U.S. patent application number 11/022416 was filed with the patent office on 2006-01-05 for polymeric devices for controlled release of active agents.
Invention is credited to John W. Gibson, Arthur J. Tipton.
Application Number | 20060003008 11/022416 |
Document ID | / |
Family ID | 34799603 |
Filed Date | 2006-01-05 |
United States Patent
Application |
20060003008 |
Kind Code |
A1 |
Gibson; John W. ; et
al. |
January 5, 2006 |
Polymeric devices for controlled release of active agents
Abstract
Polymeric devices for controlled release of an active agent of
interest are provided. The active agent is provided within a
biodegradable polymer system to supply a polymeric device for
controlled release of the active agent. The polymer system is a
copolymer or a polymer blend comprising a hydrophobic component and
a hydrophilic component, and the polymer system does not form a
hydrogel when contacted with, or immersed in an aqueous system, for
example when the device is implanted in a subject. When the device
is administered to a subject, for example, when it is implanted,
the device releases the active agent in a controlled fashion
without a lag period, or with a minimal lag period. Methods for
producing the polymeric devices are also provided, as are methods
of using the polymeric devices to provide for controlled release of
an active agent in a subject.
Inventors: |
Gibson; John W.;
(Springville, AL) ; Tipton; Arthur J.;
(Birmingham, AL) |
Correspondence
Address: |
DURECT CORPORATION
10240 BUBB ROAD
CUPERTINO
CA
95014
US
|
Family ID: |
34799603 |
Appl. No.: |
11/022416 |
Filed: |
December 23, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60533301 |
Dec 30, 2003 |
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60563377 |
Apr 19, 2004 |
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60575199 |
May 28, 2004 |
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Current U.S.
Class: |
424/486 ;
424/85.1; 514/10.3 |
Current CPC
Class: |
A61K 38/09 20130101;
A61K 38/24 20130101; A61K 9/2031 20130101; A61K 9/1647 20130101;
A61K 9/0024 20130101; A61K 47/34 20130101; A61K 9/1635
20130101 |
Class at
Publication: |
424/486 ;
424/085.1; 514/015 |
International
Class: |
A61K 38/09 20060101
A61K038/09; A61K 9/14 20060101 A61K009/14 |
Claims
1. A polymeric device for controlled release of an active agent of
interest, said device comprising a biodegradable polymer system
selected from the group consisting of copolymers and polymeric
blends comprising a hydrophobic component and a hydrophilic
component; and an active agent, wherein the polymer system does not
form a hydrogel when the device is contacted with an aqueous
system, and further wherein the device releases the agent without a
lag period or with a minimal lag period.
2. The device of claim 1 wherein the active agent is present in an
amount up to 40 wt %.
3. The device of claim 1, wherein the active agent is a
peptide.
4. The device of claim 3, wherein the peptide is a therapeutic
and/or prophylactic peptide selected from the group consisting of
hormones, growth factors, neuroactive agents, melanotropic
peptides, cell adhesion factors, cytokines, and biological response
modifiers.
5. The device of claim 4, wherein the peptide is a GNRH molecule or
a GnRH analog.
6. The device of claim 5, wherein the GnRH analog is selected from
the group consisting of desorelin, tryptorelin, goserelin, and
leuprolide.
7. The device of claim 1, wherein polymer system is a copolymer
comprising a hydrophobic component and a hydrophilic component.
8. The device of claim 1, wherein polymer system is a blend of a
hydrophobic polymer and a hydrophilic polymer.
9. The device of claim 1, wherein the hydrophilic component is
present in an amount of up to 25%.
10. The device of claim 1, wherein the hydrophilic component is
present in an amount of up to 15%.
11. The device of claim 1, wherein the hydrophilic component is
present in an amount of between 0.5 and 10 weight percent.
12. The device of claim 1, wherein the polymer system is an AB
copolymer wherein the A component is a copolymer of lactide,
glycolide, or caprolactone, and the B component is a
polyalkyleneglycol.
13. The device of claim 11, wherein the B component is a
polyalkyleneglycol at 1.25 weight percent and the hydrophobic
polymer is poly(lactide-co-glycolide).
14. The device of claim 1, wherein the active agent is distributed
uniformly within the polymer.
15. The device of claim 1, wherein the active agent is incorporated
using a non-solvent process.
16. The device of claim 1, wherein the device is formed by dry melt
extrusion.
17. The device of claim 1, wherein the device is formed by melt
extrusion of the copolymer mixed with peptide.
18. The device of claim 1, wherein the active agent is released
with linear or near zero order release kinetics.
19. The device of claim 1, wherein the polymer system comprises
greater than 75 wt % hydrophobic polymer.
20. The device of claim 19, wherein the polymer system comprises
greater than 85 wt % hydrophobic polymer.
21. The device of claim 20, wherein the polymer system comprises
greater than 91 wt % hydrophobic polymer.
22. The device of claim 21, wherein the polymer system comprises
greater than 98 wt % hydrophobic polymer.
23. The device of claim 1, wherein the hydrophobic component of the
polymer system is selected from the group consisting of polyhydroxy
acids, such as poly(lactide)s, poly(glycolide)s,
poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic
acid)s, and poly(lactic acid-co-glycolic acid)s, polyanhydrides,
polyorthoesters, polyetheresters, polycaprolactone,
polyesteramides, polyphosphazines, polycarbonates, polyamides, and
copolymers thereof.
24. The device of claim 1, wherein the hydrophilic component of the
polymer system is polyethylene glycol.
25. The device of claim 1 provided in the form of a fiber, needle
or rod.
26. The device of claim 1 provided in the form of a sheet, film or
coating.
27. The device of claim 1 provided in microparticulate form.
28. The device of claim 1 free of solvent residue.
29. The device of claim 1 for treating disease wherein the active
agent is a GnRH molecule or a GnRH analogue.
30. The device of claim 1, wherein the active agent is a GnRH
molecule or a GnRH analogue used for lowering gonadotropin
levels.
31. A method of making the device of claim 1, said method
comprising mixing the polymer system and the active agent,
extruding the mixture of the polymer system and active agent,
grinding or milling the extruded mixture, and feeding the ground or
milled extruded mixture into an extruder to produce a solid
implant.
Description
TECHNICAL FIELD
[0001] The present invention is generally in the field of
controlled release devices for delivery of active agents such as
peptide or protein biopharmaceuticals where there is a need for
uniform, zero-order or linear release kinetics with minimal or no
lag period.
BACKGROUND OF THE INVENTION
[0002] Biodegradable controlled release systems for active agents
are well known in the art. Biodegradable matrices for drug delivery
are useful because they obviate the need to remove the
drug-depleted device.
[0003] The most common matrix materials used for controlled release
systems are polymers. The field of biodegradable polymers has
developed rapidly since the synthesis and biodegradability of
polylactic acid was reported by Kulkarni et al. (1966) Arch. Surg.
93:839. Examples of other polymers which have been reported as
useful as a matrix material for controlled release systems include
polyanhydrides, polyesters such as polyglycolides and
polylactide-co-glycolides, polyamino acids such as polylysine,
polymers and copolymers of polyethylene oxide, acrylic terminated
polyethylene oxide, polyamides, polyurethanes, polyorthoesters,
polyacrylonitriles, and polyphosphazenes. See, e.g., U.S. Pat. Nos.
4,891,225 and 4,906,474 to Langer (polyanhydrides), U.S. Pat. No.
4,767,628 to Hutchinson (polylactide, polylactide-co-glycolide
acid), U.S. Pat. No. 4,530,840 to Tice, et al. (polylactide,
polyglycolide, and copolymers), and U.S. Pat. No. 5,234,520 (Dunn
et al., biodegradable polymers for controlled delivery in treating
periodontal disease).
[0004] Degradable materials of biological origin are well known
including, for example, crosslinked gelatin. Hyaluronic acid has
been crosslinked and used as a degradable swelling polymer for
biomedical applications (see, e.g., U.S. Pat. No. 4,957,744 and
Della Valle et al. (1991) Polym. Mater. Sci. Eng., 62:731-735).
[0005] Biodegradable hydrogels have also been developed for use in
controlled release systems and serve as carriers of biologically
active materials such as hormones, enzymes, antibiotics,
antineoplastic agents, and cell suspensions. See, e.g., U.S. Pat.
No. 5,149,543 to Cohen.
[0006] Hydrogel compositions are also commonly used as substrates
for cell and tissue culture, impression materials for prosthetics,
wound-packing materials, or as solid phase materials in size
exclusion or affinity chromatography applications. For example,
nonporous, deformed and/or derivatized agarose hydrogel
compositions have been used in high-performance liquid
chromatography and affinity chromatography methods (Li et al.
(1990) Preparative Biochem. 20:107-121), and superporous agarose
hydrogel beads have been used as a support in hydrophobic
interaction chromatography (Gustavsson et al. (1999) J.
Chromatography 830:275-284).
[0007] In the pharmaceutical fields, hydrogel monomers (natural or
synthetic) are commonly added to pharmaceutical compositions (with
an initiator and, sometimes, cross-inking agents) and then allowed
to polymerize, thereby encapsulating a guest pharmaceutical within
a hydrogel matrix. Proper choice of hydrogel macromers can produce
membranes with a range of permeability, pore sizes and degradation
rates suitable for a variety of applications in surgery, medical
diagnosis and treatment. These techniques are used to provide
microsphere carrier systems for drug targeting or controlled
release systems. For example, cross-linked hydrogel microspheres
have been used to encapsulate islet cells for the treatment of
diabetes (Lim et al. (1980) Science 210:908-910) or cancer cells
that produce cancer-suppressing materials (U.S. Pat. No.
