Note: Descriptions are shown in the official language in which they were submitted.
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DEVICES AND METHODS FOR CHOLESTEROL MANAGEMENT
FIELD OF THE INVENTION
The invention relates to implanted devices for management of cholesterol
levels.
BACKGROUND OF THE INVENTION
Coronary heart disease (CHD) remains the leading cause of death in the
industrialized
countries. Despite recent declines in CHD mortality, CHI) is still responsible
for more than
500,000 deaths in the U.S. annually. It is estimated that CHD, directly and
indirectly, costs the
U.S. more than $100 billion a year.
A primary cause of CHI) is atherosclerosis, a disease characterized by the
deposition of
lipids in the arterial vessel wall and a resulting narrowing of the vessel
passages, and ultimately
by a hardening of the vascular system. Atherosclerosis as manifested in its
major clinical
complication, ischemic heart disease, is thought to begin with local injury to
the arterial
endothelium, followed by proliferation of arterial smooth muscle cells from
the medial layer to
the intimal layer, which is accompanied by deposition of lipid and
accumulation of foam cells in
the lesion. As the atherosclerotic plaque develops, it progressively occludes
more and more
blood vessel and can eventually lead to ischemia or infarction.
Hypercholesterolemia is an important risk factor associated with CHD. For
example, in
December 1984, a National Institute of Health Consensus Development Conference
Panel
concluded that lowering plasma cholesterol levels (specifically blood levels
of low-density
lipoprotein cholesterol) will reduce the risk of heart attacks due to CHD.
Elevated cholesterol
levels are also associated with a number of disease states, including
restenosis, angina, cerebral
arteriosclerosis, and xanthoma.
Therapeutic agents for management of hypercholesterolemia include: (1) a
hydroxy-
methylglutaryl-CoA (HMG-CoA) reductase inhibitor which restrains synthesis of
cholesterol,
(2) probucol which mainly promotes catabolism from cholesterol to a bile acid
and excretion
thereof, (3) an anion exchange resin which mainly restrains absorption of
cholesterol and
promotes excretion of a bile acid (cholestyramine, for example), and (4) a
clofibrate-type drug
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(clofibrate, for example). Currently, HMG-CoA reductase inhibitors are the
most effective
agents currently available for lowering plasma levels of low-density
lipoprotein cholesterol
(LDL-C) and are the mainstay therapy for hyperlipidemia. Several large,
controlled clinical trials
have confirmed significant reductions in rates of coronary heart disease
morbidity and death with
long-term statin therapy in patients with mild to severe hypercholesterolemia
(see, e.g.,
Blumenthal RS Am Heart J 2000 Apr;139(4):577-83).
As is evident from the above, there is a great need for devices and methods
for effective
and practical management of cholesterol, particularly serum cholesterol
levels, with better
efficacy and reduced side effects. The present invention addresses this
problem.
SUMMARY OF THE INVENTION
The invention features devices and methods for the delivery of a cholesterol
lowering
agent (e.g., an inhibitor of endogenous cholesterol biosynthesis such as an
HMG CoA reductase
inhibitor) to reduce levels of serum cholesterol and/or cholesterol
accumulation and deposition.
In the present invention, a drug formulation comprising a cholesterol lowering
agent is provided
parenterally in a sustained release dosage form, e.g., as an injected matrix
or stored within a drug
delivery device.
Various embodiments of this invention provide an implantable sustained-release
dosage form for lowering cholesterol in a subject, said dosage form comprising
a drug
delivery device and a cholesterol lowering agent, wherein said cholesterol
lowering agent
is released at a volume of about 2 to about 250 L per day from said drug
delivery
device, for a period of at least seven days, the amount sufficient to
measurably lower
cholesterol in said subject.
Other embodiments of this invention provide the use of a dosage form of this
invention for lowering of cholesterol in a subject or for manufacture of a
medicament for
such lowering.
The drug delivery device may be an implantable device such as an osmotic pump,
an
electrochemical pump, an electromechanical pump, an electroosmotic pump, a
piezoelectric
pump, an effervescent pump, a vapor pressure pump, an electrolytic pump, a
hydrolytic system,
an electrodiffusion system, an elastomeric system, an osmotic bursting matrix,
a bioerodable
implant, a sustained release injectable, a microparticulate suspension, a
liposome formulation, a
micelle formulation, an oil suspension, an encapsulated particulate suspension
system, and
microsphere system, an erosion-based system, or a depot.
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Once released from the dosage form, the drug formulation enters the systemic
circulation
and is transported to the site of action in the body to modulate cholesterol
levels, (e.g. the liver,
heart, brain or other site of cholesterol synthesis or deposition).
s Alternatively, in another embodiment, the dosage form maybe implanted or
injected into
a site in the body (i.e., implantation site) and a conduit, e.g. a catheter,
can be used to transport
the formulation from the dosage form for release at a site in the body distal
from the implantation
site, for example, the liver, brain, heart, etc.
In one aspect, the invention features methods of reducing cholesterol levels
by delivery of
a formulation comprising a cholesterol lowering agent to the subject from a
sustained release
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dosage form. The formulation can be introduced to a subject via any parenteral
delivery system
with the ability to provide release of the formulation for a pre-selected
period of time. In specific
embodiments, the formulation is released at a low volume rate (e.g., from
about 0.001 ml/day to
1 ml/day or from about 0.01 mg/day to 20 mg/day). Exemplary delivery methods
include, but
are not limited to, injectable sustained release dosage forms such as a depo-
type preparations or
an injectable formulation containing a sustained-release particulate
preparation, e.g.,
microspheres or microcapsules.
In a particular aspect, the invention features devices for and methods of
treating elevated
cholesterol levels in a subject comprising the steps of implanting a drug
delivery device within
an implantation site in the body of a subject, where the drug delivery device
is capable of drug
release over a period of time. A formulation comprising a cholesterol lowering
agent can be
introduced from the device to a delivery site in an amount effective to reduce
serum cholesterol
levels and/or prevent accumulation of cholesterol and cholesterol by-products,
e.g.,
atherosclerotic plaques. A long-term release formulation for use in such a
device can be, e.g.,
contained in a reservoir or impregnated within a matrix within the drug
delivery device.
A drug formulation comprising a cholesterol lowering agent is stored within a
drug
delivery device (e.g., contained in a reservoir or impregnated within a matrix
within the
controlled drug delivery device). The drug delivery device is implanted in the
subject's body at
an implantation site, and the drug formulation is released from the drug
delivery device to a
delivery site. The delivery site may be the same as, near, or distant from the
implantation site.
Exemplary delivery methods and devices include, but are not limited to,
injectable
sustained release dosage forms including Sucrose Acetate Isobutyrate (SAIB),
microspheres or
microcapsules. ). Non-injectable implants include preformed monolithic or
coaxially extruded
rods made of biodegradable polymer impregnated with drug. These rods may be
prepared by
melt extrusion or other techniques well known to those skilled in the art.
Depots may include, for
example, non-polymeric, biocompatible materials that can provide for release
of drug over time.
Exemplary non-polymeric materials include, but are not necessarily limited to,
those described in
U.S. Patent Nos. 6,051,558; 5,747,058; and 5,968,542 .
A depot may comprise a high viscosity liquid, such as a non-polymeric non-
water-
soluble liquid carrier material, e.g., SAIB or another compound such as a
compound described in
U.S. Patent No. 5,747,05 8 .
