U.S. patent application number 12/792309 was filed with the patent office on 2010-12-02 for biodegradable bioactive agent releasing matrices with particulates.
Invention is credited to Robert Hergenrother, Joram Slager.
Application Number | 20100303878 12/792309 |
Document ID | / |
Family ID | 43220492 |
Filed Date | 2010-12-02 |
United States Patent
Application |
20100303878 |
Kind Code |
A1 |
Slager; Joram ; et
al. |
December 2, 2010 |
BIODEGRADABLE BIOACTIVE AGENT RELEASING MATRICES WITH
PARTICULATES
Abstract
The present invention is directed to biodegradable polymeric
matrices for the controlled release of a hydrophilic bioactive
agent. Generally, the biodegradable matrices include an aliphatic
polyester copolymer and microparticulates that include the
hydrophilic bioactive agent. In some embodiments, the matrix
includes a second biodegradable polymer comprising hydrophilic and
hydrophobic portions. Exemplary matrix forms are device coatings
and medical implants. Matrices of the invention demonstrated high
bioactive agent loading, were able to modulate release of the
bioactive agent in a therapeutic manner, and also maintained high
levels of activity for therapeutically useful large molecule
bioactive agents, such as proteins.
Inventors: |
Slager; Joram; (St. Louis
Park, MN) ; Hergenrother; Robert; (Eden Prairie,
MN) |
Correspondence
Address: |
Kagan Binder, PLLC
221 Main Street North, Suite 200
Stillwater
MN
55082
US
|
Family ID: |
43220492 |
Appl. No.: |
12/792309 |
Filed: |
June 2, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61217615 |
Jun 2, 2009 |
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Current U.S.
Class: |
424/422 ;
424/130.1; 514/1.1 |
Current CPC
Class: |
A61L 31/16 20130101;
C07K 2317/55 20130101; A61L 29/16 20130101; A61L 2300/256 20130101;
A61L 2300/624 20130101; A61L 31/10 20130101; A61L 31/10 20130101;
A61L 29/085 20130101; A61P 35/00 20180101; Y10T 428/31663 20150401;
A61K 39/39591 20130101; A61L 27/34 20130101; A61L 17/145 20130101;
A61L 27/34 20130101; A61L 17/145 20130101; A61L 31/10 20130101;
C08L 71/02 20130101; C08L 71/02 20130101; C08L 67/04 20130101; C08L
67/04 20130101; C08L 71/02 20130101; C08L 67/04 20130101; A61L
29/085 20130101; C08L 67/04 20130101; A61L 17/005 20130101; A61L
17/145 20130101; A61L 27/54 20130101; A61L 27/34 20130101 |
Class at
Publication: |
424/422 ;
514/1.1; 424/130.1 |
International
Class: |
A61K 39/395 20060101
A61K039/395; A61K 38/00 20060101 A61K038/00; A61F 2/02 20060101
A61F002/02; A61P 35/00 20060101 A61P035/00 |
Claims
1. A biodegradable bioactive agent-releasing matrix, comprising a
polymeric matrix comprising: a biodegradable aliphatic polyester
copolymer comprising monomeric units of formula I: ##STR00009##
wherein R.sup.1 is a divalent saturated or unsaturated hydrocarbon
group that includes two carbon atoms, and wherein the monomeric
units of formula I are present in the biodegradable aliphatic
polyester copolymer in an amount of greater than 17% by weight; and
a plurality of microparticles dispersed within the matrix; wherein
the microparticles comprise a hydrophilic bioactive agent, wherein
the biodegradable bioactive agent-releasing matrix comprises a
surface that is placed in direct contact with body fluid and/or
body tissue.
2. A biodegradable bioactive agent-releasing matrix, comprising a
polymeric matrix comprising: a first biodegradable copolymer
comprising a biodegradable aliphatic polyester copolymer comprising
monomeric units of formula II: ##STR00010## wherein R.sub.2 is a
divalent saturated or unsaturated hydrocarbon group that includes
four or five carbon atoms, and wherein the monomeric units of
formula II are present in the biodegradable aliphatic polyester
copolymer in an amount of greater than 15% by weight; a second
biodegradable copolymer comprising hydrophobic and hydrophilic
portions; and a plurality of microparticles dispersed within the
matrix; wherein the microparticles comprise a hydrophilic bioactive
agent.
3. The biodegradable bioactive agent-releasing matrix of claim 2,
wherein the monomeric units of formula II are present in the
biodegradable aliphatic polyester copolymer in an amount in the
range of 15% to 80% by weight.
4. The biodegradable bioactive agent-releasing matrix of claim 3,
wherein the monomeric units of formula I are present in the
biodegradable aliphatic polyester copolymer in an amount in the
range of 25% to 75% by weight.
5. The elution control matrix of claim 2, wherein the monomeric
units of formula II are derived from the polymerization of
caprolactone.
6. The biodegradable bioactive agent-releasing matrix of claim 2,
wherein the biodegradable aliphatic polyester copolymer further
comprises monomeric units of formula I: ##STR00011## wherein
R.sup.1 is a divalent saturated or unsaturated hydrocarbon group
that includes two carbon atoms.
7. The biodegradable bioactive agent-releasing matrix of claim 6,
wherein the monomeric units of formula II are present in the
biodegradable aliphatic polyester copolymer in an amount in the
range of 20% to 85% by weight.
8. The biodegradable bioactive agent-releasing matrix of claim 7,
wherein the monomeric units of formula II are present in the
biodegradable aliphatic polyester copolymer in an amount in the
range of 25% to 75% by weight.
9. The biodegradable bioactive agent-releasing matrix of claim 6,
wherein the monomeric units of formula I are derived from the
polymerization of lactide.
10. The biodegradable bioactive agent-releasing matrix of claim 2,
wherein the first biodegradable polymer and second biodegradable
polymer are present in the matrix in a ratio in the range of 1:10
to 10:1 by weight.
11. The biodegradable bioactive agent-releasing matrix of claim 10,
wherein the first biodegradable polymer and second biodegradable
polymer are present in the matrix in a ratio in the range of 1.5:10
to 10:1.5 by weight.
12. The biodegradable bioactive agent-releasing matrix of claim 2
wherein the second biodegradable polymer includes hydrophilic
polymeric blocks and hydrophobic polymeric blocks, with one or both
blocks including degradable linkages
13. The biodegradable bioactive agent-releasing matrix of claim 2
wherein the second biodegradable polymer includes polyethylene
glycol blocks.
14. The biodegradable bioactive agent-releasing matrix of claim 2
wherein the second biodegradable copolymer comprises a polyether
ester copolymer.
15. The biodegradable bioactive agent-releasing matrix of claim 14
wherein the second biodegradable copolymer comprises a poly(ether
ester) block copolymer comprising poly(ethylene glycol) (PEG) and
poly(butylene terephthalate) (PBT) blocks.
16. The biodegradable bioactive agent-releasing matrix of claim 14
wherein the second biodegradable copolymer comprises a block
copolymer comprising poly(ethylene glycol) (PEG) and poly(lactic
acid) (PLA) blocks.
17. The biodegradable bioactive agent-releasing matrix of claim 2
wherein the microparticles are present in the matrix in an amount
in the range of 1% to 50% by weight of a total solids content of
the matrix.
18. The biodegradable bioactive agent-releasing matrix of claim 16
wherein the microparticles are present in the matrix in an amount
in the range of 20% to 40% by weight of a total solids content of
the matrix.
19. The biodegradable bioactive agent-releasing matrix of claim 2
wherein the microparticles comprise a polypeptide.
20. The biodegradable bioactive agent-releasing matrix of claim 19,
wherein the microparticles comprises a polypeptide that is an
antibody or fragment thereof.
21. The biodegradable bioactive agent-releasing matrix of claim 20,
wherein the microparticles comprises a Fab fragment.
22. The biodegradable bioactive agent-releasing matrix of claim 2,
wherein the microparticles are formed predominantly of the
hydrophilic bioactive agent.
23. The biodegradable bioactive agent-releasing matrix of claim 2,
which is in the form of a coating on an implantable medical
device.
24. A method for affecting a condition in a subject comprising the
steps of introducing the biodegradable bioactive agent-releasing
matrix of claim 2 in a subject, and allowing hydrophilic bioactive
agent to be released from the elution control matrix which affects
the condition in a subject.
Description
PRIORITY CLAIM
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 61/217,615 filed Jun. 2, 2009, entitled
BIODEGRADABLE BIOACTIVE AGENT RELEASING MATRICES WITH PARTICULATES,
the disclosure of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to biodegradable polymeric
matrices for hydrophilic drug delivery and related methods. More
specifically, the present invention relates to biodegradable
polymeric matrices containing particulates and related methods.
BACKGROUND OF THE INVENTION
[0003] In recent years, much attention has been given to
site-specific delivery of drugs within a patient. Site-specific
drug delivery focuses on delivering the drugs locally, i.e., to the
area of the body requiring treatment. One benefit of the local
release of bioactive agents is the avoidance of toxic
concentrations of drugs that are at times necessary, when given
systemically, to achieve therapeutic concentrations at the site
where they are required.
[0004] Site-specific drug delivery can be accomplished by injection
and/or implantation of an article or device that releases the drug
to the treatment site. Implantation or injection of an article or
device that delivers drug to the treatment site can provide
improvements with regards to administration, reduced complications
(such as reduced infection), and patient comfort. Therapeutic
benefits can also be achieved by providing a bioactive agent to a
subject in a manner that provides controlled release of the
bioactive agent. Controlled release of a bioactive agent can allow
the concentration of the bioactive agent at the target tissue site
to remain at a more consistent therapeutic level.
[0005] One technique for providing controlled-release site-specific
drug delivery is to use a drug-releasing polymeric matrix system,
which can be formed as a coating on a medical device. The coating
can serve to control the rate at which the bioactive agent is
released. Because the coating is formed on a medical device and
because the medical device can be positioned as desired within the
body of a patient, the delivery of the bioactive agent can be
site-specific. Another technique for providing controlled-release
site-specific drug delivery is to use polymeric matrices in the
form of implantable or injectable articles (such as polymeric
microparticles or other drug-releasing depots in the form of
filaments, etc.).
