U.S. patent application number 13/952595 was filed with the patent office on 2014-02-06 for methods for manufacturing delivery systems and systems thereof.
This patent application is currently assigned to Evonik Corporation. The applicant listed for this patent is Evonik Corporation. Invention is credited to Bruce W. Hudson, Jay K. Staas, Thomas R. Tice, Arthur J. Tipton.
Application Number | 20140037707 13/952595 |
Document ID | / |
Family ID | 36660844 |
Filed Date | 2014-02-06 |
United States Patent
Application |
20140037707 |
Kind Code |
A1 |
Staas; Jay K. ; et
al. |
February 6, 2014 |
Methods for Manufacturing Delivery Systems and Systems Thereof
Abstract
Described herein are methods for reducing and achieving the
desired release of an agent from a delivery system. The desired
release kinetics are achieved by exposing the surface of the
delivery system with a fluid for a desired period of time.
Inventors: |
Staas; Jay K.; (Madison,
AL) ; Tice; Thomas R.; (Indian Springs, AL) ;
Hudson; Bruce W.; (Pleasant Grove, AL) ; Tipton;
Arthur J.; (Birmingham, AL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Evonik Corporation |
Parsippany |
NJ |
US |
|
|
Assignee: |
Evonik Corporation
Parsippany
NJ
|
Family ID: |
36660844 |
Appl. No.: |
13/952595 |
Filed: |
July 31, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11196591 |
Aug 3, 2005 |
8541028 |
|
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13952595 |
|
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60599174 |
Aug 4, 2004 |
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Current U.S.
Class: |
424/422 ;
514/21.5; 514/21.6; 514/259.41; 514/52 |
Current CPC
Class: |
A61K 9/0024 20130101;
A61L 31/10 20130101; A61L 31/048 20130101; A61L 31/06 20130101;
A61K 9/2027 20130101; A61L 31/16 20130101; A61L 27/34 20130101;
A61L 2300/606 20130101; A61K 9/204 20130101; A61L 27/54
20130101 |
Class at
Publication: |
424/422 ; 514/52;
514/21.6; 514/21.5; 514/259.41 |
International
Class: |
A61L 31/06 20060101
A61L031/06; A61L 31/04 20060101 A61L031/04 |
Claims
1.-33. (canceled)
34. A delivery system comprising at least a first polymer and at
least one agent, wherein the agent is dispersed in the first
polymer, wherein the delivery system comprises at least two exposed
surfaces of the first polymer, wherein at least one of the exposed
surfaces or least one part of at least one exposed surface has
surface morphology different than the other exposed surface or
surfaces.
35. The delivery system of claim 34, wherein the delivery system
comprises a rod comprising two ends and a longitudinal surface,
wherein the ends of the rod have a surface morphology that is
different the surface morphology of the longitudinal surface.
36. An article comprising a substrate coated with a polymer
coating, wherein the polymer coating comprises at least two exposed
surfaces, wherein at least one of the exposed surfaces or at least
one part of at least one exposed surface has a surface morphology
different than the other exposed surface or surfaces.
37. The article of claim 36, wherein the article is in the form of
a stent, suture, surgical clip, rod, pin, anchor, mesh, scaffold,
tissue generating scaffold, medical electronic device, a wound
dressing, a membrane, an orthopedic device for delivering an
antibiotic or growth factor, a device for a dermal application for
delivering an anesthetic or growth factor.
38. The delivery system of claim 34, wherein all or a portion of
the delivery system is coated with a second polymer forming a
coated delivery system, wherein the coated delivery system
comprises at least two exposed surfaces of the second polymer, and
wherein at least one of the exposed surfaces or least one part of
at least one exposed surface has surface morphology different than
the other exposed surface or surfaces.
39. The delivery system of claim 38, wherein the exposed surface
has a surface morphology formed by a fluid treatment of the exposed
surface.
40. The delivery system of claim 39, wherein the exposed surface
has a surface morphology formed by a fluid treatment of the exposed
surface that comprises treating the exposed surface with a fluid
that comprises methylene chloride, chloroform, acetone, anisole,
ethylacetate, methylacetate, N-methyl-2-pyrrolidone, hexafluoro
isopropanol, tetrahydrofuran, dimethylsulfoxide, water,
2-pyrrolidone, triethylcitrate, ethyl lactate, propylene carbonate,
benzyl alcohol, benzyl benzoate, miglyol 810, isopropanol, ethanol,
supercritical carbon dioxide, acetonitrile, water or a mixture
thereof.
41. The delivery system of claim 38, wherein the delivery system
has the shape of a rod, a fiber, a cylinder, a beat, a ribbon, a
disc, a wafer, or a free-formed shaped solid.
42. The delivery system of claim 38, wherein the delivery system is
a depot or implant.
43. The delivery system of claim 38, wherein the first polymer
comprises poly(lactide), poly(glycolide), poly(caprolactone), or a
copolymer, mixture, or blend thereof.