There has been extensive research in the area of biodegradable controlled
release
systems for bioactive compounds. Biodegradable matrices for drug delivery are
useful because
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they obviate the need to remove the drug-depleted device. The most common
matrix materials
for drug delivery are polymers. The field of biodegradable polymers has
developed rapidly since
the synthesis and biodegradability of polylactic acid was reported by Kulkarni
et al., in 1966
("Polylactic acid for surgical implants," Arch. Surg., 93:839). Examples of
other polymers which
have been reported as useful as a matrix material for delivery devices include
polyanhydrides,
polyesters such as polyglycolides and polylactide-co-glycolides, polyamino
acids such as
polylysine, polymers and copolymers of polyethylene oxide, acrylic terminated
polyethylene
oxide, polyamides, polyurethanes, polyorthoesters, polyacrylonitriles, and
polyphosphazenes.
See, for example, U.S. Pat. Nos. 4,891,225 and 4,906,474 to Langer
(polyanhydrides), U.S. Pat.
No. 4,767,628 to Hutchinson (polylactide, polylactide-co-glycolide acid), and
U.S. Pat. No.
4,530,840 to Tice, et al. (polylactide, polyglycolide, and copolymers).
Degradable materials of biological origin are well known, for example,
crosslinked
gelatin. Hyaluronic acid has been crosslinked and used as a degradable
swelling polymer for
biomedical applications (U.S. Pat. No. 4,957,744 to Della Valle et al.; (1991)
"Surface
modification of polymeric biomaterials for reduced thrombogenicity," Polym.
Mater. Sci. Eng.,
62:731-735).
Biodegradable hydrogels have also been developed for use in controlled drug
delivery as
carriers of biologically active materials such as hormones, enzymes,
antibiotics, antineoplastic
agents, and cell suspensions. Temporary preservation of functional properties
of a carried
species, as well as the controlled release of the species into local tissues
or systemic circulation,
have been achieved. See for example, U.S. Pat. No. 5,149,543 to Cohen. Proper
choice of
hydrogel macromers can produce membranes with a range of permeability, pore
sizes and
degradation rates suitable for a variety of applications in surgery, medical
diagnosis and
treatment.
Many dispersion systems are currently in use as, or being explored for use as,
carriers of
substances, particularly biologically active compounds. Dispersion systems
used for
pharmaceutical and cosmetic formulations can be categorized as either
suspensions or emulsions.
Suspensions are defined as solid particles ranging in size from a few
nanometers up to hundreds
of microns, dispersed in a liquid medium using suspending agents. Solid
particles include
microspheres, microcapsules, and nanospheres. Emulsions are defined as
dispersions of one
liquid in another, stabilized by an interfacial film of emulsifiers such as
surfactants and lipids.
Emulsion formulations include water in oil and oil in water emulsions,
multiple emulsions,
microemulsions, microdroplets, and liposomes. Microdroplets are unilamellar
phospholipid
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vesicles that consist of a spherical lipid layer with an oil phase inside, as
defined in U.S. Pat.
Nos. 4,622,219 and 4,725,442 issued to Haynes. Liposomes are phospholipid
vesicles prepared
by mixing water-insoluble polar lipids with an aqueous solution. The
unfavorable entropy caused
by mixing the insoluble lipid in the water produces a highly ordered assembly
of concentric
closed membranes of phospholipid with entrapped aqueous solution.
U.S. Pat. No. 4,938,763 to Dunn, et al., discloses a method for forming an
implant in situ
by dissolving a non-reactive, water insoluble thermoplastic polymer in a
biocompatible, water
soluble solvent to form a liquid, placing the liquid within the body, and
allowing the solvent to
dissipate to produce a solid implant. The polymer solution can be placed in
the body via syringe.
The implant can assume the shape of its surrounding cavity. In an alternative
embodiment, the
implant is formed from reactive, liquid oligomeric polymers which contain no
solvent and which
cure in place to form solids, usually with the addition of a curing catalyst.
The invention also may employ "microspheres" (also known as "microparticles"
or
nanospheres" or "nanoparticles") which are small particles, typically prepared
from a polymeric
material and typically no greater in size than about 10 micrometers in
diameter. For reference,
please refer generally to "Encyclopedia of Controlled Drug Delivery" 1999,
published by John
Wiley & Sons Inc, edited by Edith Mathiowitz. For example, U.S. Pat. No.
6,291,013 discloses
polylactic acid microspheres, prepared by emulstion techniquescontaining a
physiologically
active substance and having an average particle size of about 1 to 250
micrometers.
In another particular aspect, the invention features methods of treating a
subject having
elevated serum cholesterol levels by systemic delivery of a formulation
comprising an inhibitor
of cholesterol synthesis (e.g., an HMG CoA reductase inhibitor) to the subject
via an implantable
drug delivery device, where such formulation is delivered at a rate and/or
concentration
sufficient to lower cholesterol in a subject. In specific embodiments, the
formulation comprises
a statin such as cerivastatin, which can be administered at a rate of from
about 0.1 g per hour to
200 g per hour for a period of at least a week, and can be delivered for a
period of at least about
a month, and or at least about six months.
In another aspect, the invention features local administration of a
cholesterol biosynthesis
inhibitor to suppress cholesterol production, deposition and/or the
accumulation in a specific
region, e.g., near the liver, heart or brain.
In various exemplary embodiments of the invention and various aspects thereof,
drug of
the drug formulation administered is delivered at a low dose rate due the
potency of the subject
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drugs, e.g., from about 0.01 pg/hr or 0.1 g/hr, 0.25 g/hr, 1 gg/hr,
generally up to about 200
gg/hr. Specific ranges of amount of drug delivered will vary depending upon,
for example, the
potency and other properties of the drug used and the therapeutic requirements
of the subject. In
one specific embodiment, the formulation comprises a statin and, in a specific
embodiment, is
delivered at a rate of from about 0.01 gg/hr or 0.1 g/hr, 0.25 g/hr, 1
g/hr, generally up to
about 200 g/hr. In another exemplary embodiment, the drug formulation is
delivered at a low
volume rate e.g., a volume rate of from about 0.001 ml/day to about 1 ml/day.
A primary object of the invention is provide a method for convenient, long-
term
management of cholesterol production.
One advantage of the invention is that the devices and methods described
herein provide
effective management of cholesterol levels by administration of a relatively
small quantity of a
cholesterol lowering agent (e.g., an HMG CoA reductase inhibitor such as a
statin). Given the
long-term, chronic effects of cholesterol production, esterification, and/or
deposition, this
advantage is of considerable benefit for relatively long term (e.g., 1-4
months) dosage regimes.
Furthermore, the method may be more cost-effective than current prescription
drugs, and thus
may make cholesterol management available to a broader population.
Another advantage of the invention is that the cholesterol lowering agent can
be
administered to provide for a substantially constant lowered cholesterol
levels. In contrast, oral
delivery of these agents provides for intermittent lowering of cholesterol
levels, a product of
underdosing inherently associated with bolus administration.
The present invention is also advantageous in that it can provide for safe,
effective
therapy while minimizing the risk of undesirable side effects.
Another advantage of the invention is that the invention can be used to
deliver relatively
small quantities of cholesterol lowering agents accurately and precisely.
Thus, the invention
allows for the convenient use of these drugs for treatment, and particularly
for the delivery of
small amounts locally, e.g., to control the production of (3-amyloid
production in the brain.
Another notable advantage of the invention is that the implanted device
increases patient
compliance with a prescribed therapeutic regimen. This is particularly
important since
compliance is particularly difficult to achieve in prophylactic treatment
before the onset of
disease or symptom and since the population that needs treatment often has
difficulty with
compliance, e.g., the infirmed, the elderly and/or people with neurological
disorders. Improved
compliance will provide an improved therapeutic outcome in the patient.
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A further advantage is that a therapeutically effective dose of a cholesterol
lowering
agent can be delivered at such relatively low volume rates, e.g., from about
0.001 ml/day to
I ml/day so as to minimize tissue disturbance or trauma near the site where
the formulation is
released. The formulation may be released at a rate of, for example, 0.01
micrograms per day up
to about 20 milligrams per day. Dosage depends on a number of factors such as
potency,
bioavailability, and toxicity.
