U.S. patent application number 12/132562 was filed with the patent office on 2009-12-03 for microparticles for the treatment of disease.
This patent application is currently assigned to Abbott Cardiovascular Systems Inc.. Invention is credited to Thierry Glauser, Florencia Lim, Michael Ngo, Mikael Trollsas, Jinping Wan.
Application Number | 20090297621 12/132562 |
Document ID | / |
Family ID | 41111043 |
Filed Date | 2009-12-03 |
United States Patent
Application |
20090297621 |
Kind Code |
A1 |
Lim; Florencia ; et
al. |
December 3, 2009 |
Microparticles For The Treatment Of Disease
Abstract
Microparticle-bioactive agent based treatments for local
treatment of diseased tissues/organs are disclosed.
Inventors: |
Lim; Florencia; (Union City,
CA) ; Trollsas; Mikael; (San Jose, CA) ; Ngo;
Michael; (San Jose, CA) ; Glauser; Thierry;
(Redwood City, CA) ; Wan; Jinping; (Sunnyvale,
CA) |
Correspondence
Address: |
SQUIRE, SANDERS & DEMPSEY LLP
1 MARITIME PLAZA, SUITE 300
SAN FRANCISCO
CA
94111
US
|
Assignee: |
Abbott Cardiovascular Systems
Inc.
Santa Clara
CA
|
Family ID: |
41111043 |
Appl. No.: |
12/132562 |
Filed: |
June 3, 2008 |
Current U.S.
Class: |
424/501 ;
424/158.1; 514/266.22; 514/29 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61K 9/1647 20130101; A61K 9/5031 20130101; A61P 13/12
20180101 |
Class at
Publication: |
424/501 ;
424/158.1; 514/29; 514/266.22 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 39/395 20060101 A61K039/395; A61K 31/7048 20060101
A61K031/7048; A61K 31/517 20060101 A61K031/517 |
Claims
1. A drug delivery system, comprising: a plurality of narrow
polydispersity microparticles, wherein the microparticles comprise
a polymer selected from the group consisting of
poly(lactide-co-glycolide-co-caprolactone),
poly(lactide-bl-glycolide),
poly(lactide-co-glycolide)-bl-polyethyleneglycol,
poly(lactide-co-glycolide)-bl-polyethylene
glycol-bl-poly(lactide-co-glycolide),
poly(lactide-co-glycolide-co-caprolactone),
poly(lactide-co-glycolide-co-hydroxybutyric acid),
poly(lactide-co-glycolide-co-trimethylene carbonate),
poly(lactide-co-glycolide)-bl-polycaprolactone,
poly(lactide-co-glycolide)-bl-poly(hydroxybutyric acid),
poly(lactide-co-glycolide)-bl-poly(methylene carbonate) and blends
of two or more of the preceding; and, a bioactive agent adhered to
surfaces of, incorporated into or integrated into the structure of
the microparticles.
2. The drug delivery system of claim 1, wherein the lactide is
selected from the group consisting of l-lactide, d-lactide,
d,l-lactide or meso-lactide.
3. The drug delivery system of claim 1, wherein the microparticles
have a mean particle size of about 8 to about 20 microns.
4. The drug delivery system of claim 3, wherein the microparticles
have a mean particle size of about 10 to about 15 microns.
5. The drug delivery system of claim 3, wherein the microparticles
are substantially spherical and the mean particle size is a mean
diameter.
6. The drug delivery system according to claim 1, wherein the mole
percent of caprolactone in the
poly(lactide-co-glycolide-co-caprolactone) is about 10% to about
70%.
7. The drug delivery system according to claim 6, wherein the mole
percent of caprolactone in the
poly(lactide-co-glycolide-co-caprolactone) is less than about
50%.
8. The drug delivery system according to claim 1, wherein the mole
percent of glycolide in the
poly(lactide-co-glycolide-co-caprolactone) is about 10% to about
50%.
9. The drug delivery system according to claim 8, wherein the mole
percent of glycolide in the
poly(lactide-co-glycolide-co-caprolactone) is less than 50%.
10. The drug delivery system according to claim 1, wherein the mole
percent of lactide in the
poly(lactide-co-glycolide-co-caprolactone) is more than about
50%.
11. The drug delivery system according to claim 1, wherein the mole
percent of glycolide in the
poly(lactide-co-glycolide)-bl-polyethylene glycol is about
10-50%.
12. The drug delivery system according to claim 11, wherein the
mole percent of glycolide in the
poly(lactide-co-glycolide)-bl-polyethylene glycol is less than
50%.
13. The drug delivery system according to claim 1, wherein the mole
percent of polyethylene glycol in the
poly(lactide-co-glycolide)-bl-polyethylene glycol is about
1-50%.
14. The drug delivery system according to claim 1, wherein the mole
percent of lactide in the poly(lactide-glycolide)-bl-polyethylene
glycol is about 50% to about 90%.
15. The drug delivery system according to claim 1, wherein the
bioactive agent is selected from the group consisting of a
TGF-.beta. pathway inhibitor, a protein kinase C pathway inhibitor,
a CTGF pathway inhibitor, an mTOR pathway inhibitor, an antibody
against TGF-.beta., an antibody against CTGF, an
angiotensin-converting enzyme inhibitor, an angiotensin II receptor
blocker, a diuretic, a beta-blocker, a calcium channel blocker, a
vasodilator, a direct renin inhibitor, erythropoietin, an inhibitor
of AGE-RAGE signaling, an inhibitor of SMAD signaling, iron and
immuno-suppressives.
16. The drug delivery system according to claim 15, wherein the
TGF-.beta. pathway inhibitor is halofuginone.
17. The drug delivery system according to claim 15, wherein the
protein kinase C pathway inhibitor is reboxistaurin.
18. The drug delivery system according to claim 15, wherein the
mTOR inhibitor is selected from the group consisting of sirolimus,
everolimus, zotarolimus, pimecrolimus, temsirolimus and
biolimus.