5,888,497), and biodegradable hydrogel microspheres are widely used
to encapsulate a wide variety of drug compositions, most commonly
peptides and proteins (Wang et al. (1997) Pharm. Dev. and
Technology 2:135-142). In these applications, the particular
hydrogel system employed in the formulation is selected to provide
long-term entrapment of the guest cell or pharmaceutical substance
(e.g., to provide for targeted delivery or sustained- or
delayed-release pharmacokinetics). Alternatively, hydrogels are
employed in amphipathic copolymer systems as a hydrophilic
component. In such cases the hydrogel is present in relatively
large amounts such that the polymer system is capable of absorbing
large amounts of water. See, e.g., U.S. Pat. Nos. 4,526,938 and
4,942,035 to Churchill et al.
SUMMARY OF THE INVENTION
[0008] Polymeric devices for controlled release of an active agent
of interest are provided. The devices comprise a biodegradable
polymer system selected from the group consisting of copolymers and
polymeric blends comprising a hydrophobic component and a
hydrophilic component combined with an active agent. The polymer
system does not form a hydrogel when the device is contacted with
an aqueous system. In addition, the device releases the agent
without a lag period or with a minimal lag period. In this manner,
the polymeric devices of the invention provide for zero order or
linear controlled release of active agents.
[0009] The active agent can be present in the devices in an amount
of up to about 40 wt % or more. In certain embodiments, the active
agent is a peptide therapeutic and/or prophylactic. For example,
the therapeutic and/or prophylactic peptide may be selected from
the group consisting of hormones, growth factors, neuroactive
agents, melanotropic peptides, cell adhesion factors, cytokines,
and biological response modifiers. In one preferred embodiment, the
active agent is a GnRH molecule or a GnRH analogue. In certain
preferred embodiments, the GnRH analog can be selected from the
group consisting of desorelin, tryptorelin, goserelin, and
leuprolide.
[0010] In the practice of the invention, the hydrophobic polymer
component is co-polymerized with a hydrophilic polymer, or
monomers, to yield a polymer system, most preferably a block
copolymer, or blended with a hydrophilic polymer to yield a blended
polymer system. These resultant polymer systems are characterized
as having a small amount of hydrophilic character, but they will
not form a hydrogel following immersion in an aqueous system. For
example, preferred polymer systems for use in the compositions of
the present invention may contain a water-soluble polymer such as
polyethylene glycol (PEG) in amounts typically up to 25 to 30 wt %,
not imparting hydrogel properties as seen with prior controlled
release devices but still producing devices that exhibit monophasic
or zero-order or near zero-order release kinetics. If a PEG is used
in the system, the preferred molecular weight may be between about
700 Da and about 500 kDa. Other particularly preferred hydrophilic
polymers for use in the polymer systems of the invention include
polyvinyl pyrolidone, polyvinyl alcohols, poly (alkyleneamine)s and
poly (alkyleneoxide)s.
[0011] In certain embodiments, the hydrophilic component is present
in an amount of up to 25%. In other embodiments, the hydrophilic
component is present in an amount of up to 15%, or present in an
amount of between 0.5 and 10 weight percent. In certain other
embodiments, the polymer system comprises greater than 75 wt %
hydrophobic polymer. In still further embodiments, the polymer
system comprises greater than 85 wt % hydrophobic polymer, greater
than 91 wt % hydrophobic polymer, or even greater than 98 wt %
hydrophobic polymer.
[0012] In a preferred embodiment, the hydrophobic component of the
polymer system is selected from the group consisting of polyhydroxy
acids, such as poly(lactide)s, poly(glycolide)s,
poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic
acid)s, and poly(lactic acid-co-glycolic acid)s, polyanhydrides,
polyorthoesters, polyetheresters, polycaprolactone,
polyesteramides, polyphosphazines, polycarbonates, polyamides, and
copolymers thereof. In another preferred embodiment, the polymer
system is an AB copolymer wherein the A component is a copolymer of
lactide, glycolide, or caprolactone, and the B component is a
polyalkyleneglycol. In a particularly preferred embodiment, the B
component is a polyalkyleneglycol at 1.25 weight percent and the
hydrophobic polymer is poly(lactide-co-glycolide).
[0013] In any of the devices of the present invention, the active
agent can be distributed uniformly within the polymer. The devices
may be formed wherein the active agent is incorporated into the
polymer system using a non-solvent process. Additionally, the
devices may be formed by dry melt extrusion, or melt extrusion of a
copolymer. In one preferred embodiment, the device is made with a
double extrusion step, to insure maximum dispersion of the active
agent in the polymer, without the use of solvent. The hydrophilic
component of the polymer is present in an amount facilitating
uptake of water, but less than that which would result in the
formation of a hydrogel, typically less than 25 wt % of the
polymer. The active agent is typically incorporated in an amount of
up to 40 wt %, although it can be higher, preferably in the case of
peptides.
[0014] The devices of the present invention can be provided in any
suitable form depending upon the manner in which the device will be
administered. In this regard, the present devices may be
administered by oral routes (e.g., as capsules such as hard
capsules and soft capsules, solid preparations such as granules,
tablets, pills, troches or lozenges, cachets, pellets, powders,
particulates, microparticulates (and any other particulate form)
and non-oral routes (e.g., as intramuscular, subcutaneous,
transdermal, visceral, IV (intravenous), IP (intraperitoneal),
intraarterial, intrathecal, intracapsular, intraorbital,
intraocular, intratumoral, perivascular, intracranial,
periophthalmic, inside the eyelid, intranasal, intrasinus,
intrabladder, intravaginal, intraurethral, intrarectal,
adventitial, injectable, pulmonary, inhalable, transmucosal, and
other suitable forms).
[0015] In preferred embodiments, the devices are administered by
implantation, and are thus configured as a shaped article, such as
a sphere, rod, slab, film, fiber, needle, cylinder, sheet, tube, or
any other suitable geometry including microparticles, microspheres,
and/or microcapsules. The devices can be provided in any suitable
size and shape of implantable device for specialized locations, for
example as a catheter, shunt, device for continuous subarachnoid
infusion, feeding tube, solid implant to prevent surgical adhesion,
uterine implant, artificial sphincter, periurethral implant,
splint, opthlamic implant, contact lens, plastic surgery implant,
stent (containing or coated with the active agent) including an
esophageal stent, gastrointestinal stent, vascular stent, biliary
stent, colonic stent, pancreatic stent, ureteric stent, urethral
stent, lacrimal stent, Eustachian tube stent, fallopian stent,
nasal stent, sinus stent, tracheal stent, or bronchial stent, or a
port including a venous access device, implanted port, epidural
catheter or central catheter (PICC).
[0016] The devices can be implanted at a desired site surgically,
or using minimally invasive techniques employing trocars,
catherers, etc. Such implants can thus be implanted into any
suitable tissue using standard techniques, such as implanted
intradermally, subdermally, subcutaneously, intraperitoneally,
intramuscularly, or intralumenally (e.g., intraarterially,
intravenously, intravaginally, rectally, or into the periodontal
space). The devices can alternatively be fabricated as part of a
matrix, graft, prosthetic or coating. If an implantable device is
manufactured in particulate form, e.g., as a microparticle,
microsphere or microcapsule, it can then be implanted into suitable
tissue using a cannula, needle and syringe or like instrument to
inject a suspension of the particles.
[0017] In the methods of the invention, the devices can be
administered using any suitable procedure. Depending upon the
active agent to be administered, the selected form (size, shape,
etc.) and the selected site of administration, the devices can be
delivered or implanted using minimally invasive procedures at a
site where release is desired. These procedures can include
implantation using trocars or catheters, injection using standard
needle and syringes (of, e.g., powders, particles, microparticles,
microspheres, microcapsules), ingrafting or surgical or
non-surgical placement (of, e.g., a matrix, graft, prosthetic or
coating), inhalation (of, e.g., powders or particulates), and the
like. The devices are designed so that the active agent is released
in the desired dosage over a defined period of time. The devices
are designed so that they degrade during and after release of the
active agent is achieved.
[0018] In one preferred method, the device is formulated to include
a GnRH molecule or GnRH analogue in a solid implant form. The
device is then administered to a subject in order achieve a certain
target blood level, production, function, or activity of a
gonadotrophin (LH or FSH) in the subject.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 is a graph of water uptake and swelling of
mPEG-5000-DL-PLG, (90:10) at 37.degree. C., measured as increase in
hydration over time.
[0020] FIG. 2 is a graph of cumulative release and rate of release
of peptide over time (days) from various sized devices prepared
with 30 weight percent (wt %) leuprolide acetate in mPEG-750 DL-PLG
90:10 block copolymer.
[0021] FIG. 3 is a graph of the effect of device dimensions on in
vitro release of leuprolide acetate ("LA") from devices containing
30 wt % LA in mPEG 5K DL-PLG (90:10) block copolymer.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0022] Before describing the present invention in detail, it is to
be understood that this invention is not limited to particularly
exemplified polymer systems or process parameters as such may, of
course, vary. It is also to be understood that the terminology used
herein is for the purpose of describing particular embodiments of
the invention only, and is not intended to be limiting.
[0023] All publications, patents and patent applications cited
herein, whether supra or infra, are hereby incorporated by
reference in their entirety.
[0024] It must be noted that, as used in this specification and the
appended claims, the singular forms "a," "an" and "the" include
plural referents unless the content clearly dictates otherwise.
Thus, for example, reference to "a hydorphobic polymer" includes a
mixture of two or more such polymers, reference to "an agent" or
"an active agent" includes mixtures of two or more such agents, and
the like.
[0025] It is an object of the present invention to provide a
controlled release device which is biodegradable, that releases an
active agent such as a drug over a prolonged period of time, and
that provides more controlled zero-order or linear release kinetics
rather than biphasic release kinetics.