44. The delivery system of claim 38, wherein the second polymer
comprises poly(lactide), poly(glycolide), poly(caprolactone), or a
copolymer, mixture, or blend thereof.
45. The delivery system of claim 38, wherein the agent comprises a
bioactive agent.
46. The delivery system of claim 38, wherein the bioactive agent
comprises a drug, an immunological agent, an antigen, a protein, a
peptide, an oligonucleotide, or a mixture thereof.
47. The delivery system of claim 38, wherein the agent comprises an
adhesive, a pesticide, a fragrance, an antifoulant, a dye, a salt,
an oil, an ink, a cosmetic, a catalyst, a detergent, a curing
agent, a flavor, a fuel, a herbicide, a metal, a paint, a
photographic agent, a biocide, a pigment, a plasticizer, a
propellant, a stabilizer, a polymer additive, or any combination
thereof.
48. The delivery system of claim 38, wherein the delivery system is
partially coated and has been obtained by contacting only a portion
of the exposed polymer with the fluid or by removing part of the
polymer surface to expose untreated surface.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 60/599,174, filed on Aug. 4, 2004, which
application is hereby incorporated by reference in its entirety for
all of its teachings.
BACKGROUND
[0002] In the realm of pharmaceutical formulations, there is a
class of drug-delivery formulations that are designed to release
bioactive agents for a desired period of time following a single
administration. Depot formulation is one name used to describe
these long-acting formulations. Depot formulations can be
fabricated in many ways. A typical formulation approach to prepare
a depot formulation or implant is by manufacturing a solid matrix
that includes a bioactive agent and a polymeric excipient. The
purpose of the polymeric excipient of the implant is to restrict
the influx of water, which in turns controls the dissolution of the
bioactive agent followed by the release of the bioactive agent from
the implant matrix. In addition to the physical and chemical
properties of the bioactive agent, the amount of bioactive agent in
the implant contributes to the rate of bioactive agent release.
That is, increasing the amount of bioactive agent increases the
rate of release. Unfortunately, some implant formulations require a
high amount of bioactive agent inside in order to have enough
bioactive agent available to achieve dose and duration requirements
for a particular medical indication. A high amount of bioactive
agent incorporated inside the implant, however, may cause the
release the bioactive agent to occur too fast or even at an
uncontrollable rate.
[0003] It is an object of the present invention to provide delivery
systems with a controlled release even at high loadings. Moreover,
it is an object of the present invention to provide delivery
systems and methods for their manufacture having decreased
microbial contamination. It is a further object of the present
invention to provide delivery systems having a smooth or smoother
(than untreated) surface for easy administration. It is another
object of the present invention to provide delivery systems where
the delivery rate can be adjusted by modifying the surface.
[0004] The present invention solves this rapid release problem,
i.e., the bioactive agent being released too fast, by modifying the
polymeric surface or polymer skin of a delivery system by exposing
the polymer present in the system to a fluid. The fluid-treatment
causes the properties of the polymer on the surface of the delivery
system to change such that the system is less permeable. It is the
fluid treatment of the delivery system that is responsible for the
slower release of the bioactive agent from the delivery system. In
addition, the delivery systems produced herein are generally
smoother than other delivery systems, which can facilitate the
administration of the system to the subject. Additionally, the
methods described herein can lower the bioburden of the delivery
system by reducing the presence of microorganisms present on the
system. Finally, the delivery systems produced herein have
increased tensile strength, i.e., reduced friability, which aids in
the preparation and administration of the system.
SUMMARY
[0005] Described herein are methods for reducing and achieving the
desired release of an agent from a delivery system. The desired
release kinetics are achieved by exposing the surface of the
delivery system to a fluid for a predetermined period of time. The
advantages of the invention will be set forth in part in the
description which follows, and in part will be obvious from the
description, or may be learned by practice of the aspects described
below. The advantages described below will be realized and attained
by means of the elements and combinations particularly pointed out
in the appended claims. It is to be understood that both the
foregoing general description and the following detailed
description are exemplary and explanatory only and are not
restrictive.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] FIG. 1 shows the in vitro release of vitamin B.sub.12 (45 wt
%) from poly(DL-lactide) implants with and without fluid
exposure.
[0007] FIG. 2 shows the in vitro release characteristics of
Deslorelin implants (44 wt %) made with poly(DL-lactide) with and
without fluid exposure.
[0008] FIG. 3 shows the in vitro release characteristics of
Risperidone implants (50 wt %) made with poly(DL-lactide) with and
without fluid exposure.
[0009] FIG. 4 shows the in vitro release of vitamin B.sub.12 (50 wt
%) from poly(DL-lactide) implants with and without fluid
exposure.
[0010] FIG. 5 shows the in vitro release of vitamin B.sub.12 (45 wt
%) from ethyl vinyl acetate implants with and without fluid
exposure.