19. A method of treating a disease comprising administering the
drug delivery system of claim 1 into the artery of a patient in
need thereof, wherein: less than 10% of the microparticles degrade
under physiological conditions to release a therapeutic amount of
the bioactive agent within 1 week of administration and more than
90% of the microparticles degrade under physiological conditions to
release a therapeutic amount of the bioactive agent within 12
months of administration.
20. The method according to claim 19, wherein the microparticles
have a mean diameter such that at least 80% of them are trapped in
glomeruli of the kidney on a first pass.
21. The method of claim 20, wherein at least 90% of the
microparticles are trapped in the glomeruli of the kidney on the
first pass.
22. The method of claim 21, wherein at least 99% of the
microparticles are trapped in the glomeruli of the kidney on the
first pass.
23. The method according to claim 19, wherein the disease is a
kidney disease selected from a group consisting of chronic kidney
disease, diabetic nephropathy, focal segmental glomerulosclerosis,
IgA Nephritis, lupus nephritis, reflux nephropathy,
glomerulonephritis, glomerulonephrosis and polycystic renal
disease.
24. A method comprising: dissolving a polymer and a hydrophobic
bioactive agent in a water immiscible solvent mixture comprising at
least one solvent with a boiling point less than about 60.degree.
C. and at least one solvent with a boiling point more than about
60.degree. C. to make an organic phase solution; adding the organic
phase solution under high shear to an aqueous phase and sonicating
to form an emulsion; passing the emulsion through a porous membrane
of a selected pore size; removing the organic solvents; and
creating a release rate curve for the bioactive agent from the
resulting microparticles.
25. The method according to claim 24, wherein if a slower release
rate is desired, the relative amount of the solvent with a boiling
point more than about 60.degree. C. is decreased within the solvent
mixture.
26. The method according to claim 24, wherein if a faster release
rate is desired, the relative amount of the solvent with a boiling
point more than about 60.degree. C. is increased within the solvent
mixture.
27. The method according to claim 24, wherein the solvent with a
boiling point less than about 60.degree. C. comprises
dichloromethane or chloroform.
28. The method according to claim 24, wherein the solvent with a
boiling point more than about 60.degree. C. comprises ethyl
acetate, methyl ethyl ketone or methyl isobutyl ketone.
29. The method according to claim 24, wherein the solvent mixture
comprises 90/10 dichloromethane/ethyl acetate.
30. The method according to claim 24, wherein the solvent mixture
comprises 80/20 dichloromethane/ethyl acetate.
31. The method according to claim 24, wherein the bioactive agent
is selected from the group consisting of a TGF-.beta. pathway
inhibitor, a protein kinase C pathway inhibitor, a CTGF pathway
inhibitor, an mTOR pathway inhibitor, an antibody against
TGF-.beta., an antibody against CTGF, an angiotensin-converting
enzyme inhibitor, an angiotensin II receptor blocker, a diuretic, a
beta-blocker, a calcium channel blocker, a vasodilator, a direct
renin inhibitor, erythropoietin, an inhibitor of AGE-RAGE
signaling, an inhibitor of SMAD signaling, iron and
immunosuppresives.
32. The method according to claim 31, wherein the TGF-.beta.
pathway inhibitor is halofuginone.
33. The method according to claim 31, wherein the protein kinase C
pathway inhibitor is reboxistaurin.
34. The method according to claim 31, wherein the mTOR inhibitor is
selected from the group consisting of sirolimus, everolimus,
zotarolimus, pimecrolimus, temsirolimus and biolimus.
Description
FIELD
[0001] The present invention relates to drug delivery systems that
include bioactive-agent loaded microparticles and methods of using
them for the treatment of tissue or organ specific diseases.
BACKGROUND
[0002] Delivery of drug to a specific treatment site represents a
substantial challenge in the design of drug delivery systems. While
drugs designed for action at or within a specific tissue or organ,
e.g., the kidney, may be suitable for systemic delivery, the amount
of drug delivered by this route often must be quite high if a
therapeutically effective amount is to be delivered to the desired
site. Delivery of large amounts of drug, however, can increase the
likelihood and severity of side effects and can be otherwise
disadvantageous, e.g., increased costs of therapy. One approach to
addressing this issue is to use site-specific drug delivery, which
can involve the use of a catheter positioned at a treatment site.
Delivery of drug to a site within a tissue/organ, however,
generally requires breaking the surface of the organ to implant the
catheter tip within the tissue/organ. This may be undesirable where
the tissue/organ is sensitive or already damaged and may compromise
the integrity of structures surrounding the tissue/organ. Thus,
other methods for tissue- or organ- specific drug delivery would be
desirable.
[0003] The kidney is an organ of particular interest for
organ-specific therapy. Diabetic nephropathy, for example, is a
disease that develops over a prolonged period, 10-15 years, during
which the ability of the kidneys to properly function diminishes.
Diabetic nephropathy eventually leads to end-stage renal disease
(ESRD), a condition that requires the individual to undergo
dialysis or a kidney transplant to stay alive. A therapy that can
slow or prevent patients from developing ESRD, or any other tissue
or organ specific disease or disorder, without delivering high
amounts of drug systemically would be extremely useful. The present
invention provides such a therapy.
SUMMARY
[0004] Thus, in one aspect the present invention relates to a A
drug delivery system, comprising:
[0005] a plurality of narrow polydispersity microparticles, wherein
the microparticles comprise a polymer selected from the group
consisting of poly(lactide-co-glycolide-co-caprolactone),
poly(lactide-bl-glycolide),
poly(lactide-co-glycolide)-bl-polyethyleneglycol,
poly(lactide-co-glycolide)-bl-polyethylene
glycol-bl-poly(lactide-co-glycolide),
poly(lactide-co-glycolide-co-caprolactone),
poly(lactide-co-glycolide-co-hydroxybutyric acid),
poly(lactide-co-glycolide-co-trimethylene carbonate),
poly(lactide-co-glycolide)-bl-polycaprolactone,
poly(lactide-co-glycolide)-bl-poly(hydroxybutyric acid),
poly(lactide-co-glycolide)-bl-poly(methylene carbonate) and blends
of two or more of the preceding; and, a bioactive agent adhered to
surfaces of, incorporated into or integrated into the structure of
the microparticles.