[0026] It is a further object of the present invention to provide a
method of making such devices that is cost-effective, highly
reproducible, and efficient, and utilizes minimal if any
solvent.
[0027] Compositions and methods that enable a more constant or
linear rate of release of active agents such as peptide or protein
drugs from monolithic compositions prepared with a hydrolytically
biodegradable hydrophobic polymer such as poly
(DL-lactide-co-glycolide), DL-PLG, have been developed which
incorporates a small amount of hydrophilic polymer into the device.
The use of hydrophobic polymers such as PLGs with incorporation of
small amounts of hydrophilic polymer such as poly (ethylene
glycol), PEG, preferably covalently linked into the hydrophobic
polymer backbone provides particularly beneficial release profiles.
In addition, the combination of such material choices with a simple
process involving for example dry blending, compounding (first-pass
extrusion), grinding, and re-extrusion can further provide for
beneficial release profiles. The monolithic compositions or device
can be any shaped article such as a sphere, cylinder, sheet, or
other geometry including microparticles, microspheres, and/or
microcapsules comprising a mixture of a drug such as peptide and a
hydrophobic polymer incorporating a small amount of hydrophilic
polymer, either in the form of a copolymer or a blend. A preferred
manufacturing process avoids the use of solvent to mix polymer and
drug.
[0028] The device is designed to provide monophasic release, i.e.,
where release is typically linear or zero order, but may include
continuous release where the initial "burst" or "lag" effect is
minimal or not present.
[0029] There are a number of problems facing the skilled artisan
associated with the long-term delivery of biologically active
polypeptides such as polypeptide hormones from biodegradable,
implantable delivery systems. Because peptides are generally not
soluble in hydrophobic polymers such as DL-polylactide-co-glycolide
("DL-PLG"), solid compositions comprising a mixture of peptide and
DL-PLG are typically provided as two-phase compositions in which
the minor component (e.g. the peptide) exists as a dispersed phase
within the major component (e.g. the DL-PLG). In addition, because
of the glassy nature of the DL-PLGs, these materials are generally
not very permeable to molecules the size of peptides, especially
those that are water-soluble. As a result, the release of peptides
from DL-PLGs typically does not occur by simple diffusion through
the polymer matrix. Rather, release occurs by diffusion through
aqueous channels that form when the solid composition is placed
into an aqueous environment.
[0030] When a prior art polymeric composition is placed into an
aqueous environment, water is absorbed and dissolves the dispersed
peptide, resulting in domains of a concentrated aqueous solution of
the peptide dispersed within the polymer matrix. The peptide that
is in contact with the surface of the formulation is released by
diffusion through the aqueous channels formed by hydration of the
polymer. This occurs almost instantaneously as the diffusion path
and resistance are low. At relatively low loadings of peptide in
the DL-PLG matrix, however, release ceases or slows dramatically
once the surface-associated peptide is depleted, because peptide
that is remote from the surface has no pathway through which it can
diffuse to the surface. Then as degradation proceeds, the increase
in hydroxyl and carboxylic acid end groups results in a gradual
increase in the hydrophilicity of the matrix. As the water content
of the matrix increases, new aqueous channels form, providing
pathways through which the more remote peptide can diffuse to the
surface and be released. The resulting release profile tends to be
biphasic in which two periods of release are separated by a period
during which little or no peptide release occurs. The "dead" period
that occurs between the two release phases is particularly
problematic for many peptides such as gonadotrophin releasing
hormone ("GnRH") agonists where the objective is continuous
suppression of the gonadotrophic hormone such as leutinizing
hormone ("LH").
[0031] One approach to minimize or eliminate the "dead" period
involves increasing the peptide content of the composition. As the
peptide content of the composition is increased, inter-particle
contact between the peptide particles increases, providing a more
extensive network of pores, and the proportion of peptide that is
released during the initial phase increases, ultimately comprising
most if not all of the drug in the composition. Release typically
follows the well-known Higuchi model for release from a
dispersed-drug monolithic device and exhibits square-root-of-time
kinetics.
[0032] Another approach to minimizing the dead period and achieving
a more constant release of drug involves the use of polymer
compositions that degrade relatively rapidly. For example, U.S.
Pat. Nos. 4,767,628, 5,004,602, 5,366,734 to Hutchinson describe
continuous release compositions in which the initial
diffusion-controlled phase of release and the second
degradation-controlled phase of release are made to overlap by
careful choice of the monomer ratio and the molecular weight of the
DL-PLG. The art describes blending two or more excipients of
different monomer composition and molecular weight to achieve the
desired release profile. The method of producing such implant
systems involves solvent blending the peptide and the excipient(s)
in glacial acetic acid, freeze-drying the mixture to remove the
acetic acid, and molding or extruding the freeze-dried composition
to form the implant.
[0033] Still another approach involves the use of biodegradable
hydrogels so that the permeability of the peptide in the polymer
matrix is significantly increased. For example, U.S. Pat. Nos.
4,526,938 and 4,942,035 to Churchill describe continuous release
compositions comprising a pharmacologically active peptide and an
amphipathic block copolymer in which the hydrophobic component is
biodegradable and the hydrophilic component may or may not be
biodegradable. Generally, these compositions contain relatively
large amounts of the hydrophilic component such that the resulting
polymers are hydrogels capable of absorbing large amounts of water.
For example, a polymer containing 25 parts of PEG and 75 parts of
poly (DL-lactide) having an inherent viscosity of 0.41 dL/g when
pressed into a thin film of 0.2 mm, takes up its own weight in
water over 24 hours at 37.degree. C. Churchill et al. describe
implants prepared from the same polymer composition as well as
implants prepared from a block copolymer comprising 5 wt % PEG-6000
and 95 wt % of DL-PL. The implants contain 23.8 wt % goserelin
acetate. Goserelin was released continuously in vitro from these
systems for approximately 18 days from the more hydrophilic and for
more than 250 days from the less hydrophilic implants. These
compositions are also prepared by solvent blending the peptide and
polymer using glacial acetic acid, followed by lyophilization.
[0034] U.S. Pat. No. 6,159,490 to Deghenghi describes a method for
producing implants for delivery of peptides from copolymers of
lactide and glycolide for periods of from 1 to 12 months.
Deghenghi's process involves first producing an intimate mixture of
the peptide and polymer by: (1) grinding the polymer; (2) combining
the ground polymer with an aqueous slurry of the peptide; and (3)
drying the mixture to remove the water. Afterwards, the mixture is
melt extruded at 70 to 110.degree. C. U.S. Pat. No. 6,217,893 to
Pellet et al. describes compositions providing continuous release
of peptides from polymers or copolymers of lactide and glycolide
having inherent viscosities of between 0.5 and 1.6 dL/g in
CHCl.sub.3 and a hydrophilic character. Hydrophilic character is
defined as a polymer having polar chain ends and further defined as
those having an acid number of 1 or greater and preferably of 1.5
to 2. Pellet also describes the need for a peptide of high specific
surface area. No examples of the preparation of or release from
implants are given.
[0035] The method described by Hutchinson and Churchill utilizes
polymer and drug blending using glacial acetic acid as a solvent.
An alternative aqueous process is described in U.S. Pat. No.
6,159,490 to Deghenghi for producing implants for delivery of
peptides from copolymers of lactide and glycolide for periods of
from 1 to 12 months. Deghenghi's process involves first producing
an intimate mixture of the peptide and polymer by: (1) grinding the
polymer; (2) combining the ground polymer with an aqueous slurry of
the peptide; and (3) drying the mixture to remove the water.
Afterwards, the mixture is melt extruded at 70 to 110.degree.
C.
[0036] These past approaches to eliminate the "dead" period for
release involve approaches that either require a mix of two
different polymers, require a polymer that swells to form a
hydrogel, or require a polymer with an increased number of
endgroups with acidic function or other hydrophilic end group. The
mix of two polymers requires inventorying and performing all steps
with two materials as well as providing for an additional process
step in manufacture. PLGs with the addition of enough PEG to form
hydrogels after placement in an aqueous environment will swell to a
large extent, and may not be homogeneous. Polymers with a higher
amount of acidic endgroups can only be varied over a narrow range,
as there are typically only one acidic end group per molecule, and
an alcohol function that is uniformly present. In terms of the
process for manufacture, all of the above examples involve some
type of solvent blending using either an organic solvent or water.
This creates the potential for solvent residues that may have an
adverse effect on the polymer or subject. In addition the solvent
mixing step may create the potential for drug or polymer
degradation, and has time and cost consequences for scale up.
[0037] These same considerations apply to non-peptide agents as
well.
I. Materials and Compositions
[0038] A. Polymer Systems
[0039] The processes disclosed herein can be used to form devices
from a variety of biocompatible and biodegradable polymers.
Biodegradable, as defined herein, means the polymer will degrade or
erode in vivo to form smaller chemical species, wherein the
degradation can result, for example, from enzymatic, chemical, and
physical processes. In the most preferred embodiment, the polymer
is substantially hydrophobic and degrades by hydrolysis. The term
"biocompatible" is used herein to refer to a polymer and any
degradation products of the polymer that present no significant,
deleterious or untoward effects on the recipient's body.
[0040] Examples of biodegradable polymers and oligomers suitable
for use in the compositions and methods of the present invention
include, but are not limited to: poly(lactide)s; poly(glycolide)s;
poly(lactide-co-glycolide)s; poly(lactic acid)s; poly(glycolic
acid)s; and poly(lactic acid-co-glycolic acid)s;
poly(caprolactone)s; poly(malic acid)s; polyamides; polyanhydrides;
polyamino acids; polyorthoesters; polyetheresters;
polycyanoacrylates; polyphosphazines; polyphosphoesters;
polyesteramides; polydioxanones; polyacetals; polyketals;
polycarbonates; polyorthocarbonates; degradable polyurethanes;
polyhydroxybutyrates; polyhydroxyvalerates; polyalkylene oxalates;
polyalkylene succinates; chitins; chitosans; oxidized celluloses;
and copolymers, terpolymers, blends, combinations or mixtures of
any of the above materials.