[0006] The present invention is directed to biodegradable polymeric
matrices for hydrophilic drug delivery, wherein the hydrophilic
drug is present in the matrix in particulate form and the polymeric
matrix includes an aliphatic polyester copolymer. The matrices of
the invention have been found to provide one or more of the
following: improvements in maintaining activity of therapeutically
useful large molecule drugs like proteins; improvements in drug
loading in the matrix; and improvements in drug-release
characteristics.
SUMMARY OF THE INVENTION
[0007] The present invention generally relates to biodegradable
polymeric matrices including a hydrophilic bioactive agent which
can be released at a target location following implantation or
injection of the matrix in a subject. The invention also relates to
methods for preparing these matrices, and using these matrices for
the treatment of a medical condition in a subject.
[0008] Generally, the biodegradable bioactive agent-releasing
matrices of the invention include (a) a biodegradable polymer
comprising an aliphatic polyester copolymer, and (b)
microparticulates, the microparticulates including a hydrophilic
bioactive agent. In many cases, the hydrophilic bioactive agent is
a "large molecule drug," such as a therapeutic polypeptide,
polynucleotide, or polysaccharide.
[0009] The hydrophilic bioactive agent, being in the form of
microparticulates, can be dispersed throughout the biodegradable
matrix in discrete microdomains. The use of microparticulates is
advantageous over other matrix-forming processes that may result in
the hydrophilic bioactive agent becoming aggregated or grossly
non-dispersed in the matrix. Further, using microparticulates, the
elution control matrix can have high bioactive agent loading.
Finally, the use of bioactive agent in microparticulate form, along
with the processing steps described herein, allows the bioactive
agent that is incorporated into the matrix to retain most or all of
its activity.
[0010] The matrices of the invention provide desirable properties
for use in association with, or in the form of, an implantable or
injectable medical article. For example, when used in the form of
coating on the surface of an implantable medical device, the
matrices demonstrate good adhesion to the device surface,
compliance, and durability.
[0011] In addition, it has been found that the matrices of the
invention can include a high load of hydrophilic bioactive. Even at
high loads, the hydrophilic bioactive agent was capable of being
released from the matrix in a controlled manner. Therefore,
following implantation, an initial release burst, which can deplete
a substantial amount of bioactive agent from the biodegradable
polymeric matrix, can be avoided. In addition, the matrix can be
completely degraded, making all of the bioactive agent contained in
the matrix available to the subject after a period of implantation.
This allows the implants to be useful for the prolonged release of
therapeutically effective amounts of bioactive agents to treat
medical conditions. For example, the matrices can be used to
deliver a hydrophilic bioactive agent requiring a course of
treatment for a period of time of greater than a month. Given the
prolonged release of bioactive agent, the need for periodic
administration of the bioactive agent is not required. This is
beneficial as it eliminates or significantly reduces need for
patient compliance.
[0012] In some aspects the implantable or injectable article is
formed entirely of the biodegradable polymeric matrix, or is
associated with another implant material that is erodable or
degradable in the body. In these cases, the implantable or
injectable article is entirely degradable after a period of time in
the body, and an explantation process does not need to be
performed.
[0013] In one aspect, the invention provides a biodegradable
bioactive agent-releasing matrix that includes a biodegradable
polymer comprising an aliphatic polyester copolymer, the aliphatic
polyester comprising monomeric units of the following formula
##STR00001##
wherein R.sup.1 is a divalent saturated or unsaturated hydrocarbon
group that includes two carbon atoms (such as a monomeric unit
derived from lactide), and wherein the monomeric unit is present in
the aliphatic polyester copolymer in an amount of greater than 17%
by weight. The biodegradable bioactive agent-releasing matrix also
includes microparticulates that comprise a hydrophilic bioactive
agent. In an implantable or injectable form, the biodegradable
bioactive agent-releasing matrix comprises a surface that is in
direct contact with body fluid and/or body tissue. It was found
that using this arrangement, polymeric matrices formed using the
aliphatic polyester with amounts of lactide greater than 17% by
were able to suppress the burst of the hydrophilic bioactive agent,
even at high loading levels.
[0014] In another aspect, the invention provides a biodegradable
bioactive agent-releasing matrix that includes at least two
biodegradable polymers. The first biodegradable polymer comprises
an aliphatic polyester copolymer, the aliphatic polyester
comprising a monomeric unit of formula II:
##STR00002##
wherein R.sup.2 is a divalent saturated or unsaturated hydrocarbon
group that includes four or five carbon atoms (such as a monomeric
unit derived from caprolactone). The monomeric unit of formula II
is present in the aliphatic polyester copolymer in an amount of
greater than 15% by weight. The second biodegradable polymer
comprises hydrophobic and hydrophilic portions. The biodegradable
bioactive agent-releasing matrix also includes microparticulates
that comprise a hydrophilic bioactive agent.
[0015] In this embodiment of the invention, it was found that the
use of aliphatic polyesters with amounts of a monomeric unit of
formula II greater than 15% rendered the matrix very sensitive to
the inclusion of second biodegradable polymer and its effect on
elution of the hydrophilic bioactive agent. In other words, the
aliphatic polyesters comprising the higher caprolactone content,
when combined with the second polymer, provided biodegradable
matrices that not only showed the ability to suppress the burst of
the hydrophilic bioactive agent (even when the bioactive agent was
used at high loads), but also revealed remarkable tunability for
providing a desired bioactive agent release rate. It was found that
the release rate could be readily tuned by adjusting the ratio
between the first and second biodegradable polymers in the
matrix.
[0016] In other aspects, the invention provides implantable or
injectable medical articles that are formed from, or are associated
with, the biodegradable bioactive agent-releasing matrices of the
invention that include a biodegradable polymer comprising an
aliphatic polyester copolymer, and microparticulates, the
microparticulates including a hydrophilic bioactive agent. The
invention also provides methods for the treatment of a medical
condition using an implantable or injectable medical article formed
from, or are associated with, the bioactive agent-releasing
matrices of the invention.
BRIEF DESCRIPTION OF THE FIGURES
[0017] FIG. 1 is a graph showing release of Fab from metal coils
coated with various poly(lactide-co-glycolide)s and
microparticulates.
[0018] FIG. 2 is a graph showing release of Fab from metal coils
coated with various poly(lactide-co-glycolide)s and
microparticulates and having topcoats.
[0019] FIG. 3A-3D are micrographs of metal coils coated with
various poly(lactide-co-glycolide)s and PEG.sub.1000-45PBT-55
mixtures, and microparticulates.
[0020] FIG. 4A-4D are micrographs of metal coils coated with
various poly(lactide-co-glycolide)s and PEG.sub.1000-45PBT-55
mixtures, and microparticulates.
[0021] FIG. 5A-5D are micrographs of metal coils coated with
various poly(lactide-co-glycolide)s and PEG.sub.1000-45PBT-55
mixtures, and microparticulates.
[0022] FIG. 6 is a graph showing release of Fab from metal coils
coated with a combination of various poly(lactide-co-glycolide)s
and PEG.sub.1000-45PBT-55 mixtures, and microparticulates.
[0023] FIG. 7 is a graph showing release of Fab from metal coils
coated with a combination of various poly(lactide-co-glycolide)s
and PEG.sub.1000-45PBT-55 mixtures, and microparticulates.
[0024] FIG. 8 is a graph showing release of Fab from metal coils
coated with a combination of various poly(lactide-co-glycolide)s
and PEG.sub.1000-45PBT-55 mixtures, and microparticulates.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The embodiments of the present invention described herein
are not intended to be exhaustive or to limit the invention to the
precise forms disclosed in the following detailed description.
Rather, the embodiments are chosen and described so that others
skilled in the art can appreciate and understand the principles and
practices of the present invention.
[0026] All publications and patents mentioned herein are hereby
incorporated by reference. The publications and patents disclosed
herein are provided solely for their disclosure. Nothing herein is
to be construed as an admission that the inventors are not entitled
to antedate any publication and/or patent, including any
publication and/or patent cited herein.
[0027] The present invention generally relates to
microparticulate-containing biodegradable polymeric matrices for
the controlled release of a hydrophilic bioactive agent. Generally,
the matrix is configured for placement in contact with body tissue
or fluid (an "elution environment") in which the hydrophilic
bioactive agent becomes released from the matrix and available to a
subject. The release of the bioactive agent can be site specific,
and used to treat a medical condition. As used herein, the
polymeric "matrix" refers to a three dimensional material structure
which is based on one or more types of polymeric material(s) which
form such a structure. The polymeric matrix can be in a particular
form, such as a coating, and can have properties typical and/or
desirable for desirable for that particular matrix form. The matrix
can also include secondary, tertiary, etc., components, but that
may not necessarily be a structural (polymeric) component of the
matrix. For example, the matrix includes non-structural components,
such as the microparticulates that include the hydrophilic
bioactive agent. Other, optional, non-structural components can be
included in the matrix.
[0028] The biodegradable bioactive agent-releasing matrices can be
in any one or more various forms that provide an effective vehicle
for release of the bioactive agent. In some aspects, the matrix is
present in the form of a coating on the surface of an implantable
medical device. Many particular compositions of the invention are
suitable for forming biodegradable matrices in the form of coatings
having desirable properties, such as strength, compliance,
durability, etc. The biodegradable bioactive agent-releasing
matrices can also be in other forms. For example, the matrix can be
formed within a medical device, such as within an inner space
(e.g., a lumen) of a device, with the device arranged so that the
bioactive agent can be released through a part of the device, such
as an aperture or a membrane that is associated with the
device.
[0029] In another form, the biodegradable bioactive agent-releasing
matrix can be fabricated as an implant itself. For example, the
matrix can be in the form of an implant, such as a filament, coil,
or prosthesis. The matrix in the form of an implant can serve as
reservoir for release of the hydrophilic bioactive agent, or may
also include some structure that (in addition to its drug releasing
capability) can be placed in a subject to provide a mechanical
feature.
[0030] Given the use of degradable polymers for the matrix,
bioactive agent release is not dependent solely on the process of
the bioactive agent diffusing through the matrix. Portions of the
matrix that erode (e.g., through bulk or surface erosion) are able
to contribute to the release of the bioactive agent into the local
environment.