[0006] In an aspect of the present invention, the lactide is
selected from the group consisting of I-lactide, d-lactide,
d,l-lactide or meso-lactide.
[0007] In an aspect of the present invention, the microparticles
have a mean particle size of about 8 to about 20 microns.
[0008] In an aspect of the present invention, the microparticles
have a mean particle size of about 10 to about 15 microns.
[0009] In an aspect of the present invention, the microparticles
are substantially spherical and the mean particle size is a mean
diameter.
[0010] In an aspect of the present invention, the mole percent of
caprolactone in the poly(lactide-co-glycolide-co-caprolactone) is
about 10% to about 70%.
[0011] In an aspect of the present invention, the mole percent of
caprolactone in the poly(lactide-co-glycolide-co-caprolactone) is
less than about 50%.
[0012] In an aspect of the present invention, the mole percent of
glycolide in the poly(lactide-co-glycolide-co-caprolactone) is
about 10% to about 50%.
[0013] In an aspect of the present invention, the mole percent of
glycolide in the poly(lactide-co-glycolide-co-caprolactone) is less
than 50%.
[0014] In an aspect of the present invention, the mole percent of
lactide in the poly(lactide-co-glycolide-co-caprolactone) is more
than about 50%.
[0015] In an aspect of the present invention, the mole percent of
glycolide in the poly(lactide-co-glycolide)-bl-polyethylene glycol
is about 10-50%.
[0016] In an aspect of the present invention, the mole percent of
glycolide in the poly(lactide-co-glycolide)-bl-polyethylene glycol
is less than 50%.
[0017] In an aspect of the present invention, the mole percent of
polyethylene glycol in the
poly(lactide-co-glycolide)-bl-polyethylene glycol is about
1-50%.
[0018] In an aspect of the present invention, the mole percent of
lactide in the poly(lactide-glycolide)-bl-polyethylene glycol is
about 50% to about 90%.
[0019] In an aspect of the present invention, the bioactive agent
is selected from the group consisting of a TGF-.beta. pathway
inhibitor, a protein kinase C pathway inhibitor, a CTGF pathway
inhibitor, an mTOR pathway inhibitor, an antibody against
TGF-.beta., an antibody against CTGF, an angiotensin-converting
enzyme inhibitor, an angiotensin II receptor blocker, a diuretic, a
beta-blocker, a calcium channel blocker, a vasodilator, a direct
renin inhibitor, erythropoietin, an inhibitor of AGE-RAGE
signaling, an inhibitor of SMAD signaling, iron and
immunosuppresives.
[0020] In an aspect of the present invention, the TGF-.beta.
pathway inhibitor is halofuginone.
[0021] In an aspect of the present invention, the protein kinase C
pathway inhibitor is reboxistaurin.
[0022] In an aspect of the present invention, the mTOR inhibitor is
selected from the group consisting of sirolimus, everolimus,
zotarolimus, pimecrolimus, temsirolimus and biolimus.
[0023] An aspect of the present invention is a method of treating a
disease comprising administering the drug delivery system of claim
1 into the artery of a patient in need thereof, wherein less than
10% of the microparticles degrade under physiological conditions to
release a therapeutic amount of the bioactive agent within 1 week
of administration and more than 90% of the microparticles degrade
under physiological conditions to release a therapeutic amount of
the bioactive agent within 12 months of administration.
[0024] In an aspect of this invention, in the above method, the
microparticles have a mean diameter such that at least 80% of them
are trapped in glomeruli of the kidney on a first pass.
[0025] In an aspect of this invention, in the above method, at
least 90% of the microparticles are trapped in the glomeruli of the
kidney on the first pass.
[0026] In an aspect of this invention, in the above method, at
least 99% of the microparticles are trapped in the glomeruli of the
kidney on the first pass.
[0027] In an aspect of this invention, in the above method, the
disease is a kidney disease selected from a group consisting of
chronic kidney disease, diabetic nephropathy, focal seqmental
glomerulosclerosis, IgA Nephritis, lupus nephritis, reflux
nephropathy, glomerulonephritis, glomerulonephrosis and polycystic
renal disease.
[0028] An aspect of this invention is a method comprising
dissolving a polymer and a hydrophobic bioactive agent in a water
immiscible solvent mixture comprising at least one solvent with a
boiling point less than about 60.degree. C. and at least one
solvent with a boiling point more than about 60.degree. C. to make
an organic phase solution; adding the organic phase solution under
high shear to an aqueous phase and sonicating to form an emulsion;
passing the emulsion through a porous membrane of a selected pore
size; removing the organic solvents; and creating a release rate
curve for the bioactive agent from the resulting
microparticles.
[0029] In an aspect of this invention, in the above method, if a
slower release rate is desired, the relative amount of the solvent
with a boiling point more than about 60.degree. C. is decreased
within the solvent mixture.
[0030] In an aspect of this invention, in the above method, if a
faster release rate is desired, the relative amount of the solvent
with a boiling point more than about 60.degree. C. is increased
within the solvent mixture.
[0031] In an aspect of this invention, in the above method, the
solvent with a boiling point less than about 60.degree. C.
comprises dichloromethane or chloroform.
[0032] In an aspect of this invention, in the above method, the
solvent with a boiling point more than about 60.degree. C.
comprises ethyl acetate, methyl ethyl ketone or methyl isobutyl
ketone.
[0033] In an aspect of this invention, in the above method, the
solvent mixture comprises 90/10 dichloromethane/ethyl acetate.
[0034] In an aspect of this invention, in the above method, the
solvent mixture comprises 80/20 dichloromethane/ethyl acetate.
[0035] In an aspect of this invention, in the above method, the
bioactive agent is selected from the group consisting of a
TGF-.beta. pathway inhibitor, a protein kinase C pathway inhibitor,
a CTGF pathway inhibitor, an mTOR pathway inhibitor, an antibody
against TGF-.beta., an antibody against CTGF, an
angiotensin-converting enzyme inhibitor, an angiotensin 11 receptor
blocker, a diuretic, a beta-blocker, a calcium channel blocker, a
vasodilator, a direct renin inhibitor, erythropoietin, an inhibitor
of AGE-RAGE signaling, an inhibitor of SMAD signaling, iron and
immunosuppresives.