DETAILED DESCRIPTION
[0011] Before the present compounds, compositions, and/or methods
are disclosed and described, it is to be understood that the
aspects described below are not limited to specific compounds,
synthetic methods, or uses as such may, of course, vary. It is also
to be understood that the terminology used herein is for the
purpose of describing particular aspects only and is not intended
to be limiting.
[0012] In this specification and in the claims that follow,
reference will be made to a number of terms that shall be defined
to have the following meanings:
[0013] Throughout this specification, unless the context requires
otherwise, the word "comprise," or variations such as "comprises"
or "comprising," will be understood to imply the inclusion of a
stated integer or step or group of integers or steps but not the
exclusion of any other integer or step or group of integers or
steps.
[0014] It must be noted that, as used in the specification and the
appended claims, the singular forms "a," "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a pharmaceutical carrier" includes
mixtures of two or more such carriers, and the like.
[0015] "Optional" or "optionally" means that the subsequently
described event or circumstance can or cannot occur, and that the
description includes instances where the event or circumstance
occurs and instances where it does not.
[0016] Ranges may be expressed herein as from "about" one
particular value, and/or to "about" another particular value. When
such a range is expressed, another aspect includes from the one
particular value and/or to the other particular value. Similarly,
when values are expressed as approximations, by use of the
antecedent "about," it will be understood that the particular value
forms another aspect. It will be further understood that the
endpoints of each of the ranges are significant both in relation to
the other endpoint, and independently of the other endpoint.
[0017] A weight percent of a component, unless specifically stated
to the contrary, is based on the total weight of the formulation or
composition in which the component is included.
[0018] By "contacting" is meant an instance of exposure by close
physical contact of at least one substance to another
substance.
[0019] By "combination" when referring to components of the
polymer, it is meant a physical mixture (blend), a non-homogeneous
mixture, multiple layers of the individual polymers, or a copolymer
thereof.
[0020] The term "admixing" is defined as mixing the two components
together. Depending upon the components to be admixed, there may or
may not be a chemical or physical interaction between two or more
components.
[0021] By "sufficient amount" and "sufficient time" means an amount
and time needed to achieve the desired result or results.
[0022] Disclosed are compounds, compositions, and components that
can be used for, can be used in conjunction with, can be used in
preparation for, or are products of the disclosed methods and
compositions. These and other materials are disclosed herein, and
it is understood that when combinations, subsets, interactions,
groups, etc. of these materials are disclosed that while specific
reference of each various individual and collective combinations
and permutation of these compounds may not be explicitly disclosed,
each is specifically contemplated and described herein. For
example, if a number of different polymers and agents are disclosed
and discussed, each and every combination and permutation of the
polymer and agent are specifically contemplated unless specifically
indicated to the contrary. Thus, if a class of molecules A, B, and
C are disclosed as well as a class of molecules D, E, and F and an
example of a combination molecule, A-D is disclosed, then even if
each is not individually recited, each is individually and
collectively contemplated. Thus, in this example, each of the
combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are
specifically contemplated and should be considered disclosed from
disclosure of A, B, and C; D, E, and F; and the example combination
A-D. Likewise, any subset or combination of these is also
specifically contemplated and disclosed. Thus, for example, the
sub-group of A-E, B-F, and C-E are specifically contemplated and
should be considered disclosed from disclosure of A, B, and C; D,
E, and F; and the example combination A-D. This concept applies to
all aspects of this disclosure including, but not limited to, steps
in methods of making and using the disclosed compositions. Thus, if
there are a variety of additional steps that can be performed it is
understood that each of these additional steps can be performed
with any specific embodiment or combination of embodiments of the
disclosed methods, and that each such combination is specifically
contemplated and should be considered disclosed.
[0023] Described herein are methods for producing delivery systems.
As used herein, "delivery systems" refer to both devices and coated
articles as defined herein. The methods described herein allow for
the manufacture of controlled-release, extended-release,
modified-release, sustained-release, pulsatile-release,
delayed-release, or programmed-release delivery of an agent. The
term "delivery" as used herein includes all different types of
delivery. In a further aspect, the delivery system is a device. In
another further aspect, the delivery system is a coated
article.
[0024] The term "device" is any formulation or article that is
greater than 1 mm in length in at least one dimension of the
device. The device can comprise a polymer and an agent. In a
further aspect, the device has one dimension that is from 1 mm to
50 mm, 1.2 mm to 45 mm, 1.4 mm to 42 mm, 1.6 mm to 40 mm, 1.8 mm to
38 mm, or 2.0 mm to 36 mm, 5.0 mm to 33 mm, or 10 mm to 30 mm. In a
further aspect, the device has one dimension that is greater than 3
cm, even up to or greater than 10 cm, 20 cm, or even 30 cm.
