsule, in which case the active agent-containing composition
may be encapsulated in the form of a liquid or solid (including particulates such as granules,
beads, powders, or pellets). Suitable capsules may be either hard or soft, and are generally
made of gelatin, starch, or a cellulosic material, with gelatin capsules preferred. Two-piece hard
gelatin capsules are preferably sealed, such as with gelatin bands or the like.
In one embodiment, then, the cholesterol-lowering agent, . Peroxisome proliferator activator
agent (Fibric acid derivatives), and the aspirin are each individually contained within a separate
layer of a multilayered tablet. Tablet may further comprise a layer of excipient, , between the
layers containing aspirin and the layer(s) containing the other active agents. Additionally, tablet
may include a layer that contains at least one of vitamin B.sub.6, vitamin B.sub.12, and folate.
Preferably, a single layer contains vitamin B.sub.6, vitamin B.sub.12, and folate blended
together. In a particularly preferred embodiment, the cholesterol-lowering agent, . Peroxisome
proliferator activator agent , and the aspirin are each individually contained within a separate
layer of a multilayered tablet in unit doses appropriate for once-daily dosing, further wherein the
cholesterol-lowering agent and peroxisome proliferator activator agent (Fibric acid derivatives)
are each in a controlled release dosage unit (e.g., a sustained release and/or delayed release
dosage unit) and the aspirin is in an immediate release dosage unit. In a particularly preferred
embodiment, tablet may further comprises a layer that comprises vitamin B.sub.6, vitamin
B.sub.12, and folate blended together.
21

In a highly preferred embodiment, the tablet comprises 80 mg Atorvastatin as the cholesterol-
lowering agent, 150 mg Peroxisome proliferator activator agent (Fibric acid derivatives), 80 mg
aspirin, 50 mg vitamin B.sub.6, 1 mg vitamin B.sub.12, and 3 mg folic acid.
In another embodiment, wherein the dosage form of the invention comprises a table containing
active agent beads in a blended matrix, at least one of the active agents is formulated into
beads and at least one of the other active agents is formulated into the matrix of the tablet that
surrounds the beads. The beads may be uncoated, be coated with a protective layer, be
enterically coated, be coated or otherwise formulated for sustained released, or be coated or
otherwise formulated for delayed release. The matrix may be formulated for immediate release,
delayed release, or sustained release. In a preferred embodiment, the cholesterol-lowering
agent and Peroxisome proliferator activator agent (Fibric acid derivatives) are each individually
formulated into a plurality of beads, said beads being formulated for sustained release, while the
aspirin is comprised within the matrix, said matrix being formulated for immediate release. In a
particularly preferred embodiment, tablet further comprises vitamin B.sub.6, vitamin B.sub.12,
and folate blended together with the aspirin in the matrix, and each of the active agents is
present in a unit dosage appropriate for once-daily dosing.
In a further embodiment, wherein the dosage form of the invention comprises blended
immediate release tablets or capsules, all the active agents are blended together as one dosage
unit in one immediate release dosage form, either a tablet or a capsule. In this embodiment,
care is taken to ensure the stability and compatibility of the active agents; appropriate buffers
and other excipients are used, when necessary, to help ensure said stability and compatibility.
In a preferred embodiment, the tablet or capsule comprises 80 mg atorvastatin as the
cholesterol-lowering agent, 40 mg Peroxisome proliferator activator agent (Fenofibrate), 80mg
aspirin, 50 mg vitamin B.sub.6, 1 mg vitamin B.sub.12, and 3 mg folic acid.
In a further embodiment, wherein the dosage form of the invention is comprised of coated beads
or granules in a tablet or capsule, each active agent is individually formulated into a plurality of
coated beads or granules, the coating serving to prevent or inhibit chemical interaction among
the active agents and, optionally, serving to sustain or delay release of the active agent. In a
preferred embodiment, the cholesterol-lowering agent and fibric acid derivatives are each
formulated into beads or granules coated and otherwise formulated for sustained release, while
22

