Note: Descriptions are shown in the official language in which they were submitted.
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NANOPARTICULATE FORMULATIONS COMPRISING HMG COA REDUCTASE INHIBITOR
DERIVATIVES ("STATINS"), COMBINATIONS THEREOF AS WELL AS MANUFACTURING
OF THESE PHARMACEUTICAL COMPOSITIONS
FIELD OF THE INVENTION
The present invention relates to nanoparticulate compositions comprising
statin,
preferably lovastatin or simvastatin, and novel statin combinations. The
nanoparticulate
statin particles preferably have an effective average particle. size of less
than about 2000
nm. In another aspect, this invention includes novel combinations of statins
and other
cholesterol lowering agents and methods of using the same.
BACKGROUND OF THE INVENTION
1. Background Regarding Nanoparticulate Active Agent Compositions
Nanoparticulate active agent compositions, first described in U.S. Patent No.
5,145,684 ("the `684 patent"), are particles consisting of a poorly soluble
therapeutic or
diagnostic agent having adsorbed onto, or associated with, the surface thereof
a non-
crosslinked surface stabilizer. Many factors can affect bioavailability
including the
dosage form and various properties, e.g., dissolution rate of the drug. Poor
bioavailability
is a significant problem encountered in the development of pharmaceutical
compositions,
particularly those containing an active ingredient that is poorly soluble in
water. By
decreasing the particle size of an active agent, the surface area of the
composition is
increased, thereby generally resulting in an increased bioavailability. The
`684 patent
does not teach nanoparticulate compositions of statins.
Methods of making nanoparticulate active agent compositions are described in,
for
example, U.S. Patent Nos. 5,518,187 and 5,862,999, both for "Method of
Grinding
Pharmaceutical Substances;" U.S. Patent No. 5,718,388, for "Continuous Method
of
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Grinding Pharmaceutical Substances;" and U.S. Patent No. 5,510,118 for
"Process of
Preparing Therapeutic Compositions Containing Nanoparticles."
Nanoparticulate active agent compositions are also described, for example, in
U.S.
Patent Nos. 5,298,262 for "Use of Ionic Cloud Point Modifiers to Prevent
Particle
Aggregation During Sterilization;" 5,302,401 for "Method to Reduce Particle
Size
Growth During Lyophilization;" 5,318,767 for "X-Ray Contrast Compositions
Useful in
Medical Imaging;" 5,326,552 for "Novel Formulation For Nanoparticulate X-Ray
Blood
Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;"
5,328,404
for "Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;"
5,336,507 for
"Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;" 5,340,564
for
"Formulations Comprising Olin 10-G to Prevent Particle Aggregation and
Increase
Stability;" 5,346,702 for "Use of Non-Ionic Cloud Point Modifiers to Minimize
Nanoparticulate Aggregation During Sterilization;" 5,349,957 for "Preparation
and
Magnetic Properties of Very Small Magnetic-Dextran Particles;" 5,352,459 for
"Use of
Purified Surface Modifiers to Prevent Particle Aggregation During
Sterilization;"
5,399,363 and 5,494,683, both for "Surface Modified Anticancer Nanoparticles;"
5,401,492 for "Water Insoluble Non-Magnetic Manganese Particles as Magnetic
Resonance Enhancement Agents;" 5,429,824 for "Use of Tyloxapol as a
Nanoparticulate
Stabilizer;" 5,447,710 for "Method for Making Nanoparticulate X-Ray Blood Pool
Contrast Agents Using High Molecular Weight Non-ionic Surfactants;" 5,451,393
for "X-
Ray Contrast Compositions Useful in Medical Imaging;" 5,466,440 for
"Formulations of
Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with
Pharmaceutically Acceptable Clays;" 5,470,583 for "Method of Preparing
Nanoparticle
Compositions Containing Charged Phospholipids to Reduce Aggregation;"
5,472,683 for
"Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents
for
Blood Pool and Lymphatic System Imaging;" 5,500,204 for "Nanoparticulate
Diagnostic
Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;"
5,518,738 for "Nanoparticulate NSAID Formulations;" 5,521,218 for
"Nanoparticulate
lododipamide Derivatives for Use as X-Ray Contrast Agents;" 5,525,328 for
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"Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood
Pool and
Lymphatic System Imaging;" 5,543,133 for "Process of Preparing X-Ray Contrast
Compositions Containing Nanoparticles;" 5,552,160 for "Surface Modified NSAID
Nanoparticles;" 5,560,931 for "Formulations of Compounds as Nanoparticulate
Dispersions in Digestible Oils or Fatty Acids;" 5,565,188 for "Polyalkylene
Block
Copolymers as Surface Modifiers for Nanoparticles;" 5,569,448 for "Sulfated
Non-ionic
Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle
Compositions;"
5,571,536 for "Formulations of Compounds as Nanoparticulate Dispersions in
Digestible
Oils or Fatty Acids;" 5,573,749 for "Nanoparticulate Diagnostic Mixed
Carboxylic
Anydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System
Imaging;"
5,573,750 for "Diagnostic Imaging X-Ray Contrast Agents;" 5,573,783 for
"Redispersible
Nanoparticulate Film Matrices With Protective Overcoats;" 5,580,579 for "Site-
specific
Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular
Weight,
Linear Poly(ethylene Oxide) Polymers;" 5,585,108 for "Formulations of Oral
Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically
Acceptable
Clays;" 5,587,143 for "Butylene Oxide-Ethylene Oxide Block Copolymers
Surfactants as
Stabilizer Coatings for Nanoparticulate Compositions;" 5,591,456 for "Milled
Naproxen
with Hydroxypropyl Cellulose as Dispersion Stabilizer;" 5,593,657 for "Novel
Barium
Salt Formulations Stabilized by Non-ionic and Anionic Stabilizers;" 5,622,938
for "Sugar
Based Surfactant for Nanocrystals;" 5,628,981 for "Improved Formulations of
Oral
Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal
Therapeutic
Agents;" 5,643,552 for "Nanoparticulate Diagnostic Mixed Carbonic Anhydrides
as X-
Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,718,388
for
"Continuous Method of Grinding Pharmaceutical Substances;" 5,718,919 for
"Nanoparticles Containing the R(-)Enantiomer of Ibuprofen;" 5,747,001 for
"Aerosols
Containing Beclomethasone Nanoparticle Dispersions;" 5,834,025 for "Reduction
of
Intravenously Administered Nanoparticulate Formulation Induced Adverse
Physiological
Reactions;" 6,045,829 "Nanocrystalline Formulations of Human Immunodeficiency
Virus
(HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;" 6,068,858 for
"Methods
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of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (11W)
Protease Inhibitors Using Cellulosic Surface Stabilizers;" 6,153,225 for
"Injectable
Formulations of Nanoparticulate Naproxen;" 6,165,506 for "New Solid Dose Form
of
Nanoparticulate Naproxen;" 6,221,400 for "Methods of Treating Mammals Using
Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease
Inhibitors;" 6,264,922 for "Nebulized Aerosols Containing Nanoparticle
Dispersions;"
6,267,989 for "Methods for Preventing Crystal Growth and Particle Aggregation
in
Nanoparticle Compositions;" 6,270,806 for "Use of PEG-Derivatized Lipids as
Surface
Stabilizers for Nanoparticulate Compositions;" 6,316,029 for "Rapidly
Disintegrating
Solid Oral Dosage Form," 6,375,986 for "Solid Dose Nanoparticulate
Compositions
Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and
Dioctyl
Sodium Sulfosuccinate;" 6,428,814 for "Bioadhesive Nanoparticulate
Compositions
Having Cationic Surface Stabilizers;" 6,431,478 for "Small Scale Mill;" and
6,432,381
for "Methods for Targeting Drug Delivery to the Upper and/or Lower
Gastrointestinal
Tract. In addition, U.S. Patent Application No. 20020012675 Al. published on
January 31. 2002, for "Controlled Release Nanoparticulate Compositions,"
describes
nanoparticulate compositions. None of these references describe
nanoparticulate
statin compositions.
Amorphous small particle compositions are described, for example, in U.S.
Patent
Nos. 4,783,484 for "Particulate Composition and Use Thereof as Antimicrobial
Agent;"
4,826,689 for 'Method for Making Uniformly Sized Particles from Water-
Insoluble
Organic Compounds;" 4,997,454 for "Method for Making Uniformly-Sized Particles
From Insoluble Compounds;" 5,741,522 for "Ultrasmall, Non-aggregated Porous
Particles
of Uniform Size for Entrapping Gas Bubbles Within and Methods;" and 5,776,496,
for
"Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter."
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II. Background Regarding Statins
Recently, a number of new drugs collectively known as statins or vastatins
have
been introduced to reduce serum LDL cholesterol levels (representative
examples of these
drugs are detailed in The Merck Index). High LDL cholesterol levels have been
shown to
be an important risk factor in the development of arteriosclerosis and
ischaemic heart
disease. Statins have been found to lower serum LDL cholesterol levels in a
dose
dependent manner. Additionally, these drugs lower serum triglyceride levels,
which is
another risk factor for heart disease.
Statins lower serum LDL cholesterol levels by competitive inhibition of 3-
hydroxyl-3-methylglutaryl-Coenzyme A reductase (HMG-COA reductase), an enzyme
involved in the biosynthesis of cholesterol. By binding tightly to the active
site of the
enzyme, statins block the reduction of HMG-CoA, a step necessary in the
biosynthesis of
cholesterol. This inhibition of cholesterol biosynthesis by a statin results
in a decrease in
the production and secretion of LDL cholesterol. In addition, the upregulation
of LDL
receptors, especially in the liver, leads to the removal of LDLs from the
serum. Thus, by
reducing the production of LDL cholesterol and by causing LDL cholesterol to
be
removed from the serum, statins effectively reduce overall serum LDL
cholesterol levels.