[0041] As used herein, "hydrophobic" refers to a polymer that is
substantially not soluble in water. As used herein, "hydrophilic"
refers to a polymer that may be water-soluble or to a polymer
having affinity for absorbing water, but typically not when
covalently linked to the hydrophobic component as a co-polymer, and
which attracts water into the device.
[0042] Hydrophilic polymers suitable for use herein can be obtained
from various commercial, natural or synthetic sources well known in
the art. Suitable hydrophilic polymers include, but are not limited
to: polyanions including anionic polysaccharides such as alginate;
agarose; heparin; polyacrylic acid salts; polymethacrylic acid
salts; ethylene maleic anhydride copolymer (half ester);
carboxymethyl amylose; carboxymethyl cellulose; carboxymethyl
dextran; carboxymethyl starch; carboxymethyl chitin/chitosan;
carboxy cellulose; 2,3-dicarboxycellulose; tricarboxycellulose;
carboxy gum arabic; carboxy carrageenan; carboxy pectin; carboxy
tragacanth gum; carboxy xanthan gum; carboxy guar gum; carboxy
starch; pentosan polysulfate; curdlan; inositol hexasulfate;
beta.-cyclodextrin sulfate; hyaluronic acid; chondroitin-6-sulfate;
dermatan sulfate; dextran sulfate; heparin sulfate; carrageenan;
polygalacturonate; polyphosphate; polyaldehydo-carbonic acid;
poly-1-hydroxy-1-sulfonate-propen-2; copolystyrene maleic acid;
mesoglycan; sulfopropylated polyvinyl alcohols; cellulose sulfate;
protamine sulfate; phospho guar gum; polyglutamic acid;
polyaspartic acid; polyamino acids; and any derivatives or
combinations thereof. One skilled in the art will appreciate other
hydrophilic polymers that are also within the scope of the present
invention.
[0043] Various water-soluble polymers suitable for use herein
include, but are not limited to: poly (alkyleneglycol),
polyethylene glycol ("PEG"); propylene glycol; ethylene
glycol/propylene glycol copolymers; carboxylmethylcellulose;
dextran; polyvinyl alcohol ("PVOH"); polyvinyl pyrolidone; poly
(alkyleneamine)s; poly (alkyleneoxide)s; poly-1,3-dioxolane;
poly-1,3,6-trioxane; ethylene/maleic anhydride copolymers;
polyaminoacids; poly (n-vinyl pyrolidone); polypropylene
oxide/ethylene oxide copolymers; polyoxyethylated polyols;
polyvinyl alcohol succinate; glycerine; ethylene oxides; propylene
oxides; poloxamers; alkoxylated copolymers; water soluble
polyanions; and any derivatives or combinations thereof. In
addition, the water-soluble polymer may be of any suitable
molecular weight, and may be branched or unbranched.
[0044] In the practice of the invention, the hydrophobic polymer
component is co-polymerized with a hydrophilic polymer, or
monomers, to yield a polymer system, most preferably a block
copolymer, or blended with a hydrophilic polymer to yield a blended
polymer system. These resultant polymer systems are characterized
as having a small amount of hydrophilic character, but they will
not form a hydrogel following immersion in an aqueous system. For
example, preferred polymer systems for use in the compositions of
the present invention may contain a water-soluble polymer such as
polyethylene glycol (PEG) in amounts typically up to 25 to 30 wt %,
not imparting the hydrogel properties cited by Churchill but
producing devices that exhibit monophasic or zero-order or near
zero-order release kinetics. If a PEG is used in the system, the
preferred molecular weight may be between about 700 Da and about
500 kDa. Other particularly preferred hydrophilic polymers for use
in the polymer systems of the invention include polyvinyl
pyrolidone, polyvinyl alcohols, poly (alkyleneamine)s and poly
(alkyleneoxide)s.
[0045] As used herein, "polymer" and "polymer system" include
copolymers and blends unless otherwise expressly defined. The
polymer systems can be produced using standard copolymerization
techniques, such as graft copolymerisation, polycondensation and
polyaddition, optionally with an appropriate catalyst. These
techniques can be carried out in conventional manner well known in
the polymer art as regards to time and temperature. Alternatively,
the polymer systems can be produced using standard blending
techniques of polymers or blending of copolymers, again carried out
in conventional manner well known in the polymer art as regards to
time and temperature.
[0046] The polymer system, method of manufacture, and drug loading
are selected such that the device does not form a hydrogel when
contacted with or immersed in an aqueous system, for example, when
implanted in vivo into an animal or human subject. The polymer
system is characterized by a reduced hydrophobicity relative to the
pure hydrophobic polymer component by virtue of the inclusion of
the hydrophilic component. This facilitates uptake of water by the
device and dissolution and release of the incorporated active agent
or agents, avoiding a lag period and leading to linear or near zero
order release kinetics.
[0047] As used herein, the term "hydrogel" is used in its usual
manner within the art, for example to refer to a polymer or polymer
system that swells in the presence of water or other aqueous
system, shrinks in the absence or reduction of the amount of water,
is able to retain a significant fraction of water within its
structure, and typically does not dissolve in water. One skilled in
the art will appreciate that there are a number of standard tests
that one can employ in order to determine if a polymer or polymer
system will act as a hydrogel, e.g., form a hydrogel, when immersed
in an aqueous system such as when it is implanted in vivo into an
animal or human subject.
[0048] For example, a polymer or polymer system can be prepared in
particulate form, or comminuted or rendered into particles to form
a powder. The powder can then be mixed with distilled water in a
suitable container and allowed sufficient time to form a gel, for
example from about 15 minutes to 24 hours or more. The resultant
solution can then be viewed using standard optical microscopy to
look for the formation of a characteristic gel-like suspension and
thereby determine that a hydrogel has formed, or to see if the
particles have failed to form a suspension and/or precipitated out
of the solution, indicating that the polymer system does not form a
hydrogel when immersed in an aqueous system.
[0049] Alternatively, or in addition to the above-noted procedure,
the absorbency of the polymer or polymer system in an aqueous
system can be assessed, wherein the ability of a polymer to absorb
water is a characteristic feature of a hydrogel-forming polymer.
The term "absorbency" as used herein can thus mean a value
determined according to the following procedure. In the case of
deionized water-absorbency, 2 liters of deionized water and 1 g of
the dried polymer can be placed in a 3-liter beaker, and water
allowed to be absorbed by the polymer for from about 30 minutes to
24 hours or more with stirring, after which the polymer is
collected by filtration with a 100-mesh metallic wire gauze, the
volume of the swollen polymer obtained as a filtered cake can then
be measured by means of a messcylinder. The value thus taken can
then be used as the deionized water-absorbency value of the
polymer. A higher absorbency value, such as a value up to the
starting weight of the polymer, indicates that a hydrogel was
formed, whereas low values indicate that no hydrogel was
formed.
[0050] In the case of saline solution-absorbency, 200-ml of saline
solution (0.9% by weight aqueous sodium chloride solution) and 1 g
of dried polymer can be placed in a 300-ml beaker and the polymer
allowed to absorb the solution for from about 30 minutes to about
24 hours or more with stirring, after which it is filtered with a
200-mesh metallic wire gauze, the volume of the swollen polymer
obtained as a filtered cake can be measured by means of a
messcylinder. The value obtained can then be used as the saline
solution-absorbency value of the polymer. Here again, high values,
such as those approaching or exceeding the starting weight of the
polymer, indicate the formation of a hydrogel.
[0051] In another test, referred to as a centrifuge retention
capacity test, a small amount of the polymer can be weighed into a
teabag that is subsequently welded shut. The teabag is then placed
in an excess of 0.9% by weight sodium chloride solution (at least
1.25 to 1 of sodium chloride solution/1 g of the suspected
hydrogel). After a swelling time of about 20 minutes to about 24
hours or more, the teabag is removed from the sodium chloride
solution and centrifuged at 250 g for three minutes. The
centrifuged teabag can then be weighed to determine the amount of
liquid retained by the hydrogel. Retention of any significant
amount of liquid by the test composition indicates that a hydrogel
was formed.
[0052] In addition to the above-described assessments, there are
numerous other tests readily available to the skilled artisan
whereby the ability of a selected polymer or polymer system to form
a hydrogel when immersed in an aqueous system can be
determined.
[0053] B. Active Agents
[0054] Essentially any active agent can be incorporated with the
polymer system to form a device according to the present invention
using conventional processes including those methods described
herein. Accordingly, as used herein an "active agent" can include
any compound or composition of matter which, when administered to
an organism (human or animal subject) induces a desired
pharmacologic and/or physiologic effect by local and/or systemic
action. The term therefore encompasses those compounds or chemicals
traditionally regarded as drugs, biopharmaceuticals (including
molecules such as peptides, proteins, nucleic acids), and vaccines.
The term further encompasses those compounds or chemicals
traditionally regarded as diagnostic agents.