[0031] The term "degradable" as used herein with reference to
polymers, shall refer to those natural or synthetic polymers that
break down under physiological conditions (such as by enzymatic or
non-enzymatic processes) into constituent components over a period
of time. The terms "erodible," "bioerodible," and "biodegradable,"
shall be used herein interchangeably with the term
"degradable".
[0032] Degradable polymers (including aliphatic polyester
copolymers, such as those described herein) include those having
hydrolyzable linkages between some or all of the monomeric units of
the polymeric backbone. These linkages can be broken without
requiring enzymatic assistance and are referred to as non-enzymatic
hydrolyzable linkages (or "hydrolyzable linkages" for short). The
cleavage of these hydrolyzable linkages leads to degradation of the
polymer. Other degradable polymers can include enzymatically
cleavable linkages that can be cleaved by enzymes in the body,
leading to degradation of the polymer. Polymers that can be used in
the biodegradable bioactive agent-releasing matrix of the invention
can have both enzymatically cleavable linkages and non-enzymatic
hydrolyzable linkages.
[0033] In a first matrix embodiment of the invention, the
biodegradable bioactive agent-releasing matrix includes at least
two components. One component is a biodegradable polymer comprising
an aliphatic polyester copolymer. The aliphatic polyester copolymer
comprises monomeric units of formula I which are present in the
copolymer in an amount of greater than 17% (wt). This biodegradable
aliphatic polyester copolymer can form all, or at least part of the
polymeric matrix in which the microparticulates are present.
Another component is a set of microparticulates comprising
hydrophilic bioactive agent. The microparticulates, which are
immobilized by the matrix, release hydrophilic bioactive agent when
the matrix is implanted at or injected into a target location in
the body. The matrix is arranged so that its surface is in direct
contact with the environment (e.g., body fluid or tissue) that
causes bioactive agent release when in use. In a second matrix
embodiment of the invention, the biodegradable bioactive
agent-releasing polymeric matrix includes at least three
components: a first biodegradable polymer, a second biodegradable
polymer, and microparticulates. The polymeric matrix in which the
microparticulates are present is formed from at least the first and
second biodegradable polymers. The first polymer comprises a
biodegradable aliphatic polyester copolymer, the aliphatic
polyester comprising a monomeric unit of formula II in an amount of
greater than 15% by weight. The second biodegradable polymer
comprises hydrophobic and hydrophilic portions. The
microparticulates, which are immobilized by the matrix, release
hydrophilic bioactive agent when the matrix is implanted at or
injected into a target location in the body. The matrix is arranged
so that its surface is in direct or indirect contact with the
environment (e.g., body fluid or tissue) that causes bioactive
agent release when in use.
[0034] The biodegradable bioactive agent-releasing matrix can
contain one or more bioactive agents. The hydrophilic bioactive
agent is provided in the microparticulates. In the biodegradable
bioactive agent-releasing matrix, the microparticulates of the
invention are, in essence, microdomains of hydrophilic bioactive
agent. The use of hydrophilic bioactive agent in the form of
microparticulates is advantageous because it allows bioactive agent
to be included in the matrix without necessarily having to dissolve
the bioactive agent in a solvent that dissolves the one or more
polymeric materials used to form the matrix. In this regard, the
microparticulate form can preserve bioactive agent activity
because, in theory, within the microparticulate the bioactive agent
is not subject to the same structurally altering forces as it would
be if it were simply solvated in the solvent or in an emulsion with
the solvent. Bioactive agent in microparticulate form also allows
for the preparation of matrices with a desired distribution of
bioactive agent in the matrix. The use of microparticulates, in
combination with the biodegradable matrix materials described
herein, provides an advantageous system for the controlled release
of hydrophilic bioactive agents.
[0035] Aspects of the microparticulate may affect release of the
bioactive agent from the biodegradable matrix. These aspects may
include the size of the microparticulate, the presence or absence
of other optional components in the microparticulate such as an
optional polymer, an additive, or a solvent, the erosion
characteristics of the material in the microparticulate, the
structural features of the microparticulate including porosity,
overcoats and the like.
[0036] The term "microparticulate" as used herein shall refer to
non-dissolved particulate matter having a size of less than 1 mm in
diameter (when observed as individual, discrete microparticulates).
The term "microparticulate" also encompasses nanoparticles.
[0037] In many aspects, the biodegradable bioactive agent-releasing
matrix includes particles that are spherical or substantially
spherical in shape (also referred to as "microspheres"). In a
spherical particle, distances from the center (of the microsphere)
to the outer surface of the microsphere will about the same for any
point on the surface of the microsphere. A substantially spherical
microparticulate is where there may be a difference in radii, but
the difference between the smallest radii and the largest radii is
generally not greater than about 40% of the smaller radii, and more
typically less than about 30%, or less than 20%.
[0038] In specific aspects, the biodegradable bioactive
agent-releasing matrix includes a set of microparticulates having
an average diameter ("dn", number average) from about 10 nm to
about 100 .mu.m. In some more specifically aspects, the
biodegradable bioactive agent-releasing matrix comprises a set of
microparticulates is used having an average diameters from about,
from about 100 nm to about 25 .mu.m, from about 500 nm to about 15
.mu.m, or even more specifically from about 1 .mu.m to about 10
.mu.m. In an embodiment, microparticulates are equal to or less
than about 5 .mu.m.
[0039] In some aspects of the invention, a microparticulate set
having a smaller average diameter is used to prepare the
biodegradable bioactive agent-releasing matrix. The use of smaller
diameter microparticulates may improve control over release of the
hydrophilic bioactive agent, such as in terms of rate and duration
of release from the matrix. The use of smaller diameter
microparticulates can also improve aspects of matrix formation. For
example, smaller microparticulates can provide smoother coatings
and are also less likely to clog coating equipment. In some aspects
the small microparticulates have a diameter of less than about 10
.mu.m.
[0040] The microparticles of the biodegradable bioactive
agent-releasing matrix comprise a hydrophilic bioactive agent. The
hydrophilic bioactive agent can have a solubility of at least 1
part agent per 50 parts water. In more specific aspects, the
hydrophilic bioactive agent may be soluble (having a solubility of
at least 1 part agent per from 10 to 30 parts water), freely
soluble (having a solubility of at least 1 part agent per from 1 to
10 parts water), or very soluble (having a solubility of greater
than 1 part agent per 1 part water). These descriptive terms for
solubility are standard terms used in the art (see, for example,
Remington: The Science and Practice of Pharmacy, 20.sup.th ed.
(2000), Lippincott Williams & Wilkins, Baltimore Md.).
[0041] In some aspects the hydrophilic bioactive agent is a
macromolecule. Hydrophilic macromolecules are exemplified by
compounds such as polypeptides, polynucleotides, and
polysaccharides. The hydrophilic macromolecules can have a
molecular weight of about 1000 Da or greater, 5,000 Da or greater,
or 10,000 Da or greater.
[0042] In some specific aspects, the microparticulate comprises a
polypeptide. A polypeptide refers to an oligomer or polymer
including two or more amino acid residues, and is intended to
encompass compounds referred to in the art as proteins,
polypeptides, oligopeptides, peptides, and the like. By way of
example, peptides can include antibodies (both monoclonal and
polyclonal), antibody derivatives (including diabodies, F(ab)
fragments, humanized antibodies, etc.), cytokines, growth factors,
receptor ligands, enzymes, and the like. Polypeptides can also
include those that are modified with, or conjugated to, another
biomolecule or biocompatible compound. For example, the polypeptide
can be a peptide-nucleic acid (PNA) conjugate,
polysaccharide-peptide conjugates (e.g., glyosylated polypeptides;
glycoproteins), a poly(ethyleneglycol)-polypeptide conjugate
(PEG-ylated polypeptides).
[0043] In some modes of practice, the microparticulates are
prepared from polypeptides having a molecular weight of about
10,000 Da or greater, or about 20,000 Da or greater; more
specifically in the range of about 10,000 Da to about 100,000 Da,
or in the range of about 25,000 Da to about 75,000 Da.
[0044] One class of polypeptides that can be formed into the
microparticulates includes antibodies and antibody fragments. A
variety of antibody and antibody fragments are commercially
available, obtainable by deposit or deposited samples, or can be
prepared by techniques known in the art. For example, monoclonal
antibodies (mAbs) can be obtained by any technique that provides
for the production of antibody molecules by continuous cell lines
in culture. These include, for example, the hybridoma technique
(Kohler and Milstein, Nature, 256:495-497 (1975)); the human B-cell
hybridoma technique (Kosbor et al., Immunology Today, 4:72 (1983);
and the EBV-hybridoma technique (Cole et al., Monoclonal Antibodies
and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96 (1985)). Such
antibodies may be of any immunoglobulin class including IgG, IgM,
IgE, IgA, IgD and any subclass thereof.
[0045] Fab or Fab'2 fragments can be generated from monoclonal
antibodies by standard techniques involving papain or pepsin
digestion, respectively. Kits for the generation of
[0046] Fab or Fab'2 fragments are commercially available from, for
example, Pierce Chemical (Rockford, Ill.).
[0047] Examples of antibodies and antibody fragments that can be
used to prepare the microparticulates include, but are not limited
to, therapeutic antibodies such as trastuzumab (Herceptin.TM.), a
humanized anti-HER2 monoclonal antibody (mAb); alemtuzumab
(Campath.TM.), a humanized anti-CD52 mAb; gemtuzumab
(Mylotarg.TM.), a humanized anti-CD33 mAb; rituximab (Rituxan.TM.),
a chimeric anti-CD20 mAb; ibritumomab (Zevalin.TM.), a murine mAb
conjugated to a beta-emitting radioisotope; tositumomab
(Bexxar.TM.), a murine anti-CD20 mAb; edrecolomab (Panorex.TM.), a
murine anti-epithelial cell adhesion molecule mAb; cetuximab
(Erbitux.TM.), a chimeric anti-EGFR mAb; bevacizumab (Avastin.TM.),
a humanized anti-VEGF mAb, Ranibizumab (Lucentis.TM.), an
anti-vascular endothelial growth factor mAb fragment, satumomab
(OncoScint.TM.) an anti-pancarcinoma antigen (Tag-72) mAb,
pertuzumab (Omnitarg.TM.) an anti-HER2 mAb, and daclizumab
(Zenapax.TM.) an anti IL-2 receptor mAb.