Two-thirds of the total cholesterol found in the body is of endogenous origin.
The major site of cholesterol biosynthesis is in the liver. Such liver-derived
cholesterol is
the main cause of the development of hyper-cholesterolaemia. In contrast,
cholesterol
production in non-hepatic cells is needed for normal cell function. Therefore,
selective
inhibition of HMG-CoA reductase in the liver is an important requirement for
HMG-COA
reductase inhibitors. In this regard, statins typically have high oral
availability and high
hepatic extraction during their first pass through the liver. Statins have
been associated
with significant liver toxicity.
Even though the current HMG-CoA reductase inhibitors are quite potent, a need
exists for safer, and higher potency HMG-CoA reductase inhibitors. The present
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invention satisfies these needs.
SUMMARY OF THE INVENTION
The present invention relates to nanoparticulate active agent compositions
comprising at least one statin, such as lovastatin or simvastatin, and novel
statin
combinations. The compositions preferably comprise at least one statin and at
least one
surface stabilizer adsorbed on or associated with the surface of the one or
more statin
particles. The nanoparticulate statin particles preferably have an effective
average particle
size of less than about 2000 nm.
Another aspect of the invention is directed to pharmaceutical compositions
comprising a nanoparticulate statin composition of the invention. The
pharmaceutical
compositions preferably comprise at least one statin, at least one surface
stabilizer, and at
least one pharmaceutically acceptable carrier, as well as any desired
excipients known to
those in the art and formulated into the dosage form desired.
In another aspect of this invention, novel combinations of statins and at
least one
other cholesterol lowering agent are described and methods of using the same
are taught.
Another aspect of the invention is directed to a nanoparticulate statin
composition
having improved pharmacokinetic profiles as compared to conventional
microcrystalline
statin formulations, such as improved Tma,,, Cmax, and AUC parameters.
One embodiment of the invention encompasses a statin composition, wherein the
pharmacokinetic profile of the statin is not substantially affected by the fed
or fasted state
of a subject ingesting the composition, preferably as defined by Cmax and AUC
guidelines
given by the U.S. Food and Drug Administration and/or the corresponding
European
regulatory agency (EMEA).
In yet another embodiment, the invention encompasses a statin composition of
the
invention, wherein administration of the composition to a subject in a fasted
state is
bioequivalent to administration of the composition to a subject in a fed
state, in particular
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as defined by Cmax and AUC guidelines given by the U.S. Food and Drug
Administration
and the corresponding European regulatory agency (EMEA).
Other embodiments of the invention include, but are not limited to,
nanoparticulate statin compositions which, as compared to conventional non-
nanoparticulate formulations of the same statin, preferably have one or more
of the
following properties: (1) smaller tablet or other solid dosage form size; (2)
smaller doses
of drug required to obtain the same pharmacological effect; (3) increased
bioavailability;
(4) an increased rate of dissolution for the nanoparticulate statin
compositions; and
(6) bioadhesive statin compositions.
This invention further discloses a method of making a nanoparticulate statin
composition according to the invention. Such method comprises contacting one
or more
statins and at least one surface stabilizer for a time and under conditions
sufficient to
provide a nanoparticulate statin composition. The one or more surface
stabilizers can be
contacted with the statin before, preferably during, or after size reduction
of the statin.
The present invention is also directed to methods of treatment using the
nanoparticulate statin compositions of the invention for conditions such as
hypercholesterolemia, hypertriglyceridemia, coronary heart disease, and
peripheral
vascular disease (including symptomatic carotid artery disease). In one
aspect, the
compositions of the invention can be used as adjunctive therapy to diet for
the reduction
of LDL-C, total-C, triglycerides, and Apo B in adult patients with primary
hypercholesterolemia or mixed dyslipidemia (Fredrickson Types Ha and IIb). In
another
aspect, the compositions can be used as adjunctive therapy to diet for
treatment of adult
patients with hypertriglyceridemia (Fredrickson Types IV and V
hyperlipidemia).
Markedly elevated levels of serum tryglycerides (e.g., > 2000 mg/dL) may
increase the
risk of developing pancreatitis. Other diseases that may be directly or
indirectly
associated with elevated, uncontrolled cholesterol metabolism, e.g.,
restenosis and
Alzheimer's disease, may also be treated with the compositions of this
invention. Other
methods of treatment using the nanoparticulate statin compositions of the
present
invention are know to those of skill in the art.
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Such methods comprise administering to a subject a therapeutically effective
amount of a nanoparticulate statin pharmaceutical composition according to the
invention.
Both the foregoing general description and the following detailed description
are
exemplary and explanatory and are intended to provide further explanation of
the
invention as claimed. Other objects, advantages, and novel features will be
readily
apparent to those skilled in the art from the following detailed description
of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to nanoparticulate active agent compositions
comprising at least one statin, such as lovastatin or simvastatin, and novel
statin
combinations. The compositions preferably comprise at least one statin and at
least one
surface stabilizer adsorbed on or associated with the surface of the statin
particles. The
nanoparticulate statin particles preferably have an effective average particle
size of less
than about 2000 nm.
As taught in the `684 patent, not every combination of surface stabilizer and
active
agent will result in a stable nanoparticulate composition. It was surprisingly
discovered
that stable nanoparticulate statin formulations can be made.
Even though the current HMG-CoA reductase inhibitors are quite potent, a need
exists for safer and higher potency HMG-CoA reductase inhibitors. Compositions
of
nanoparticulate statins decrease the amount of drug needed and the amount that
escapes
from the liver and this, in turn, decreases adverse side effects while
providing maximum
dose response. Additionally, a longer plasma half-life is believed to be
associated with
nanoparticulate statin compositions of the invention. Moreover, increasing the
duration
of effect of the HMG-CoA reductase inhibitor is expected to result in even
lower serum
cholesterol levels, with a further reduction in dose expected.
In general, the rate of dissolution of a particulate drug can increase with
increasing
surface area, e.g., decreasing particle size. Consequently, methods of making
finely
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divided drugs have been studied and efforts have been made to control the size
and size
range of drug particles in pharmaceutical compositions. However,
nanoparticulate active
agent formulations suitable for administration as a pharmaceutical require
formulation of
the active ingredient into a colloidal dispersion exhibiting the acceptable
nanoparticle size
range and the stability to maintain such size range and not agglomerate.
Merely
increasing surface area by decreasing particle size does not assure success.
Further
challenges include forming solid dose forms redispersible into the
nanoparticle form upon
administration to the patient to maintain the benefit of the nanoparticle
statin over the
traditional dosage form.
Advantages of the nanoparticulate statin formulations of the invention as
compared to conventional non-nanoparticulate formulations of the same statin
preferably
include, but are not limited to: (1) smaller tablet or other solid dosage form
size;
(2) smaller doses of drug required to obtain the same pharmacological effect;
(3) increased bioavailability; (4) substantially similar pharmacokinetic
profiles of the
nanoparticulate statin compositions when administered in the fed versus the
fasted state;
(5) improved pharmacokinetic profiles; (6) bioequivalency of the
nanoparticulate statin
compositions when administered in the fed versus the fasted state; (7) an
increased rate of
dissolution for the nanoparticulate statin compositions; (8) bioadhesive
statin
compositions; and (9) the nanoparticulate statin compositions can be used in
conjunction
with other active agents.
The present invention also includes nanoparticulate statin compositions
together
with one or more non-toxic physiologically acceptable carriers, adjuvants, or
vehicles,
collectively referred to as carriers. The compositions can be formulated for
parenteral
injection (e.g., intravenous, intramuscular, or subcutaneous), oral
administration in solid,
liquid, or aerosol form, vaginal, nasal, rectal, ocular, local (powders,
ointments or drops),
buccal, intracisternal, intraperitoneal, or topical administration, and the
like.
A preferred dosage form of the invention is a solid dosage form, although any
pharmaceutically acceptable dosage form can be utilized. Exemplary solid
dosage forms
include, but are not limited to, tablets, capsules, sachets, lozenges,
powders, pills, or
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granules. The solid dosage form can be, for example, a fast melt dosage form,
controlled
release dosage form, lyophilized dosage form, delayed release dosage form,
extended
release dosage form, pulsatile release dosage form, mixed immediate release
and
controlled release dosage form, or a combination thereof. A solid dose tablet
formulation
is preferred.
The present invention is described herein using several definitions, as set
forth
below and throughout the application.
"About" will be understood by persons of ordinary skill in the art and will
vary to
some extent on the context in which the term is used. If there are uses of the
term which
are not clear to persons of ordinary skill in the art given the context in
which it is used,
"about" will mean up to plus or minus 10% of the particular term.
"Conventional" or "non-nanoparticulate active agent" shall mean an active
agent
which is solubilized or which has an effective average particle size of
greater than about 2
microns.
"Poorly water soluble drugs" as used herein means those having a solubility of
less than about 30 mg/ml, preferably less than about 20 mg/ml, preferably less
than about
mg/ml, or preferably less than about 1 mg/ml. Such drugs tend to be eliminated
from
the gastrointestinal tract before being absorbed into the circulation.
Moreover, poorly
water soluble drugs tend to be unsafe for intravenous administration
techniques, which are
used primarily in conjunction with highly water soluble drug substances.