Another advantage of the invention is that substantially continuous delivery
of small
quantities of cholesterol lowering agent (e.g., a HMG CoA reductase inhibitor
such as a statin) is
effective in long-term (e.g., chronic) administration (e.g., from several
weeks or from about 1 to
12 months or more).
Yet another advantage is that the invention provides for precise delivery of
the selected
cholesterol lowering agent, thus allowing delivery of lower doses and/or for
delivery of precisely
metered doses at consistent delivery volume rates (e.g., on the order of
microliters to milliliters
per hour).
These and other objects, advantages and features of the present invention will
become
apparent to those persons skilled in the art upon reading the details of the
methodology and
compositions as more fully set forth below.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates systemic delivery of the drug formulation using an
implanted drug
delivery device.
Fig. 2 is a cut-away view of an exemplary drug delivery device useful in the
present
invention.
Fig. 3 is a cut-away view of an exemplary drug delivery device comprising a
catheter.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention is not limited to the specific methodology, devices, therapeutic
formulations, and syndromes described. 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 limit
the scope of the present invention which will be limited only by the appended
claims.
It must be noted that as used herein and in the appended claims, the singular
forms "a",
"and", and "the" include plural referents unless the context clearly dictates
otherwise. Thus, for
example, reference to "a drug delivery device" includes a plurality of such
devices and reference
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to "the method of delivery" includes reference to equivalent steps and methods
known to those
skilled in the art, and so forth.
Unless defined otherwise, all technical and scientific terms used herein have
the same
meaning as commonly understood to one of ordinary skill in the art to which
this invention
belongs. Although any methods, devices and materials similar or equivalent to
those described
herein can be used in the practice or testing of the invention, the preferred
methods, devices and
materials are now described.
The
publications discussed herein are provided solely for their disclosure prior
to the filing date of
the present application. Nothing herein is to be construed as an admission
that the invention is
not entitled to antedate such a disclosure by virtue of prior invention.
Definitions
The terms "reduced cholesterol levels" and "lowered cholesterol levels" as
used
interchangeably herein are intended to encompass a reduction in serum
cholesterol, reduction in
cholesterol accumulation and/or deposition, and a reduction of cholesterol by-
products, i.e.
products associated with elevated cholesterol levels such as amyloid plaques.
Generally, reduced
cholesterol levels are between, for example, 50-95% of the levels in the
untreated subject, or
between 70-85% of the levels, preferably between 60-85% of the levels, in the
subject prior to
treatment.
The term "cholesterol lowering agent" as used herein is generally meant to
refer to
compounds which reduce the level of serum cholesterol, reduce cholesterol
accumulation and
deposition, and/or reduce the production of by-products of cholesterol (e.g.,
amyloid plaques).
These agents may function by a variety of mechanisms and include compounds
which increase
uptake of cholesterol by the liver, compounds which block endogenous
cholesterol biosynthesis,
compounds which prevent uptake of dietary cholesterol, compounds which enhance
clearance of
cholesterol from the body, and the like. Use of the term "cholesterol lowering
agent" is not
meant to be limiting to use of, or formulations comprising, only one of these
selected
compounds. Furthermore, reference to a selected specific compound, e.g.,
reference to "a statin,"
is understood to be only exemplary of the drugs suitable for delivery
according to the methods of
the invention, and is not meant to be limiting in any way. The term is also
meant to encompass
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compounds that specifically decrease LDL and/or alter the LDL:HDL ratio, i.e.
that reduce the
level of the unwanted form of cholesterol without actually reducing the
overall serum cholesterol
levels. Additional exemplary cholesterol lowering agents include, but are not
necessarily limited
to hypolipidemic agents (e.g., nicotinic acid, probucol, etc.), bile acid-
binding resins (e.g.,
cholestyramine), and fibric acid derviatives (e.g., clofibrate).
The term "inhibitor of cholesterol biosynthesis" as used herein refers to a
compound with
the ability to inhibit an enzyme in a subject's endogenous cholesterol
biosynthetic pathway. This
includes any compound that inhibits an enzyme involved in the biosynthetic
pathway from the
starting product 3 -hydroxy-3 -methylglutaryl coenzyme A (HMG CoA) to the
production of
cholesterol. Examples of agents that inhibit cholesterol biosynthesis by
disrupting the cholesterol
biosynthetic pathway include but are not limited to HMG CoA reductase
inhibitors, HMG CoA
synthase inhibitors, squalene synthase inhibitors, and squalene epoxidase
inhibitors. In a
particular embodiment, the inhibitor of biosynthesis is an HMG CoA reductase
inhibitor, and
more particularly the drug is a statin, e.g., lovastatin, cerivastatin,
fluvastatin, pravastatin,
simvaststin, etc.
The term "drug delivery device" refers to any means for containing and
releasing a drug
wherein the drug is released into a subject. The means for containment is not
limited to
containment in a walled vessel, but may be any type of containment device,
including non-
injectable devices (pumps etc) and injectable devices, including a gel, a
viscous or semi-solid
material or even a liquid. Drug delivery devices are split into five major
groups: inhaled, oral,
transdermal, parenteral and suppository. Inhaled devices include gaseous,
misting, emulsifying
and nebulizing bronchial (including nasal) inhalers; oral includes mostly
pills; whereas
transdermal includes mostly patches. Parenteral includes two sub-groups:
injectable and non-
injectable devices. Non-injectable devices are generally referred to as
"implants" or "non-
injectable implants" and include e.g., pumps and solid biodegradable polymers.
Injectable
devices are split into bolus injections, that are injected and dissipate,
releasing a drug all at once,
and depots, that remain discrete at the site of injection, releasing drug over
time. Depots include
e.g., oils, gels, liquid polymers and non-polymers, and microspheres. Many
drug delivery
devices are described in Encyclopedia of Controlled Drug Delivery (1999),
Edith Mathiowitz
(Ed.), John Wiley & Sons, Inc.
The term "drug" as used herein, refers to any substance meant to alter animal
physiology.
The term "dosage form" refers to a drug plus a drug delivery device.
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The term "formulation" means any drug together with a pharmaceutically
acceptable
excipient or carrier such as a solvent such as water, phosphate buffered
saline or other acceptable
substance. A formulation may include one or more cholesterol lowering agents,
for example, a
two or more cholesterol lowering agents that are HMG CoA reductase inhibitors.
An inhibitor of
cholesterol biosynthesis can be combined with an additional ingredient that
increases cholesterol
metabolism, e.g., probucol. A formulation may have an active agent that
mediates a separate
biological response (e.g., an anticoagulant). A formulation may also encompass
one or more
carrier materials such as SAIB or other carrier materials such as described in
U.S. Patent Nos.
5,747,058 and 5,968,542.
The term "subject" is meant any subject, generally a mammal (e.g., human,
canine, feline,
equine, bovine, ursine, lepine, lupine, bufine, porcine, ungulate etc).
The term "systemic delivery" means delivery which permits drug to enter into
the
systemic circulation, e.g., intravenous, intra-arterial, intramuscular,
subcutaneous, intra-adipose
tissue, intra-lymphatic, etc.
The term "therapeutically effective amount" means an amount sufficient to
bring about a
desired physiological effect (e.g., a decrease in serum cholesterol levels
and/or cholesterol
deposition).
"Delivery site" as used herein is meant to refer to an area of the body to
which drug is
released from the dosage form, e.g., subcutaneous, intravenous, intra-
arterial, intra-muscular,
intra-adipose tissue, and intra-lymphatic sites.
The term "implantation site" is used to refer to a site within the body of a
subject at
which a dosage form is introduced and positioned.