[0048] The polypeptide can also be selected from cell response
modifiers. Cell response modifiers include chemotactic factors such
as platelet-derived growth factor (PDGF), pigmented
epithelium-derived factor (PEDF), neutrophil-activating protein,
monocyte chemoattractant protein, macrophage-inflammatory protein,
SIS (small inducible secreted) proteins, platelet factor, platelet
basic protein, melanoma growth stimulating activity, epidermal
growth factor, transforming growth factor (alpha), fibroblast
growth factor, platelet-derived endothelial cell growth factor,
insulin-like growth factor, nerve growth factor, vascular
endothelial growth factor, bone morphogenic proteins, and bone
growth/cartilage-inducing factor (alpha and beta). Other cell
response modifiers are the interleukins, interleukin inhibitors or
interleukin receptors, including interleukin 1 through interleukin
10; interferons, including alpha, beta and gamma; hematopoietic
factors, including erythropoietin, granulocyte colony stimulating
factor, macrophage colony stimulating factor and
granulocyte-macrophage colony stimulating factor; tumor necrosis
factors, including alpha and beta; transforming growth factors
(beta), including beta-1, beta-2, beta-3, inhibin, and activin.
[0049] The polypeptide can also be selected from therapeutic
enzymes, such as proteases, phospholipases, lipases, glycosidases,
cholesterol esterases, and nucleases.
[0050] Specific examples include recombinant human tissue
plasminogen activator (alteplase), RNaseA, RNaseU, chondroitinase,
pegaspargase, arginine deaminase, vibriolysin, sarcosidase,
N-acetylgalactosamine-4-sulfatase, glucocerebrocidase,
.alpha.-galactosidase, and laronidase.
[0051] In some aspects, the microparticulate is composed
predominantly of, or entirely of, hydrophilic bioactive agent. For
example, the microparticulate polypeptide can include hydrophilic
bioactive agent in an amount of about 50% wt or greater, about 60%
wt or greater, about 70% wt or greater, or even about 90% wt or
greater. This can be important in many therapeutic methods, as the
amount of hydrophilic bioactive agent that is available to a
subject following implantation or injection of the biodegradable
bioactive agent-releasing matrix is maximized.
[0052] In some preparations, the biodegradable bioactive
agent-releasing matrix comprises microparticulates composed
predominantly of polypeptides. For example, polypeptide
microparticulates can be formed as described in commonly owned U.S.
patent application Ser. No. 12/215,504, and published as
US2009/0028956, entitled "Polypeptide Microparticulates."
Generally, these microparticulates are formed in a solution, by
coalescing polypeptides with a nucleating agent to form polypeptide
nuclei; mixing a phase separation agent with the solution to
further coalesce polypeptide around the polypeptide nuclei, thereby
forming a mixture; cooling the mixture to form polypeptide
microparticulates; and removing all or part of the phase separation
agent from the polypeptide microparticulates. This method has been
found to be particularly advantageous for the preparation of
microparticulates formed predominantly of antibody or antibody
fragments, and provides microparticulate sets having
microparticulates of desired sizes, with low size polydispersity,
and which maintains good polypeptide activity.
[0053] Optionally, the microparticulate can include a component
that is different than the hydrophilic bioactive agent. In some
aspects, the microparticulate includes a hydrophilic bioactive
agent and a bioactive agent-stabilizing compound. The stabilizing
compound can be of a type and present in an amount in the
microparticulate useful for a particular bioactive agent. Exemplary
stabilizing compounds include, but are not limited to, small
carbohydrate sugars, such as trehalose, glucose, fructose, sucrose,
lactose, maltose, and raffinose, with trehalose being a
particularly effective stabilizing compound for polypeptides. In
some cases an amount of bioactive agent to stabilizing agent is
present in the microparticulate in a range of about 5:1 to about
1:1 (w:w), such as about a 2:1 polypeptide to trehalose. Other
components such as biocompatible surfactants can be present in the
microparticulate, such as poloxamer
(polyoxypropylene-polyoxyethylene block copolymers) surfactants and
polysorbate (polyoxyethylene sorbitan fatty acid ester)
surfactants.
[0054] Optionally, the microparticulate can include a component can
provide an additional control over the release of the bioactive
agent, or protection of the bioactive agent in the
microparticulate. This component can be a polymer, and can be
different than, or the same as, the one or more polymers that are
used to form polymer of the degradable matrix.
[0055] If used, the optional polymer is degradable and further
selected based on various factors including compatibility with the
bioactive agent, degradation characteristics, and compatibility or
incompatibility with solvents used to form the matrix.
[0056] In some embodiments, the microparticulates used are
substantially monodisperse. In other embodiments, the
microparticulates used are polydisperse. In some applications, the
use of substantially monodisperse microparticulates is advantageous
because elution rates from substantially monodisperse
microparticulates can be more consistent than those from
polydisperse microparticulates.
[0057] Optionally, one or more additional bioactive agents that are
different than the hydrophilic bioactive agent can be present in
the elution control matrix. For example, one or more additional
hydrophilic bioactive agents can be present in the
microparticulate, such as two different polypeptides.
[0058] The aliphatic polyester copolymer provides desirable
properties when the elution control matrix is provided in certain
forms. For example, when the matrix is in the form of a coating,
the aliphatic polyester copolymer can provide one or more
properties of durability, compliance, and adherence in association
with a substrate surface, an in the context of biodegradable
coatings. As used herein, the term "durability" refers to the wear
resistance of a polymer coating, or the ability of a coating to
adhere to an article surface when subjected to forces typically
encountered during use (for example, normal force, shear force, and
the like). A more durable coating is less easily removed from a
substrate by abrasion. A compliant coating is one that it shapes
well to the article to which is has been coated and that conforms
to the changes in the shape of the article without introducing any
substantial physical deformities.
[0059] As a general matter, in both first and second matrix
embodiments of the invention, the aliphatic polyester copolymers
are formed from two or more aliphatic polyester-forming monomers.
Exemplary aliphatic polyester-forming monomers include lactide,
glycolide, dioxanone, tartronic acid, hydroxyvalerate,
hydroxybutyrate, malonic acid, valerolactone, and caprolactone.
Exemplary aliphatic polyester-forming monomers also include
different enantiomeric forms of these monomers.
[0060] Aliphatic polyester copolymers suitable for use in both
matrix embodiments of the invention can be obtained commercially.
For example, aliphatic polyester copolymers having levels of
lactide and caprolactone falling within the scope of the invention
can be obtained from Lakeshore Pharmaceuticals (Birmingham, Ala.).
Alternatively, suitable aliphatic polyester copolymers can be
obtained through the polymerization of aliphatic polyester-forming
monomers using known techniques. Such techniques commonly include
direct condensation and ring opening polymerization techniques. For
example, see Jacobson, S., et al. Polymer Engineering and Science,
39:1311-1319 (1999).
[0061] As described herein, in the first matrix embodiment, the
biodegradable bioactive agent-releasing matrix includes at least
one polymeric component and a microparticulate component. The
polymeric component is a biodegradable polymer comprising an
aliphatic polyester copolymer comprising monomeric units of the
following formula I
##STR00003##
wherein R.sup.1 is a divalent saturated or unsaturated hydrocarbon
group that includes two carbon atoms (such as monomeric units
derived from lactide), and wherein the monomeric unit is present in
the aliphatic polyester copolymer in an amount of greater than 17%
by weight. Exemplary R.sup.1 groups include divalent saturated
hydrocarbon groups that include two carbon atoms. For example, the
aliphatic polyester copolymer can have monomeric units with one or
both of the following structures:
##STR00004##
Structure (a) is a monomeric unit derived from the polymerization
of lactide or lactic acid, and (b) a monomeric unit derived from
the polymerization of butyric acid.
[0062] In more specific aspects of the first matrix embodiment, the
biodegradable aliphatic polyester copolymer comprises monomeric
units of formula I in an amount in the range of greater than 17% to
about 99% wt, in the range of about 20% to about 85% wt, in the
range of about 25% to about 85% wt, in the range of about 35% to
about 85% wt, in the range of about 50% to about 85% wt, or in the
range of about 65% to about 85% wt. In some aspects the
biodegradable aliphatic polyester copolymer includes an amount of
lactic acid monomeric units in these ranges.
[0063] A lactide copolymer includes lactide monomeric units, the
lactide monomeric units being derived from the polymerization of a
monomer mixture that includes lactide or lactic acid. Lactic acid
has one asymmetric carbon atom and is a chiral molecule.
Accordingly, lactide is available in two different optical isomeric
forms (enantiomeric forms), D-lactic acid and L-lactic acid (also
known as R and S enantiomers, respectively). The cyclic dimer
lactide is formed by the combination of two lactic acid molecules.
The cyclic lactidc dimer can exist is three possible stereoisomer
forms, (a) a cyclic dimer of two D-lactic acid moieties, (b) a
cyclic dimer of two L-lactic acid moieties, or (c) a cyclic dimer
of D-lactic acid and L-lactic acid moieties. The aliphatic
polyester copolymer comprising lactide that is used to form the
matrix of the invention can be formed from the lactide dimers (a),
(b), or (C), or a mixture thereof. As such, the lactide portion of
the aliphatic polyester copolymer can include monomeric units
formed from D-lactic acid, L-lactic acid, or combinations
thereof.
[0064] In some preparations, the aliphatic polyester copolymer
comprising lactide is formed substantially or entirely from
L-lactide. The use of L-lactide is advantageous because its
degradation product is a naturally occurring stereoisomer that can
be readily metabolized by the body.
[0065] The biodegradable aliphatic polyester copolymer including
monomeric units of formula I can include one or more other
co-monomers that, when included in the copolymer, provide an
aliphatic polyester copolymer capable of being degraded in vivo.
For example, the lactide copolymer can be a random copolymer and
can include one or more other aliphatic polyester-forming monomers.