As used herein with reference to stable statin particles, "stable" includes,
but is not
limited to, one or more of the following parameters: (1) that the statin
particles do not
appreciably flocculate or agglomerate due to interparticle attractive forces,
or otherwise
significantly increase in particle size over time; (2) that the physical
structure of the statin
particles is not altered over time, such as by conversion from an amorphous
phase to
crystalline phase; (3) that the statin particles are chemically stable; and/or
(4) where the
statin has not been subject to a heating step at or above the melting point of
the statin in
the preparation of the nanoparticles of the invention.
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"Therapeutically effective amount" as used herein with respect to a drug
dosage,
shall mean that dosage that provides the specific pharmacological response for
which the
drug is administered in a significant number of subjects in need of such
treatment. It is
emphasized that "therapeutically effective amount," administered to a
particular subject in
a particular instance will not always be effective in treating the diseases
described herein,
even though such dosage is deemed a `therapeutically effective amount' by
those skilled
in the art. It is to be further understood that drug dosages are, in
particular instances,
measured as oral dosages, or with reference to drug levels as measured in
blood.
1. Preferred Characteristics of the Statin Compositions of the Invention
A. Increased Bioavailability and Lower Dosages
The statin compositions of the invention preferably exhibit increased
bioavailability, at the same dose of the same statin, require smaller doses,
and show
longer plasma half-life as compared to prior conventional statin formulations.
In one aspect of the invention, pharmaceutical statin compositions have
enhanced
bioavailability such that the statin dosage can be reduced, resulting in a
decrease in
toxicity associated with such statins. It has been surprisingly found in the
present
invention that stable compositions of nanoparticulate statins can be formed
that permit
therapeutic levels at desirably lower dosage.
Greater bioavailability of the statin compositions of the invention can enable
a
smaller solid dosage size. This is particularly significant for patient
populations such as
the elderly, juvenile, and infant.
B. Improved Pharmacokinetic Profiles
The invention also preferably provides statin compositions having a desirable
pharmacokinetic profile when administered to mammalian subjects. The desirable
pharmacokinetic profile of the statin compositions preferably includes, but is
not limited
to: (1) that the Tmax of a statin when assayed in the plasma of a mammalian
subject
following administration is preferably less than the Tmax for a conventional,
non-
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nanoparticulate form of the same statin, administered at the same dosage; (2)
that the Cmax
of a statin when assayed in the plasma of a mammalian subject following
administration
is preferably greater than the Cmax for a conventional, non-nanoparticulate
form of the
same statin, administered at the same dosage; and/or (3) that the AUC of a
statin when
assayed in the plasma of a mammalian subject following administration, is
preferably
greater than the AUC for a conventional, non-nanoparticulate form of the same
statin,
administered at the same dosage.
The desirable pharmacokinetic profile, as used herein, is the pharmacokinetic
profile measured after the initial dose of a statin. The compositions can be
formulated in
any way as described below and as known to those of skill in the art.
A preferred statin composition of the invention exhibits in comparative
pharmacokinetic testing with a non-nanoparticulate formulation of the same
statin,
administered at the same dosage, a Tmax not greater than about 90%, not
greater than
about 80%, not greater than about 70%, not greater than about 60%, not greater
than about
50%, not greater than about 30%, not greater than about 25%, not greater than
about 20%,
not greater than about 15%, or not greater than about 10% of the Tmax,
exhibited by the
non-nanoparticulate formulation of the same statin.
A preferred statin composition of the invention exhibits in comparative
pharmacokinetic testing with a non-nanoparticulate formulation of the same
statin,
administered at the same dosage, a Cmax which is at least about 10%, at least
about 20%,
at least about 30%, at least about 40%, at least about 50%, at least about
60%, at least
about 70%, at least about 80%, at least about 90%, or at least about 100%
greater than the
Cmax exhibited by the non-nanoparticulate formulation of the same statin.
A preferred statin composition of the invention exhibits in comparative
pharmacokinetic testing with a non-nanoparticulate formulation of the same
statin,
administered at the same dosage, an AUC which is at least about 10%, at least
about 20%,
at least about 30%, at least about 40%, at least about 50%, at least about
60%, at least
about 70%, at least about 80%, at least about 90%, or at least about 100%
greater than the
AUC exhibited by the non-nanoparticulate formulation of the same statin.
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Any formulation giving the desired pharmacokinetic profile is suitable for
administration according to the present methods. Exemplary types of
formulations giving
such profiles are liquid dispersions, gels, aerosols, ointments, creams, solid
dose forms,
etc. of a nanoparticulate statin.
C. The Pharmacokinetic Profiles of the Statin Compositions
of the Invention are not Affected by the Fed or Fasted State
of the Subject Ingesting the Compositions
The invention encompasses a statin composition wherein the pharmacokinetic
profile of the statin is preferably not substantially affected by the fed or
fasted state of a
subject ingesting the composition, when administered to a human. This means
that there
is no substantial difference in the quantity of drug absorbed or the rate of
drug absorption
when the nanoparticulate statin compositions are administered in the fed
versus the fasted
state.
The invention also encompasses a statin composition in which administration of
the composition to a subject in a fasted state is bioequivalent to
administration of the
composition to a subject in a fed state. "Bioequivalency" is preferably
established by a
90% Confidence Interval (CI) of between 0.80 and 1.25 for both Cmax and AUC
under
U.S. Food and Drug Administration regulatory guidelines, or a 90% Cl for AUC
of
between 0.80 to 1.25 and a 90% Cl for Cma, of between 0.70 to 1.43 under the
European
EMEA regulatory guidelines (Tmax is not relevant for bioequivalency
determinations
under USFDA and EMEA regulatory guidelines).
In the prior art, lovastatin given under fasting conditions, has been shown to
result
in plasma concentrations of total inhibitors that were on average about two-
thirds those
found when lovastatin was administered immediately after a standard test meal.
This
significant difference of about 33% in absorption observed with conventional
statin
formulations is undesirable. The nanoparticulate statin formulations of the
invention
alleviate this problem, as the nanoparticulate statin formulations of the
invention reduce
differences in or preferably do not produce significantly different,
absorption levels when
administered under fed as compared to fasting conditions.
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Benefits of a dosage form which substantially eliminates the effect of food
include
an increase in subject convenience, thereby increasing subject compliance, as
the subject
does not need to ensure that they are taking a dose either with or without
food. This is
significant, as with poor subject compliance an increase in the medical
condition for
which the drug is being prescribed may be observed.
The difference in absorption of the statin compositions of the invention, when
administered in the fed versus the fasted state, preferably is less than about
100%, less
than about 90%, less than about 80%, less than about 70%, less than about 60%,
less than
about 50%, less than about 40%, less than about 30%, less than about 25%, less
than
about 20%, less than about 15%, less than about 10%, less than about 5%, or
less than
about 3%.
D. Dissolution Profiles of the Statin Compositions of the Invention
The statin compositions of the invention preferably have unexpectedly dramatic
dissolution profiles. Rapid dissolution of an administered active agent is
preferable, as
faster dissolution generally leads to faster onset of action and greater
bioavailability. To
improve the dissolution profile and bioavailability of statins it would be
useful to increase
the drug's dissolution so that it could attain a level close to 100%.
The statin compositions of the invention preferably have a dissolution profile
in
which within about 5 minutes at least about 20% of the composition is
dissolved. In other
embodiments of the invention, at least about 30% or about 40% of the statin
composition
is dissolved within about 5 minutes. In yet other embodiments of the
invention,
preferably at least about 40%, about 50%, about 60%, about 70%, or about 80%
of the
statin composition is dissolved within about 10 minutes. Finally, in another
embodiment
of the invention, preferably at least about 70%, about 80%, about 90%, or
about 100% of
the statin composition is dissolved within about 20 minutes.
Dissolution is preferably measured in a medium which is discriminating. Such a
dissolution medium will produce two very different dissolution curves for two
products
having very different dissolution profiles in gastric juices; i.e., the
dissolution medium is
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predictive of in vivo dissolution of a composition. An exemplary dissolution
medium is
an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025 M.
Determination of the amount dissolved can be carried out by spectrophotometry.
The
rotating blade method (European Pharmacopoeia) can be used to measure
dissolution.
E. Redispersibility Profiles of the Statin Compositions of the Invention
An additional feature of the statin compositions of the invention is that the
compositions preferably redisperse such that the effective average particle
size of the
redispersed statin particles is less than about 2 microns. This is
significant, as if upon
administration the nanoparticulate statin compositions of the invention did
not redisperse
to a substantially nanoparticulate particle size, then the dosage form may
lose the benefits
afforded by formulating the statin into a nanoparticulate particle size.
This is because nanoparticulate active agent compositions benefit from the
small
particle size of the active agent; if the active agent does not redisperse
into the small
particle sizes upon administration, then "clumps" or agglomerated active agent
particles
are formed, owing to the extremely high surface free energy of the
nanoparticulate system
and the thermodynamic driving force to achieve an overall reduction in free
energy. With
the formation of such agglomerated particles, the bioavailability of the
dosage form may
fall well below that observed with the liquid dispersion form of the
nanoparticulate active
agent.
Moreover, the nanoparticulate statin compositions of the invention preferably
exhibit dramatic redispersion of the nanoparticulate statin particles upon
administration to
a mammal, such as a human or animal, as demonstrated by
reconstitution/redispersion in a
biorelevant aqueous media such that the effective average particle size of the
redispersed
statin particles is less than about 2 microns. Such biorelevant aqueous media
can be any
aqueous media that exhibit the desired ionic strength and pH, which form the
basis for the
biorelevance of the media. The desired pH and ionic strength are those that
are
representative of physiological conditions found in the human body. Such
biorelevant
aqueous media can be, for example, aqueous electrolyte solutions or aqueous
solutions of
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any salt, acid, or base, or a combination thereof, which exhibit the desired
pH and ionic
strength.