"Patterned" or "temporal" as used in the context of drug delivery means
delivery of drug
in a pattern, over a pre-selected period of time (e.g., other than a period
associated with, for
example a bolus administration, encompasses delivery of drug at an increasing,
decreasing,
substantially constant, or pulsatile, rate or range of rates (e.g., amount of
drug per unit time, or
volume of drug formulation for a unit time), and further encompasses delivery
that is continuous
or substantially continuous, or chronic.
The term "substantially continuous" means delivery of drug (e.g., a statin) in
a manner
that is substantially uninterrupted for a pre-selected period of drug
delivery.
The term "sustained release dosage form" is meant to refer to a drug dosage
form that is
capable of release of a drug formulation (e.g., a statin) over a pre-selected
period of time rather
than at one time as in a bolus administration.
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The term "treatment" and the like refers to obtaining a desired pharmacologic
and/or
physiologic effect. The effect may be prophylactic in terms of completely or
partially preventing
a condition or symptom thereof or may be therapeutic in terms of a partial or
complete cure for,
relief from, or suppression of a disease. Treatment includes: (a) Preventing
or diminishing the
incidence of elevated cholesterol levels in a subject that may be predisposed
but is not at the time
displaying such elevated levels; (b) Reducing endogenous production of
cholesterol; (c) reducing
uptake of dietary cholesterol; (d) Inhibiting accumulation and deposition of
cholesterol; and (e)
Causing regression and/or amelioration in a subject with a disease or
condition associated with
elevated cholesterol levels.
INDICATIONS FOR ADMINISTRATION OF CHOLESTEROL LOWERING FORMULATIONS
In general, administration of a formulation comprising a cholesterol lowering
agent
according to the invention can be used to facilitate management of elevated
cholesterol levels
associated with any of a wide variety of risk factors, disorders, conditions,
or diseases.
Conditions amenable to alleviation include, but are not necessarily limited
to, diseases involving
elevated serum cholesterol such as hypercholesterolemia; diseases involving
cholesterol
esterification and/or deposition, such as atherosclerosis; and diseases
involving cholesterol-
induced plaques, such as (3-amyloid-associated neurological disorders.
Specific examples of conditions, diseases, disorders, and risk factors
associated with
elevated cholesterol production according to the present invention include,
but are not
necessarily limited to cardiovascular disease including atherosclerosis of
coronary arteries and
myocardial infarctions; cerebrovascular disease including atherosclerosis of
the intracranial
and/or extracranial arteries, stroke, and transient ischemic attacks; and
disease involving
cholesterol-associated plaque formation, e.g., Alzheimer's disease. The
methods of the
invention can be used to treat a subject that has displayed the symptoms of
and/or been
diagnosed with one or more of such conditions. The methods of the invention
can also be used
prophylactically to treat a subject at risk of a condition, e.g., a coronary
and/or cerebrovascular
event. Such risk factors include, but are not limited to,
hypercholesterolemia, coronary artery
disease (CAD), family history of coronary artery disease, hypertension,
diabetes, cigarette
smoking, and cerebrovascular disease. For example, where the risk factor is
hypercholesterolemia, the serum total cholesterol concentrations of a subject
are generally at
least 5.2 mmol/liter (at least 200 mg/dl).
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CHOLESTEROL LOWERING AGENTS AND FORMULATIONS
The present invention provides methods for reducing cholesterol levels in a
subject by
long-term administration of a cholesterol lowering agent.
In one embodiment, the cholesterol lowering agent is an inhibitor of
cholesterol
biosynthesis, e.g., an inhibitor of HMG-CoA reductase enzyme. The primary rate
limiting
enzyme in the pathway is HMG CoA reductase, and thus cholesterol lowering
agents of a
specific embodiment regulate HMG CoA reductase at the level of transcription,
translation,
degradation, and/or at the switch from an inactive HMG CoA reductase to an
active form.
In a preferred embodiment, the cholesterol lowering agents are HMG CoA
reductase
inhibitors of the statin family. These agents are described in detail, for
example, mevastatin and
related compounds as disclosed in U.S. Pat. No. 3,983,140, lovastatin
(mevinolin) and related
compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin and related
compounds such as
disclosed in U.S. Pat. No. 4,346,227, simvastatin and related compounds as
disclosed in U.S. Pat.
Nos. 4,448,784 and 4,450,171; fluvastatin and related compounds as disclosed
in U.S. Pat. No.
5,354,772; atorvastatin and related compounds as disclosed in U.S. Pat Nos.
4,681,893,
5,273,995 and 5,969,156; and cerivastatin and related compounds as disclosed
in U.S. Pat. Nos.
5,006,530 and 5,177,080. Additional compounds are disclosed in U.S. Pat. Nos.
5,208,258,
5,130,306, 5,116,870, 5,049,696, RE 36,481, and RE 36,520. The lipophilicity
of certain statins
make them particularly suitable for subcutaneous delivery.
Other HMG CoA reductase inhibitors which may be employed herein include, but
are not
limited to, pyrazole analogs of mevalonolactone derivatives as disclosed in
U.S. Pat. No.
4,613,610, indene analogs of mevalonolactone derivatives as disclosed in PCT
application WO
86/03488, Trans-6-[2-(substitutedpyrrol-1-yl)alkyl]-pyran-2-ones and
derivatives thereof as
disclosed in U.S. Pat. No. 4,647,576, 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. Pat. No. 4,686,237, octahydronaphthalenes
such as
disclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin (lovastatin)
as disclosed in
European Patent Application No. 0,142,146 A2, as well as other known HMG CoA
reductase
inhibitors. In addition, phosphinic acid compounds useful in inhibiting HMG
CoA reductase are
disclosed in GB 2205837.
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Agents which target other enzymes involved in cholesterol biosynthesis can
also be used
in the present methods. For example, squalene synthetase inhibitors suitable
for use herein
include, but are not limited to a-phosphonosulfonates disclosed in U.S.
application Ser. No.
08/266,888, filed Jul. 5, 1994, now U.S. Pat. No. 5,712,396 (HX59b), those
disclosed by Biller et
al, J. Med. Chem. 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid
(phosphinylmethyl) phosphonates including the triacids thereof, triesters
thereof and tripotassium
and trisodium salts thereof as well as other squalene synthetase inhibitors
disclosed in U.S. Pat.
Nos. 4,871,721 and 4,924,024 and in Biller et al, J. Med. Chem., 1988, Vol.
31, No. 10, pp 1869
to 1871. In addition, other squalene synthetase inhibitors suitable for use
herein include the
terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med.
Chem.; 1977, 20,
243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-
PP) analogs as
disclosed by Corey and Volante, J. Am. Chem. Soc. 1976, 98, 1291-1293,
phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987, 109,
5544 and
cyclopropanes.
Other cholesterol lowering agents mechanistically distinct from inhibitors of
cholesterol
biosynthesis that are suitable for use in the present methods include, but are
not limited to,
antihyperlipoproteinemic agents such as fibric acid derivatives, e.g.,
fenofibrate, gemfibrozil,
clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol and
related compounds as
disclosed in U.S. Pat. No. 3,674,836. Probucol and the fibrates increase the
metabolism of
cholesterol-containing lipoproteins. Other compounds, including bile acid
sequestrants such as
cholestyramine, colestipol and DEAE-Sephadex (Secholex , Polidexide ),
lipostabil (Rhone-
Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil
(HOE-402),
tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche),
aminocyclodextrin
(Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide
(Sumitomo), Sandoz 58-
035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea
derivatives), nicotinic
acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,
poly(diallylmethylamine)
derivatives such as disclosed in U.S. Pat. No. 4,759,923, quaternary amine
poly
(diallyldimethylammonium chloride) and ionenes such as disclosed in U.S. Pat.