[0036] In an aspect of this invention, in the above method, the
TGF-.beta. pathway inhibitor is halofuginone.
[0037] In an aspect of this invention, in the above method, the
protein kinase C pathway inhibitor is reboxistaurin.
[0038] In an aspect of this invention, in the above method, the
mTOR inhibitor is selected from the group consisting of sirolimus,
everolimus, zotarolimus, pimecrolimus, temsirolimus and
biolimus.
BRIEF DESCRIPTION OF THE FIGURES
[0039] FIG. 1 is a graphical representation of drug release rate as
a function of the solvent used to create the drug/matrix
medium.
DETAILED DESCRIPTION
Discussion
[0040] It is understood that use of the singular herein includes
the plural and vice versa unless expressly stated otherwise. That
is, "a" and "the" are to be construed as referring to one or more
of whatever the word modifies. For example, "a" therapeutic agent
is understood to include one such agent, two such agents or, under
the right circumstances as determined by those skilled in the
treatment of diseased tissues, even more such agents, again, unless
it is expressly stated or is unambiguously obvious from the context
that such is not intended.
[0041] As used herein, "substantial" or "substantially" means that
the object of the adjective or adverb may not be a perfect example
of such object but would still be immediately envisaged by the
skilled artisan to warrant the general designation. That is, when
modified by the word "substantially," it is understood that the
object of the modifier would be considered close enough to be
recognized by those of ordinary skill in the art as being within
the general genus of such objects. For example, "substantially
spherical" refers to an object that, while not a mathematically
perfect sphere, would be easily recognized as being within
reasonable bounds of that which those skilled in the art would
readily consider "spherical."
[0042] The use of other words of approximation herein, such as
"about" or "approximately" when used to describe numerical values
or ranges likewise are understood to mean that those skilled in the
art would readily consider a value different from the exact number
or outside the actual range to be close enough to be within the
aegis of that number or range. At the very least, "about" or
approximately is understood to mean .+-.15% of a given numerical
value or range starting and ending point.
[0043] As used herein, "polydispersity" refers to the range of
sizes of microparticles within a particular microparticle
population. That is, an extremely polydisperse population might
involve particles having a mean size of, say, 10 microns with
individual particles ranging from 1 to 100 microns. For the
purposes of this invention, a "narrow polydispersity" is preferred.
That is, given a particular mean particle size, it is presently
preferred that individual particles in the population differ by no
more than .+-.20%, preferably no more than .+-.15% and most
preferably at present no more than +10% from the mean particle
size. More specifically, a microparticle population of this
invention preferably has a mean particle size of about 8 to about
20 microns, more preferably at present from about 10 to about 15
microns. Thus, if a mean particle size of 12.5 microns is selected,
individual particles in the population would most preferably be
within the range of from about 11 to about 13 microns.
[0044] As used herein, "microparticle" refers to a polymeric solid
that can have any desired shape such as, without limitation,
spherical, ellipsoid, rod-like, entirely random shaped, etc.,
although substantially spherical microparticles are well-known in
the art, are readily prepared and are presently preferred. The
polymers of which the microparticles are made are biocompatible and
may be biostable or biodegradable.
[0045] As used herein, "biocompatible" refers to a material that in
its original intact state and when biologically decomposed into its
degradation products is not toxic or at least is minimally toxic to
living tissue. A biocompatible material does not, or at least
minimally and reparably, injure living tissue. Further, a
biocompatible material does not, or at least minimally and
controllably, cause an immunological reaction in living tissue.
[0046] By "biostable" is meant that the material of which a
microparticle herein is comprised does not appreciably decompose
over relatively long periods of time which may reach many years in
a physiological environment, for example, without limitation, at
physiological pHs or in the presence of enzymes.
[0047] As used herein, "biodegradable" refers to a polymer that
decomposes under physiological conditions such as body temperature,
pH, enzyme activity and the like and thereafter is absorbed or
eliminated by a patient's body, the foregoing occurring over a
relatively short period of time that may be as short as hours or up
to a year or more.
[0048] Microparticles herein may be solid or they may be porous so
as to provide a large surface area to which bioactive agents may be
physically or chemically adhered or to facilitate elution of the
bioactive agent from within the particles by rendering the interior
of the particles closer to a surface in contact with the external
environment.
[0049] As used herein, "mean particle size" is arrived at by
measuring the size of each individual microparticle and then
dividing by the total number of microparticles. To accomplish this
generally requires sophisticated equipment and techniques but such
are well-known and readily available to those skilled in the art;
that is, determination of mean particle size is commonplace in the
art. To assure efficient capture of the microparticles of this
invention at the capillary bed of a tissue/organ, e.g., glumeruli
in the kidneys, not only should the microparticles have the stated
mean particle size but the polydispersity of the microparticles
should be as narrow as can be achieved, that is, as close to
monodisperse as possible. While several techniques are discussed
below for arriving at relatively narrow size distributions, as
technology advances equipment and procedures for attaining even
narrower size distributions will likely become available and all
such equipment, procedures and size distributions are within the
scope of this invention.
[0050] When the microparticles herein are substantially spherical,
a presently preferred configuration, mean particle size is
synonymous with mean diameter.
[0051] The microparticles of this invention are sized to be
entrapped by the capillary system of an organ, although it is
possible to adjust particle size upward, i.e., to use larger
particles, if such would be more advantageous for the treatment of
a particular tissue or organ disease to entrap the particles in a
larger vessel.
[0052] The reason for selecting the capillaries as a presently
preferred target for the entrapment of microparticles of this
invention lies in the physiology of the capillary system. That is,
the capillary system comprises a vast network of minute (averaging
approximately 1 millimeter in length and 8 microns in diameter)
vessels that permeates virtually every tissue in the mammalian
body. As testament to the ubiquity of capillaries, it has been
estimated that their number in the average human body is
approximately 19,000,000,000 and that most living tissue cells lie
within 1-3 cell lengths of a capillary. Thus, to achieve maximum
deployment of a bioactive agent in a target tissue, it makes sense
that the vehicle carrying the bioactive agent be capable of
maneuvering through the circulatory system to the capillary level.