In more specific aspects of the first matrix embodiment, the
aliphatic polyester copolymer comprises monomeric units of one of
formula I in an amount of greater than 17% by weight, and a
monomeric unit of formula II:
##STR00005##
wherein R.sup.2 is a divalent saturated or unsaturated hydrocarbon
group that includes four or five carbon atoms. Exemplary R.sup.2
groups include divalent saturated linear or branched hydrocarbon
groups that include four or five carbon atoms. In some aspects,
R.sup.2 group is a divalent saturated linear hydrocarbon group that
includes five carbon atoms, which can be provided by the ring
opening and polymerization of caprolactone into the aliphatic
polyester copolymer. In some aspects, R.sup.2 is a divalent
saturated linear hydrocarbon group that includes four carbon atoms,
which can be provided by the ring opening and polymerization of
valerolactone into the aliphatic polyester copolymer.
[0066] In more specific aspects of the first matrix embodiment, the
biodegradable aliphatic polyester copolymer comprises a monomeric
unit of formula I in an amount in the range of greater than 17% to
about 99% wt and a monomeric unit of formula II in an amount in the
range of about 1% to less than 83% wt; a monomeric unit of formula
I in an amount in the range of about 20% to about 85% wt and a
monomeric unit of formula II in an amount in the range of about 15%
to about 80% wt; a monomeric unit of formula I in an amount in the
range of about 25% to about 85% wt and a monomeric unit of formula
II in an amount in the range of about 15% to about 75% wt; a
monomeric unit of formula I in an amount in the range of about 35%
to about 85% wt and a monomeric unit of formula II in an amount in
the range of about 15% to about 65% wt; a monomeric unit of formula
I in an amount in the range of about 50% to about 85% wt and a
monomeric unit of formula II in an amount in the range of about 15%
to about 50% wt; or a monomeric unit of formula I in an amount in
the range of about 65% to about 85% wt and a monomeric unit of
formula II in an amount in the range of about 15% to about 35%
wt.
[0067] For example, an exemplary biodegradable aliphatic polyester
copolymer of the first matrix embodiment includes monomeric units
formed from lactide in an amount in the range of about 25% to about
85% wt, and caprolactone in an amount in the range of about 15% to
about 75%.
[0068] In the second matrix embodiment, the biodegradable bioactive
agent-releasing matrix includes at least two polymeric components
(a first biodegradable polymer, a second biodegradable polymer) and
a microparticulate component. The polymeric matrix in which the
microparticulates are present is formed from at least the first and
second biodegradable polymers. The first polymer comprises a
biodegradable aliphatic polyester copolymer, the aliphatic
polyester comprising a monomeric unit of formula II:
##STR00006##
wherein R.sup.2 is as described herein, and the monomeric unit is
present in the biodegradable aliphatic polyester copolymer in an
amount of greater than 15% by weight. The second biodegradable
polymer comprises hydrophobic and hydrophilic portions. The
microparticulates are immobilized by the matrix.
[0069] In more specific aspects of the second matrix embodiment,
the biodegradable aliphatic polyester copolymer comprises monomeric
units of formula II (such as caprolactone) in an amount in the
range of greater than 15% to about 99% wt, in the range of about
20% to about 83% wt, in the range of about 25% to about 83% wt, in
the range of about 35% to about 83% wt, in the range of about 50%
to about 83% wt, or in the range of about 75% to about 83% wt.
[0070] In more specific aspects of the second matrix embodiment,
the biodegradable aliphatic polyester copolymer comprises a
monomeric unit of formula II in an amount in the range of greater
than 15% to about 99% wt and a monomeric unit of formula I in an
amount in the range of about 1% to less than 85% wt; a monomeric
unit of formula II in an amount in the range of about 20% to about
83% wt and a monomeric unit of formula I in an amount in the range
of about 17% to about 80% wt; a monomeric unit of formula II in an
amount in the range of about 25% to about 83% wt and a monomeric
unit of formula I in an amount in the range of about 17% to about
75% wt; a monomeric unit of formula II in an amount in the range of
about 35% to about 83% wt and a monomeric unit of formula I in an
amount in the range of about 17% to about 65% wt; a monomeric unit
of formula II in an amount in the range of about 50% to about 83%
wt and monomeric unit of formula I in an amount in the range of
about 17% to about 50% wt; a monomeric unit of formula II in an
amount in the range of about 75% to about 83% wt and a monomeric
unit of formula I in an amount in the range of about 17% to about
25% wt.
[0071] For example, an exemplary biodegradable aliphatic polyester
copolymer of the second embodiment of the invention includes
caprolactone in an amount in the range of about 20% to about 83%
wt, and monomeric units derived from lactide in an amount in the
range of about 17% to about 80%.
[0072] In the second matrix embodiment, the biodegradable matrix
also includes a second biodegradable polymer. The second
biodegradable polymer includes hydrophilic and hydrophobic
portions. The presence of the second biodegradable polymer
modulates release of the hydrophilic bioactive agent from the
matrix. It was shown that the rate of release of the bioactive
agent from the matrix was very sensitive to the relative amounts of
the first and second biodegradable polymers in the matrix. In
addition, the matrices formed from the first and second
biodegradable polymers were able to suppress the burst of the
hydrophilic bioactive agent at high loading levels.
[0073] In some aspects the second biodegradable polymer includes
hydrophilic and hydrophobic portions, and the portions are in the
form of polymeric blocks. For example, the second biodegradable
polymer includes hydrophilic polymeric blocks and hydrophobic
polymeric blocks, with one or both blocks including degradable
linkages. In some aspects, the second biodegradable polymer
includes a hydrophobic polymeric blocks that are degradable, and
hydrophilic polymeric blocks including a biocompatible polymer.
[0074] Exemplary degradable hydrophobic polymeric blocks also
include those that are blocks of copolymers having a hydrophobic
property. Such hydrophobic copolymeric blocks can be formed from
formed from polyester-forming monomers such as glycolic acid,
glycolide, lactic acid, lactide, dioxanone, caprolactone,
3-hydroxybutyrate, 3-hydroxyvalerate, valerolactone, tartronic
acid, .beta.-malonic acid, propylene fumarate, and butylene
terephthalate.
[0075] Exemplary degradable hydrophobic polymeric blocks include
those that are formed from degradable polyesters such as
poly(glycolic acid), poly(lactic acid), poly(lactic-co-glycolic
acid), poly(dioxanone), poly(caprolactone),
poly(3-hydroxybutyrate), poly(3-hydroxyvalerate),
poly(valerolactone), poly(tartronic acid), poly(.beta.-malonic
acid), polypropylene fumarate), and poly(butylene
terephthalate).
[0076] Exemplary biocompatible hydrophilic polymeric blocks include
those that are formed from hydrophilic biocompatible polymers such
as poly(ethylene oxide) (PEO), poly(ethyloxazoline), poly(ethylene
glycol) (PEG), PEG-PPO (copolymers of polyethylene glycol and
polypropylene oxide), tetraethylene glycol, triethylene glycol,
trimethylolpropane ethoxylate, or pentaerythritol ethoxylate,
hydrophilic segmented urethanes, and polyvinyl alcohol.
[0077] In some aspects the hydrophilic polymeric blocks of the
second biodegradable polymer have a molecular weight in the range
of about 250 Da to about 5000 Da.
[0078] The hydrophilic and hydrophobic portions of the second
biodegradable polymer can also be defined in terms of their weight
ratios in the polymer. For example, in some aspects, the weight
ratio of the hydrophilic portion to the hydrophobic portions can be
in the range of about 5:1 to about 1:5, about 3:1 to about 1:3,
about 2:1 to about 1:2, or about 1:1 to about 1:1.5.
[0079] Specific examples of degradable polymers having hydrophilic
and hydrophobic blocks include poly(ether ester) multiblock
copolymers. Exemplary poly(ether ester) multiblock copolymers are
based on poly(ethylene glycol) (PEG) and poly(butylene
terephthalate) (PBT) that can be described by the following general
structure:
[--(OCH.sub.2CH.sub.2).sub.n--O--C(O)--C.sub.6H.sub.4--C(O)--].sub.x[--O-
--(CH.sub.2).sub.4--O--C(O)--C.sub.6H.sub.4--C(O)--].sub.y,
where --C.sub.6H.sub.4-- designates the divalent aromatic ring
residue from each esterified molecule of terephthalic acid, n
represents the number of ethylene oxide units in each hydrophilic
PEG block, x represents the number of hydrophilic blocks in the
copolymer, and y represents the number of hydrophobic blocks in the
copolymer. n can be selected such that the molecular weight of the
PEG block is between about 300 and about 4000. X and y can be
selected so that the multiblock copolymer contains from about 55%
up to about 80% PEG by weight. For example a
(poly(butyleneterephthalate-co-ethylene glycol) copolymer with 45
wt. % polyethylene glycol (having an average molecular weight of
1000 kD) and 55 wt. % butyleneterephthalate, would have a weight
ratio of hydrophilic portion to hydrophobic portion of about
1:1.22. Examples of these types of multiblock copolymers are
described in, for example, U.S. Pat. No. 5,980,948. PEG/PBT
polymers are also commercially available from Octoplus BV, under
the trade designation PolyActive.TM..
[0080] Another example of a degradable polymer having hydrophilic
and hydrophobic blocks are those including PEG and polylactic acid
(PLA) blocks. These include PEG-PLA AB-block and ABA-triblock
copolymers, which can be linear or star shaped. See, for example,
U.S. Pat. Nos. 4,745,160 and 6,004,573, and Li Y., et al. (1998)
Synthesis, characteristics and in vitro degradation of star-block
copolymers consisting of L-lactide, glycolide, and branched
multi-arm poly(ethylene oxide), Polymer 39:4421-4427.
[0081] Another type of poly(ether ester) block copolymers suitable
as the second polymer are those composed of various pre-polymer
building blocks of different combinations of DL-lactide, glycolide,
.epsilon.-caprolactone and polyethylene glycol (PEG). These are
referred to herein as PEG-aliphatic polyester block copolymers.
Exemplary PEG-aliphatic polyester block copolymers can have a
formula as shown below:
##STR00007##
wherein,
[0082] m and p are each independently glycolide;
[0083] n is polyethylene glycol, Mw 300-1000;
[0084] o is .epsilon.-caprolactone; and
[0085] q is DL-lactide.