Biorelevant pH is well known in the art. For example, in the stomach, the pH
ranges from slightly less than 2 (but typically greater than 1) up to 4 or 5.
In the small
intestine the pH can range from 4 to 6, and in the colon it can range from 6
to 8.
Biorelevant ionic strength is also well known in the art. Fasted state gastric
fluid has an
ionic strength of about 0. 1M while fasted state intestinal fluid has an ionic
strength of
about 0.14. See e.g., Lindahl et al., "Characterization of Fluids from the
Stomach and
Proximal Jejunum in Men and Women," Pharm. Res., 14 (4): 497-502 (1997).
It is believed that the pH and ionic strength of the test solution is more
critical than
the specific chemical content. Accordingly, appropriate pH and ionic strength
values can
be obtained through numerous combinations of strong acids, strong bases,
salts, single or
multiple conjugate acid-base pairs (i.e., weak acids and corresponding salts
of that acid),
monoprotic and polyprotic electrolytes, etc.
Representative electrolyte solutions can be, but are not limited to, HCl
solutions,
ranging in concentration from about 0.001 to about 0.1 M, and NaCl solutions,
ranging in
concentration from about 0.001 to about 0.1 M, and mixtures thereof. For
example,
electrolyte solutions can be, but are not limited to, about 0.1 M HCl or less,
about 0.01 M
HCl or less, about 0.001 M HCl or less, about 0.1 M NaCl or less, about 0.01 M
NaCl or
less, about 0.001 M NaCl or less, and mixtures thereof. Of these electrolyte
solutions,
0.01 M HCl and/or 0.1 M NaCl, are most representative of fasted human
physiological
conditions, owing to the pH and ionic strength conditions of the proximal
gastrointestinal
tract.
Electrolyte concentrations of 0.001 M HCI, 0.01 M HCI, and 0.1 M HCl
correspond to pH 3, pH 2, and pH 1, respectively. Thus, a 0.01 M HCl solution
simulates
typical acidic conditions found in the stomach. A solution of 0.1 M NaCl
provides a
reasonable approximation of the ionic strength conditions found throughout the
body,
including the gastrointestinal fluids, although concentrations higher than 0.1
M may be
employed to simulate fed conditions within the human GI tract.
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Exemplary solutions of salts, acids, bases or combinations thereof, which
exhibit
the desired pH and ionic strength, include but are not limited to phosphoric
acid/phosphate salts + sodium, potassium and calcium salts of chloride, acetic
acid/acetate
salts + sodium, potassium and calcium salts of chloride, carbonic
acid/bicarbonate salts +
sodium, potassium and calcium salts of chloride, and citric acid/citrate salts
+ sodium,
potassium and calcium salts of chloride.
In other embodiments of the invention, the redispersed statin particles of the
invention (redispersed in an aqueous, biorelevant, or any other suitable
media) have an
effective average particle size of less than about 1900 nm, less than about
1800 nm, less
than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less
than about
1400 nm, less than about 1300 nm, less than about 1200 nm, less than about
1100 nm,
less than about 1000 nm, less than about 900 nm, less than about 800 nm, less
than about
700 nm, less than about 600 nm, less than about 500 nm, less than about 400
nm, less
than about 300 nm, less than about 250 nm, less than about 200 nm, less than
about 150
nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm,
as measured
by light-scattering methods, microscopy, or other appropriate methods.
By "an effective average particle size of less than about 2000 nm" it is meant
that
at least 50% of the statin particles have a particle size less than the
effective average, by
weight, i.e., less than about 2000 nm, 1900 nm, 1800 nm, etc., when measured
by the
above-noted techniques. Preferably, at least about 70%, about 90%, about 95%,
or about
99% of the statin particles have a particle size less than the effective
average, i.e., less
than about 2000 nm, 1900 nm, 1800 nm, 1700 nm, etc.
Redispersibility can be tested using any suitable means known in the art. See
e.g.,
the example sections of U.S. Patent No. 6,375,986 for "Solid Dose
Nanoparticulate
Compositions Comprising a Synergistic Combination of a Polymeric Surface
Stabilizer
and Dioctyl Sodium Sulfosuccinate."
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F. Bloadhesive Statin Compositions
Bioadhesive statin compositions of the invention comprise at least one
cationic
surface stabilizer, which are described in more detail below. Bioadhesive
formulations of
statins exhibit exceptional bioadhesion to biological surfaces, such as
mucous. The term
bioadhesion refers to any attractive interaction between two biological
surfaces or
between a biological and a synthetic surface. In the case of bioadhesive
nanoparticulate
statin compositions, the term bioadhesion is used to describe the adhesion
between the
nanoparticulate statin compositions and a biological substrate (i.e.
gastrointestinal mucin,
lung tissue, nasal mucosa, etc.). See e.g., U.S. Patent No. 6,428,814 for
"Bioadhesive
Nanoparticulate Compositions Having Cationic Surface Stabilizers".
There are basically two mechanisms which may be responsible for this
bioadhesion phenomena: mechanical or physical interactions and chemical
interactions.
The first of these, mechanical or physical mechanisms, involves the physical
interlocking
or interpenetration between a bioadhesive entity and the receptor tissue,
resulting from a
good wetting of the bioadhesive surface, swelling of the bioadhesive polymer,
penetration
of the bioadhesive entity into a crevice of the tissue surface, or
interpenetration of
bioadhesive composition chains with those of the mucous or other such related
tissues.
The second possible mechanism of bioadhesion incorporates forces such as ionic
attraction, dipolar forces, van der Waals interactions, and hydrogen bonds. It
is this form
of bioadhesion which is primarily responsible for the bioadhesive properties
of the
nanopartieulate statin compositions of the invention. However, physical and
mechanical
interactions may also play a secondary role in the bioadhesion of such
nanoparticulate
compositions.
The bioadhesive statin compositions of the invention are useful in any
situation in
which it is desirable to apply the compositions to a biological surface. The
bioadhesive
statin compositions coat the targeted surface in a continuous and uniform film
which is
invisible to the naked human eye.
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A bioadhesive statin composition slows the transit of the composition, and
some
statin particles would also most likely adhere to tissue other than the mucous
cells and
therefore give a prolonged exposure to the statin, thereby increasing
absorption and the
bioavailability of the administered dosage.
G. Statin Compositions Used in Conjunction with Other Active Agents
The statin compositions of the invention can additionally comprise one or more
compounds useful: (1) in treating conditions such as dyslipidemia,
hyperlipidemia,
hypercholesterolemia, cardiovascular disorders, hypertriglyceridemia, coronary
heart
disease, and peripheral vascular disease (including symptomatic carotid artery
disease), or
related conditions; (2) as adjunctive therapy to diet for the reduction of LDL-
C, total-C,
triglycerides, and/or Apo B in adult patients with primary
hypercholesterolemia or mixed
dyslipidemia (Fredrickson Types Ha and IIb); (3) as adjunctive therapy to diet
for
treatment of adult patients with hypertriglyceridemia (Fredrickson Types IV
and V
hyperlipidemia); (4) in treating pancreatitis; (5) in treating restenosis;
and/or (6) in
treating Alzheimer's disease.
Exemplary non-statin compositions useful in the claimed invention include, but
are not limited to, cholesterol lowering agents, polycosanols, alkanoyl L-
carnitines,
antihypertensives, sterols and/or stanols.
Useful cholesterol lowering agents are well known to those of skill in the art
and
include, but are not limited to, ACE inhibitors, nicotinic acid, niacin, bile
acid
sequestrants, fibrates, vitamins, fatty acid derivatives such as fish oil,
long chain plant
extract alcohols such as policosinol, ezetimibe, and celluloses.
Useful polycosanols include, but are not limited to, triacontanol,
hexacontanol,
ecocosanol, hexacosanol, tetracosanol, dotriacontanol, tetracontanol, or
natural products
or extracts from natural products containing such compounds.
Useful alkanoyl L-carnitines include, but are not limited to, acetyl L-
carnitine,
propionyl L-carnitine, butyryl L-camitine, valeryl L-carnitine, and isovaleryl
L-carnitine,
or a pharmacologically acceptable salt thereof.
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Examples of antihypertensives include, but are not limited to diuretics
("water
pills"), beta blockers, alpha blockers, alpha-beta blockers, sympathetic nerve
inhibitors,
angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers,
angiotensin
receptor blockers (formal medical name angiotensin-2-receptor antagonists,
known as
"sartans" for short).
Examples of sterols and stanols include, but are not limited to plant sterols,
plant
sterol esters, fish oil, sitosterol, sitostanol, phytosterol, campestanol,
stigmasterol,
coprostanol, cholestanol, beta-sitosterol, and the like.
Such additional compounds can have a conventional non-nanoparticulate particle
size, i.e., an effective average particle size greater than about 2 microns,
or such
additional compounds can be formulated into a nanoparticulate particle size,
i.e., an
effective average particle size of less than about 2 microns. If such one or
more non-
statin compounds have a nanoparticulate particle size, then preferably such
non-statin
compounds are poorly soluble in at least one liquid media (poorly soluble as
defined in
the "Definitions" section, above), and have at least one surface stabilizer
adsorbed on or
associated with the surface of the non-statin compound. The one or more
surface
stabilizers utilized in the composition of the non-statin compound can be the
same as or
different from the one or more surface stabilizers utilized in the statin
composition. A
description of surface stabilizers useful in the invention is provided below.