Entrapping the microparticles at the capillary level assures that
the target disease tissue receives the maximum benefit of the
bioactive agent attached to or adhered to the surface of the
microparticles.
[0053] To assure that microparticles herein are delivered to the
desired capillary system, the microparticles containing an
appropriate bioactive agent or combination of agents are
administered into an artery that directly services a tissue/organ
of interest. By "directly services" it is meant that blood flowing
through the artery proceeds in a single direction through the
labyrinthine maze comprising
artery.fwdarw.arterioles.fwdarw.metarterioles.fwdarw.capillaries.fwdarw.p-
ostcapillary venules.fwdarw.venules--vein such that, once placed
into the artery, microparticles have nowhere to go but to the
capillaries of the target tissue/organ. It is noted that the
kidneys have a rather unique circulatory system:
arteries.fwdarw.afferent arterioles.fwdarw.glomerular
capillaries.fwdarw.efferent arterioles and the methods of this
invention are eminently suitable for use in treating the kidneys.
It is noted that arterioles are generally regarded as having
interior diameters in the range of approximately 10 to 50 microns,
metarterioles about 10 to 20 microns and capillaries approximately
4 to 15 (average about 8) microns in diameter. Thus, microparticles
having a mean size of about 10 to 15 micrometers should be
efficiently entrapped once they reach the capillaries.
[0054] As noted previously, however, while capillaries are a
presently preferred entrapment region, if desired the methods and
particle sizes of this invention can be readily modified by those
skilled in the art to effect entrapment in the lumen of any size
vessel found at a target location.
[0055] It is presently preferred that at least 80% of
microparticles, more preferably at least 90% and most preferably at
least 99% of microparticles administered into an artery of a
patient will be entrapped at a target location, preferably that of
the capillary bed. It is understood that any tissues of interest
can be treated with microparticles of the invention, although the
treatment of the kidney is presently preferred.
[0056] As used herein, "incorporated into" a microparticle refers
to a bioactive agent that is physically entrapped within the matrix
formed by the polymer forming the particle.
[0057] As used herein, "adhered to a surface" of a microparticle
refers a bioactive agent that is chemically or physically attached
to a surface of a particle that is in direct contact with the
external environment.
[0058] As used herein, "integrated into the structure" of a
microparticle refers to a bioactive agent that is a part of the
chemical structure of the polymer forming the microparticle.
[0059] As used herein, "bioactive agent" refers to any substance
that, when administered in a therapeutically effective amount to a
patient suffering from a disease, has a therapeutic beneficial
effect on the health and well-being of the patient. A therapeutic
beneficial effect on the health and well-being of a patient
includes, but is not limited to: (1) curing the disease; (2)
slowing the progress of the disease; (3) causing the disease to
regress; or (4) alleviating one or more symptoms of the disease.
The terms "bioactive agent", "therapeutic agent" and "drug" can be
used interchangeably herein unless the context dictates
otherwise.
[0060] As used herein, a bioactive agent also includes any
substance that has a prophylactic beneficial effect on the health
and well-being of the patient, when administered to a patient known
or suspected of being particularly susceptible to a disease. A
prophylactic beneficial effect includes, but is not limited to: (1)
preventing or delaying on-set of a disease; (2) maintaining a
disease at a regressed level once such level has been achieved by a
therapeutically effective amount of a therapeutic agent, which may
be the same as or different from the therapeutic agent used in a
prophylactically effective amount; or (3) preventing or delaying
recurrence of a disease after a course of treatment with a
therapeutically effective amount of a therapeutic agent, which may
be the same as or different from the therapeutic agent used in a
prophylactically effective amount.
[0061] The amount of bioactive agent in microparticles of the
invention will depend on the required minimum effective
concentration (MEC) of the agent and the length of time over which
it is desired that the MEC be maintained. As used herein, "MEC"
refers to the minimal blood or tissue level at which an agent
exerts the desired effect. For most bioactive agents the MEC will
be known, or readily derivable by those skilled in the art from the
literature. For experimental bioactive agents or those for which
the MEC by localized delivery is not known, such can be empirically
determined using techniques well-known to those skilled in the
art.
[0062] Bioactive agents can be incorporated into microparticles of
this invention by a number of techniques well-known in the art. For
example, without limitation, a bioactive agent may be dissolved (if
it is hydrophobic) or suspended (if it is hydrophilic) in an inner
organic phase during microparticle fabrication. A bioactive agent
(hydrophilic) can form an emulsion with an organic phase then form
a secondary emulsion in a water phase. Or a bioactive agent can be
incorporated into microparticles through a series of secondary
steps where the finished microparticles are flooded with an
agent-containing solution and then dried, typically by
lyophilization. Another alternative would be to affix a bioactive
agent by chemical means to the surface of a microparticle. Also,
particles can be prepared by spraying a solution of a polymer/drug
in a low volatility solvent into a heated chamber so the solvent is
rapidly evaporated, leaving the polymer/drug as a small particle.
The size of the particle can be adjusted by changing the polymer
concentration, the spray rate and/or the type and setting of the
spray nozzle. This process can be further refined by using a
laminar flow jet technology combined with an electrostatic field, a
vibrating nozzle and or a coaxial fluid (gas or liquid
non-solvent). Other suitable methods will be easily discernable to
those skilled in the art using the disclosures herein and are
encompassed by the present invention.
[0063] Any manner of bioactive agent that is known or suspected to
have a beneficial effect on a diseased tissue or organ may be used
with the method of this invention. Thus, a bioactive agent may be
selected from, without limitation, an anti-restenotic, an
antiproliferative, an anti-inflammatory, an antineoplastic, an
antimitotic, an antiplatelet, an anticoagulant, an antifibrin, an
antithrombin, a cytostatic, an antibiotic, an anti-allergenic, an
anti-enzymatic, an angiogenic, a cyto-protective, a
cardioprotective, a proliferative, an ABC A1 agonistic or an
antioxidative agent or any combination thereof. Presently preferred
bioactive agents include, without limitation, antibiotics,
antifungals, anti-virals and anti-fibrotics.