No. 4,027,009,
and other known serum cholesterol lowering agents.
Two or more cholesterol lowering agents having either the same mechanism
(e.g., two
agents that inhibit HMG CoA reductase) or two different mechanisms (e.g., one
agent that
inhibits HMG CoA reductase and another agent which inhibits uptake of dietary
cholesterol) can
be used in a single formulation. For example, an inhibitor of cholesterol
biosynthesis (e.g., a
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statin) can be combined with an additional ingredients including, but not
limited to, farnesyl ester
and ether compounds, probucol, fibric acids, clofibrate, niacin, gemfibrozol,
LDL-receptor gene
inducers, and zaragozic acid. Formulations of the invention may also comprise
at least one
cholesterol lowering agent and another active agent, i.e. an active agent that
mediates a separate
biological response (e.g., an anticoagulant).
A newer cholesterol lowering agent that may be used with the invention is
rosuvastatin
calcium.
A cholesterol lowering agent can be provided in any of a variety of
formulations
compatible with parenteral delivery, provided that such formulation is stable
(i.e., not subject to
degradation to an unacceptable amount at body temperature). The concentration
of cholesterol
lowering agent in the formulation may vary from about 0.1 wt. % to about 50 or
75 wt.%. The
agent can be provided in any form suitable to be carried by the sustained
release dosage from and
released parenterally for systemic distribution, e.g., solid, semi-solid, gel,
liquid, suspension,
emulsion, osmotic dosage formulation, diffusion dosage formulation, erodible
formulation, etc.
Formulations of the invention comprise a cholesterol lowering agent in a
concentration of
at least about 0.1 mg/mL, 0.5 mg/mL, 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, 75
mg/mL,
100 mg/mL, 150 mg/mL, 200 mg/mL, 225 mg/mL, 250 mg/mL, 300 mg/mL, 350 mg/mL,
400
mg/mL, 450 mg/mL, 500 mg/mL, or greater. Formulations of the invention
comprising
cholesterol lowering agent are preferably in solution, e.g., are dissolved in
a liquid.
Pharmaceutical grade organic or inorganic carriers and/or diluents suitable
for parenteral
delivery can be included in the formulations suitable for delivery according
to the invention.
Such physiologically acceptable carriers are well known in the art. Exemplary
liquid carriers for
use in accordance with the present invention can be sterile non-aqueous or
aqueous solutions
which contain no materials other than the active ingredient. The formulations
can optionally
further comprise a buffer such as sodium phosphate at physiological pH value,
physiological
saline or both (i.e., phosphate-buffered saline). Suitable aqueous carriers
may optionally further
comprise more than one buffer salt, as well as other salts (such as sodium and
potassium
chlorides) and/or other solutes.
In some exemplary embodiments, the cholesterol lowering agent is present in
the
formulation in a concentration of from about 0.1 mg/mL, 0.5 mg/mL to about 500
mg/mL, from
about 1 mg/mL to about 450 mg/mL, from about 50 mg/mL to about 400 mg/mL, from
about
75 mg/mL to about 300 mg/mL, or from about 100 mg/mL to about 250 mg/mL.
Suitable low
molecular weight alcohols include those which are pharmaceutically acceptable,
and which can
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comprise an aromatic moiety, and which are relatively immiscible in water
(e.g., less than about
5, less than about 4, less than about 3, less than about 2, less than about 1
gram can dissolve in
25 ml H20), including, but not limited to, benzyl alcohol, and derivatives
thereof. Small
amounts of other pharmaceutically acceptable substances such as other
pharmaceutically
acceptable alcohols, e.g., ethanol, or water, may also be present, and, if
present, are present in an
amount of less than about 10%, less than about 5%, or less than about 1%.
Formulations of particular interest for delivery are characterized in that the
cholesterol
lowering agent is present in a high concentration, as described above. The
cholesterol lowering
agent may be provided to the subject as a solution, a suspension, and/or a
precipitate.
Suitable excipients can comprise dextrose, glycerol, alcohol (e.g., ethanol),
and the like,
and combinations of one or more thereof with vegetable oils, propylene glycol,
polyethylene
glycol, benzyl alcohol, benzyl benzoate, dimethyl sulfoxide (DMSO), organics,
and the like to
provide a suitable composition. In addition, if desired, the composition can
comprise
hydrophobic or aqueous surfactants, dispersing agents, wetting or emulsifying
agents, isotonic
agents, pH buffering agents, dissolution promoting agents, stabilizers,
antiseptic agents and other
typical auxiliary additives employed in the formulation of pharmaceutical
preparations.
Of particular interest is a formulation in a depot form, such as a depot
comprising sucrose
acetate isobutyrate (SAIB). SAIB may be formulated with one or more suitable
solvents which
may be hydroxylic or nonhydroxylic and which may be used alone or in
combination. Examples
of solvents include ethanol, NMP, benzyl benzoate, benzoic acid, ethyl
lactate, proplyene
carbonate, glycofurol, and Miglyol 810, or mixtures thereof. The solvent can
be added to SAIB
in a ratio of from about 5 wt% - 65 wt% solvent, usually 50 wt% or less The
active agent, , in a
lypholized or dry powder form, may then be added to the SAIB/solvent mixture.
The mixture is
then mixed until homogeneous. The resulting mixture is then ready for
parenteral injection.
A reduction in cholesterol in a subject may be measured using any technique
that will be
apparent to one skilled in the art upon reading the present disclosure. Such
methods include, but
are not limited to measurement of plasma cholesterol, measurement plasma
triglycerides,
measurement in plasma apolipoproteins, and measurement of HMG-CoA reductase
activity in
liver microsomes. Each of these can be either directly associated with or
predictive of changes
in cholesterol levels in a subject.
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IMPLANTATION AND DELIVERY SITES
The formulation can be introduced to a subject by injection or implantation at
any
suitable site using methods and devices well known in the art. Implantation
sites include, but are
not necessarily limited to a subdermal, subcutaneous, intramuscular, or other
suitable site within
a subject's body. Subcutaneous implantation sites are preferred because of
convenience in
implantation and, if necessary, removal of the drug dosage form. In some
embodiments, the
implantation site is at or near the delivery site (e.g., the delivery site is
not distant from the
implantation site). Exemplary subcutaneous delivery sites include external
subcutaneous sites
(e.g., under the skin of the arm, shoulder, neck, back, or leg) and internal
subcutaneous sites
within a body cavity (e.g., within the mouth). In addition, the delivery site
can be the desired site
of action (e.g., specific vessels at or near the heart or brain, etc.). In
some embodiments, the
delivery site is distant form the implantation site. Delivery of drug from a
dosage form at an
implantation site that is distant from a delivery site can be accomplished by
providing the drug
delivery device with a catheter, as described in more detail below.
An example of delivery and implantation for a SAIB depot formulation would be
to inject
a depot subcutaneously into the upper are of a subject using a needle and a
standard syringe.
Once the needle is withdrawn, the depot remains under the skin and becomes
more viscous as
hydrophilic solvent is released from the bulk of the hydrophobic matrix into
surrounding tissue.
From this stable location, the depot then releases the active at a relatively
steady rate into the
surrounding tissue, from where the drug finds its way into the circulatory
system, and thence to
its site of action. The depot may release the drug for weeks or months.
DELIVERY OF CHOLESTEROL LOWERING AGENTS
Subjects suffering from or susceptible to high cholesterol levels and/or
cholesterol
deposition can receive prophylactic and/or therapeutic amounts of a
cholesterol lowering agent
according to the methods of the invention for any desired period of time. As
elevated cholesterol
levels and the conditions associated with such elevated levels are generally
chronic, long-term
administration is preferred (e.g.: continuous administration for at least 4
weeks) at, and the
administration of a cholesterol lowering agent according to the invention can
be sustained for
several days (e.g., 2 to 5 days or more), to several weeks, months or years.