II. Compositions
The present invention is directed to nanoparticulate active agent compositions
comprising at least one statin, such as lovastatin or simvastatin, and novel
statin
combinations. The compositions preferably comprise at least one statin and at
least one
surface stabilizer adsorbed on, or associated with, the surface of the statin.
The
nanoparticulate statin particles preferably have an effective average particle
size of less
than about 2000 nm. In another aspect of this invention, novel combinations of
statins
and other cholesterol lowering agents are described and methods of using the
same are
taught.
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The present invention also includes nanoparticulate statin compositions
together
with one or more non-toxic physiologically acceptable carriers, adjuvants, or
vehicles,
collectively referred to as carriers. The compositions can be formulated for
various routes
of administration including but not limited to, oral, rectal, ocular, and
parenteral injection
(e.g., intravenous, intramuscular, or subcutaneous), oral administration in
solid (the
preferred route), liquid, or aerosol form, vaginal, nasal, rectal, ocular,
local (e.g., in
powder, ointment or drop form), buccal, intracisternal, intraperitoneal, or
topical
administration, and the like.
A. Statin Particles
As used herein "statin" means any HMG-CoA Reductase Inhibitor (including their
analogs), or a salt thereof, having preferably the solubility in water of
lovastatin or
simvastatin, or a solubility in water of less than about 30 mg/ml, less than
about 20
mg/ml, less than about 10 mg/ml, or more preferably less than about 1 mg/ml.
The one or more statin particles, or salt thereof, can be in a crystalline
phase, an
amorphous phase, a semi-crystalline phase, a semi-amorphous phase, or a
mixture thereof.
Such statin compounds include, but are not limited to, atorvastatin
(Lipitor(D)
(U.S. Patent No. 4,681,893) and other 6-[2-(substituted-pyrrol-1-
yl)alkyl]pyran-2-ones
and derivatives as disclosed in U.S. Patent No. 4,647,576); fluvastatin
(Lescolo) (U.S.
Patent No. 5,354,772); lovastatin (U.S. Patent No. 4,231,938); pravastatin
(U.S. Patent
No. 4,346,227); simvastatin (U.S. Patent No. 4,444,784); velostatin;
fluindostatin (Sandoz
XU-62-320); pyrazole analogs of mevalonolactone derivatives, as disclosed in
PCT
application WO 86/03488; rivastatin and other pyridyldihydroxyheptenoic acids,
as
disclosed in European Patent 491226A; Searle's SC-45355 (a 3-substituted
pentanedioic
acid derivative); dichloroacetate; imidazole analogs of mevalonolactone, as
disclosed in
PCT application WO 86/07054; 3-carboxy-2-hydroxy-propane-phosphonic acid
derivatives, as disclosed in French Patent No. 2,596,393; 2,3-di-substituted
pyrrole, furan,
and thiophene derivatives, as disclosed in European Patent Application No.
0221025;
naphthyl analogs of mevalonolactone, as disclosed in U.S. Patent No.
4,686,237;
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octahydronaphthalenes, such as those disclosed in U.S. Patent No. 4,499,289;
keto
analogs of mevinolin (lovastatin), as disclosed in European Patent Application
No.
0,142,146 A2; phosphinic acid compounds; as well as other HMG CoA reductase
inhibitors.
Lovastatin is one of the most important known cholesterol lowering agents.
Lovastatin as used herein (CAS Registry No. 75330-75-5) is also known as
mevinolin or
monacolin K and is chemically known as beta,beta-dihydroxy-7-[1,2,6,7,8,8a-
hexahydro-
2,6-dimethyl-8-(2-methyl -butyryloxy)-1-napthalen-1-yl]-heptanoic acid beta-
lactone.
Lovastatin is one member of a class of compounds which are referred to
generally as
statins and which are known to exist in open ring hydroxy acid and in lactone
form.
Lovastatin and its analogs inhibit HMG-CoA reductase. Lovastatin is
specifically
advantageous because, as a result of its application, biosynthetic
intermediates that have a
toxic steroid skeleton formed at a later stage of biosynthesis fail to
accumulate.
Lovastatin also increases the number of LDL-receptors at the surface of the
cell
membrane, which remove the LDL cholesterol circulating in the blood, thereby
inducing
the lowering of blood plasma cholesterol level.
Lovastatin is routinely produced via fermentation and is a white,
nonhygroscopic
crystalline powder that is insoluble in water and sparingly soluble in
ethanol, methanol,
and acetonitrile.
Lovastatin tablets are commercially supplied as 10 mg, 20 mg, and 40 mg
tablets
for oral administration. In addition to the active ingredient lovastatin, each
tablet contains
cellulose, lactose, magnesium stearate, and starch. Butylated hydroxyanisole
(BHA) is
added as a preservative.
Lovastatin is well known in the art and is readily recognized by one of
ordinary
skill. High LDL cholesterol is usually first treated with exercise, weight
loss in obese
individuals, and a diet low in cholesterol and saturated fats. When these
measures fail,
cholesterol-lowering medications such as lovastatin can be added. The National
Cholesterol Education Program (NCEP) has published treatment guidelines for
use of
statins such as lovastatin. These treatment guidelines take into account the
level of LDL
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cholesterol as well as the presence of other risk factors such as diabetes,
hypertension,
cigarette smoking, low HDL cholesterol level, and family history of early
coronary heart
disease. The effectiveness of the statin medications in lowering cholesterol
is dose-
related. Blood cholesterol determinations are performed in regular intervals
during
treatment so that dosage adjustments can be made. A reduction in LDL
cholesterol level
can be seen two weeks after starting therapy with a statin.
B. Surface Stabilizers
Surface stabilizers especially useful herein physically adhere on or associate
with
the surface of the nanoparticulate statin but do not chemically react with the
statin
particles or itself. Preferably, individual molecules of the surface
stabilizer are essentially
free of intermolecular cross-linkages.
The choice of a surface stabilizer for a statin is non-trivial and required
extensive
experimentation to realize a desirable formulation for the active ingredient's
therapeutic
effect desired. For example, the effectiveness of using of a particular
stabilizer with an
active ingredient is unpredictable because the stabilizer among other factors,
will effect
dissolution and pharmacokinetic profiles for a statin. Accordingly, the
present invention
is directed to the surprising discovery that stable, therapeutically useful,
nanoparticulate
statin compositions can be made.
Combinations of more than one surface stabilizer can preferably be used in the
invention. Useful surface stabilizers which can be employed in the invention
include, but
are not limited to, known organic and inorganic pharmaceutical excipients.
Such
excipients include various polymers, low molecular weight oligomers, natural
products,
and surfactants. Preferred surface stabilizers include nonionic, anionic,
cationic, and
zwitterionic surfactants.
Representative examples of surface stabilizers include
hydroxypropylmethylcellulose (anionic), hydroxypropylcellulose,
polyvinylpyrrolidone,
sodium lauryl sulfate, dioctylsulfosuccinate (anionic), gelatin, casein,
lecithin
(phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid,
benzalkonium
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chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol,
cetomacrogol
emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol
ethers such
as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene
sorbitan
fatty acid esters (e.g., the commercially available Tweens such as e.g.,
Tween 20" and
Tween 80" (ICI Speciality Chemicals)); polyethylene glycols (e.g., Carbowaxs
3550 and
934 (Union Carbide)), polyoxyethylene stearates, colloidal silicon dioxide,
phosphates,
carboxymethylcellulose calcium, carboxymethylcellulose sodium, methyl
cellulose,
hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline
cellulose,
magnesium aluminium silicate, triethanolamine, polyvinyl alcohol (PVA), 4-
(1,1,3,3-
tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also
known as
tyloxapol, superione, and triton), poloxamers (e.g., Pluronics F68 and F1080,
which are
block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g.,
Tetronic
9080, also known as Poloxamine 908 , which is a tetrafunctional block
copolymer
derived from sequential addition of propylene oxide and ethylene oxide to
ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508
(T-
1508) (BASF Wyandotte Corporation), Triton X-2000, which is an alkyl aryl
polyether
sulfonate (Dow Chemical); Crodestas F-110 , which is a mixture of sucrose
stearate and
sucrose distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol), also known
as Olin-
lOG or Surfactant 10-G" (Olin Chemicals, Stamford, CT); Crodestas SL-40"
(Croda,
Inc.); and SA9OHCO, which is C18H37CH2(CON(CH3)-CH2(CHOH)4(CH2OH)2
(Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl (3-D-glucopyranoside;
n-
decyl (3-D-maltopyranoside; n-dodecyl f-D-glucopyranoside; n-dodecyl (3-D-
maltoside;
heptanoyl-N-methylglucamide; n-heptyl-(3-D-glucopyranoside; n-heptyl Q-D-
thioglucoside; n-hexyl Q-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl
P-D-
glucopyranoside; octanoyl-N-methylglucamide; n-octyl-(3-D-glucopyranoside;
octyl (3-D-
thioglucopyranoside; PEG-derivatized phospholipid, PEG- derivatized
cholesterol, PEG-
derivatized cholesterol derivative, PEG- derivatized vitamin A, PEG-
derivatized vitamin
E, lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate, and the
like such
as Plasdone S630 in a 60:40 ratio of the pyrrolidone and vinyl acetate.
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More examples of useful surface stabilizers include, but are not limited to,
polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids,
and
nonpolymeric compounds, such as zwitterionic stabilizers, poly-n-
methylpyridinium,
anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine,
polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide
bromide (PMMTMABr), hexadecyltrimethylammonium bromide (HDMAB), and
polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate.