[0025] In a further aspect, described herein is method for
preparing a device comprising an agent, comprising [0026] (a)
admixing at least one polymer and at least one agent to produce an
admixture; [0027] (b) processing the admixture to produce a device
of a desired shape, wherein the device comprises at least two
exposed surfaces; and [0028] (c) contacting the device with a
sufficient amount of a fluid for a sufficient time to change the
surface morphology of the polymer, wherein at least one exposed
surface or at least one part of at least one exposed surface of the
device is not contacted with the fluid, and [0029] wherein steps
(a) and (b) do not involve the use of a solvent.
[0030] In another aspect, described herein is a method for
preparing a device comprising an agent, comprising
[0031] (a) admixing at least one polymer and at least one agent to
produce an admixture;
[0032] (b) processing the admixture to produce a device of a
desired shape; and
[0033] (c) contacting the device with a sufficient amount of a
fluid for a sufficient time to change the surface morphology of the
polymer,
[0034] wherein steps (a) and (b) do not involve the use of a
solvent.
[0035] In another aspect, described herein is a method for
preparing a device comprising an agent, comprising
[0036] (a) admixing at least one polymer and at least one agent to
produce an admixture;
[0037] (b) processing the admixture to produce a device of a
desired shape; and
[0038] (c) contacting the device with a sufficient amount of a
fluid for a sufficient time to change the surface morphology of the
polymer,
[0039] wherein steps (a) and (b) involves the use of a non-solvent
for the polymer.
[0040] In a further aspect, described herein is method for
preparing a device comprising at least one polymer and at least one
agent, comprising contacting the device with the agent incorporated
therein with a sufficient amount of a fluid for a sufficient time
to change the surface morphology of the polymer.
[0041] In another method, described herein is a method for
preparing a device comprising at least one polymer and at least one
agent, comprising contacting the device with the agent incorporated
therein with a sufficient amount of a fluid for a sufficient time
to change the surface morphology of the polymer, wherein at least
one exposed surface or at least one part of at least one exposed
surface of the device is not contacted with the fluid.
[0042] In certain aspects, the polymer and agent are admixed to
form a blend or admixture. Admixing step (a) can be performed using
techniques known in the art. For example, the polymer and agent can
be dry blended (i.e., mixing of particulates of the polymer and the
agent) using, for example, a Patterson-Kelley V-blender, or
granulated prior to processing step (b). It is contemplated that
other components such as, for example, excipients, can be admixed
with the polymer and the agent prior to processing.
[0043] In certain aspects of the methods described herein, the
admixing step does not involve the use of a solvent. There are a
number of disadvantages associated with the use of a solvent during
the admixing of the polymer and the agent. First, the use of a
solvent during admixing requires additional processing steps to
remove the solvent. Second, if the delivery system is to be
implanted into a subject, the selected solvent has to be
biocompatible if any residual solvent remains in the device. The
solvent can adversely affect the overall morphology of the delivery
system, which can lead to undesirable release patterns. The solvent
can adversely affect the stability of the bioactive agent during
the manufacturing process. Finally, the solvent level requires
control, because it has to be low enough to meet regulatory
guidelines.
[0044] It is contemplated that steps (a) and/or (b) can be
performed in batch or continuously. In another aspect, steps (a)
and (b) can employ a non-solvent for the polymer. The phrase
"non-solvent for a polymer" is defined herein as any component or
compound that can facilitate the mixing of the polymer and the
agent, wherein the polymer is substantially insoluble in the
component or compound. In a further aspect, the non-solvent is any
solvent that dissolves less than 5%, less than 4%, less than 3%,
less than 2%, less than 1%, less than 0.75%, less than 0.5%, less
than 0.25%, or 0% by weight of the polymer. In a further aspect,
admixing step (a) involves the use the use of a non-solvent for the
polymer in granulating the polymer and the agent.
[0045] The processing of the admixture is performed under
conditions such that the agent is intimately mixed or dispersed
throughout the polymer. The admixture can be processed by a variety
of techniques, such as, for example, melt extruding, injection
molding, compression molding, or roller compacting the admixture
into a desired shape or structure. Compression manufacturing
techniques can include, but are not limited to tabletting.
Depending upon processing conditions, the polymer used as a
starting material in the admixing step may or may not be the same
polymer present in the final device. For example, the polymer
during processing may undergo polymerization or depolymerization
reactions, which ultimately can produce a different polymer that
was used prior to processing. Thus, the term "polymer" as used
herein covers the polymers used as starting materials as well as
the final polymer present in the device produced by the methods
described herein.
[0046] The device can have various shapes and sizes depending upon
the processing technique that is selected. In a further aspect, the
device comprises at least two exposed surfaces. The term "exposed
surface" as defined herein is any surface of the device that can be
contacted with the fluid. For example, when the device is a
cylindrical rod, the device has three exposed surfaces (the two
ends and the longitudinal surface). In further aspects, the device
has one exposed surface, two exposed surfaces, three exposed
surfaces, or greater than three exposed surfaces that have not been
contacted with the fluid. This allows for greater controllability
of the rate and direction of the release of the agent. The exposed
polymer surface not being contacted with the fluid includes the
aspects of both (a) controlling the fluid so as not to contact at
least one surface of the device during the contacting step or (b)
by removing a portion of the treated polymer layer of the treated
device to thereby expose uncontacted polymer surface. For aspect
(b), for a rod, for example, the entire rod can be fluid treated
and then the rod end(s) sliced, cut, sheared, chopped off, or
removed in some other manner to expose untreated surface.