the aspirin is formulated into beads or granules coated and otherwise formulated for immediate
release.
In related embodiment, a capsule, preferably a hard gelatin capsule that is preferably sealed,
comprises within the interior of the capsule compressed or molded tablets, beads, or granules,
plus a pharmaceutically acceptable carrier. Each active agent is individually formulated into a
tablet, a plurality of tablets, a plurality of beads, or a plurality of granules. The tablets, beads, or
granules may be coated and/or otherwise formulated for immediate release, delayed release, or
sustained release. The capsule may contain a mixture of tablets, beads, or granules; further, the
capsule may contain a mixture of said dosage units in coated and uncoated forms. A preferred
dosage form is a hard, sealed gelatin capsule comprising a cholesterol-lowering agent and an
inhibitor of the peroxisome proliferator activator (Fibric acid derivatives) each individually
formulated in a tablet, a plurality of tablets, a plurality of beads, or a plurality of granules
formulated for sustained release, plus aspirin, vitamin B.sub.6, vitamin B.sub.12, and folate
each individually formulated into a tablet, a plurality of tablets, a plurality of beads, or a plurality
of granules formulated for immediate release.
The methods and compositions of this invention are directed at individuals who are at elevated
cardiovascular risk, where cardiovascular risk comprises the potential for cardiac arrest, acute
or chronic myocardial infarction, coronary heart disease, ischemia, stroke, peripheral vascular
disease, claudication, worsening angina, restenosis, and/or atherosclerosis. Individuals who are
at elevated cardiovascular risk include those with systemic lupus erythematosus; diabetes;
angina pectoris; manifest coronary artery disease; hypertension; hypercholesterolemia; kidney
disease; Chlamydia infection; Bartonella infection; obstructive pulmonary disease; who are on
hemodialysis; who have received an organ transplant; who are obese; who are elderly; who
have a family history of heart disease, atherosclerosis, or stroke; who are or have been
cigarette smokers; or who have a history of myocardial infarction, transient ischemic attacks,
stroke, atherosclerosis, or peripheral vascular disease.
Many individuals who are at elevated cardiovascular risk are not treated for this condition,
commonly due to the lack of an effective, safe, and convenient therapy. For example, women
with systemic lupus erythematosus are at increased risk of myocardial infarction and stroke,
likely due to an increased propensity for premature atherosclerosis, but are rarely treated
adequately to reduce this risk. As therapy would be chronic for individuals at elevated
23

cardiovascular risk, probably for the life of the patient, it should be simple and convenient for the
patient. A high compliance rate for chronic therapy is found when a drug is administered orally
once per day, preferably at bedtime. The present invention provides a combination of
cholesterol-lowering agent, inhibitor of the fibric acid derivatives, aspirin, and optionally B
vitamins comprised within a single unit-dose tablet or capsule for once-daily dosing, preferably
at bedtime. The present invention thus addresses a major medical need by providing an
effective, safe, simple, and convenient way to reduce the risk of cardiovascular events in
patients at elevated cardiovascular risk. Such a dosage form provides convenience and
simplicity for the patient, thus increasing the chances for patient compliance, especially in
patients who already take multiple medications due to existing heart disease or other diseases.
Since three or more active agents are being used together in a combination therapy, the
potency of each of the agents and the interactive effects achieved by combining them together
must be taken into account. A consideration of these factors is well within the purview of the
ordinarily skilled clinician for the purpose of determining the therapeutically effective or
prophylactically effective dosage amounts.
Preferred oral dosage forms contain a therapeutically effective unit dose of each active agent,
wherein the unit dose is suitable for once-daily oral administration. The therapeutically effective
unit dose of any particular active agent will depend, of course, on the active agent, the needs of
the patient, and on other factors known to the prescribing physician. Those of ordinary skill in
the art of pharmaceutical formulation can readily deduce suitable unit doses for various active
agents. The therapeutically useful doses are;
About 10 mg to about 120 mg, preferably about 5 mg to about 80 mg, of an HMG CoA
reductase inhibitor selected from the group consisting of atorvastatin, fluvastatin, lovastatin,
pravastatin, and simvastatin.
About 1 mg to about 160 mg, preferably about 30 mg to about 150 mg, of an Peroxisome
proliferator activator agent selected from the group consisting of Fenofibrate, Benzafibrate, and
the like
About 20 mg to about600 mg, preferably about20 mg to about325 mg, of aspirin.
24