Other useful cationic stabilizers include, but are not limited to, cationic
lipids,
sulfonium, phosphonium, and quarternary ammonium compounds, such as
stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium
bromide,
coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl
ammonium chloride or bromide, decyl triethyl ammonium chloride, decyl dimethyl
hydroxyethyl ammonium chloride or bromide, C12-15dimethyl hydroxyethyl
ammonium
chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or
bromide,
myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium
chloride or bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride or bromide,
N-alkyl
(C12_18)dimethylbenzyl ammonium chloride, N-alkyl (C14_18)dimethyl-benzyl
ammonium
chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl
didecyl
ammonium chloride, N-alkyl and (C12-14) dimethyl 1-napthylmethyl ammonium
chloride,
trimethylammonium halide, alkyl-trimethylammonium salts and dialkyl-
dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl ammonium
salt,
diallcylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride,
N-
tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C12_14)
dimethyl 1-
naphthylmethyl ammonium chloride and dodecyldimethylbenzyl ammonium chloride,
dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride,
allcylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide,
C12,
C15, C17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium
chloride,
poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides,
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alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride,
decyltrimethylammonium bromide, dodecyltriethylammonium bromide,
tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride (ALIQUAT
336TM), POLYQUAT 1OTM, tetrabutylammonium bromide, benzyl trimethylammonium
bromide, choline esters (such as choline esters of fatty acids), benzalkonium
chloride,
stearalkonium chloride compounds (such as stearyltrimonium chloride and Di-
stearyldimonium chloride), cetyl pyridinium bromide or chloride, halide salts
of
quaternized polyoxyethylalkylamines, MIRAPOLTM and ALKAQUATTM (Alkaril
Chemical Company), alkyl pyridinium salts; amines, such as alkylamines,
dialkylamines,
alkanolamines, polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, and
vinyl
pyridine, amine salts, such as lauryl amine acetate, stearyl amine acetate,
alkylpyridinium
salt, and alkylimidazolium salt, and amine oxides; imide azolinium salts;
protonated
quaternary acrylamides; methylated quaternary polymers, such as poly[diallyl
dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium chloride]; and
cationic guar.
Such exemplary cationic surface stabilizers and other useful cationic surface
stabilizers are described in J. Cross and E. Singer, Cationic Surfactants:
Analytical and
Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor),
Cationic
Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond,
Cationic
Surfactants: Organic Chemistry, (Marcel Dekker, 1990).
Nonpolymeric surface stabilizers are any nonpolymeric compound, such
benzalkonium chloride, a carbonium compound, a phosphonium compound, an
oxonium
compound, a halonium compound, a cationic organometallic compound, a
quarternary
phosphorous compound, a pyridinium compound, an anilinium compound, an
ammonium
compound, a hydroxylammonium compound, a primary ammonium compound, a
secondary ammonium compound, a tertiary ammonium compound, and quarternary
ammonium compounds of the formula NR1R2R3R4(+). For compounds of the formula
NRIR2R3R4(+):
(i) none of R1-R4 are CH3;
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(ii) one of R1-R4 is CH3;
(iii) three of R1-R4 are CH3;
(iv) all of Rl-R4 are CH3;
(v) two of R1-R4 are CH3, one of R1-R4 is C6HSCH2, and one of RI-R4 is an
alkyl chain of seven carbon atoms or less;
(vi) two of R1-R4 are CH3, one of R1-R4 is C6HSCH2, and one of R1-R4 is an
alkyl chain of nineteen carbon atoms or more;
(vii) two of R1-R4 are CH3 and one of R1-R4 is the group C6H5(CH2),,, where
n>1;
(viii) two of R1-R4 are CH3, one of RI-R4 is C6H5CH2, and one of R1-R4
comprises at least one heteroatom;
(ix) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1-R4
comprises at least one halogen;
(x) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1-R4
comprises at least one cyclic fragment;
(xi) two of R1-R4 are CH3 and one of R1-R4 is a phenyl ring; or
(xii) two of R1-R4 are CH3 and two of RI-R4 are purely aliphatic fragments.
Such compounds include, but are not limited to, behenalkonium chloride,
benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride,
lauralkonium
chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride,
cethylamine
hydrofluoride, chlorallylmethenamine chloride (Quaternium-15),
distearyldimonium
chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium
chloride(Quaternium-
14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite,
dimethylaminoethylchloride hydrochloride, cysteine hydrochloride,
diethanolammonium
POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether
phosphate,
tallow alkonium chloride, dimethyl dioctadecylammoniumbentonite, stearalkonium
chloride, domiphen bromide, denatonium benzoate, myristalkonium chloride,
laurtrimonium chloride, ethylenediamine dihydrochloride, guanidine
hydrochloride,
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pyridoxine HCI, iofetamine hydrochloride, meglumine hydrochloride,
methylbenzethouium chloride, myrtrimonium bromide, oleyltrimonium chloride,
polyquaternium-1, procainehydrochloride, cocobetaine, stearalkonium bentonite,
stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine
dihydrofluoride,
tallowtrimonium chloride, and hexadecyltrimethyl ammonium bromide.
Most of these surface stabilizers are known pharmaceutical excipients and are
described in detail in the Handbook of Phamiaceutical Excipients, published
jointly by
the American Pharmaceutical Association and The Pharmaceutical Society of
Great
Britain (The Pharmaceutical Press, 2000).
The surface stabilizers are commercially available and/or can be prepared by
techniques known in the art.
C. Other Pharmaceutical Excipients
Pharmaceutical compositions according to the invention may also comprise one
or
more binding agents, filling agents, lubricating agents, suspending agents,
sweeteners,
flavoring agents, preservatives, buffers, wetting agents, disintegrants,
effervescent agents,
and other excipients depending upon the route of administration and the dosage
form
desired. Such excipients are known in the art.
Examples of filling agents are lactose monohydrate, lactose anhydrous, and
various starches; examples of binding agents are various celluloses and cross-
linked
polyvinylpyrrolidone, microcrystalline cellulose, such as Aviecl PHI 01, and
Aviccl
PH102, microcrystalline cellulose, and silicified microcrystalline cellulose
(ProSolv
SMCCT"').
Suitable lubricants, including agents that act on the flowability of the
powder to be
compressed, are colloidal silicon dioxide, such as Aerosil 200, talc, stearic
acid,
magnesium stearate, calcium stearate, and silica gel.
Examples of sweeteners are any natural or artificial sweetener, such as
sucrose,
xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame. Examples of
flavoring
agents are Magnasweet (trademark of MAFCO), bubble gum flavor, and fruit
flavors,
and the like.
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Examples of preservatives are potassium sorbate, methylparaben, propylparaben,
benzoic acid and its salts, other esters of parahydroxybenzoic acid such as
butylparaben,
alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol,
or
quarternary compounds such as benzalkonium chloride.
Suitable diluents include pharmaceutically acceptable inert fillers, such as
microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides,
and/or
mixtures of any of the foregoing. Examples of diluents include
microcrystalline cellulose,
such as Avicel PH101 and Avicel PH102; lactose such as lactose monohydrate,
lactose
anhydrous, and Pharmatose DCL21; dibasic calcium phosphate such as Emcompress
;
mannitol; starch; sorbitol; sucrose; and glucose.
Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn
starch, potato starch, maize starch, and modified starches, croscarmellose
sodium, cross-
povidone, sodium starch glycolate, and mixtures thereof.
Examples of effervescent agents are effervescent couples such as an organic
acid
and a carbonate or bicarbonate. Suitable organic acids include, for example,
citric,
tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides
and acid salts.
Suitable carbonates and bicarbonates include, for example, sodium carbonate,
sodium
bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate,
sodium
glycine carbonate, L-lysine carbonate, and arginine carbonate. Alternatively,
only the
sodium bicarbonate component of the effervescent couple may be present.
D. Nanoparticulate Statin Particle Size
The compositions of the invention contain statin nanoparticles, such as
lovastatin
or simvastatin nanoparticles, which have an effective average particle size of
less than
about 2000 nm (i.e., 2 microns). In a preferred embodiment of the invention,
the statin
nanoparticles have an effective average particle size of less than about 1900
nm, less than
about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than
about 1500
nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm,
less than
about 1100 nm, less than about 1000 nm, less than about 900 nm, less than
about 800 nm,
less than about 700 nm, less than about 600 nm, less than about 500 nm, less
than about
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400 nm, less than about 300 nm, less than about 250 nm, less than about 200
nm, less
than about 150 nm, less than about 100 nm, less than about 75 nm, or less than
about 50
nm, as measured by light-scattering methods, microscopy, or other appropriate
methods.
By "an effective average particle size of less than about 2000 nm" it is meant
that
at least 50% of the statin particles have a particle size less than the
effective average, by
weight, i.e., less than about 2000 nm, about 1900 nm, about 1800 nm, etc.,
when
measured by the above-noted techniques. Preferably, at least about 70%, about
90%,
about 95%, or about 99% of the statin particles have a particle size of less
than the
effective average, i.e., less than about 2000 nm, about 1900 nm, about 1800
nm, etc..
In the present invention, the value for D50 of a nanoparticulate statin
composition
is the particle size below which 50% of the statin particles fall, by weight.
Similarly, D90
is the particle size below which 90% of the statin particles fall, by weight.
E. Concentration of Nanoparticulate Statin and Surface Stabilizers
The relative amounts of at least one statin and one or more surface
stabilizers can
vary widely. The optimal amount of the individual components depends, for
example,
upon one or more of the physical and chemical attributes of the particular
statin selected
and surface stabilizer(s) selected, such as the hydrophilic lipophilic balance
(HLB),
melting point, and the surface tension of water solutions of the stabilizer,
etc.