[0064] Examples of antibiotics include, without limitation,
ampicillin, ampicillin/sulbactam, amoxicillin,
amoxicillin/clavulanate, azithromycin, aztreonam, cefaclor,
cefadroxil, cefazolin, cefdinir, cefepime, cefixime, cefoperazone,
cefotaxime, cefotetan, cefoxitin, cefpodoxime, cefprozil,
ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime,
cefuroxime, cephalexin, chloramphenicol, ciprofloxacin,
ciprofloxacin, clarithromycin, clindamycin, cloxacillin, dapsone,
dicloxacillin, doxycycline, erythromycin, ethambutol, fosfomycin
gatifloxacin, imipenem/cilastatin, isoniazid, levofloxacin,
linezolid, loracarbef, meropenem, metronidazole, minocycline,
moxifloxacin, nitrofurantoin, nafcillin, norfloxacin, penicillin,
piperacillin, piperacillin/tazobactam, pyrazinamide,
quinupristin/dalfopristin, rifampin, tetracycline, ticarcillin,
ticarcillin/clavulanate, tmp/smx and trimethoprim.
[0065] Examples of antivirals include, without limitation,
amprenavir, delavirdine, didanosine, efavirenz, famciclovir,
ganciclovir, indinavir, lamivudine, lamivudine/zidovudine,
nelfinavir, nevirapine, ritonavir, saquinavir, stavudine,
valacyclovir, zalcitabine, zidovudine.
[0066] Examples of anti-fungals include, without limitation,
caspofungin, fluconazole, flucytosine, itraconazole, terbinafine,
voriconazole.
[0067] Examples of anti-fibrotics include, without limitation,
inhibitors of the TGF-.beta. pathway, for example halofuginone and
monoclonal antibodies against TGF-.beta. or its receptor, protein
kinase C inhibitors such as ruboxistaurin, CTGF inhibitors such as
FG-3019 and metalloproteinase-ADAM-10 inhibitors such as
XL-784.
[0068] Other compounds that may be used as bioactive agents of this
invention include, without limitation, allopurinol, carbamazepine,
cetirizine, cimetidine, famotidine, fexofenadine, gabapentin,
ketorolac, metoclopramide, primidone, ranitidine, sotalol,
tirofiban and paracalcitol (Zemplar.RTM.).
[0069] It is presently particularly preferred that the bioactive
agent be selected from the group of a TGF-.beta. pathway inhibitor,
a protein kinase C pathway inhibitor, a CTGF pathway inhibitor, an
mTOR pathway inhibitor, an antibody against TGF-.beta., an antibody
against CTGF, an angiotensin-converting enzyme inhibitor, an
angiotensin II receptor blocker, a diuretic, a beta-blocker, a
calcium channel blocker, a vasodilator, a direct renin inhibitor,
erythropoietin, an inhibitor of AGE-RAGE signaling, an inhibitor of
SMAD signaling, iron and immunosuppresives.
[0070] The presently preferable TGF-.beta. pathway inhibitor is
halofuginone, the protein kinase C pathway inhibitor is
reboxistaurin and the mTOR inhibitor is selected from a group that
includes sirolimus, everolimus, zotarolimus, pimecrolimus,
temsirolimus and biolimus.
[0071] As used herein, "treating" refers to the administration of a
therapeutically effective amount of a bioactive agent to a patient
known or suspected to be suffering from a tissue/organ disease.
[0072] As used herein, "patient" refers to any organism that can
benefit from the administration of a bioactive agent. For example,
without limitation, a patient refers to a mammal such as, without
limitation, a cat, dog, horse, cow, pig, sheep, rabbit, goat, or,
preferably at present, a human being.
[0073] As used herein, a "therapeutically effective amount" refers
to the amount of bioactive agent that has a beneficial effect,
which may be curative or palliative, on the health and well-being
of a patient with regard to a tissue/organ disease with which the
patient is known or suspected to be afflicted. A therapeutically
effective amount may be administered as a single bolus, as
intermittent bolus charges, as short, medium or long term sustained
release formulations or as any combination of these.
[0074] As used herein, "mole percent" refers to the percent of a
polymer unit present within a block co-polymer of the invention,
wherein the amount of each polymer unit is measured in moles. For
example, if there is a block-copolymer of the form (A-B)-(C) where
the polymer unit A is present in 10 moles, B is present in 20 moles
and C is present in 70 moles, then the mole percent of A would be
10 moles/(10 moles+20 moles+70 moles) which equals a mole percent
of 10%.
[0075] The microparticles of this invention comprise either
terpolymers or A-B or A-B-A block copolymers. While other monomers
that provide the same benefits as the following may be used and are
within the scope of this invention, it is presently preferred that
the terpolymer is poly(lactide-co-glycolide-co-caprolactone). The
terpolymer may be an alternating, random alternating or purely
random copolymer or a block copolymer. It is also presently
preferred that the A block of the block copolymers comprise lactide
or a lactide/glycolide copolymer (PLGA), which may be an
alternating, purely random or a lactide-bl-glycolide block to
ultimately create a block-within-a-block configuration where the
B-block comprises glycolide (if the A block comprises lactide but
not glycolide), poly(ethylene glycol) (PEG) or caprolactone
(PCL).
[0076] As used herein, an alternating polymer has the general
structure: . . . x-y-z-x-y-z-x-y-z- . . . while a random
alternating polymer has the general structure: . . .
x-y-x-z-x-y-z-y-z-x-y- . . . and a purely random polymer has the
general structure x-y-z-y-z-y-z-x-x-z-y . . . , it being understood
that the exact juxtaposition of the various constitutional x, y and
z units may vary. A regular block polymer has the general
structure: . . . x-x-x-y-y-y-z-z-z-x-x-x . . . , while a random
block polymer has the general structure: . . .
x-x-x-z-z-x-x-y-y-y-y-z-z-z-x-x-z-z-z- . . . Similar to the
situation above regarding regular and alternating polymers, the
juxtaposition of blocks, the number of constitutional units in each
block and the number of blocks in block polymers of this invention
are not in any manner limited by the preceding illustrative generic
structures.