[0055] Active agents useful in the practice of the present
invention thus include compounds or compositions acting at synaptic
and neuroeffector junctional sites (cholinergic agonists,
anticholinesterase agents, atropine, scopolamine, and related
antimuscarinic drugs, catecholamines and sympathomimetic drugs, and
adrenergic receptor antagonists); drugs acting on the central
nervous systems; autacoids (drug therapy of inflammation); drugs
affecting renal function and electrolyte metabolism; cardiovascular
drugs; drugs affecting gastrointestinal function; chemotherapy of
neoplastic diseases; drugs acting on the blood and the
blood-forming organs; and hormones and hormone antagonists. As used
herein, the term "drug" includes any substance intended for use in
the cure, mitigation, treatment, or prevention of any disease,
disorder, or condition or intended to affect the structure or
function of the body, other than food. The term can include any
beneficial agent or substance that is biologically active or meant
to alter animal physiology. Drugs may be natural or synthetic
organic compounds, proteins, peptides, nucleic acid molecules,
glycoproteins, sugars, carbohydrates, lipids, or combinations
thereof. Peptides and proteins are particularly preferred drugs for
use in the compositions of the present invention.
[0056] More specifically, classes of active agents useful in the
present compositions include, but are not limited to,
anti-infectives such as antibiotics and antiviral agents;
analgesics and analgesic combinations; local and general
anesthetics; anorexics; antiarthritics; antiasthmtic agents;
anticonvulsants; antidepressants; antihistamines; anti-inflammatory
agents; antinauseants; antimigrane agents; antineoplastics;
antipruritics; antipsychotics; antipyretics; antispasmodics;
cardiovascular preparations (including calcium channel blockers,
beta-blockers, beta-agonists and antiarrythmics);
antihypertensives; diuretics; vasodilators; central nervous system
stimulants; cough and cold preparations; decongestants;
diagnostics; hormones; bone growth stimulants and bone
resorptioninhibitors; immunosuppressives; muscle relaxants;
psychostimulants; sedatives; tranquilizers; proteins, peptides, and
fragments thereof; and nucleic acid molecules (polymeric forms of
two or more nucleotides, either ribonucleotides (RNA) or
deoxyribonucleotides (DNA) including double- and single-stranded
molecules and supercoiled or condensed molecules, gene constructs,
expression vectors, plasmids, antisense molecules and the like.
[0057] One class of drugs of particular interest for use herein as
an active agent is the class of anesthetics, such as benzocaine,
bupivacaine, etidocaine, lidocaine, mepivacaine, pramoxine,
prilocaine, procaine, proparacaine, ropivacaine, tetracaine,
levobupivacaine, chloroprocaine, butacaine, propoxycaine,
phenacaine, hexylcaine, isobucaine, cyclomethycaine, benoxinate,
diperodon, dibucaine, meprylcaine, dimethisoquin, pramoxine,
butamben, dyclonine (with and without augmenting agents such as
dexamethasone or epinephrine).
[0058] Another class of drug of particular interest for use as an
active agent herein is the opioids class, which includes
alfentanil, allylprodine, alphaprodine, anileridine, apomorphine,
apocodeine, benzylmorphine, bezitramide, buprenorphine,
butorphanol, clonitazene, codeine, cyclazocine, cyclorphen,
cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide,
dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,
dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine,
ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,
fentanyl, heroin, hydrocodone, hydroxymethylmorphinan,
hydromorphone, hydroxypethidine, isomethadone, ketobemidone,
levallorphan, levorphanol, levophenacylmorphan, lofentanil,
meperidine, meptazinol, metazocine, methadone, methylmorphine,
metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine,
norlevorphanol, normethadone, nalorphine, normorphine, norpipanone,
ohmefentanyl, opium, oxycodone, oxymorphone, papaveretum,
pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,
pholcodine, piminodine, piritramide, propheptazine, promedol,
profadol, properidine, propiram, propoxyphene, remifentanyl,
sufentanyl, tramadol, tilidine, naltrexone, naloxone, nalmefene,
methylnaltrexone, naloxone methiodide, nalorphine, naloxonazine,
nalide, nalmexone, nalbuphine, nalorphine dinicotinate, naltrindole
(NTI), naltrindole isothiocyanate, (NTII), naltriben (NTB),
nor-binaltorphimine (nor-BNI), beta-funaltrexamine (b-FNA), BNTX,
cyprodime, ICI-174,864, LY117413, MR2266, etorphine, DAMGO, CTOP,
diprenorphine, naloxone benzoylhydrazone, bremazocine,
ethylketocyclazocine, U50,488, U69,593, spiradoline, DPDPE,
[D-Ala2,Glu4] deltorphin, DSLET, Met-enkephalin, Leu-enkephalin,
13-endorphin, dynorphin A, dynorphin B, a-neoendorphin, or an
opioid having the same pentacyclic nucleus as nalmefene,
naltrexone, buprenorphine, levorphanol, meptazinol, pentazocine,
dezocine, or their pharmacologically effective esters or salts.
[0059] Still another class of drugs of particular interest for use
herein as an active agent is the class of non-steroidal
antinflammatory drugs ("NSAIDs") which includes salicylates,
pyrazolons, indomethacin, sulindac, the fenamates, tolmetin, and
propionic acid derivatives; for example, salicylic acid, aspirin,
methyl salicylate, diflunisal, salsalate, phenylbutazone,
indomethacin, oxyphenbutazone, apazone, mefenamic acid,
meclofenamate sodium, ibuprofen, naproxen, naproxen sodium,
fenoprofen, ketoprofen, flurbiprofen, piroxicam, diclofenac,
etodolac, ketorolac, aceclofenac, nabumetone, and the like.
[0060] Proteins are yet an even further preferred class of drugs
for use as the active agent in the practice of the present
invention. The term "protein" includes peptides, polypeptides,
consensus molecules, analogs, derivatives or combinations thereof.
The term thus encompasses recombinant or naturally occurring
molecules, whether human or animal in origin, including naturally
occurring, synthetic, semi-synthetic or recombinantly produced.
Examples of suitable peptide and/or protein active agents for use
in the present compositions include hormones, growth factors,
neuroactive agents, hematopoietic factors, melanotropic peptides,
cell adhesion factors, cytokines and biological response modifiers,
anti-obesity factors, trophic factors, anti-inflammatory factors,
enzymes and antibody molecules. Preferred cytokines and biological
response modifiers include interferons (see, e.g., U.S. Pat. Nos.
5,372,808; 5,541,293; 4,897,471; and 4,695,623) and interleukins
(see, e.g., U.S. Pat. No. 5,075,222). Preferred hematopoietic
factors include erythropoietins (see, e.g., U.S. Pat. Nos.
4,703,008; 5,441,868; 5,618,698; 5,547,933; and 5,621,080) and
preferred anti-obesity factors include the OB protein (see, e.g.,
International Publication Nos. WO 96/40912; WO 96/05309; WO
97/00128; WO 97/01010 and WO 97/06816). Preferred growth factors
include granulocyte-colony stimulating factors (see, e.g., U.S.
Pat. Nos. 4,999,291; 5,581,476; 5,582,823; 4,810,643 and
International Publication No. WO 94/17185); stem cell factor (see,
e.g., International Publication Nos. WO 91/05795; WO 92/17505 and
WO 95/17206); bovine and human forms of basic fibroblast growth
factor including analogs thereof (see, e.g., U.S. Pat. Nos.
5,859,208; 5,604,293; 5,514,566; 5,439,616; 5,464,774; 5,155,214;
and 4,956,455); and bovine and human forms of vascular endothelial
growth factor including analogs thereof (see, e.g., Ferrara et al.
(1991) J. Cellular Biochem. 47:211-218; Connolly (1991) J. Cellular
Biochem. 47:219-223; Joukov et al. (1996) EMBO J. 15:290-298, and
International Publication Nos. WO 96/26736 and WO 95/24473).
[0061] A particularly preferred hormone for use as an active agent
is gonadotropin releasing hormone ("GnRH"), also known as
luteinizing hormone releasing hormone ("LHRH"), and analogs
thereof. GnRH is of central importance to the regulation of
fertility. Johnson et al. (1988) Essential Reproduction, 3rd Edn.
Blackwell Scientific Publications. In males and females, GnRH is
released from the hypothalamus into the bloodstream and travels via
the blood to the pituitary, where it induces the release of the
gonadotropins, luteinizing hormone ("LH") and follicle stimulating
hormone ("FSH") by gonadotroph cells, and regulates androgens,
estrogens, and progestins.
[0062] As used herein, the term "GnRH analogue" is intended to
encompass peptidic compounds that mimic the structure of
luteinizing hormone releasing hormone. A GnRH analogue may be a
GnRH agonist or a GnRH antagonist.
[0063] As used herein, a "GNRH agonist" is intended to refer to a
compound that stimulates the GnRH receptor such that release of
luteinizing hormone and/or FSH is stimulated. Examples of GnRH
agonists include leuprolide (trade name: Lupron.RTM., Abbott/TAP;
Viadur.RTM., Alza), goserelin (trade name: Zoladex.RTM.; Zeneca),
buserelin (Hoechst), triptorelin (also known as Decapeptyl,
D-Trp-6-LHRH and Debiopharm.RTM.; Ipsen/Beaufour), nafarelin (trade
name Synarel.RTM.; Syntex), lutrelin (Wyeth), cystorelin (Hoechst),
gonadorelin (Ayerst) and histrelin (Ortho), luliberin, desorelin,
avorelin, cetrrelix, teverelix, ramorelix, ganirelix, antide,
nictide, and azaline. Leuprolide agonists are particularly
preferred for use in the compositions of the present invention.
[0064] As used herein, the term "GnRH antagonist" is intended to
refer to a compound that inhibits the GnRH receptor such that
release of luteinizing hormone or FSH is inhibited. Examples of
GnRH antagonists include Antide, Cetrorelix, Ganirelix, and
compounds described in U.S. Pat. Nos. 5,470,947; 5,413,990;
5,371,070; 5,300,492; 5,296,468; 5,171,835; 5,003,011; 4,992,421;
4,851,385; 4,801,577; 4,689,396; and 4,431,635, and International
Publication No. WO 89/01944.