[0047] In further aspects, the exposed surface or surfaces that
have not been contacted with the fluid can be just a portion of the
surface, i.e., not the entire surface. That is, in certain aspects,
it is not necessary to fluid treat the entire polymer surface,
thus, partial surface treatment can be acceptable. For example,
when the device is a rod, one entire end surface can be free of
contact with the fluid or just part of the one end surface can be
free of contact with the fluid. In further aspects, the exposed
surface or surfaces that have not been contacted with the fluid can
be both one or more entire surfaces and one or more partial
surfaces. For example, when the device is a rod, the entire first
end surface can be free of fluid contact and part of the surface of
the second end can be free of fluid contact.
[0048] In a further aspect, the device can be a depot or implant.
In a further aspect, the device can be in the shape of a rod, a
fiber, a cylinder, a bead, a ribbon, a disc, a wafer, a free-formed
shaped solid, or a variety of other shaped solids. In a further
aspect, the device is not a sphere such as, for example, a
microsphere or microparticle. The device can have any regular or
irregular shape and can have any cross section like circular,
rectangular, triangular, oval, and the like. In a further aspect,
the device comprises a rod comprising two ends and a longitudinal
surface, wherein the ends of the rod are not contacted with the
surface, and wherein the longitudinal surface is contacted with the
fluid.
[0049] The delivery systems produced herein can also include a
coated article. In a further aspect, described herein is a method
for producing a coated article, comprising
[0050] (a) coating the outer surface of the article with at least
one polymer to produce the coated article; and
[0051] (b) contacting the coated article with a sufficient amount
of a fluid to change the surface morphology of at least part of the
surface of the polymer.
[0052] In this aspect, depending upon the end-use, an agent can be
incorporated in the article prior to coating, the agent can be
incorporated in the polymer prior to coating the article, or the
agent can be incorporated in the article and the polymer coating.
It is contemplated that one or more agents can be incorporated in
the article and/or the polymer coating. The term "article" is
defined herein as any substrate that is capable of being coated
with a polymer. In a further aspect, the article to be coated can
be a medical device such as, for example, a stent, suture, surgical
clip, rod, pin, anchor, mesh, scaffold, tissue-generating scaffold,
medical electronic device, a wound dressing, a membrane, an
orthopedic device for delivering an antibiotic or growth factor, a
device for a dermal application for delivering an anesthetic or
growth factor, and the like.
[0053] The coating of the article can be accomplished using
techniques known in the art. In a further aspect, the coating can
be applied by using a solution or dispersion of the polymer. In
this aspect, if the agent is not incorporated into the article
prior to coating, the agent can be dissolved or dispersed in the
polymer solution. In another aspect, the polymer and, optionally,
the agent are melt blended then applied to the outer surface of the
article. In another aspect, the polymer and, optionally, the agent
are prepared as a powder then powder coated on the article. It is
also contemplated that all or a portion of the article can be
coated with the polymer or polymer and agent.
[0054] For the coated article, typically the entire polymer exposed
surfaces are contacted with the fluid. However, similar to the
device above, partial contacting, i.e., only a portion of the
exposed polymer is contacted with the fluid, can be performed or
part of the polymer surface is removed to expose untreated
surface.
[0055] In a further aspect, once the delivery system (i.e. device
or coated article) has been produced, it is contacted with a fluid
in order to change the surface properties of the device or coated
article and, thus, alter the release properties of the device or
coated article. In a further aspect, the device or coated article
is contacted with a fluid in a sufficient amount for a sufficient
time to change the surface morphology of the polymer. Not wishing
to be bound by theory, it is believed that the fluid diffuses into
the outer layer (a) to lower the Tg of the polymer or (b) to
dissolve and/or gel the polymer, so that the polymer molecules
rearrange to produce a smooth or smoother surface coating on the
device or coated article. This fluid effect results in changing or
altering the surface properties on the device or coated article
such as, for example, porosity and permeability, which can
ultimately reduce the release of the agent incorporated in the
device or the coated article. It is also contemplated that all or a
portion of the polymer of the device or coated article can be
contacted with the fluid.
[0056] The fluid used for the surface treatment can include a
single fluid or a mixture of two or more fluids in any ratio. In a
further aspect, the fluid can be selected based upon the solubility
of the polymer to be used. For example, the fluid can be a mixture
of liquids, one of which will solubilize the polymer and the other
that does not or both will solubilize the polymer. By selecting the
fluid system to be used and the duration of the contacting step, it
is possible to change the morphology of the polymer and,
ultimately, the release pattern of the device. For example, if
slower release of the agent from the device is desired, the device
can be contacted with the fluid for longer periods of time in order
to change the surface morphology of the device to a greater
extent.