[0086] These PEG-aliphatic polyester block copolymers can degrade
completely via hydrolysis into non-toxic degradation products which
are metabolized and/or excreted through the urinary pathway.
Consequently, there can be no accumulation of biomaterials, thereby
minimizing the chance of long-term foreign body reactions.
[0087] PEG-aliphatic polyester block copolymers are described in,
for example, WO 2005/068533.
[0088] The multi-block copolymers can specifically include two
hydrolysable segments having a different composition, linked by a
multifunctional, specifically an aliphatic chain-extender, and
which are specifically essentially completely amorphous under
physiological conditions (moist environment, body temperature,
which is approximately 37.degree. C. for humans).
[0089] The resulting multi-block copolymers can specifically have a
structure according to any of the formulas (1)-(3):
[--R.sup.8-Q1--R.sup.11-Q2-].sub.x--[R.sup.9-Q3--R.sup.11-Q4-].sub.y--[R-
.sup.10-Q5---R.sup.11-Q6-].sub.x- (1)
[--R.sup.8--R.sub.2--R.sup.8-Q1--R.sup.11-Q2-].sub.x--[R.sup.10-Q2--R.su-
p.11-Q1].sub.x- (2)
[--R.sup.9--R.sup.8.sub.1--R.sup.9-Q1--R.sup.11-Q2-].sub.x--[R.sup.10-Q2-
--R.sup.11-Q1]z- (3)
wherein
[0090] R.sup.8 and R.sup.9 can be amorphous polyester, amorphous
poly ether ester or amorphous polycarbonate; or an amorphous
pre-polymer that is obtained from combined ester, ether and/or
carbonate groups. R.sup.8 and R.sup.9 can contain polyether groups,
which can result from the use of these compounds as a
polymerization initiator, the polyether being amorphous or
crystalline at room temperature. However, the polyether thus
introduced will become amorphous at physiological conditions.
R.sup.8 and R.sup.9 are derived from amorphous pre-polymers or
blocks A and B, respectively, and R.sup.8 and R.sup.9 are not the
same. R.sup.8 and R.sup.9 can contain a polyether group at the same
time. In a specific embodiment, only one of them will contain a
polyether group;
[0091] z is zero or a positive integer;
[0092] R.sup.10 is a polyether, such as poly(ethylene glycol), and
may be present (z.noteq.0) or not (z=0). R.sup.10 will become
amorphous under physiological conditions;
[0093] R.sup.11 is an aliphatic C.sub.2-C.sub.8 alkylene group,
optionally substituted by a C.sub.i-C.sub.1-C.sub.10 alkylene, the
aliphatic group being linear or cyclic, wherein R.sup.11 can
specifically be a butylene, --(CH.sub.2).sub.4-- group, and the
C.sub.1-C.sub.10 alkylene side group can contain protected S, N, P
or O moieties;
[0094] x and y are both positive integers, which can both
specifically be at least 1, whereas the sum of x and y (x+y) can
specifically be at most 1000, more specifically at most 500, or at
most 100. Q1-Q6 are linking units obtained by the reaction of the
pre-polymers with the multifunctional chain-extender. Q1-Q6 are
independently amine, urethane, amide, carbonate, ester or
anhydride. The event that all linking groups Q are different being
rare and not preferred.
[0095] Typically, one type of chain-extender can be used with three
pre-polymers having the same end-groups, resulting in a copolymer
of formula (1) with six similar linking groups. In case
pre-polymers R.sup.8 and R.sup.9 are differently terminated, two
types of groups Q will be present: e.g. Q1 and Q2 will be the same
between two linked pre-polymer segments R.sup.8, but Q1 and Q2 are
different when R.sup.8 and R.sup.9 are linked. Obviously, when Q1
and Q2 are the same, it means that they are the same type of group
but as mirror images of each other.
[0096] In copolymers of formula (2) and (3) the groups Q1 and Q2
are the same when two pre-polymers are present that are both
terminated with the same end-group (which is usually hydroxyl) but
are different when the pre-polymers are differently terminated
(e.g. PEG which is diol terminated and a di-acid terminated
`tri-block` pre-polymer). In case of the tri-block pre-polymers
(R.sup.8R.sup.9R.sup.8 and R.sup.9R.sup.8R.sup.9), the outer
segments should be essentially free of PEG, because the coupling
reaction by ring opening can otherwise not be carried out
successfully. Only the inner block can be initiated by a PEG
molecule.
[0097] The examples of formula (1), (2) and (3) show the result of
the reaction with a di-functional chain-extender and di-functional
pre-polymers.
[0098] With reference to formula (1) the polyesters can also be
represented as multi-block or segmented copolymers having a
structure (ab)n with alternating a and b segments or a structure
(ab)r with a random distribution of segments a and b, wherein `a`
corresponds to the segment R.sup.8 derived from pre-polymer (A) and
`b` corresponds to the segment R.sup.9 derived from pre-polymer (B)
(for z=0). In (ab)r, the ail) ratio (corresponding to x/y in
formula (1)) may be unity or away from unity. The pre-polymers can
be mixed in any desired amount and can be coupled by a
multifunctional chain extender, viz. a compound having at least two
functional groups by which it can be used to chemically link the
pre-polymers. Specifically, this is a di-functional chain-extender.
In case z.noteq.0, then the presentation of a random distribution
of all the segments can be given by (abc)r were three different
pre-polymers (one being e.g. a polyethylene glycol) are randomly
distributed in all possible ratio's. The alternating distribution
is given by (abc)n. In this particular case, alternating means that
two equally terminated pre-polymers (either a and c or b and c) are
alternated with a differently terminated pre-polymer b or a,
respectively, in an equivalent amount (a+c=b or b+c=a). Those
according to formula (2) or (3) have a structure (aba)n and (bab)n
wherein the aba and bab `triblock` pre-polymers are chain-extended
with a di-functional molecule.
[0099] The method to obtain a copolymer with a random distribution
of a and b (and optionally c) is far more advantageous than when
the segments are alternating in the copolymer such as in (ab)n with
the ratio of pre-polymers a and b being 1. The composition of the
copolymer can then only be determined by adjusting the pre-polymer
lengths. In general, the a and b segment lengths in (ab)n
alternating copolymers are smaller than blocks in block-copolymers
with structures ABA or AB.
[0100] The pre-polymers of which the a and b (and optionally c)
segments are formed in (ab)r, (abc)r, (ab)n and (abc)n are linked
by the di-functional chain-extender. This chain-extender can
specifically be a diisocyanate chain-extender, but can also be a
diacid or diol compound. In case all pre-polymers contain hydroxyl
end-groups, the linking units will be urethane groups. In case (one
of) the pre-polymers are carboxylic acid terminated, the linking
units are amide groups. Multi-block copolymers with structure (ab)r
and (abc)r can also be prepared by reaction of di-carboxylic acid
terminated pre-polymers with a diol chain extender or vice versa
(diol terminated pre-polymer with diacid chain-extender) using a
coupling agent such as DCC (dicyclohexyl carbodiimide) forming
ester linkages. In (aba)n and (bab)n the aba and bab pre-polymers
are also specifically linked by an aliphatic di-functional
chain-extender, more specifically, a diisocyanate
chain-extender.
[0101] The term "randomly segmented" copolymers refers to
copolymers that have a random distribution (i.e. not alternating)
of the segments a and b: (ab)r or a, b and c: (abc)r.
[0102] Other exemplary second biodegradable polymers include those
of copolymers containing both hydrophilic poly(alkylene oxides)
(PAO) and degradable sequences, wherein the hydrocarbon portion of
each PAO unit contains from 1 to 4 carbon atoms, or 2 carbon atoms
(i.e., the PAO is poly(ethylene oxide)). For example, useful
degradable polymeric materials can be made of block copolymers
containing PAO and amino acids or peptide sequences and contain one
or more recurring structural units independently represented by the
structure --L--R.sup.3--L--R.sup.4--, wherein R.sup.3 is a
poly(alkylene oxide), L is --O-- or --NH--, and R.sup.4 is an amino
acid or peptide sequence containing two carboxylic acid groups and
at least one pendent amino group.
[0103] Other useful degradable polymeric materials are composed of
polyarylate or polycarbonate random block copolymers that include
tyrosine-derived diphenol monomeric units and poly(alkylene oxide),
such as the polycarbonate shown below:
##STR00008##
wherein R.sup.5 is --CH.dbd.CH-- or (--CH.sub.2--).sub.j, in which
j is 0 to 8; R.sup.6 is selected from straight and branched alkyl
and alkylaryl groups containing up to 18 carbon atoms and
optionally containing at least one ether linkage, and derivatives
of biologically and pharmaceutically active compounds covalently
bonded to the copolymer; each R.sup.7 is independently selected
from alkylene groups containing 1 to 4 carbon atoms; y is between 5
and about 3000; and f is the percent molar fraction of alkylene
oxide in the copolymer and ranges from about 0.01 to about
0.99.
[0104] In some embodiments, pendent carboxylic acid groups can be
incorporated within the polymer bulk for polycarbonates,
polyarylates, and/or poly(alkylene oxide) block copolymers thereof,
to further control the rate of polymer backbone degradation and
resorption.
[0105] The biodegradable bioactive agent-releasing matrix can also
be discussed in terms of the amounts of the components of the
matrix (at particular percentages by weight solids), or amounts of
components in the formed matrix, in relation to one another.
[0106] The first and second biodegradable polymers can be present
in the second matrix embodiment of the invention at a desired
ratio. For example the second biodegradable polymer can be present
and have an affect on the modulation of bioactive agent release in
amounts as little as 10% or about 15%, and up to about 85% or about
90% (by weight) of the total polymeric material that is used to
form the matrix. For example, the ratio of the first biodegradable
polymer to the second biodegradable polymer can be in the range of
about 1:10 to about 10:1, or about 1.5:10 to about 10:1.5.
[0107] In some aspects, the biodegradable bioactive agent-releasing
matrix has an amount of microparticulates (i.e., the amount of
microparticulates as a percentage of the total weight of the
coating) of up to about 50% wt, such as in the range of about 1% wt
to about 50% wt, about 10% wt to about 45% wt, or about 20% wt to
about 40% wt.