Optionally,
About 25 mg to About 75 mg, preferably about40 mg to about60 mg, of vitamin B.sub.6. or
About 0.25 mg to About 2 mg, preferably about0.5 mg to about1.5 mg, of vitamin B.sub.12. or
About 0.5 mg to About 8 mg, preferably about1.5 mg to about5 mg, of folic acid.
The formulations of the invention will be administered for as long as the patient is at elevated
cardiovascular risk; very likely, this will be for a prolonged period and possibly for the life of the
patient. Administration for a least one to two weeks is required for minimal benefit to be
achieved. In addition to the preferred formulations designed for daily dosing, sustained release
forms of such formulations may be employed, which may provide for dosing biweekly, weekly,
monthly, or the like.
In another embodiment, a packaged kit is provided that contains a plurality of oral dosage forms
for self administration; a container means, preferably sealed, for housing the dosage forms
during storage and prior to use; and instructions for a patient to carry out drug administration.
The instructions will typically be written instructions on a package insert, a label, and/or on other
components of the kit, and the oral dosage forms are as described herein. Each dosage form
may be individually housed, as in a sheet of a metal foil-plastic laminate with each dosage form
isolated from the others in individual cells or bubbles, or the dosage forms may be housed in a
single container, as in a plastic bottle. The present kits will also typically include means for
packaging the individual kit components, i.e., the dosage forms, the container means, and the
written instructions for use. Such packaging means may take the form of a cardboard or paper
box, a plastic or foil pouch, etc.
It is to be understood that while the invention has been described in conjunction with the
preferred specific embodiments thereof, that the foregoing description as well as the examples
that follow are intended to illustrate and not limit the scope of the invention. Other aspects,
advantages, and modifications within the scope of the invention will be apparent to those skilled
in the art to which the invention pertains. The invention is not limited to the examples given in
the specification it may include other excipients which are known in the field of invention.
25

The practice of the present invention will employ, unless otherwise indicated, conventional
techniques of pharmaceutical formulation and the like, which are within the skill of the art. Such
techniques are fully explained in the literature. The foregoing examples are illustrative
embodiments of the invention and are merely exemplary. A person skilled in the art may make
variations and modifications without deviating from the spirit and scope of the invention. All such
modifications and variations are intended to be included within the scope of the invention.
Example 1.

Composition of First layer Mg/Tab
Atorvastatin 80
Xanthan Gum 40.00
Sodium Alginate 55.00
HPMC 70.00
MCC 50.00
PVP 75.00
Composition of Second layer Qty. (mg/tab.)
Fenofibrate 150
Hypermellose 65
Poloxamer 10
Mannitol 15
Composition of Third layer Qty. (mg/tab.)
Aspirin 100
Vitamin B 10
Microcrystalline cellulose 90
Procedure: A multilayered tablet are prepared as follows. The ingredients of each layer are
blended separately, and then compressed to produce a layered tablet using a suitable layered
press.
Example 2.