[0065] In addition, other protein active agents for use herein
include, but are not limited to, anti-obesity related products,
insulin, gastrin, prolactin, adrenocorticotropic hormone (ACTH),
thyroid stimulating hormone (TSH), luteinizing hormone (LH),
follicle stimulating hormone (FSH), human chorionic gonadotropin
(HCG), motilin, interferons (alpha, beta, gamma), interluekins
(IL-1 to IL-12), tumor necrosis factor (TNF), tumor necrosis
factor-binding protein (TNF-bp), brain derived neurotrophic factor
(BDNF), glial derived neurotrophic factor (GDNF), neurotrophic
factor 3 (NT3), fibroblast growth factors (FGF), neurotrophic
growth factor (NGF), bone growth factors such as osteoprotegerin
(OPG), insulin-like growth factors (IGFs), macrophage colony
stimulating factor (M-CSF), granulocyte macrophage colony
stimulating factor (GM-CSF), megakeratinocyte derived growth factor
(MGDF), thrombopoietin, platelet-derived growth factor (PGDF),
colony simulating growth factors (CSFs), bone morphogenetic protein
(BMP), superoxide dismutase (SOD), tissue plasminogen activator
(TPA), urokinase, streptokinase, kallikrein, blood factors such as
Factor VIII and Factor IX, and polyclonal, monoclonal antibodies,
chimeric antibody molecules, and antibody fragments.
[0066] In those devices intended for use as a vaccine, the active
agent may be an antigen, i.e., a molecule that contains one or more
epitopes that will stimulate a host's immune system to make a
cellular antigen-specific immune response and/or a humoral antibody
response. Thus, suitable antigens include proteins, polypeptides,
antigenic protein fragments, oligosaccharides, polysaccharides, and
the like. The antigen can be derived from any known virus,
bacterium, parasite, plants, protozoans, or fungus, and can be a
whole organism (active, split, attenuated or inactivated) or
immunogenic parts thereof, e.g., cell wall components. An antigen
can also be derived from a tumor. An oligonucleotide or
polynucleotide that expresses an antigen, such as in DNA
immunization applications, is also included in the definition of
antigen. Synthetic antigens are also included in the definition of
antigen, for example, haptens, polyepitopes, flanking epitopes, and
other recombinant or recombinant or synthetically derived antigens
(Bergmann et al (1993) Eur. J. Immunol. 23:2777-2781; Bergmann et
al (1996) J. Immunol. 157:3242-3249; Suhrbier, A. (1997) Immunol.
And Cell Biol. 75:402-408; Gardner et al (1998)12.sup.th World AIDS
Conference, Geneva, Switzerland (Jun. 28-Jul. 3, 1998).
[0067] C. Additives, Excipients and Pore Forming Agents
[0068] The active agent may be combined with one or more additional
component, for example pharmaceutically acceptable excipient
materials that can act as dispersing agents, bulking agents,
binders, carriers, stabilizers, glidants, antioxidants, pH
adjusters, anti-irritants, and the like. The skilled artisan will
appreciate that certain excipient materials can serve several of
the above-referenced functions in any particular formulation. Thus,
any number of suitable excipient materials can be mixed with or
incorporated into the device to provide bulking properties, alter
active agent release rates, increase or impede water uptake,
control pH, provide structural support, facilitate manufacturing
processes and other uses known to those skilled in the art. The
term "excipient" generally refers to a substantially inert material
that is nontoxic and does not interact with other components of the
device in a deleterious manner. The proportions in which a
particular excipient may be present in the device depend upon the
purpose for which the excipient is provided and the identity of the
excipient.
[0069] For example, suitable carrier excipients that can also act
as stabilizers for peptides include pharmaceutical grades of
dextrose, sucrose, lactose, trehalose, mannitol, sorbitol,
inositol, dextran, and the like. Such carriers may thus be a
saccharide such as a monosaccharide, a disaccharide, a
polysaccharide or a sugar alcohol. Other suitable carriers include
starch, cellulose, sodium or calcium phosphates, calcium sulfate,
citric acid, tartaric acid, glycine, and combinations thereof.
Examples of hydrophobic excipients that can be added to the devices
to slow hydration and dissolution kinetics include fatty acids and
pharmaceutically acceptable salts thereof (e.g., magnesium
stearate, steric acid, zinc stearate, palimitic acid, and sodium
palitate).
[0070] It may also be useful to em ploy a charged lipid and/or
detergent excipient in the devices of the present invention.
Suitable charged lipids include, without limitation,
phosphatidylcholines (lecithin), and the like. Detergents will
typically be a nonionic, anionic, cationic or amphoteric
surfactant. Examples of suitable surfactants include, for example,
Tergitol.RTM. and Triton.RTM. surfactants (Union Carbide Chemicals
and Plastics); polyoxyethylenesorbitans, e.g., TWEEN.RTM.
surfactants (Atlas Chemical Industries); polysorbates;
polyoxyethylene ethers, e.g. Brij; pharmaceutically acceptable
fatty acid esters, e.g., lauryl sulfate and salts thereof;
ampiphilic surfactants (glycerides, etc.); and like materials.
[0071] Other excipient materials can be added to the devices to
alter porosity, for example, materials like sucrose, dextrose,
sodium chloride, sorbitol, lactose, polyethylene glycol, mannitol,
fructose, polyvinyl pyrrolidone or appropriate combinations
thereof. Additionally, the active agents may be dispersed with oils
(e.g., sesame oil, corn oil, vegetable), or a mixture thereof with
a phospholipid (e.g., lecitin), or medium chain fatty acid
triglycerides (e.g., Miglyol 812) to provide an oily
suspension.
[0072] Still further excipeint materials that can be incorporated
into the devices of the present invention include diluents of
various buffer content (e.g., Tris-HCl, acetate); pH and ionic
strength altering agents; additives such as antioxidants (e.g.,
ascorbic acid, glutathione, sodium metabisulfite); preservatives
(e.g., Thimersol, benzyl alcohol, methyl paraben, propyl paraben);
and dispersing agents such as water-soluble polysaccharides (e.g.,
mannitol, lactose, glucose, starches), hyaluronic acid, glycine,
fibrin, collagen and inorganic salts (e.g., sodium chloride).
[0073] D. Devices
[0074] The polymeric devices of the present invention are in a
general sense formed by the combination of an active agent with a
polymer system having a hydrophobic component and a hydrophilic
component, wherein the device provides for controlled release of
the active agent under suitable conditions and has the physical
properties as described in detail throughout the present
specification. Accordingly, the term "device," as used herein,
refers to a polymeric device for controlled release of an active
agent of interest. The device includes a biodegradable polymer
system that is either a copolymer or a polymeric blend having a
hydrophobic component and a hydrophilic component, where the
polymer system does not form a hydrogel when contacted with, or
immersed in an aqueous system, for example when the device is
implanted in a living subject. The active agent is incorporated
within the polymer system such that the polymer system can provide
for controlled release of the agent from the device. Optionally,
one or more excipient material can also be incorporated within the
polymer system in order to provide bulking properties, alter active
agent release rates, increase or impede water uptake for the
device, control pH, provide structural support, facilitate
manufacturing processes, or like uses. When the device is
administered to a subject, for example, when a device is implanted,
the device releases the active agent in a controlled fashion
without a lag period, or with a minimal lag period.
[0075] In the construction of devices pursuant to the present
invention, the polymer system is made when a hydrophobic polymer
component is co-polymerized with a hydrophilic polymer, or
monomers, to yield a suitable copolymer system, most preferably a
block copolymer, or when the hydrophobic polymer component is
blended with a hydrophilic polymer to yield a suitable blended
polymer system. The polymer system can be produced using standard
copolymerization techniques, such as graft copolymerisation,
polycondensation and polyaddition, optionally with an appropriate
catalyst. These techniques can be carried out in conventional
manner with regard to time and temperature. Alternatively, the
polymer system can be produced using standard blending techniques
of polymers or blending of copolymers, again carried out in
conventional manner with regard to time and temperature for the
procedure.
[0076] Within the polymer system itself, the hydrophobic and
hydrophilic components can be present in any suitable ratio, where
the specific amount of each component is selected based on the
relative degree of hydrophobicity or hydrophilicity of each
component, respectively, but always such that the final device
product will not form a hydrogel following contact with, or
immersion in an aqueous system. The resultant polymer system will
thus be characterized as having a small amount of hydrophilic
character, but the hydrophilic component will typically be present
in the polymer system in a lesser amount relative to the
hydrophobic component, not imparting hydrogel properties to the
device but still producing a device that exhibits monophasic or
zero-order or near zero-order release kinetics of the active agent.
Accordingly, the hydrophilic component will typically be present in
the polymer system in an amount of about 25 to 30 wt % or less, in
some instances in an amount of about 15 wt % or less, and in some
other instances in an amount of about 0.5 to 10 wt %.
[0077] In certain preferred embodiments, the polymer system is a
copolymer or a polymer blend comprising greater than about 75 wt %
of the hydrophobic polymer component. In other preferred
embodiments the polymer system is a copolymer or a polymer blend
comprising greater than about 85 wt % of the hydrophobic polymer
component, and in still other embodiments, the polymer system is a
copolymer or a polymer blend comprising greater than about 91 to
about 98 wt % of the hydrophobic polymer component. In particular
embodiments, the hydrophobic component in the polymer system is a
polyhydroxy acid, such as poly(lactide), poly(glycolide),
poly(lactide-co-glycolide), poly(lactic acid), poly(glycolic acid),
and poly(lactic acid-co-glycolic acid), polyanhydride,
polyorthoester, polyetherester, polycaprolactone, polyesteramide,
polyphosphazine, polycarbonate, polyamide, or any copolymer
thereof. In a particularly preferred embodiment, the hydrophobic
component of the polymer system is a poly (lactide-co-glycolide)
present in the system in an amount of 90 wt % or greater.