Typically, delivery
can be continued for a period ranging from about 1 week to about 1 month or
about 12 months or
more. The cholesterol lowering agent may be administered to an individual for
a period of, for
example, from about 20 days, from about 7 days or more, from about 10 days or
more, from
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about 100 days or more, from about 1 week to about 4 weeks, from about 1 month
to about 24
months, from about 2 months to about 12 months, from about 3 months to about 9
months, from
about 1 month or more, from about 2 months or more, or from about 6 months or
more; or other
ranges of time, including incremental ranges, within these ranges, as needed.
Preferably, delivery of cholesterol lowering agent is substantially
uninterrupted for a pre-
selected period of drugdelivery, and more preferably at a substantially
constant, pre-selected rate
or range of rates (e.g., amount of agent per unit time, or volume of drug
formulation for a unit
time). The agent can be delivered at a low volume rate of, for example, from
about 0.001 l/day
or 0.04 d/day to about 1 ml/day, usually from about 0.001 ml/day (1 I/day)
to at least about
500 l/day or about 1 ml/day (i.e., from about 0.04 l/hr to about 21 l/hr to
about 42 l/hr),
from about 2 l/day to about 250 l/day to 500 l/day, from about 4 l/day to
about 100 l/day,
from about 5 l/day to about 50 l/day to 250 l/day.
As many conditions and diseases associated with cholesterol are chronic, the
methods of
the present invention are particularly advantageous in providing long-term
control and
management of cholesterol levels in a subject. Sustained release dosage forms
are convenient to
the subject for long-term drug administration and can allow drug therapy to be
conducted on an
out-patient basis where the patient's health allows such. Implantable dosage
forms, e.g., osmotic
pumps and depots, have an added benefit in that they reduce the risk of
infection associated with
external pumps or other methods that require repeated breaking of the skin
and/or maintenance
of a port for administration.
Delivery of drug to a subcutaneous site at a low volume rate is a particularly
preferred
embodiment of the invention. In general, low volume rate drug delivery avoids
accumulation of
drug at the delivery site (e.g., depot or pooling effect) by providing for a
rate of administration
that is less than, the same as, or only very slightly greater than the rate of
removal of drug from
the delivery site (e.g., by absorption of drug in tissues at the site,
movement of drug away from
the site by flow of blood or other bodily fluids, etc.). Thus, in addition to
providing an
implantable system for long-term delivery of cholesterol lowering agents
(e.g., a statin), the
present invention also provides a method for treating chronic cholesterol
level elevation by
elegantly balancing the rates of drug absorption and drug delivery to
accomplish administration
of a therapeutically effective amount of drug, while avoiding accumulation of
drug at the
delivery site.
Subcutaneous delivery of a statin, the agent can be delivered at a rate of
from about
0.01 g/hr to about 200 g/hr, usually from about 0.01 g/hr, 0.25 g/hr, or 3
g/hr to about
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85 g/hr, and typically between about 5 g/hr to about 100 gg/hr. In a
specific exemplary
embodiment, a statin is delivered at a rate of from about 0.01 gg/hr, 0.1
gg/hr, 0.25 pg/hr,
1 gg/hr, generally up to about 200 g/hr. In another exemplary embodiment, the
statin is
delivered at a rate of from about 0.1 g/hr to about 100 g/hr, typically
between about 1 g/hr to
about 100 g/hr. Appropriate amounts of cholesterol lowering agent can be
readily determined
by the ordinarily skilled artisan based upon, for example, the relative
potency of these drugs.
The actual dose of drug delivered will vary with a variety of factors such as
the potency and
other properties of the selected drug used (e.g., lipophilicity, etc.).
DOSAGE FORMS FOR USE IN THE INVENTION
Any of a variety of parenteral dosage forms can be used in the present
invention to
accomplish delivery of a formulation according to the methods of the present
invention. In
general the drag release methods or dosage forms suitable for use in the
invention are capable of
retaining a quantity of drug formulation (e.g., contained in a drug reservoir
or integrated into a
substrate or matrix such as a polymer, binding solid, etc.) sufficient for
treatment for a pre-
selected period of sustained release. Exemplary dosage forms include pumps,
depots, and
implants. Drug delivery dosage forms that may be suitable for use with the
present invention are
described in Encyclopedia of Controlled Drug Delivery (1999), Edith Mathiowitz
(Ed.), John
Wiley & Sons, Inc.
The drug delivery device may deliver a formulation for several days e.g., at
least 2 to at
least 5 days or more, or from at least 1 month to at least 12 months or more,
or from at least 10
days to at least 30 days to 100 days or more, from about 20 days to about 100
days or more; from
about 2 week to about 4 weeks, from about 1 month to about 24 months, from
about 2 months to
about 12 months, from about 3 months to about 9 months, from about 1 month or
more, from
about 2 months or more, or from about 6 months or more; or other ranges of
time, including
incremental ranges, within these ranges, as needed. Release of drug from the
device can be
accomplished in any of a variety of ways according to methods well known in
the art as
discussed herein. Where the drug delivery device comprises a drug delivery
catheter, drug can
be delivered through the drug delivery catheter to the delivery site as a
result of capillary action,
as a result of pressure generated from the drug device, by diffusion, by
electrodiffusion or by
electroosmosis through the device and/or the catheter.
In general, the dosage form must be capable of carrying the drug formulation
in such
quantities and concentration as therapeutically required for treatment over
the pre-selected
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period, and must provide sufficient protection to the formulation from
degradation by body
processes for the duration of treatment. For example, the dosage form can be
surrounded by an
exterior made of a material that has properties to protect against degradation
from metabolic
processes and the risk of, e.g., leakage, cracking, breakage, or distortion.
This can prevent
expelling of the dosage form contents in an uncontrolled manner under stresses
it would be
subjected to during use, e.g., due to physical forces exerted upon the drug
release device as a
result of movement by the subject or for example, in convective drug delivery
devices, physical
forces associated with pressure generated within the reservoir. The drug
reservoir or other
means for holding or containing the drug must also be of such material as to
avoid unintended
reactions with the active agent formulation, and is preferably biocompatible
(e.g., where the
dosage form is implanted, it is substantially non-reactive with respect to a
subject's body or body
fluids).
Suitable materials for the reservoir or drug holding means for use in the
delivery devices
of the invention are well known in the art. For example, the reservoir
material may comprise a
non-reactive polymer or a biocompatible metal or alloy. Suitable polymers
include, but are not
necessarily limited to, acrylonitrile polymers such as acrylonitrile-butadiene-
styrene polymer,
and the like; halogenated polymers such as polytetrafluoroethylene,
polyurethane,
polychlorotrifluoroethylene, copolymer tetrafluoroethylene and
hexafluoropropylene;
polyethylene vinylacetate (EVA), polyimide; polysulfone; polycarbonate;
polyethylene;
polypropylene; polyvinylchloride-acrylic copolymer; polycarbonate-
acrylonitrile-butadiene-
styrene; polystyrene; cellulosic polymers; and the like. Further exemplary
polymers are
described in The Handbook of Common Polymers, Scott and Roff, CRC Press,
Cleveland
Rubber Co., Cleveland, Ohio.
Metallic materials suitable for use in the reservoir of the drug delivery
devices include
stainless steel, titanium, platinum, tantalum, gold and their alloys; gold-
plated ferrous alloys;
platinum-plated titanium, stainless steel, tantalum, gold and their alloys as
well as other ferrous
alloys; cobalt-chromium alloys; and titanium nitride-coated stainless steel,
titanium, platinum,
tantalum, gold, and their alloys.