[0057] In a further aspect, the fluid comprises a liquid. Examples
of liquids include, but are not limited to, hydrocarbons,
halogenated hydrocarbons, ethers, esters, acids, bases, alcohols,
ketones, alkanes, aromatics, and the like. In another aspect, the
fluid is methylene chloride, chloroform, acetone, anisole, ethyl
acetate, methyl acetate, N-methyl-2-pyrrolidone,
hexafluoroisopropanol, tetrahydrofuran, dimethylsulfoxide, water,
2-pyrollidone, triethyl citrate, ethyl lactate, propylene
carbonate, benzyl alcohol, benzyl benzoate, Miglyol 810,
isopropanol, ethanol, super critical carbon dioxide, acetonitrile,
water, or a mixture thereof.
[0058] In another aspect, the fluid comprises a gas. Compounds that
are gaseous at standard temperature and pressure can be used herein
as the fluid. In a further aspect, the gas comprises nitrogen,
ethylene oxide, a polyfluorochloro compound, water vapor, a vapor
of an organic solvent, or a mixture thereof. The device or coated
article can be contacted with the gas at operating conditions, such
as ambient, elevated, or reduced temperatures, depending upon the
composition of the device or coated article and the gas
selected.
[0059] The delivery system can be exposed to the fluid once or
multiple times. In another aspect, after the contacting step, the
fluid can optionally be removed from the delivery system. The
amount of fluid that is removed from the delivery system in this
aspect can vary, and will depend upon the desired release profile
to be achieved. The device or coated article can be contacted with
the fluid using techniques known in the art. In a further aspect,
when the fluid is a liquid, the device or article can be contacted
with the liquid by immersing the device in the liquid or spraying
the liquid on the device. In another aspect, during the processing
of the polymer/agent admixture, the admixture can be extruded with
the fluid. In a further aspect, the polymer/agent admixture can be
extruded through a liquid rich dye. In another aspect, the
contacting step can be continuous, where a steady stream of fluid
is in contact with the device. In other aspects, when the fluid is
a liquid, the contacting step can be performed by an annular ring
with an aerosol solvent, a pan coating, or by vapor phase
equilibration. When the fluid is a gas, in a further aspect, the
device or coated article can be contacted with a steady stream of
the gas. Alternatively, the device or coated article can be placed
in a chamber that is to be filled with the gas. In further aspects,
an entire exposed surface or a portion of the exposed surface of
the polymer of the delivery systems (devices and coated articles)
can be fluid treated. That is, it is not necessary in certain
aspects to treat the entire polymer surface.
[0060] The time of the fluid exposure can vary depending upon the
fluid and polymer selected and the desired release pattern to be
achieved. The contacting step can range from greater than zero,
such as just over a second, to minutes, to hours, or to several
days. In various aspects, the contacting time is from 0.1 seconds
to one hour, 0.5 seconds to 30 minutes, one second to 10 minutes,
two seconds to 5 minutes, three seconds to 60 seconds, or five
seconds to 30 seconds. In another aspect, the contacting time is
from one second to 10 seconds or one second to five seconds. In
further aspects, different fluids or different mixtures of fluids
can be used during a series of fluid exposures.
[0061] Other process conditions can include, but are not limited
to, temperature and pressure. In a further aspect, when the fluid
is a liquid, the temperature of the contacting step is less than
the boiling point of the liquid. In another aspect, the temperature
of the contacting step is less than the melting point of the
polymer. In another aspect, when the fluid is a gas, the pressure
of the contacting step can be at atmospheric pressure or greater
than atmospheric pressure.
[0062] Typically, after the contacting step the delivery system is
dried to remove some or all of the fluid. In a further aspect,
after the contacting step, the delivery system is washed with
water.
[0063] In a further aspect, the device is prepared by dry blending
a bioactive agent with a poly(lactide-co-glycolide) polymer (PLG)
such as, for example, 85:15 PLG. In a further aspect, when the
delivery system is a device, the device is prepared by dry blending
poly(lactide-co-glycolide), poly(lactide), or a combination
thereof, with a bioactive agent to produce an admixture, melt
extruding the admixture to produce a rod, contacting the rod with
ethyl acetate, and cutting the rod into one or more smaller rods
having a predetermined length. In this aspect, the two ends of the
cut up rods have not been contacted with the fluid. Thus, the
surface morphology of the ends of the rod is different when
compared to longitudinal surface of the rod.
[0064] A variety of agents can be used in the methods described
herein. As used herein, in reference to the invention, "agent"
includes both a bioactive agent or a non-bioactive agent.