Preferably, the concentration of the at least one statin can vary from about
99.5%
to about 0.001%, preferably from about 95% to about 0.1%, preferably from
about 90% to
about 0.5%, by weight, based on the total combined weight of the statin and at
least one
surface stabilizer, not including other excipients. Higher concentrations of
the active
ingredient are generally preferred from a dose and cost efficiency standpoint.
Preferably, the concentration of the at least one surface stabilizer can vary
from
about 0.5% to about 99.999%, from about 5.0% to about 99.9%, or from about 10%
to
about 99.5%, by weight, based on the total combined dry weight of the statin
and at least
one surface stabilizer, not including other excipients.
Exemplary useful ratios of active ingredient to stabilizers herein are
preferably
about 1:1, preferably about 2:1, preferably about 3:1, preferably about 4:1,
preferably
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about 5:1, preferably about 6:1, preferably about 7:1, preferably about 8:1,
and preferably
about 10:1, by weight, based on the total combined dry weight of the statin
and at least
one surface stabilizer, not including other excipients.
IJI. Methods of Makinn Nanoparticulate Stalin Compositions
The nanoparticulate statin compositions can be made using any suitable method
known in the art such as, for example, milling, homogenization, or
precipitation
techniques. Exemplary methods of making nanoparticulate compositions are
described in
the '684 patent. Methods of making nanoparticulate compositions are also
described in
U.S. Patent No. 5,518,187 for "Method of (.minding Pharmaceutical Substances;"
U.S.
Patent No. 5,718,388 for "Continuous Method of Grinding Pharmaceutical
Substances;"
U.S. Patent No. 5,862,999 for "Method of Grinding Pharmaceutical Substances;"
U.S.
Patent No. 5,665,331 for "Co-Microprecipitation of Nanoparticulate
Pharmaceutical
Agents with Crystal Growth Modifiers;" U.S. Patent No. 5,662,883 for "Co-
Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal
Growth
Modifiers;" U.S. Patent No. 5,560,932 for `Microprecipitation of
Nanoparticulate
Pharmaceutical Agents;" U.S. Patent No. 5,543,133 for "Process of Preparing X-
Ray
Contrast Compositions Containing Nanoparticles;" U.S. Patent No. 5,534,770 for
"Method of Preparing Stable Drug Nanoparticles;" U.S. Patent No. 5,510,118 for
"Process of Preparing Therapeutic Compositions Containing Nanoparticles;" and
U.S.
Patent No. 5,470,583 for "Method of Preparing Nanoparticle Compositions
Containing
Charged Phospholipids to Reduce Aggregation
The resultant nanoparticulate statin compositions or dispersions can be
utilized in
solid or liquid dosage formulations, such as liquid dispersions, gels,
aerosols, ointments,
creams, controlled release formulations, fast melt formulations, lyophilized
formulations,
tablets, capsules, delayed release formulations, extended release
formulations, pulsatile
release formulations, mixed immediate release and controlled release
formulations, etc.
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Solid dose forms of the dispersions of novel statin formulations according to
the present
invention can be made as described in U.S. Patent No. 6,375,986.
A. Milling to Obtain Nanoparticulate Statin Dispersions
Milling a statin to obtain a nanoparticulate statin dispersion comprises
dispersing
statin particles in a liquid dispersion medium in which the statin is poorly
soluble,
followed by applying mechanical means in the presence of grinding media to
reduce the
particle size of the statin to the desired effective average particle size.
The dispersion
medium can be, for example, water, safflower oil, ethanol, t-butanol,
glycerin,
polyethylene glycol (PEG), hexane, or glycol.
The statin particles can be reduced in size preferably in the presence of at
least one
surface stabilizer. Alternatively, the statin particles can be contacted with
one or more
surface stabilizers after attrition. Other compounds, such as a diluent, can
be added to the
statin/surface stabilizer composition during the size reduction process.
Dispersions can be
manufactured continuously or in a batch mode.
B. Precipitation to Obtain Nanoparticulate Statin Compositions
Another method of forming the desired nanoparticulate statin composition is by
microprecipitation. This is a method of preparing stable dispersions of poorly
soluble
active agents in the presence of one or more surface stabilizers and one or
more colloid
stability enhancing surface active agents free of any trace toxic solvents or
solubilized
heavy metal impurities. Such a method comprises, for example: (1) dissolving
statin in a
suitable solvent; (2) adding the formulation from step (1) to a solution
comprising at least
one surface stabilizer; and (3) precipitating the formulation from step (2)
using an
appropriate non-solvent. The method can be followed by removal of any formed
salt, if
present, by dialysis or diafiltration and concentration of the dispersion by
conventional
means.
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C. Homogenization to Obtain Statin Nanoparticulate Compositions
Exemplary homogenization methods of preparing active agent nanoparticulate
compositions are described in U.S. Patent No. 5,510,118, for "Process of
Preparing
Therapeutic Compositions Containing Nanoparticles." Such a method comprises
dispersing statin particles in a liquid dispersion media in which the statin
is poorly
soluble, followed by subjecting the dispersion to homogenization to reduce the
particle
size of the statin to the desired effective average particle size. The statin
particles can be
reduced in size in the presence of at least one surface stabilizer.
Alternatively, the statin
particles can be contacted with one or more surface stabilizers either before
or after
attrition. Other compounds, such as a diluent, can be added to the
statin/surface stabilizer
composition either before, during, or after the size reduction process.
Dispersions can be
manufactured continuously or in a batch mode.
IV. Methods of Using Statin Formulations of the Current Invention
The statin compositions of the present invention can be administered to a
subject
via any conventional means including, but not limited to, preferably orally,
rectally,
ocularly, parenterally (e.g., intravenous, intramuscular, or subcutaneous),
intracisternally,
pulmonary, intravaginally, intraperitoneally, locally (e.g., powders,
ointments or drops),
or as a buccal or nasal spray. As used herein, the term "subject" is used to
mean an
animal, preferably a mammal, including a human or non-human. The terms patient
and
subject may be used interchangeably.
The present invention provides a method of prolonging plasma levels of statin
in a
subject while achieving the desired therapeutic effect. In one aspect, such a
method
comprises orally administering to a subject an effective amount of a
composition of this
invention comprising statin.
In one aspect, the compositions of the invention are useful in treating
conditions
that may be directly or indirectly associated with elevated and/or
uncontrolled cholesterol
metabolism as described herein and known to those in the art.
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Compositions suitable for parenteral injection may comprise physiologically
acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions
or
emulsions, and sterile powders for reconstitution into sterile injectable
solutions or
dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents, or
vehicles include water, ethanol, polyols (propyleneglycol, polyethylene-
glycol, glycerol,
and the like), suitable mixtures thereof, vegetable oils (such as olive oil)
and injectable
organic esters such as ethyl oleate. Proper fluidity can be maintained, for
example, by the
use of a coating such as lecithin, by the maintenance of the required particle
size in the
case of dispersions, and by the use of surfactants.
The nanoparticulate statin compositions may also contain adjuvants such as
preserving, wetting, emulsifying, and dispensing agents. Prevention of the
growth of
microorganisms can also be ensured by various antibacterial and antifungal
agents, such
as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to
include isotonic agents, such as sugars, sodium chloride, and the like.
Prolonged
absorption of the injectable pharmaceutical form can be brought about by the
use of
agents delaying absorption, such as aluminum monostearate and gelatin.
Solid dosage forms for oral administration are preferred and include, but are
not
limited to, capsules, tablets, pills, powders, caplets, and granules. In such
solid dosage
forms, the active agent (i.e. the composition of this invention) is admixed
with at least one
of the following: (a) one or more inert excipients (or carriers), such as
sodium citrate or
dicalcium phosphate; (b) fillers or extenders, such as starches, lactose,
sucrose, glucose,
mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose,
alignates, gelatin,
polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol;
(e) disintegrating agents, such as agar-agar, calcium carbonate, potato or
tapioca starch,
alginic acid, certain complex silicates, and sodium carbonate; (f) solution
retarders, such
as paraffin; (g) absorption accelerators, such as quaternary ammonium
compounds;
(h) wetting agents, such as cetyl alcohol and glycerol monostearate; (i)
adsorbents, such as
kaolin and bentonite; and (j) lubricants, such as talc, calcium stearate,
magnesium
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stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures
thereof. For
capsules, tablets, and pills, the dosage forms may also comprise buffering
agents.
Liquid dosage forms for oral administration include pharmaceutically
acceptable
dispersions, emulsions, solutions, suspensions, syrups, and elixirs. In
addition to the
active agent, the liquid dosage forms may comprise inert diluents commonly
used in the
art, such as water or other solvents, solubilizing agents, and emulsifiers.
Exemplary
emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl
acetate, benzyl
alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,
dimethylformamide, oils,
such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil,
and sesame oil,
glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, fatty acid esters
of sorbitan, or
mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such
as
wetting agents, emulsifying and suspending agents, sweetening, flavoring, and
perfuming
agents.
The effective amounts of the statin composition of this invention can be
determined empirically and can be employed in pure form or, where such forms
exist, in
pharmaceutically acceptable salt, ester, or prodrug form. Actual dosage levels
of statin in
the nanoparticulate compositions of the invention may be varied to obtain an
amount of
statin that is effective to obtain a desired therapeutic response for a
particular composition
and method of administration and the condition to be treated. The selected
dosage level
therefore depends upon the desired therapeutic effect, the route of
administration, the
potency of the administered statin, the desired duration of treatment, and
other factors.