Exemplary materials for use in polymeric matrices include, but are not
necessarily
limited to, biocompatible polymers, including biostable polymers and
biodegradable polymers.
Exemplary biostable polymers include, but are not necessarily limited to
silicone, polyurethane,
polyether urethane, polyether urethane urea, polyamide, polyacetal, polyester,
poly ethylene-
chlorotrifluoro ethylene, polytetrafluoroethylene (PTFE or "Teflon"), styrene
butadiene rubber,
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polyethylene, polypropylene, polyphenylene oxide-polystyrene, poly-a-chloro-p-
xylene,
polymethylpentene, polysulfone and other related biostable polymers. Exemplary
biodegradable
polymers include, but are not necessarily limited to, polyanhydrides,
cyclodextrans, polylactic-
glycolic acid, polyorthoesters, polycaprolactone, n-vinyl alcohol,
polyethylene
oxide/polyethylene terephthalate, polyglycolic acid, polylactic acid and other
related
bioabsorbable polymers.
Where the drug formulation is stored in a reservoir comprising metal or a
metal alloy,
particularly titanium or a titanium alloy having greater than 60%, often
greater than 85%
titanium is preferred for the most size-critical applications, for high
payload capability and for
long duration applications and for those applications where the formulation is
sensitive to body
chemistry at the implantation site or where the body is sensitive to the
formulation. Most
preferably, the drug delivery devices are designed for storage with drug at
room temperature or
higher.
Drug release devices suitable for use in the invention may be an osmotic pump,
an
electroosmotic pump, a vapor pressure pump, or osmotic bursting matrix, e.g.,
where the drug is
incorporated into a polymer and the polymer provides for release of drug
formulation
concomitant with degradation of a drug-impregnated polymeric material (e.g., a
biodegradable,
drug-impregnated polymeric material). In other embodiments, the drug release
device is based
upon an electrodiffusion system, an electrolytic pump, an effervescent pump, a
piezoelectric
pump, a hydrolytic system, etc. In other embodiments, the drug release device
comprises a high
viscosity non-polymeric depot, such as SAIB, that may be injected under the
skin or other site of
parenteral administration.
Drug release devices based upon a mechanical or electromechanical infusion
pump, can
also be suitable for use with the present invention. Examples of such devices
include those
described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603;
4,360,019; 4,725,852,
and the like. In general, the present methods of drug delivery can be
accomplished using any of
a variety of refillable, non-exchangeable pump systems. Osmotic pumps are
particularly
preferred due to their combined advantages of more consistent controlled
release and relatively
small size. Exemplary osmotically-driven devices suitable for use in the
invention include, but
are not necessarily limited to, those described in U.S. Pat. Nos. 3,760,984;
3,845,770; 3,916,899;
3,923,426; 3,987,790; 3,995,631; 3,916,899; 4,016,880; 4,036,228; 4,111,202;
4,111,203;
4,203,440; 4,203,442; 4,210,139; 4,327,725; 4,627,850; 4,865,845; 5,057,318;
5,059,423;
5,112,614; 5,137,727; 5,234,692; 5,234,693; 5,728,396; 5,985,305; and the
like.
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Preferred osmotically-driven drug release systems are those that can provide
for release
of agent in a range of rates of from about 0.01 g/hr to about 200 g/hr, and
which can be
delivered at a volume rate range of, for example, from about 0.00 1 l/day to
about 100 I/day
(i.e., from about 0.0004 Whr to about 4 Whr), from about 0.04 l/day to about
10 l/day, from
about 0.2 l/day to about 5 l/day, from about 0.5 l/day to about 1 l/day In
general, in the
present invention, the drug release system is selected to provide for delivery
of a cholesterol
lowering agent at a rate of from about 0.001 ml/day (1 d/day) to at least
about 500 l/day or
about 1 ml/day (i.e., from about 0.04 l/hr to about 21 l/hr to about 42
l/hr), from about
2 l/day to about 250 gl/day to 500 d/day, from about 4 l/day to about 100
l/day, from about
5 l/day to about 50 l/day to 250 l/day.
In one embodiment of particular interest, the volume/time delivery rate is
substantially
constant (e.g., delivery is generally at a rate about 5% to 10% of the cited
volume over the
cited time period). Delivery may be from about 0.1 pg/hr to about 200 pg/hr,
and which can be
delivered at a volume rate of from about 0.25 I/day to about 100 l/day
(i.e., from about 0.0004
l/hr to about 4 l/hr), from about 0.04 l/day to about 10 p1/day, and can be
from about
0.2 l/day to about 5 l/day, or from about 0.5 l/day to about 1 l/day. In
one embodiment, the
volume/time delivery rate is substantially constant (e.g., delivery is
generally at a rate about
5% to 10% of the cited volume over the cited time period).
The drug delivery dosage form can be a depot. Depots include injectable
polymeric and
non-polymeric biodegradable materials that may be high viscosity liquids. A
depot may be
subcutaneous. In one embodiment a depot comprises sucrose acetate isobutyrate
(SAIB). SAIB
may be formulated with one or more solvents such as glycofurol, ethanol or
benzyl benzoate.
Solvents may be nonhydroxylic, such as benzyl benzoate, NMP, DMSO or mixtures
thereof, or it
may be desirable to use a hydroxylic solvent such as ethanol, or glycerol. The
solvent can be
added to SAIB in a ratio of from about 5% - 65% solvent, usually less than 50
%. The active
agent, for example a statin, in a lypholized or dry powder form, may then be
added to the
SAIB/solvent mixture. The mixture is then mixed until homogeneous. The
resulting mixture is
then ready for parenteral injection.
In other depot embodiments the dosage form includes microparticles or
microspheres.
Microparticles can be prepared by grinding to the appropriate particle size a
mixture of
biodegradable polymer and drug. The mixture may be prepared by a melt or
solvent blend.
Microspheres may be prepared by a number of methods familiar to those skilled
in the art
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including spray drying, coacervation and emulsion techniques. For example, the
methods
described in US Patent No. 6,291,013 where a polymer solution containing drug
is emulsified in
water and then the solvent is removed by extraction, evaporation or a
combination of the two
may be used.
A biodegradable monolithic rod may also be used. An experimental example of
such
an embodiment, discussed in more detail below, is one in which a monolithic
rod, wherein the
rod contains 20% statin by weight within a polymer of 65:35 poly (DL-lactide-
co-glycolide).
DELIVERY OF A FORMULATION USING A DRUG DELIVERY DEVICE COMPRISING A DRUG
DELIVERY CATHETER
In some embodiments wherein a drug delivery device is used, it may be
desirable to
provide a drug delivery catheter with the drug delivery device, e.g., where
the implantation site
and the desired delivery site are not the same or adjacent. The drug delivery
catheter is generally
a substantially hollow elongate member having a first end (or "proximal" end)
associated with
the drug release device of the drug delivery device, and a second end (or
"distal" end) for
delivery of the drug-comprising formulation to a desired delivery site. Where
a drug delivery
catheter is used, a first end of the drug delivery catheter is associated with
or attached to the drug
delivery device so that the lumen of the drug delivery catheter is in
communication with the drug
reservoir in the drug delivery device, so that a formulation contained in a
drug reservoir can
move into the drug delivery catheter, and out a delivery outlet of the
catheter which is positioned
at the desired delivery site.
The body of the catheter defines a lumen, which lumen is to have a diameter
compatible
with providing leak-proof delivery of drug formulation from the drug delivery
device. Where
the drug delivery device dispenses drug by convection, the size of the
catheter lumen leading
from the reservoir of the drug release system can be designed as described by
Theeuwes (1975)
J. Pharm. Sci. 64:1987-91.
The body of the catheter can be of any of a variety of dimensions and
geometries (e.g.,
curved, substantially straight, tapered, etc.) that can be selected according
to their suitability for
the intended site for drug delivery. The distal end of the drug delivery
catheter can provide a
distinct opening for delivery of drug, or as a series of openings.