[0065] In a further aspect, the agent is a bioactive agent. The
term "bioactive agent" (i.e., biologically active agent, drug, or
medicament) as used herein includes without limitation
physiologically or pharmacologically active substances that act
locally or systemically in the body. A biologically active agent is
a substance used for the treatment, prevention, diagnosis, cure or
mitigation of disease or illness, a substance which affects the
structure or function of the body, or pro-drugs, which become
biologically active or more active after they have been placed in a
predetermined physiological environment. Bioactive agents include
biologically, physiologically, or pharmacologically active
substances that act locally or systemically in the human or animal
body. Various forms of the medicaments or biologically active
materials can be used, which are capable of being released from the
solid matrix into adjacent tissues or fluids. A liquid or solid
bioactive agent can be incorporated in the delivery systems
described herein. The bioactive agents are at least very slightly
water soluble, preferably moderately water soluble, and are
diffusible through the polymeric composition. They can be acidic,
basic, or amphoteric salts. They can be nonionic molecules, polar
molecules, or molecular complexes capable of hydrogen bonding. The
biologically-active agent may be included in the compositions in
the form of, for example, an uncharged molecule, a molecular
complex, a salt, an ether, an ester, an amide, polymer drug
conjugate, or other form to provide the effective biological or
physiological activity. Examples of bioactive agents that
incorporated into systems herein include, but are not limited to,
peptides, proteins such as hormones, enzymes, antibodies and the
like, nucleic acids such as aptamers, iRNA, DNA, RNA, antisense
nucleic acid or the like, antisense nucleic acid analogs or the
like, low-molecular weight compounds, or high-molecular-weight
compounds. Bioactive agents contemplated for use in the delivery
systems include anabolic agents, antacids, anti-asthmatic agents,
anti-cholesterolemic and anti-lipid agents, anti-coagulants,
anti-convulsants, anti-diarrheals, anti-emetics, anti-infective
agents including antibacterial and antimicrobial agents,
anti-inflammatory agents, anti-manic agents, antimetabolite agents,
anti-nauseants, anti-neoplastic agents, anti-obesity agents,
anti-pyretic and analgesic agents, anti-spasmodic agents,
anti-thrombotic agents, anti-tussive agents, anti-uricemic agents,
anti-anginal agents, antihistamines, appetite suppressants,
biologicals, cerebral dilators, coronary dilators,
bronchiodilators, cytotoxic agents, decongestants, diuretics,
diagnostic agents, erythropoietic agents, expectorants,
gastrointestinal sedatives, hyperglycemic agents, hypnotics,
hypoglycemic agents, immunomodulating agents, ion exchange resins,
laxatives, mineral supplements, mucolytic agents, neuromuscular
drugs, peripheral vasodilators, psychotropics, sedatives,
stimulants, thyroid and anti-thyroid agents, tissue growth agents,
uterine relaxants, vitamins, or antigenic materials. Other
bioactive agents include androgen inhibitors, polysaccharides,
growth factors, hormones, anti-angiogenesis factors,
dextromethorphan, dextromethorphan hydrobromide, noscapine,
carbetapentane citrate, chlophedianol hydrochloride,
chlorpheniramine maleate, phenindamine tartrate, pyrilamine
maleate, doxylamine succinate, phenyltoloxamine citrate,
phenylephrine hydrochloride, phenylpropanolamine hydrochloride,
pseudoephedrine hydrochloride, ephedrine, codeine phosphate,
codeine sulfate morphine, mineral supplements, cholestryramine,
N-acetylprocainamide, acetaminophen, aspirin, ibuprofen, phenyl
propanolamine hydrochloride, caffeine, guaifenesin, aluminum
hydroxide, magnesium hydroxide, peptides, polypeptides, proteins,
amino acids, hormones, interferons, cytokines, and vaccines.