Dosage unit compositions may contain such amounts of such submultiples thereof
as may be used to make up the daily dose. It will be understood, however, that
the
specific dose level for any particular patient will depend upon a variety of
factors: the
type and degree of the cellular or physiological response to be achieved;
activity of the
specific agent or composition employed; the specific agents or composition
employed; the
age, body weight, general health, sex, and diet of the patient; the time of
administration,
route of administration, and rate of excretion of the agent; the duration of
the treatment;
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drugs used in combination or coincidental with the specific agent; and like
factors well
known in the medical arts.
V. Statin Combinations
Statin compositions of the present invention are also particularly useful when
given pursuant to the method of this invention in combination with a
therapeutically
effective amount of at least one other active agent useful: (1) in treating
conditions such
as dyslipidemia, hyperlipidemia, hypercholesterolemia, cardiovascular
disorders,
hypertriglyceridemia, coronary heart disease, and peripheral vascular disease
(including
symptomatic carotid artery disease), or related conditions; (2) as adjunctive
therapy to diet
for the reduction of LDL-C, total-C, triglycerides, and/or Apo B in adult
patients with
primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types Ila and
IIb); (3)
as adjunctive therapy to diet for treatment of adult patients with
hypertriglyceridemia
(Fredrickson Types IV and V hyperlipidemia); (4) in treating pancreatitis; (5)
in treating
restenosis; and/or (6) in treating Alzheimer's disease.
Exemplary non-statin compositions useful in the claimed invention include, but
are not limited to, cholesterol lowering agents, polycosanols, alkanoyl L-
carnitines,
antihypertensives, sterols and/or stanols.
Useful cholesterol lowering agents are well known to those of skill in the art
and
include, but are not limited to, ACE inhibitors, nicotinic acid, niacin, bile
acid
sequestrants, fibrates, vitamins, fatty acid derivatives such as fish oil,
long chain plant
extract alcohols such as policosinol, ezetimibe, and celluloses.
Useful polycosanols include, but are not limited to, triacontanol,
hexacontanol,
ecocosanol, hexacosanol, tetracosanol, dotriacontanol, tetracontanol, or
natural products
or extracts from natural products containing such compounds.
Useful alkanoyl L-carnitines include, but are not limited to, acetyl L-
carnitine,
propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine, and
isovaleryl L-carnitine,
or a pharmacologically acceptable salt thereof.
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Examples of antihypertensives include, but are not limited to diuretics
("water
pills"), beta blockers, alpha blockers, alpha-beta blockers, sympathetic nerve
inhibitors,
angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers,
angiotensin
receptor blockers (formal medical name angiotensin-2-receptor antagonists,
known as
"sartans" for short).
Examples of sterols and stanols include, but are not limited to plant sterols,
plant
sterol esters, fish oil, sitosterol, sitostanol, phytosterol, campestanol,
stigmasterol,
coprostanol, cholestanol, beta-sitosterol, and the like.
"Stanek" as used herein mean plant stanol esters, a food ingredient that can
help
reduce LDL cholesterol. Plant stanols are derived from naturally occurring
substances in
plants by techniques known to those in the art. The stanols are frequently
combined with
a small amount of canola oil to form stanol esters, producing an ingredient
that can be
used in a wide variety of foods and in combination with the compositions of
this
invention.
*****
The following examples are given to illustrate the present invention. It
should he
understood, however, that the invention is not to be limited to the specific
conditions or
details described in these examples.
In the examples that follow, the particle sizes were measured using a Horiba
LA-
910 Laser Scattering Particle Size Distribution Analyzer (Horiba Instruments,
Irvine, CA).
The particle mean and D90 (which is the size below which 90% of the
distribution is
located) are obtained from a weight distribution. Furthermore, all
formulations are given
in weight % (w/w).
Several of the formulations in the examples that follow were also investigated
using a light microscope.
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Example 1
The purpose of this example was to prepare nanoparticulate dispersions of
lovastatin, and to test the prepared compositions for stability at varying
temperatures.
Four formulations of lovastatin were milled, as described in Table 1, by
milling
the components of the compositions under high energy milling conditions in a
DYNO -
Mill KDL (Willy A. Bachofen AG, Maschinenfabrik, Basle, Switzerland) for 2 to
3 hours
until the desired particle size was achieved.
Formulation 1 comprised 5% (w/w) lovastatin, 1.25% (w/w)
Hydroxypropylcellulose, super-low viscosity grade (HPC-SL), and 0.05% (w/w)
dioctyl
sodium sulfosuccinate (DOSS).
Formulation 2 comprised 5% (w/w) lovastatin, 1.25% (w/w)
hydroxypropylmethylcellulose (HPMC), and 0.05% (w/w) dioctyl sodium
sulfosuccinate
(DOSS).
Formulation 3 comprised 5% (w/w) lovastatin, 1.25% (w/w) Povidone USP,
Plasdone K29/52 (PVPK29\32), and 0.05% (w/w) dioctyl sodium sulfosuccinate
(DOSS).
Formulation 4 comprised 5% (w/w) lovastatin, 1.25% (w/w) Plasdone S630
(S630), and 0.05% (w/w) dioctyl sodium sulfosuccinate (DOSS).
The particle size of the resultant compositions was measured using a Horiba LA-
910 Laser Scattering Particle Size Distribution Analyzer ((Horiba Instruments,
Irvine,
CA).
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Table I
Formulation Post-Milling Stability Stability Stability
Particle Size Particle Size @ Particle Size @ Particle Size @
(nm) 5C (nm) 25C (nm) 40C (nm)
#1 Mean: 165 Mean: 184 Mean: 188 Mean: 205
D90: 218 4 weeks D90: 247 D90: 264
4 weeks 4 weeks
#2 Mean: 174 Mean: 183 Mean: 191 Mean: 213
D90: 227 D90: 241 D90: 253 D90: 280
4 weeks 4 weeks 4 weeks
#3 Mean: 173 Mean: 169 Mean: 179 Mean: 193
D90: 229 D90: 223 D90: 237 D90: 252/
4 weeks 4 weeks 4 weeks
#4 Mean: 165 Mean: 165 Mean: 187 Mean: 235
D90: 218 D90: 220 D90: 246 D90:310
4 weeks 4 weeks 4 weeks
The results of this experiment show that all formulations or compositions were
stable.
Example 2
As described in the literature (Phannazie, Volume 56, September 2001, p 738-
740), lovastatin has a potential for oxidative degradation. To determine which
of the
formulations exhibited the least amount of degradants an HPLC analysis was
performed
on the compositions prepared in Example 1.
The method was a reversed phase HPLC method based on an existing assay
method found in the literature (Phannazie, Volume 56, September 2001, p 738-
740). The
results of these sample runs were compared to an active pharmaceutical
ingredient (API),
commercially available lovastatin, standard to determine which milled sample
was least
oxidized.
Analysis took place after 4-5 weeks of storage. The four different samples
were
compared to an API standard. For this comparison three factors were used to
determine
which formulation was optimal: (1) the percent lovastatin, (2) overall
appearance of
impurity profile, and (3) the percent area of the peak at RRT 0.87. This peak
was selected
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was because it had the largest area of all the impurity peaks and seemed to
increase as the
area of the lovastatin peak decreased.
Formulation #2 containing HPMC compared the best with the API standard. Both
had similar amount of impurities, percent lovastain, and comparable peak areas
at RRT
0.87. The sample containing PVP K29/32 had the highest amount of impurities,
lowest
percent lovastatin, and the largest peak area at RRT 0.87.
The results of this experiment showed that the formulation containing BPMC
yielded the best impurity profile. No significant differences from the
lovastatin API
profile were observed, indicating minimal oxidative degradation occurred
during milling
or subsequent storage.
Example 3
The purpose of this example was to evaluate the efficacy of nanoparticulate
lovastatin compositions.
New Zealand White rabbits were fed a diet enriched with 1% cholesterol for
four
weeks. At the four week time point the animals were maintained on a high
cholesterol
diet but were dosed (in the fed state) each day for a additional four week
period with 6
mg/kg dose of either suspensions of Formulation #2 (Example 1) or commercially
available lovastatin (Mevacor ) tablets mortarized into a crude suspension
comprising
the same quantities of HPMC and DOSS as Formulation #2. Placebo also comprised
the
same quantities of HPMC and DOSS as formulation #2.
Blood samples for total cholesterol analysis were taken at -2, 0, 2, & 4 weeks
after
dosing. Total change in cholesterol for each group was as follows:
1. Mevacor mortarized tablets dosed as a liquid suspension: -17.8% (N=6)
2. Formulation #2 dosed as a liquid suspension: -23.2% (N=8)
3. Placebo dosed as a liquid suspension: -12.3 (N=4)
4. Diet enriched with 1% cholesterol (not dosed): +0.10 (N=4)
Blood samples for liver activity (37.8 U of ALAT liver enzyme activity) showed
the following percentage of rabbits above 3X normal levels as follows:
CA 02488499 2004-12-07
WO 03/103640 PCT/US03/16206
1. Mevacor mortarized tablets dosed as a liquid: 20% (N=6)
2. Formulation #2 dosed as a liquid suspension: 7.6% (N=8)
3. Placebo dosed as a liquid: 0 (N=4)
The results indicate that Formulation #2 shows greater efficacy and lower
liver
toxicity trends than the other two groups measured.
****
It will be apparent to those skilled in the art that various modifications and
variations can be made in the methods and compositions of the present
invention without
departing from the spirit or scope of the invention. Thus, it is intended that
the present
invention cover the modifications and variations of this invention provided
they come
within the scope of the appended claims and their equivalents.
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