The drug delivery catheter may be produced from any of a variety of suitable
materials,
and may be manufactured from the same or different material as the reservoir
of the drug release
device. Impermeable materials suitable for use in production of the controlled
drug release
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device as described above are generally suitable for use in the production of
the drug delivery
catheter. Exemplary materials from which the drug delivery catheter can be
manufactured
include, but are not necessarily limited to, polymers; metals; glasses;
polyolefins (high density
polyethylene (HDPE), low density polyethylene (LDPE), linear low density
polyethylene
(LLDPE), polypropylene (PP), and the like); nylons; polyethylene
terephtholate; silicones;
urethanes; liquid crystal polymers; PEBAX ; HYTREL ; TEFLON ;
perflouroethylene (PFE)
perflouroalkoxy resins (PFA); poly(methyl methacrylate) (PMMA); multilaminates
of polymer,
metals, and/or glass; nitinol; and the like.
The drug delivery catheter can comprise additional materials or agents (e.g.,
coatings on
the external or internal catheter body surface(s)) to facilitate placement of
the drug delivery
catheter and/or to provide other desirable characteristics to the catheter.
For example, the drug
delivery catheter inner and/or outer walls can be coated with silver or
otherwise coated or treated
with antimicrobial agents, thus further reducing the risk of infection at the
site of implantation
and drug delivery.
In one embodiment, the drug delivery catheter is primed with a drug-comprising
formulation, e.g., is substantially pre-filled with drug prior to
implantation. Priming of the drug
delivery catheter reduces delivery start-up time, i. e., time related to
movement of the drug from
the drug delivery device to the distal end of the drug delivery catheter. This
feature is
particularly advantageous in the present invention where the drug release
device of the drug
delivery device releases a cholesterol lowering agent at relatively low flow
rates.
Fig. 1 illustrates one embodiment of the invention, wherein a formulation is
delivered
from an implanted drug delivery device that provides for sustained release of
a formulation from
a drug reservoir to a subcutaneous site. In this example, the drug delivery
device 10 is implanted
at a subcutaneous site in the patient's arm 5. Flow of drug from the device's
drug reservoir and to
the subcutaneous site is illustrated by arrows 200. Fig. 2 provides a
perspective view of the
exemplary drug delivery device 10 implanted in Fig. 1. The drug delivery
device 10 comprises
proximal and distal ends 11 and 12, with the distal end defining an orifice 15
through which drug
exits the drug reservoir 30 for delivery to the subcutaneous site. In the
exemplary device 10,
controlled release of drug from the reservoir 30 is provided by an osmotic
engine comprising a
piston 41 and a chamber comprising an osmotic engine 42.
As shown in the cut-away of the drug delivery device in Fig. 3, the drug
delivery
system 100 comprises a drug delivery device 10 and a drug delivery catheter
20. The walls of
the drug delivery catheter define a lumen, and the drug delivery catheter is
associated with the
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drug delivery device 10 so that a drug delivery pathway is provided from the
drug reservoir 30,
through the orifice, and out the distal end 12 of the drug delivery device.
The catheter 20 can be
positioned for systemic delivery of drug, for example, subcutaneously.
Methods for implanting or otherwise positioning the dosage forms of the
invention into
the body are well known in the art. In general, placement of parenteral dosage
forms will be
accomplished using methods and tools that are well known in the art, and
performed under
aseptic conditions with at least some local or general anesthesia administered
to the subject.
Removal and/or replacement of the dosage forms, if necessary, can also be
accomplished using
tools and methods that are readily available.
Delivery Of A Formulation Using A Depot
In one embodiment, the formulation is in the form of a depot, delivered and
injected
subcutaneously under the skin of the upper arm of a subject. In one example, a
statin maybe
mixed with SAIB, which may be formulated with one or more solvents and which
may be
hydroxylic or nonhydroxylic. Examples of solvents include ethanol, NMP, benzyl
benzoate,
benzoic acid, ethyl lactate, propylene carbonate, glycofurol, and Miglyol 810
or mixtures
thereof. The solvent can be added to SAIB in a ratio of from about 5 wt% - 65
wt%, usually 50%
solvent, or less. The active agent, for example a statin in a lypholized or
dry powder form, may
then be added to the SAIB/solvent mixture. The mixture is then mixed until
homogeneous. The
resulting mixture is then ready for parenteral injection.
Such a formulation may comprise, as an example, 1 g of cerivastatin which is
then
mixed with 9 g of a 85:15 mixture of SAIB and ethanol until a homogeneous
mixture is
achieved. Accurately weighed samples of the formulation are injected into 125
mL of
dissolution buffer (PBS, 0.01 M, pH 7.4 with sodium azide) prewarmed to 37 C
in a 250-mL
round bottom flask. The flasks are then agitated at 125 rpm in an orbital
shaker. Samples (3
mL) are then removed at 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hr and daily
thereafter. The samples are
assayed for cerivistatin by high performance liquid chromatography (HPLC).
This depot
formulation resulted in of drug over a 30-day period.
As another example, a statin depot formulation is prepared by combining 0.5 g
of
cerivastatin with 9.5 g of a 80:20 mixture of SAM and ethanol to achieve a
homogeneous
mixture. The formulation is assayed as described above. Drug release occurs
over a 30-day
period.
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As another example, 1 g of cerivastatin is added to 9g of a 50:50 mixture of
SAIB and
benzyl benzoate and mixed by stirring to achieve a homogeneous formulation.
Drug release
from this formulation occurs over a 60-day period.
In a further example, cerivistatin is added to a solution of poly(lactic acid)
(Birmingham Polymers, Inc.) in methylene chloride. The methylene chloride is
evaporated and
the resulting film is ground to form particles which are added to a mixture of
SAIB and N-
methyl pyrrolidone (NMP). The final formulation is 45:45:10
SAIB:NMP:poly(lactic acid). The
formulation is assayed as described above for statin release. Release occurs
over a 60-day
period.
Having formulated a SAIB depot it may be injected subcutaneously into the
upper are
of a subject using a needle and a standard syringe. Alternatively, other
parenteral routes of
administration may be used. The injection volume and needle size are chosen to
optimally
achieve the desired rate and duration of release of active agent while
minimizing discomfort to
the patient. Once the needle is withdrawn, the depot remains under the skin
and becomes more
viscous as solvent is released from the bulk of the hydrophobic matrix into
surrounding tissue.
From this stable location, the depot then releases the statin at a relatively
steady rate into the
surrounding tissue, from where the drug finds its way into the circulatory
system, and thence to
its site of action. The depot may release the drug for many weeks or months
A biodegradable monolithic rod may also be used. An experimental example of
such an
embodiment is one in which a monolithic rod is prepared by melt extrusion
using a Tinius Olsen
extruder, wherein the rod contains 20% statin by weight within a polymer of
65:35 poly (DL-
lactide-co-glycolide). The extruded rods are assayed for release of drug by
placing in 40 mL of
dissolution buffer (PBS, 0.01 M, pH 7.4 with sodium azide) in a 120 or 240-mL
amber bottle at
37C with no agitation. After incubation for 1 hr, 15 mL of buffer is removed
for analysis and
replaced with fresh buffer. Samples re removed for analysis daily for one week
and weekly
thereafter. The amount of drug present is determined by HPLC. This formulation
releases drug
over a 90-day period.
Many modifications may be made to adapt aparticular situation, material,
process,
process step or steps, to the objective, spirit and scope of the present
invention. All such
modifications are intended to be within the scope of the invention.