[0078] In certain other preferred embodiments, the polymer system
is a copolymer or a polymer blend comprising less than about 25 wt
% of the hydrophilic polymer component. In other preferred
embodiments the polymer system is a copolymer or a polymer blend
comprising less than about 10 wt % of the hydrophilic polymer
component. In particular embodiments, the hydrophilic component in
the polymer system is a poly (alkyleneglycol), polyvinyl pyrolidone
(PVP), polyvinyl alcohol (PVOH), poly (alkyleneamine), poly
(alkyleneoxide), or any copolymer thereof. In preferred
embodiments, the hydrophilic component in the polymer system is a
poly (ethylene glycol) (PEG), and in other embodiments, the
hydrophilic component is a PEG having molecular weight of between
about 700 Da and about 500 kDa. In particularly preferred
embodiments, the hydrophilic component is a PEG present in the
polymer system in an amount of 10 wt % or less.
[0079] In one specific embodiment, the polymer system is an AB
block copolymer formed from poly (DL-lactide-co-glycolide) and PEG
with a molecular weight of 750, wherein the PEG is present in the
polymer system at about 1.25 wt %.
[0080] Once the suitable polymer system has been selected, the
copolymerization or polymer blending step can be conducted either
prior to incorporation of the active agent into the polymer system,
or at the same time. The active agent is thus combined with the
polymer system to form the device, using standard techniques. The
active agent is combined in a manner such that it will be present
in the devices of the present invention in amounts ranging from
about 0.1 wt % to about 80 wt % and higher, although the active
agent will typically be present in an amount ranging from about 0.3
wt % to about 70 wt %, such as from about 10 wt % to 60 wt % or
from about 20 wt % to about 55 wt %. The actual amount depends upon
the activity of the active agent, the dose desired, the duration of
release desired, the administration frequency and other variables.
One skilled in the art will be able to ascertain effective amounts
for selected active agents by administration and observing the
desired therapeutic, pharmacological or diagnostic effect. The
exact amount of the active agent in the device will thus be the
amount necessary to achieve an effective concentration of the
active agent in vivo, for a given period of time. This amount
varies with the type of active agent used, the desired duration of
the release, the target condition, desired administration
frequency, the subject animal species and other factors.
Preferably, the devices will contain sufficient amounts of the
active agent such that release of between about 0.10 ug/kg/day and
100 mg/kg/day will yield the desired effect. These parameters will
be readily appreciated by the ordinarily skilled artisan upon
reading the instant specification.
[0081] Depending upon the technique used to incorporate the active
agent into the polymer system and thus form the devices of the
invention, the active agent may be distributed uniformly within the
polymer system, or may be substantially encapsulated by the polymer
system. The active agent may further be incorporated into the
polymer system using an appropriate solvent system, either aqueous
or non-aqueous, or the agent may be incorporated using a
non-solvent process.
[0082] In addition to incorporation of the active agent within the
polymer system, the devices may further include pharmaceutically
acceptable excipients such as diluents, preservatives,
solubilizers, emulsifiers and/or carriers needed for
administration. The proportions in which a particular excipient may
be present in the device depends upon the purpose for which the
excipient is provided and the identity of the excipient. The
optimal final pharmaceutical formulation for an active agent of
interest will be determined by one skilled in the art depending
upon the route of administration and desired dosage. Exemplary
pharmaceutical compositions are disclosed in Remington's
Pharmaceutical Sciences (1990) Mack Publishing Co., 18th Ed.,
Easton, Pa.
[0083] In particular embodiments of the present invention, the
above-described polymer systems are used for manufacture of one or
more polymeric devices for controlled release of an active agent,
useful in the treatment or amelioration of the conditions the
active agent is intended to treat. Thus, in one aspect of the
invention, a biodegradable polymer system is used in the
manufacture of a polymeric device for controlled release of an
active agent, wherein the polymer system is a copolymer or a
polymer blend comprising a hydrophobic component and a hydrophilic
component and the polymer system does not form a hydrogel when
contacted with, or immersed in an aqueous system, for example when
the device is implanted in a living subject. The active agent is
incorporated within the polymer system such that the polymer system
provides for controlled release of the agent from the device. When
the device is administered to a subject, for example, when a device
is implanted, the device releases the active agent in a controlled
fashion without a lag period, or with a minimal lag period. In a
preferred embodiment, the polymer systems of the present invention
are used for manufacture of a polymeric device for controlled
release of a peptide or protein active agent. In one particularly
preferred embodiment, the polymer systems are used for manufacture
of a polymeric device for controlled release of a GnRH active
agent, or an analogue thereof.
[0084] The devices of the present invention can be provided in any
suitable form depending upon the manner in which the device will be
administered. In this regard, the present devices may be
administered by oral routes (e.g., as capsules such as hard
capsules and soft capsules, solid preparations such as granules,
tablets, pills, troches or lozenges, cachets, pellets, powders,
particulates, microparticulates (and any other particulate form)
and non-oral routes (e.g., as intramuscular, subcutaneous,
transdermal, visceral, IV (intravenous), IP (intraperitoneal),
intraarterial, intrathecal, intracapsular, intraorbital,
intraocular, intratumoral, perivascular, intracranial,
periophthalmic, inside the eyelid, intranasal, intrasinus,
intrabladder, intravaginal, intraurethral, intrarectal,
adventitial, injectable, pulmonary, inhalable, transmucosal, and
other suitable forms). In preferred embodiments, the devices are
administered by implantation, and are thus configured as a shaped
article, such as a sphere, rod, slab, film, fiber, needle,
cylinder, sheet, tube, or any other suitable geometry including
microparticles, microspheres, and/or microcapsules. The devices can
be provided any suitable size and shape of implantable device for
specialized locations, for example as a catheter, shunt, device for
continuous subarachnoid infusion, feeding tube, solid implant to
prevent surgical adhesion, uterine implant, artificial sphincter,
periurethral implant, splint, opthlamic implant, contact lens,
plastic surgery implant, stent (containing or coated with the
active agent) including an esophageal stent, gastrointestinal
stent, vascular stent, biliary stent, colonic stent, pancreatic
stent, ureteric stent, urethral stent, lacrimal stent, Eustachian
tube stent, fallopian stent, nasal stent, sinus stent, tracheal
stent, or bronchial stent, or a port including a venous access
device, implanted port, epidural catheter or central catheter
(PICC). The devices can be implanted at a desired site surgically,
or using minimally invasive techniques employing trocars,
catherers, etc. The implant can be implanted into any suitable
tissue using standard techniques, such as implanted intradermally,
subdermally, subcutaneously, intraperitoneally, intramuscularly, or
intralumenally (e.g., intraarterially, intravenously,
intravaginally, rectally, or into the periodontal space). The
devices can alternatively be fabricated as part of a matrix, graft,
prosthetic or coating. If an implantable device is manufactured in
particulate form, e.g., as a microparticle, microsphere or
microcapsule, it can then be implanted into suitable tissue using a
cannula, needle and syringe or like instrument to inject a
suspension of the particles.
[0085] II. Methods of Manufacture
[0086] Methods for making fibrous polymeric devices for delivery of
active agents are well known in the art. See, e.g., Cowsar and
Dunn, Chapter 12 "Biodegradable and Nonbiodegradable Delivery
Systems" pp. 145-162; Gibson, et al., Chapter 31 "Development of a
Fibrous IUD Delivery System for Estradiol/Progesterone" pp.
215-226; Dunn, et al., "Fibrous Polymers for the Delivery of
Contraceptive Steroids to the Female Reproductive Tract" pp.
125-146; Dunn, et al. (1985) "Fibrous Delivery Systems for
Antimicrobial Agents" from Polymeric Materials in Medication ed. C.
G. Gebelein and Carraher, Plenum Publishing Corporation, pp 47-59.
Any of these known methods, and numerous other methods known in the
art, may be employed in the practice of the present invention in
order to produce fibrous devices having the unique features
described herein.
[0087] A variety of methods for processing polymers by extrusion
are described in Chris Rauwendaal (1994) "Polymer Extusion" Third
Revised Edition, Carl Hanser Vertag, Munich, such as plasticating
extrusion, where the polymer is fed to the extruder as a solid, and
melt-fed extrusion where molten polymer is fed to the extruder. As
used herein, the terms "extrusion" or "melt-spinning" encompasses
all these methods of manufacture. In melt-spinning, a thermoplastic
polymer is heated above its melting point, extruded through an
orifice, and cooled to form a filament. In one preferred embodiment
for producing the devices of the present invention, a peptide
active agent is mixed with the polymer prior to extrusion and the
mixture is then ground to form a feedstock for re-extruding the
mixture to insure uniform mixing. Although generally formed in a
geometry where the cross-section is a circle, such devices can also
be prepared with any other cross-sectional geometry, for example,
an ellipsoid, a lobe, a square, or a triangle. The polymer can also
be formed into microparticles, sheets, films or coatings, using
standard processing technology.
[0088] The devices may be prepared in a variety of sizes depending
on the total dose of drug and the envisioned method and site of
administration. In a preferred embodiment, the device is a
monolithic rod with an overall diameter between 0.05 and 5.0 mm.
For subcutaneous administration in humans, an overall diameter of
between 1.0 and 4.0 mm may be more preferred. The length of the
device is typically between about 0.3 cm and 10 cm. For
subcutaneous implantation, a more preferred length is between about
0.3 cm and 3.0 cm.