[0077] It is presently preferred that the block copolymer used to
construct microparticles of this invention be selected from the
group: poly(lactide-bl-glycolide),
poly(lactide-co-glycolide)-bl-polyethyleneglycol,
poly(lactide-co-glycolide)-bl-poly(ethyleneglycol)-bl-poly(lactide-co-gly-
colide), poly(lactide-co-glycolide-co-caprolactone),
poly(lactide-co-glycolide-co-hydroxybutyric acid),
poly(lactide-co-glycolide-co-trimethylenecarbonate),
poly(lactide-co-glycolide)-bl-polycaprolactone,
poly(lactide-co-glycolide)-bl-poly(hydroxybutyric acid),
poly(lactide-co-glycolide)-bl-poly(methylene carbonate) and blends
of two or more of the preceding. The lactide may be d,l-lactide,
l-lactide, d-lactide or meso-lactide.
[0078] Glycolide can provide an accelerated or enhanced degradation
of the block co-polymer while lactide can provide mechanical
strength. Thus, by varying the ratio of glycolide and lactide, the
degradation rate of the copolymer can be optimized. The
poly(ethylene glycol) unit, on the other hand, can provide water
solubility, thus adding another measure of controlling the
degradation rate of the copolymer and in turn the agent release
rate.
[0079] In presently preferred embodiments, the mole percent of
glycolide in the poly(lactide-co-glycolide)-bl-polyethylene glycol
will be less than about 50%, preferably at present between about
10% and about 30%. The mole percent of polyethylene glycol in the
poly(lactide-co-glycolide)-bl-polyethylene glycol is about 1-50%,
preferably at present between about 1% and about 10%. Further, the
mole percent of lactide in the
poly(lactide-glycolide)-bl-polyethylene glycol) is more than 50%,
preferably at present between about 70 and 90 mole percent. The
exact molar amounts of each component will depend on the desired
mechanical strength, degradation rate and hydrophilicity of the
microparticles to be used for a particular application. Determining
each of these parameters is well within the capabilities of those
of ordinary skill in the art based on the disclosures herein and
would not require undue experimentation.
[0080] As noted above, the present invention also provides for
PLGA-PCL terpolymer-based microparticles. The presence of
caprolactone in the terpolymer can increase the miscibility of the
bioactive agent with the polymer matrix and therefore better
control release of the agent. Caprolactone-derived constitutional
units in the terpolymer can also provide a hydrophobic entity for
better phase mixing with hydrophobic drugs and increase diffusivity
of the terpolymer by lowering the glass transition temperature of
the polymers. For example, the higher the capolactone content, the
lower the Tg of the resultant terpolymer. As also noted previously,
glycolide can bestow an accelerated or enhanced degradation rate on
the terpolymer while lactide provides mechanical strength.
[0081] It is presently preferred that the mole percent of
caprolactone in the terpolymer be about 10% to about 70%,
preferably at present less than about 50% unless burst release of
the bioactive agent is desired. Glycolide content can range from
about 10% to about 50%, although about 10% to about 40% is
presently preferred. The mole percent of lactide in the terpolymer
is at least 50%, preferably at present between about 70 and about
90 mole percent.
[0082] While the mole percent of various polymer units can be
varied and preferred amounts are set forth herein, the final block
copolymer will also have a preferred molecular weight.
Specifically, the preferred molecular weight of the
poly(lactide-co-glycolide-co-caprolactone) terpolymer will be
between about 10-200 kDa and more preferably between about 70 and
150 kDa. The preferred molecular weight of the
poly(lactide-co-glycolide)-bl-polyethylene glycol polymer will be
between about 10-200 kDa and more preferably between about 70 and
150 kDa.
[0083] The present invention also provides a method for treating a
disease that involves administering bioactive agent-loaded
microparticles into an organ-specific artery, that is, an artery
that services a particular tissue/organ of a patient in need
thereof. The population of microparticles will have a mean diameter
such that they will become lodged in the capillaries of target
tissues and most preferably in the glomeruli of nephrons of the
kidneys, as described above.
[0084] The plurality of microparticles can comprise bioactive
agents in several different ways. In the simplest, the bioactive
agent is adhered to, incorporated into or integrated into the
structure of microparticles at a single concentration so that all
microparticles in a population are substantially the same with
regard to bioactive agent load. In another approach, the bioactive
agent is adhered to the surface of, incorporated into or integrated
into the structure of the microparticles or, if desired into
different microparticles, at different concentrations in separate
preparations and the microparticles formed in those separate
preparations can be combined into a single population for
administration to a patient. In yet another approach, different
bioactive agents can be separately adhered to the surface of,
incorporated into or integrated into the structure of the
microparticles, or again, if desired in different microparticles,
at various concentrations, the microparticles again being combined
for administration. Two or more bioactive agents can, of course, be
adhered to the surface of, incorporated into or integrated into the
structure of the same microparticle such that the resulting
microparticles each contain more than one bioactive agent. Those
skilled in the art will, based on the disclosure herein, be able to
devise additional combinations of microparticles and bioactive
agent(s): and all such combinations are within the scope of this
invention.
[0085] As mentioned above, in order to achieve the preceding
degrees of entrapment it is necessary to produce microparticles
having a size distribution as narrow as possible around a selected
mean size wherein the mean size is determined by the vessel lumen
size present in the tissue being treated. For instance, the average
particle size must be small enough to pass through an afferent
arteriole (in the case where a kidney is the target tissue) but
large enough to be trapped by a capillary. While there may be other
means to accomplish this and any such means is within the scope of
this invention, presently preferred means include emulsification
followed by supercritical fluid solvent extraction,
electrohydrodynamic atomization and membrane emulsification.