[0108] In some aspects, the elution control matrix has an amount of
total polymeric content (i.e., the amount of first polymer, second
polymer, and any additional polymer as a percentage of the total
weight of the elution control matrix) of greater than 30% wt, in
the range of about 30% wt to about 70% wt, about 40% wt to about
70% wt, or about 50% wt to about 70% wt.
[0109] The bioactive agent-releasing matrix can be provided in
certain forms, and one or more processing steps can be carried out
to prepare the matrix in the desired form. Generally, the process
includes obtaining or preparing a composition, the composition
including the one or more polymeric components used to form the
matrix and microparticulates. In many modes of practice, the
composition includes a liquid component, with the one or more
polymeric material(s) microparticulates present as dissolved or
suspended solids in the liquid component, and the microparticulates
present as dispersed, suspended, or suspendable material in the
liquid. Such a liquid composition can be used, for example, in a
coating process to prepare the biodegradable matrix in the form of
a coating on the surface of a device, or in a solvent casting
process to form an article.
[0110] For the first matrix embodiment, the composition includes at
least the biodegradable polymer comprising an aliphatic polyester
copolymer, the aliphatic polyester comprising a monomeric unit of
formula I in an amount greater than 17% by weight, and
microparticulates comprising hydrophilic bioactive agent.
[0111] For the second matrix embodiment, the composition includes
at least the biodegradable polymer comprising an aliphatic
polyester copolymer, the aliphatic polyester comprising a monomeric
unit of formula II in an amount greater than 17% by weight, a
second biodegradable polymer including hydrophobic and hydrophilic
portions, and microparticulates comprising a hydrophilic bioactive
agent.
[0112] In some modes of preparation, once the microparticulates are
produced or obtained, they are mixed with a solvent and one or more
polymeric material(s) that will form the biodegradable matrix. An
appropriate solvent, or solvent system, can be chosen for
preparation of the composition. Different types of solvents can be
used depending on the properties of the particles and the
properties of the one or more matrix polymer(s). Suitable solvents
include those that do not cause substantial or any dissolution of
the microparticulates during the process.
[0113] Examples of solvents suitable for dissolution of the
aliphatic polyester copolymer include halogenated alkanes such as
methylene chloride and chloroform. Halogenated alkanes are
preferred solvents when the microparticulates include or are formed
from polypeptides. Other solvents that can be used include, but are
not limited to, toluene and xylene, ethers such as tetrahydrofuran;
and amides such as dimethylformamide (DMF). Combinations of one or
more of these or other solvents can also be used.
[0114] In some modes of practice, a composition is formed by
dissolving the one or more biodegradable polymers used to form the
matrix in a solvent, and then dispersing the microparticulates in
the composition. However, the components of the composition can be
added to the solvent in any particular order, or can be combined
all at once. In many modes of practice the components are added
with agitation to keep the microparticulates dispersed and/or
suspended. The microparticulates can be provided to the composition
in dry (e.g., lyophilized form) or alternatively can be provided in
a solvent used in the microparticulate formation process. For
example, it is noted that solvents useful for extraction of phase
separation agents in the microparticulate formation process can
also be useful as solvents during the matrix formation (e.g.,
coating) process.
[0115] The one or more polymer components of the matrix (i.e., in
either the first or second matrix embodiments of the invention) can
be added to the composition to provide a concentration of suitable
for forming and holding the microparticulates in place after the
matrix forms, and providing a matrix with desired bioactive agent
release properties. The total polymer content can be at least the
first polymer; the first and second polymers; or the first, second,
and any additional polymers.
[0116] In the second matrix embodiment, the composition is prepared
including the second biodegradable polymer that has hydrophilic and
hydrophobic portions, such as a poly(ethylene glycol)-based block
copolymer. Exemplary concentrations of the second biodegradable
polymer in the solvent can be in the range of up to 20 mg/mL, such
as in the range of about 1 mg/mL to about 20 mg/mL. The first and
second biodegradable polymers can be used at concentrations to
provide a desired ratio of these materials in the formed
matrix.
[0117] The amount of microparticulates incorporated into the matrix
can be chosen based on various factors, including the type and
amount of hydrophilic bioactive agent intended to be incorporated
into the matrix, and the desired release rate and duration of
release of the bioactive agent from the matrix, and the type and
amount of the polymeric material(s) to be used to form the matrix.
There is no particular lower limit of amount of microparticulates
to be dispersed in the composition. In many aspects, the amount of
microparticulates in the composition per volume is less than the
amount of polymeric material per the same volume.
[0118] In some modes of practice, the composition is used in a
coating process so the biodegradable matrix is in the form of a
coating on the surface of a device. In a coating process, the
composition can be applied to a substrate, and then the solvent is
allowed to evaporate from the surface. This leaves the polymeric
material or materials deposited on the surface with the
microparticulates partially and/or full embedded in the polymeric
material, thereby forming a coated layer that is the biodegradable
matrix.
[0119] A coating process can be performed with a single application
of the coating composition, or multiple applications of a coating
composition. For example, the composition may be repeatedly applied
to the surface build up the coating and increase the amount of
solids. Methods forming the matrix can be quite variable, and
suited to provide a coating with desired characteristics, such as a
desired amount of bioactive agent and a desired thickness of the
coating material.
[0120] After all the components of the matrix-forming composition
have been combined, the composition can then be processed to
produce a suspension that is substantially homogenous. Depending on
the nature of the composition components, this may be done using a
sonication apparatus, homogenizer, stirring apparatus, or the like.
In some instances, the composition forms a suspension that is
stable over a period of time of about five minutes to about
twenty-four hours. In other instances, the composition is not
stable and must be stirred or otherwise agitated to maintain the
homogeneity of the suspension. In some embodiments, other agents
may be added to the suspension. If desired, antiflocculation agents
can be added to the composition.
[0121] The coating composition is then applied onto the substrate
using any one of a variety of coating techniques including
dip-coating, spray-coating (including both gas-atomization and
ultrasonic atomization), fogging, brush coating, press coating,
blade coating, and the like. The coating composition may be applied
under conditions where atmospheric characteristics such as relative
humidity, temperature, gaseous composition, and the like are
controlled.
[0122] In some embodiments, the coating solution is applied using a
spray technique. Exemplary spray coating equipment that can be used
to apply coatings of the invention can be found in U.S. Pat. Nos.
6,562,136; 7,077,910; 7,192,484; 7,125,577; U.S. Published Patent
Applications 2006/0088653, and 20051019424; and U.S. application
Ser. Nos. 11/102,465 and 60/736,995.
[0123] The spray technique can be performed by spraying the
composition on the surface of a substrate. Generally, an amount of
solvent will evaporate during spray coating and after the
composition has been applied to the surface. The composition can be
repeatedly sprayed on the surface to provide a coating with desired
properties, such as thickness and amount of bioactive agent per
unit area on the surface. The coating evaporates from the applied
composition, leaving a coating of solids on the surface. The
process can be carried out to provide a coating with desired
features.
[0124] The coating can have certain dimensions, such as thickness.
In many aspects the thickness will be relatively uniform over the
entire coating on the surface. A coating process can be carried out
to provide a coating that is at least based on the size of the
microparticulates that are included in the coating. In many
aspects, the thickness of the coating is greater than the diameter
of the microparticulates present in the coating. For example, the
thickness of the coating can be greater than about 5 .mu.m, greater
than about 10 .mu.m. Exemplary coatings have thicknesses in the
range of about 40 .mu.m to about 50 .mu.m.
[0125] In other modes of practice, the coating process is carried
out wherein components used to form the coating are separately
sprayed on the substrate, using two or more sprayed solutions. For
example, the coating process can be carried out using a spray
coating apparatus with a dual spray head as described in U.S.
Published Patent Application No, 2007/0128343, entitled "Apparatus
and Methods for Applying Coatings." To exemplify this method, and
with reference to the second embodiment of the invention, one
composition including the first polymer and microparticulates is
sprayed from a first spray head, and another composition including
the second polymer is sprayed from a second spray head. The spray
patterns from both spray heads are directed at the same location on
the surface of the substrate, and the components can mix during the
coating process to form the coating.
[0126] Other types of processes can be used to form a biodegradable
bioactive agent-releasing matrix. The matrix can be in the form of
a mass within an implantable article, such as a lumen of an
implantable article. The composition can be disposed in the lumen,
with the removal of solvent during the process, to form a matrix
within the lumen of the article. Following formation and
implantation, the matrix can be contacted with a body fluid through
a portion of the article, such as an aperture, which causes the
bioactive agent to be released from the matrix through the aperture
and degradation of the polymeric material of the matrix.
[0127] In another mode of practice, the biodegradable bioactive
agent-releasing matrix is prepared in the form of an implant, which
is composed of the matrix itself. The implant can be in the form of
a filament, coil, or prosthesis, such that when the implant is
placed in a subject, the bioactive agent can be released from the
matrix. In one mode of preparation, the implant is formed by
disposing the composition in a mold, performing solvent removal and
solidification of the matrix, and then removing the formed implant
from the mold.
[0128] Embodiments of the invention can be used to form elution
control matrices in association with many different types of
devices, including medical devices, including many different types
of substrates. Medical devices can include both implantable devices
(chronically and transiently implantable) and non-implantable
medical devices. In many aspects, a composition used to form the
elution control matrix can be formed into a device as described
herein.