[0089] Drawing may be accomplished by passing the material around
two or more sets of godets that are operated at progressively
faster speeds as the material passes further down the line. The
material may pass through heated ovens between the godets so that
the temperature can be carefully controlled to further influence
the crystallinity of the polymer. Drawing may also be used to
control the final diameter of the material.
[0090] Because such structures are prepared by a continuous
extrusion process, they can be provided in any length that is
convenient for handling. If the formulation is sufficiently
flexible, it can be wound onto a spool or into a coil and held in
this way prior to cutting. Alternatively, the material can be
collected as shorter lengths of perhaps a few centimeters or meters
and held prior to cutting. It is also possible to cut the material
to the finished device length as it is produced using a flywheel
type of cutter that is situated just downstream of the die.
[0091] The amount of active agent to be incorporated and the amount
used in the process will vary depending upon the particular agent,
the desired effect of the active agent at the planned release
levels, and the time span over which the agent should be released.
Any of the above-described processes can be used to incorporate
more than one active agent into the polymeric device.
[0092] III. Methods of Use
[0093] Devices produced in accordance with the invention can be
administered using any suitable procedure. Depending upon the
active agent to be administered, the selected form (size, shape,
etc.) and the selected site of administration, the devices can be
delivered or implanted using minimally invasive procedures at a
site where release is desired. These procedures can include
implantation using trocars or catheters, injection using standard
needle and syringes (of, e.g., powders, particles, microparticles,
microspheres, microcapsules), ingrafting or surgical or
non-surgical placement (of, e.g., a matrix, graft, prosthetic or
coating), inhalation (of, e.g., powders or particulates), and the
like. The devices are designed so that the active agent is released
in the desired dosage over a defined period of time. The devices
are designed so that they degrade during and after release of the
active agent is achieved.
[0094] In one embodiment, the device is formulated to include a
GnRH molecule or GnRH analogue in a solid implant form. The device
is then administered to a subject in order to target blood level,
production, function, or activity of a gonadotrophin LH or FSH
similar to that occurring at or near the time of greatest
reproductive function in the subject, which in humans corresponds
to 18 to 35 years of age. For example, a normal blood level of LH
around this time is approximately 0-10.0 mIU/mL for males and
approximately 0.4-92.9 mIU/mL for females (which fluctuates with
reproductive cycle). A normal blood level of FSH around this time
is approximately 2.0-22.6 mIU/mL for males and approximately
2.9-29.5 mIU/mL for females (which also fluctuates with
reproductive cycle). Administration of the GnRH or GnRH analogue
implant is suitable to alter the blood level, production, function,
or activity of a gonadotrophin LH or FSH to acheive the desired
level(s).
[0095] In another embodiment, the device is formulated to include a
GnRH molecule or GnRH analogue in a solid implant form. The device
is then administered to a subject in order to the target blood
level, production, function, or activity of LH or FSH to levels
that are undetectable or nearly undetectable. For example, a blood
level of 0.7 mIU/mL for both LH and FSH is currently undetectable
in a clinical laboratory.
[0096] In another embodiment of the invention, the device is
formulated to include a GnRH molecule or GnRH analogue in a solid
implant form. The device is then administered to a subject in order
to the target blood level, production, function, or activity of LH
or FSH to levels as low as possible without unacceptable adverse
side effects. An unacceptable adverse side effect is an adverse
side effect that, in the reasonable judgment of one of ordinary
skill in the art, has costs that outweigh the benefits of
treatment.
[0097] In the practice of these and other related methods, the
subject's blood level, production, function, or activity of LH or
FSH may be periodically monitored and the combinations, quantities,
and dosage regimens of the LH/FSH-inhibiting agents may be titrated
or varied in order to achieve the target blood level, target
production, target function or target activity of LH and FSH. In a
particularly preferred embodiment, the dosage for an GnRH analogue,
for example leuprolide acetate, may be between approximately 0.01
mcg/kg/hour and approximately 100 mg/kg/day, or other schedules
that will be apparent to one of ordinary skill in the art, in light
of this specification. In these methods, the subject may initially
be administered a low dose, for example approximately 0.01
mcg/kg/hour. After approximately two weeks, LH and FSH blood levels
may be measured. If LH and FSH bloods levels are still higher than
the target, then the dose may be increased (for example by 0.1
mcg/kg/hour). This titration can be repeated until the blood level,
production, function or activity of LH or FSH reaches the desired
target blood level, production, function, or activity for LH or
FSH, as set forth above.
[0098] For example, a 30 mg time-released dose of leuprolide
acetate can be administered to an adult male subject. The
leuprolide acetate active agent is provided in a biodegradable
polymer system to supply a polymeric device for controlled release
of the active agent. The polymer system is a copolymer or a polymer
blend comprising a hydrophobic component and a hydrophilic
component and the polymer system does not form a hydrogel when
contacted with, or immersed in an aqueous system, for example when
the device is implanted in the subject. The leuprolide acetate
active agent is incorporated within the polymer system such that
the polymer system provides for controlled release of the agent
from the device. When the device is administered to the subject,
for example, when it is implanted, the device releases the active
agent in a controlled fashion without a lag period, or with a
minimal lag period. In this manner, the leuprolide can be gradually
released over a period of several months. After a period of two
weeks, the subject's blood level of LH may be undetectable and the
subject's blood level of FSH may be approximately 5 mIU/mL.
[0099] In another example, a dose of 1.88 mg time-released dose of
leuprolide acetate can be administered to a subject. The leuprolide
acetate active agent is provided in a biodegradable polymer system
to supply a polymeric device for controlled release of the active
agent. The polymer system is a copolymer or a polymer blend
comprising a hydrophobic component and a hydrophilic component and
the polymer system does not form a hydrogel when contacted with, or
immersed in an aqueous system, for example when the device is
implanted in the subject. The leuprolide acetate active agent is
incorporated within the polymer system such that the polymer system
provides for controlled release of the agent from the device. When
the device is administered to the subject, for example, when it is
implanted, the device releases the active agent in a controlled
fashion without a lag period, or with a minimal lag period. In this
manner, the leuprolide can be gradually released over approximately
one month, and is expected to reduce LH and FSH blood levels to
undetectable levels in the subject. It will be apparent to one of
ordinary skill in the art, in light of this specification, that in
order to achieve this target, the dosage of the leuprolide active
agent will vary from subject to subject in light of factors such as
age, gender, body weight, diet, the disease being treated, the
progression of the disease, and other drugs being administered.
[0100] Below are examples of specific embodiments for carrying out
the present invention. The examples are offered for illustrative
purposes only, and are not intended to limit the scope of the
present invention in any way
EXAMPLE 1
Poly (DL-lactide-co-glycolide) PEG Block Copolymer Implant
Methods
[0101] A 90:10 poly (DL-lactide-co-glycolide) PEG block copolymer
was prepared using 8.3 wt % of a monomethoxy terminated poly
(ethylene glycol) having a molecular weight of 5,000 [mPEG-5000] as
initiator with DL-lactide-co-glycolide to produce a block copolymer
having an inherent viscosity of 0.89 dL/g in CHCl.sub.3 at
30.degree. C. The resulting copolymer was then melt extruded to
produce rods of about 1.5 mm diameter and the rods were cut into
devices of about 2 cm length. The devices were then placed into
clean scintillation vials containing 10 mL of 67 mM Sorenson's
phosphate buffer. The samples were stored in a 37.degree. C.
incubator. Complete buffer exchanges were done following 1, 2, 4,
6, 8, 10, 12, 14, and 16 weeks of exposure. At each of the above
sample periods, three devices were removed from the study, and the
wet weight was recorded. The devices were dried (ambient pressure
and RT followed by vacuum drying at less than 18 mm Hg), and the
dry weight of each device was recorded.
[0102] Results
[0103] The water uptake of the polymer is shown in FIG. 1. The
results show that the devices absorb water to a greater degree in
that the diameter increases.
EXAMPLE 2
Release Properties of Leuprolide Acetate Containing Implants
Materials
[0104] Nine parts of leuprolide acetate milled to a mean particle
size of between 3 and 10 microns and 27 parts of MPEG 750 initiated
90:10 poly (DL-lactide-co-glycolide) [mPEG-750/(90:10 DL-PLG)]
having an inherent viscosity of 0.89 dL/g in CHCl.sub.3, an mPEG
content of 1.25 wt %, and having been ground to pass through a 1 mm
screen, were combined and thoroughly mixed. The powder blend was
then compounded by melt extrusion on a 0.375-inch diameter screw
extruder at temperatures of 80 to 120.degree. C. The extrudate is
ground and re-extruded on the same equipment and within the same
temperature range to produce a rod having a diameter of about 1.5
mm diameter. The rod was then cut to form devices of about 2 cm
length.
[0105] The devices were tested in vitro by placing individual
devices in 10 mL of 67 mM Sorensen's phosphate buffer (pH 7.4)
containing 0.05 wt % sodium azide and incubated at 37.degree. C.
Periodically, the buffer was exchanged for fresh buffer, and the
old buffer was assayed to determine the amount of leuprolide that
has been released from the implants.
[0106] Results
[0107] FIG. 2 shows that the release from the devices shows a burst
over a period of about 7 days followed by a slower constant release
of leuprolide.
EXAMPLE 3
Release Properties of Leuprolide Acetate Containing Implants
[0108] The experiment of Example 2 was repeated using an
mPEG-5000/(90:10 DL-PLG) having an IV=0.89 dL/g and containing 8.3
wt % MPEG. A similar release profile was observed as is shown in
FIG. 3.
[0109] Modifications and variations of the present invention will
be obvious to those skilled in the art and are intended to come
within the scope of the appended claims.
* * * * *