[0086] Emulsification followed by supercritical fluid solvent
extraction to form microparticles having a very narrow size range
is a well-known technique in the art and therefore need not be
extensively discussed herein. In brief, the technique involves the
formation of an emulsion by dissolving a polymer and a therapeutic
agent in a solvent for both, adding the solution under high shear
to water containing emulsifying agent, sonicating to achieve a
narrow droplet size range, passing the droplets through a porous
membrane of well-defined pore size and then extracting the solvent
from the microparticles using a supercritical fluid to give a
hardened particle. A supercritical fluid, that is a fluid above its
critical temperature and pressure, is used because of the physical
properties of such fluids, which are intermediate between those of
a gas and those of a liquid. For example, supercritical carbon
dioxide has a viscosity in the range of about 0.02 to about 0.1
centipoise (cP) whereas liquids have viscosities of 0.5-1.0 cP and
gasses have viscosities around 0.01 cP. Further, the diffusivities
of solutes in supercritical carbon dioxide are up to a factor of 10
higher than in liquid solvents. This and the tunability of the
solvating properties of supercritical fluids, which are a complex
(but relatively well-understood) function of pressure and
temperature, permit extremely selective extraction of one material,
the solvent herein for instance, from others it may be combined
with.
[0087] In any event, the hardened microparticles obtained after
supercritical fluid solvent extraction may then be passed through
yet another filter with well-defined pore size to still further
control particle size distribution.
[0088] Electrohydrodynamic atomization (EDHA) is another relatively
new but nevertheless well-characterized technique in the art for
producing narrow size distribution, i.e., essentially monodisperse,
microparticles. Briefly, electrohydrodynamic atomization involves
pumping a solution through a nozzle wherein a high voltage
potential has been established between the tip of the nozzle and a
counter-electrode. The high potential causes a build-up of electric
charge in droplets at the nozzle tip and when the coulombic forces
exceed the surface tension of the droplets, they separate,
essentially explode, into smaller droplets. If parameters are
optimized to achieve a stable spray, monodispersed droplets are
obtained. Removal of solvent from the droplets yields monodisperse
solid microparticles. Parameters that may be varied to achieve a
particular average size droplet/particle include, without
limitation, the applied voltage, the flow rate, density and
conductivity.
[0089] Normal emulsification techniques generally afford droplets
of relative polydispersity, at least with regard to the narrow size
distribution desired for use in the current invention. Thus, one
and perhaps two filtrations as set forth above with regard to
emulsification/supercritical fluid solvent extraction are
required.
[0090] Membrane emulsification is another relatively new technique
for producing essentially monodisperse microparticles. As with
standard emulsification followed by multiple filtrations and
electrohydrodynamic atomization, membrane emulsification, while a
relatively recent development, is well-known to those skilled in
the art. Briefly, membrane emulsification involves the injection of
an intended discontinuous phase through a porous membrane in which
pore size is very carefully controlled into the intended continuous
phase, which is moving past the porous membrane on the side
opposite that from which the discontinuous phase is being injected.
Droplets are sheared off the membrane by the moving continuous
phase. Control of droplet size is quite exquisite compared to
normal emulsification techniques because size is determined
predominantly by easily varied parameters including the speed of
the continuous phase, viscosity of the continuous phase,
interfacial tension between the phases, the chemistry of the
system--surfactant type and physical properties of all the
constituents--and, of course, pore size. Newer techniques for
creating porous membranes with very defined pore size such as laser
drilling and lithographic procedures have made membrane
emulsification even more attractive as a technique for control of
particle size distribution.
[0091] No matter which method is used, the drug delivery system of
the invention can be used to treat a range of tissue/organ
diseases. It is presently preferred, however, that the diseased
organ to be treated be a kidney and the drug delivery system is
administered via the renal artery.
[0092] By way of example, bioactive agent released at glomeruli of
the kidney, specifically everolimus, could reach concentrations of
10 to 150 ng/gram of tissue and in so doing inhibit matrix
deposition that contributes to glomerulosclerosis. Methods of the
invention, however, are useful for the delivery of such
concentrations of agent to any diseased tissue/organ of
interest.
[0093] Another aspect of the invention relates to a method of
controlling the release rate of bioactive agent from a
microparticle preparation by varying the solvents used in the
preparation of the microparticles. Studies have shown that slower
evaporation of solvent, such as would be the case with a 90:10
acetone/methyl ethyl ketone (MEK) mixture, from a medical device
coating composition provides faster stent drug release profiles
than when a solvent is 100% acetone, which is removed faster during
drying. When the solvent removal is slower, the hydrophobic olimus
drug has more time to phase separate from the relatively
hydrophilic polymer and migrate to the surface, thereby resulting
in faster drug release. The present invention builds on these
observations.
[0094] That is, the method of this invention involves dissolving a
polymer and a hydrophobic bioactive agent in a water immiscible
solvent mixture comprising at least one solvent with a boiling
point less than about 60.degree. C. and at least one solvent with a
boiling point greater than about 60.degree. C. to make an organic
phase solution, adding the organic phase solution under high shear
to an aqueous phase, sonicating to form an emulsion, passing the
emulsion through a porous membrane of a selected pore size and then
removing the organic solvents. A release rate curve for the
specific polymer/bioactive agent microparticle can then be
determined by techniques well known to those skilled in the art. If
the release rate is too slow or too fast, manipulating the type and
amount of solvents in the solvent mixture will provide either
faster or slower release rates. It is understood that the terms
slow release and fast release are relative terms measured against
one another as they arise from the use of various solvent mixtures
within the above parameters.
[0095] If a faster release rate is desired, the relative amount of
the solvent with a boiling point above about 60.degree. C. is
increased. Solvent with a boiling point more than about 60.degree.
C. include, without limitation, MEK and methyl isobutyl ketone
(MIBK) as shown in FIG. 1.
[0096] If a faster release rate is desired, the relative amount of
the solvent with a boiling point above about 60.degree. C. is
decreased, i.e., the amount of the solvent with a boiling point
less than about 60.degree. C. would have to be increased. Solvents
with a boiling point less than about 60.degree. C. include, without
limitation, chloroform and dichloromethane.
[0097] A presently preferred solvent mixture is
dichloromethane/ethyl acetate. By varying the ratio of
dichloromethane to ethyl acetate, the release of drug from
microparticles can be optimized. An example, without limitation, is
90/10 or 80/20 dichloromethane/ethyl acetate.
[0098] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from this invention in its broader aspects. Therefore,
the appended claims are to encompass within their scope all such
changes and modifications as fall within the true spirit and scope
of this invention.
* * * * *