[0129] Embodiments of the invention can be used with implantable,
or transitorily implantable, devices including, but not limited to,
vascular devices such as grafts (e.g., abdominal aortic aneurysm
grafts, etc.), stents (e.g., self-expanding stents typically made
from nitinol, balloon-expanded stents typically prepared from
stainless steel, degradable coronary stents, etc.), catheters
(including arterial, intravenous, blood pressure, stent graft,
etc.), valves (e.g., polymeric or carbon mechanical valves, tissue
valves, valve designs including percutaneous, sewing cuff, and the
like), embolic protection filters (including distal protection
devices), vena cava filters, aneurysm exclusion devices, artificial
hearts, cardiac jackets, and heart assist devices (including left
ventricle assist devices), implantable defibrillators,
electro-stimulation devices and leads (including pacemakers, lead
adapters and lead connectors), implanted medical device power
supplies (e.g., batteries, etc.), peripheral cardiovascular
devices, atrial septal defect closures, left atrial appendage
filters, valve annuloplasty devices (e.g., annuloplasty rings),
mitral valve repair devices, vascular intervention devices,
ventricular assist pumps, and vascular access devices (including
parenteral feeding catheters, vascular access ports, central venous
access catheters); surgical devices such as sutures of all types,
staples, anastomosis devices (including anastomotic closures),
suture anchors, hemostatic barriers, screws, plates, clips,
vascular implants, tissue scaffolds, cerebro-spinal fluid shunts,
shunts for hydrocephalus, drainage tubes, catheters including
thoracic cavity suction drainage catheters, abscess drainage
catheters, biliary drainage products, and implantable pumps;
orthopedic devices such as joint implants, acetabular cups,
patellar buttons, bone repair/augmentation devices, spinal devices
(e.g., vertebral disks and the like), bone pins, cartilage repair
devices, and artificial tendons; dental devices such as dental
implants and dental fracture repair devices; drug delivery devices
such as drug delivery pumps, implanted drug infusion tubes, drug
infusion catheters, and intravitreal drug delivery devices;
ophthalmic devices including orbital implants, glaucoma drain
shunts and intraocular lenses; urological devices such as penile
devices (e.g., impotence implants), sphincter, urethral, prostate,
and bladder devices (e.g., incontinence devices, benign prostate
hyperplasia management devices, prostate cancer implants, etc.),
urinary catheters including indwelling ("Foley") and non-indwelling
urinary catheters, and renal devices; synthetic prostheses such as
breast prostheses and artificial organs (e.g., pancreas, liver,
lungs, heart, etc.); respiratory devices including lung catheters;
neurological devices such as neurostimulators, neurological
catheters, neurovascular balloon catheters, neuro-aneurysm
treatment coils, and neuropatches; ear nose and throat devices such
as nasal buttons, nasal and airway splints, nasal tampons, ear
wicks, ear drainage tubes, tympanostomy vent tubes, otological
strips, laryngectomy tubes, esophageal tubes, esophageal stents,
laryngeal stents, salivary bypass tubes, and tracheostomy tubes;
biosensor devices including glucose sensors, cardiac sensors,
intra-arterial blood gas sensors; oncological implants; and pain
management implants.
[0130] In some aspects, embodiments of the invention can be
utilized in connection with ophthalmic devices. Suitable ophthalmic
devices in accordance with these aspects can provide bioactive
agent to any desired area of the eye. In some aspects, the devices
can be utilized to deliver bioactive agent to an anterior segment
of the eye (in front of the lens), and/or a posterior segment of
the eye (behind the lens). Suitable ophthalmic devices can also be
utilized to provide bioactive agent to tissues in proximity to the
eye, when desired.
[0131] In some aspects, embodiments of the invention can be
utilized in connection with an ophthalmic device configured for
placement at an external or internal site of the eye. Suitable
external devices can be configured for topical administration of
bioactive agent. Such external devices can reside on an external
surface of the eye, such as the cornea (for example, contact
lenses) or bulbar conjunctiva. In some embodiments, suitable
external devices can reside in proximity to an external surface of
the eye.
[0132] Devices configured for placement at an internal site of the
eye can reside within any desired area of the eye. In some aspects,
the ophthalmic devices can be configured for placement at an
intraocular site, such as the vitreous. Illustrative intraocular
devices include, but are not limited to, those described in U.S.
Pat. Nos. 6,719,750 B2 ("Devices for Intraocular Drug Delivery,"
Varner et al.) and 5,466,233 ("Tack for Intraocular Drug Delivery
and Method for Inserting and Removing Same," Weiner et al.); U.S.
Patent Publication Nos. 2005/0019371 A1 ("Controlled Release
Bioactive Agent Delivery Device," Anderson et al.), 2004/0133155 A1
("Devices for Intraocular Drug Delivery," Varner et al.),
2005/0059956 A1 ("Devices for Intraocular Drug Delivery," Varner et
al.), and 2003/0014036 A1 ("Reservoir Device for Intraocular Drug
Delivery," Varner et al.); and U.S. Patent Publication Nos.
2005/0276837 A1 (filed Dec. 15, 2005, Anderson et al.),
2004/0271706 A1 (filed Dec. 8, 2005, Anderson et al.), 20050287188
A1 (filed Dec. 29, 2005, Anderson et al.), 2008/0271703 A1 (filed
Dec. 8, 2005, Anderson et al.), 2005/0281863 A1 (filed Dec. 22,
2005, Anderson et al.); and related applications.
[0133] Suitable ophthalmic devices can be configured for placement
within any desired tissues of the eye. For example, ophthalmic
devices can be configured for placement at a subconjunctival area
of the eye, such as devices positioned extrasclerally but under the
conjunctiva, such as glaucoma drainage devices and the like. In
other aspects, the ophthalmic devices can be configured for
placement at a subretinal area within the eye.
[0134] The present invention may be better understood with
reference to the following examples. These examples are intended to
be representative of specific embodiments of the invention, and are
not intended as limiting the scope of the invention.
EXAMPLE 1
Controlled Delivery of Nonspecific Fab from
Poly(Lactide-Co-Caprolactone) Microparticulate Coatings
[0135] The controlled release characteristics and capacity of
coatings formed from various poly(lactide-co-caprolactone)
copolymers were investigated using high protein loadings
(.about.40% w/w).
[0136] Helical intravitreal coil implants constructed from MP-35
alloy (see commonly assigned U.S. Pub. No. 2005/0019371) were used
as the medical device on which the coatings were formed.
[0137] Poly(lactide-co-caprolactone; pDLCL), prepared using various
DL:CL ratios, was synthesized by Lakeshore Biomaterials
(Birmingham, Ala. 35211). The pDLCL polymers used were pDLCL17/83
8E (IV=0.73), pDLCL 25/75 8E (IV=0.75), pDLCL 65/35 4A (IV=0.43)
and pDLCL 85/15 (8E IV-0.81).
[0138] Nonspecific Fab spray-dried particles containing 70%
nonspecific Fab, 30% trehalose, and 0.1% Tween-80.TM. were obtained
from SurModics Pharmaceuticals (Birmingham, Ala. 35211).
[0139] Coating compositions were prepared by dispersing 20 mg of
Fab protein particles (40% w/w) in 5 mL of chloroform containing 30
mg of polymer (pDLCL copolymers).
[0140] Eight coils per group were spray-coated on four-up. Spray
coating was performed using an Ultrasonic Spray Coater as described
U.S. Published Application 2004/0062875, or an IVEK Coater having a
syringe pump connected to an IVEK gas atomization spray system
(DIgispense.TM. 2000 Model #4065, IVEK, North Springfield, Vt.) as
described in U.S. Published Application 2005/0244453.
[0141] pDLCL base coatings were formed on the coils that contained
the protein particles with a target amount of lmg of coating
material. Subsequently, four coils of the group were topcoated with
the same pDLCL polymer solution used in the base coat minus the
protein particles. The coated coils were dried overnight at room
temperature.
[0142] Upon inspection, all coatings appeared very sticky in
nature.
[0143] Coated coils were placed in 1 mL of elution medium (PBS, pH
7.4) in 96-deep well plates, capped with tight fitting cover and
shaken at 37.degree. C. At prescribed times, 100 .mu.L of eluent of
the samples was transferred into a black 96-well plate. The
remainder of the eluent buffer was aspirated and discarded. Fab
concentrations were determined by adding 100 uL of guanidine HCl
12M to each sample, incubating at -20.degree. C. for 10 minutes and
reading at .lamda..sub.ex=290, .lamda..sub.cm=370.
[0144] The results of the elution studies are shown in FIG. 1
(various DL:CL ratios, no top coats) and FIG. 2 (various DL:CL
ratios, with top coats). After 24 hours, no burst was measured from
any of the formulations without topcoats. When used in combination
with the microparticle-containing based coats, the topcoats tended
to increase the burst release.
EXAMPLE 2
Controlled Delivery of Nonspecific Fab from
Poly(Lactide-Co-Caprolactone)/PEG.sub.1000-45PBT-55
Microparticulate Coatings
[0145] The controlled release characteristics and capacity of
coatings formed from various poly(lactide-co-caprolactone)
copolymers along with a biodegradable
poly(butyleneterephthalate-co-ethylene glycol) copolymer were
investigated using high protein loadings (.about.40% w/w).
[0146] Helical intravitreal coil implants, pDLCL copolymers, and
nonspecific Fab spray-dried particles, as described in Example 1,
were used to prepare the coatings. The polymer
PEG.sub.1000-45PBT-55 is a copolymer of
poly(butyleneterephthalate-co-ethylene glycol) copolymer with 45
wt. % polyethylene glycol having an average molecular weight of
1000 kD and 55 wt. % butyleneterephthalate. PEG.sub.1000-45PBT-55
is commercially available from OctoPlus (Leiden, Netherlands) under
the product name PolyActive.TM..
[0147] Coating compositions were prepared by dispersing 20 mg of
Fab protein particles in 5 mL of chloroform containing 30 mg of
polymer (pDLCL copolymers, 60% w/w). pDLCL copolymers and
PEG.sub.1000-45PBT-55 were blended at ratios 60/0, 50/10, 30/30 or
10/50, respectively.
[0148] Coatings were performed as described in Example 1.
[0149] Upon inspection, none of the coatings appeared sticky in
nature, but many of the coatings containing PEG.sub.1000-45PBT-55
were found to have a rougher texture as shown in the micrographs of
FIGS. 3A-3D (85/15 DL:CL ratio, various DLCL:PEG.sub.1000-45PBT-55
ratios), 4A-4D (65/35 DL:CL ratio, various
DLCL:PEG.sub.1000-45PBT-55 ratios), and 5A-5D (25/75 DL:CL ratio,
various DLCL:PEG.sub.1000-45PBT-55 ratios).
[0150] The results of the elution studies are shown in FIG. 6
(85/15 DL:CL ratio, various DLCL:PEG.sub.1000-45PBT-55 ratios),
FIG. 7 (65/35 DL:CL ratio, various DLCL:PEG.sub.1000-45PBT-55
ratios), and FIG. 8 (25/75 DL:CL ratio, various
DLCK:PEG.sub.1000-45PBT-55 ratios).
* * * * *