Composition of First layer Mg/Tab
Atorvastatin 80
26

Hydrogenated castor oil 50.00
Stearic acid 55.00
Microcrystalline cellulose 40.00
Composition of Second layer Qty. (mg/tab.)
Fenofibrate 150
Hydrogenated castor oil 65
Stearic acid 10
Microcrystalline cellulose 15
Composition of Third layer Qty. (mg/tab.)
Aspirin 100
Vitamin B 10
Microcrystalline cellulose 90
Procedure: Tablets comprising sustained release beads of Atorvastatin and Fenofibrate in a
blended matrix comprising aspirin, vitamin B.sub.6, vitamin B.sub.12, and folic acid are
prepared as follows.
The powdered ingredients of each of the bead formulations and of the matrix layer are blended
separately. To make each of the bead formulations, purified water is added to the powder of the
above components, and the mixture is kneaded and extruded from an extrusion granulator to
obtain rod-shaped granules. The granules are then rounded and dried. The sustained-release
beads are then blended with the matrix formulation and compress-molded to tablets. The
sustained release beads and the matrix are blended and then compressed into tablets or filled
in capsules
Example 3

Composition of First layer Mg/Tab
Atorvastatin 80
Hydrogenated castor oil 50.00
Stearic acid 55.00
Microcrystalline cellulose 40.00
Composition of Second layer Qty. (mg/tab.)
Fenofibrate 150
Hydrogenated castor oil 65
Stearic acid 10
27

Microcrystalline cellulose 15
Composition of Third layer Qty. (mg/tab.)
Aspirin 100
Vitamin B 10
Microcrystalline cellulose 90
Procedure: Tablets are prepared as in Example 2, except that the sustained release beads are
all coated with an enteric polymer in an aqueous or non-aqueous system. The sustained release
beads for Atorvastatin and Fenofibrate are coated separately. Eudragit was used as coating
agent.
Example 4

Composition Mg/Tab
Atorvastatin 80
Fenofibrate 40
Aspirin 100
Vitamin B 4
Corn starch 55.00
Calcium carbonate 40.00
Magnesium carbonate 65
Stearic acid 10
Magnesium oxide 2
Procedure: Tablets or capsules are prepared in which all the active agents are present in a
single dosage unit. The tablets can be prepared by any conventional method known in the prior
art. A hard gelatin capsule formulation is prepared by adding powdered ingredients, followed by
blending and then sealed in a hard gelatin capsule. The quantity of the buffering agents
(calcium carbonate, magnesium carbonate, magnesium oxide) can be added and adjusted as
necessary to minimize gastrointestinal side effects and possible interactions between the active
agents. It should be understood that these buffering agents can be replaced with other suitable
buffering agents, if desired.
Example 5
Tablets or capsules are prepared wherein all the active agents are separately present in
protectively coated or enterically coated granules or beads. In a hard gelatin capsule dosage
28

form, each of the active agents is granulated and coated with cellulose acetate phthalate
according to well-known pharmaceutical procedures.
Dated this 15th day of October 2007
29

An orally administrable pharmaceutical dosage form for the prevention and treatment of cardiovascular disorders, comprising a cholesterol-lowering agent, an inhibitor of the peroxisome proliferator activator agent and aspirin; along with at least one pharmaceutically acceptable excepient. . An orally administrable pharmaceutical dosage form for the prevention and treatment of cardiovascular disorders, comprising statin, fibric acid derivatives aspirin; along with at least one pharmaceutically acceptable excepient. . A kit for a patient with cardiovascular disorders comprising multiple oral dosage forms, the kit including instructions for carrying out drug administration therewith, the improvement comprising incorporating in said oral dosage forms a combination of active agents comprising a cholesterol-lowering agent, a inhibitor of the peroxisome proliferator activator agent and aspirin; along with at least one pharmaceutically acceptable excepient wherein the first and second actives agents are in the form of modified release, or immediate release. A kit for a patient with cardiovascular disorders
comprising multiple oral dosage forms, the kit including instructions for carrying out drug administration therewith, the improvement comprising incorporating in said oral dosage forms a combination of active agents comprising statin, fibric acid derivatives aspirin;
along with at least one pharmaceutically acceptable excepient Where in the first and second actives agents are in the form of modified release, or immediate release. A synergistic pharmaceutical combination comprising of comprising statin, fibric acid derivatives aspirin; for the prevention and treatment of cardiovascular disorders.