Representative drugs or bioactive materials that can be used in the
polymer system or solid matrix of the present invention include,
but are not limited to, peptide drugs, protein drugs, desensitizing
materials, antigens, anti-infective agents such as antibiotics,
antimicrobial agents, antiviral, antibacterial, antiparasitic,
antifungal substances and combination thereof, antiallergenics,
androgenic steroids, decongestants, hypnotics, steroidal
anti-inflammatory agents, anti-cholinergics, sympathomimetics,
sedatives, miotics, psychic energizers, tranquilizers, vaccines,
estrogens, progestational agents, humoral agents, prostaglandins,
analgesics, antispasmodics, antimalarials, antihistamines,
cardioactive agents, nonsteroidal anti-inflammatory agents,
antiparkinsonian agents, antihypertensive agents, .beta.-adrenergic
blocking agents, nutritional agents, and the benzophenanthridine
alkaloids. The agent may further be a substance capable of acting
as a stimulant, sedative, hypnotic, analgesic, anticonvulsant, and
the like. The delivery system can contain a large number of
bioactive active agents either singly or in combination. Other
bioactive agents include but are not limited to analgesics such as
acetaminophen, acetylsalicylic acid, and the like; anesthetics such
as lidocaine, xylocalne, and the like; anorexics such as dexadrine,
phendimetrazine tartrate, and the like; antiarthritics such as
methylprednisolone, ibuprofen, and the like; antiasthmatics such as
terbutaline sulfate, theophylline, ephedrine, and the like;
antibiotics such as sulfisoxazole, penicillin G, ampicillin,
cephalosporins, amikacin, gentamicin, tetracyclines,
chloramphenicol, erythromycin, clindamycin, isoniazid, rifampin,
and the like; antifungals such as amphotericin B, nystatin,
ketoconazole, and the like; antivirals such as acyclovir,
amantadine, and the like; anticancer agents such as
cyclophosphamide, methotrexate, etretinate, and the like;
anticoagulants such as heparin, warfarin, and the like;
anticonvulsants such as phenyloin sodium, diazepam, and the like;
antidepressants such as isocarboxazid, amoxapine, and the like;
antihistamines such as diphenhydramine HCl, chlorpheniramine
maleate, and the like; hormones such as insulin, progestins,
estrogens, corticoids, glucocorticoids, androgens, and the like;
tranquilizers such as thorazine, diazepam, chlorpromazine HCl,
reserpine, chlordiazepoxide HCl, and the like; antispasmodics such
as belladonna alkaloids, dicyclomine hydrochloride, and the like;
vitamins and minerals such as essential amino acids, calcium, iron,
potassium, zinc, vitamin B.sub.12, and the like; cardiovascular
agents such as prazosin HCl, nitroglycerin, propranolol HCl,
hydralazine HCl, pancrelipase, succinic acid dehydrogenase, and the
like; peptides and proteins such as LHRH, somatostatin, calcitonin,
growth hormone, glucagon-like peptides, growth releasing factor,
angiotensin, FSH, EGF, bone morphogenic protein (BMP),
erythopoeitin (EPO), interferon, interleukin, collagen, fibrinogen,
insulin, Factor VIII, Factor IX, Enbrel.RTM., Rituxam.RTM.,
Herceptin.RTM., alpha-glucosidase, Cerazyme/Ceredose.RTM.,
vasopressin, ACTH, human serum albumin, gamma globulin, structural
proteins, blood product proteins, complex proteins, enzymes,
antibodies, monoclonal antibodies, and the like; prostaglandins;
nucleic acids; carbohydrates; fats; narcotics such as morphine,
codeine, and the like, psychotherapeutics; anti-malarials, L-dopa,
diuretics such as furosemide, spironolactone, and the like;
antiulcer drugs such as rantidine HCl, cimetidine HCl, and the
like.
[0066] Immunological agents that can be used herein include,
cytokines, interleukins, interferon, colony stimulating factor,
tumor necrosis factor, and the like; allergens such as cat dander,
birch pollen, house dust mite, grass pollen, and the like; antigens
of cush bacterial organisms as Streptococcus pneumoniae,
Haemophilus influenzae, Staphylococcus aureus, Streptococcus
pyrogenes, Corynebacterium diphteriae, Listeria monocytogenes,
Bacillus anthracis, Clostridium tetani, Clostridium botulinum,
Clostridium perfringens. Neisseria meningitides, Neisseria
gonorrhoeae, Streptococcus mutans. Pseudomonas aeruginosa,
Salmonella typhi, Haemophilus parainfluenzae, Bordetella pertussis,
Francisella tularensis, Yersinia pestis, Vibrio cholerae,
Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium
leprae, Treponema pallidum, Leptspirosis interrogans, Borrelia
burgddorferi, Campylobacter jejuni, and the like; antigens of such
viruses as smallpox, influenza A and B, respiratory synctial,
parainfluenza, measles, HIV, SARS, varicella-zoster, herpes simplex
1 and 2, cytomeglavirus, Epstein-Barr, rotavirus, rhinovirus,
adenovirus, papillomavirus, poliovirus, mumps, rabies, rubella,
coxsackieviruses, equine encephalitis, Japanese encephalitis,
yellow fever, Rift Valley fever, lymphocytic choriomeningitis,
hepatitis B, and the like; antigens of such fungal, protozoan, and
parasitic organisms such as Cryptococcuc neoformans, Histoplasma
capsulatum, Candida albicans, Candida tropicalis, Nocardia
asteroids, Rickettsia ricketsii, Rickettsia typhi, Mycoplasma
pneumoniae, Chlamyda psittaci, Chlamydia trachomatis, Plasmodium
falciparum, Trypanasoma brucei, Entamoeba histolytica, Toxoplasma
gondii, Trichomonas vaginalis, Schistosoma mansoni, and the like.
These antigens may be in the form of whole killed organisms,
peptides, proteins, glycoproteins, carbohydrates, or combinations
thereof.
[0067] In a specific aspect, the bioactive agent comprises a drug,
an immunological agent, an antigen, a protein, a peptide, an
oligonucleotide, or a mixture thereof.
[0068] Although there are numerous applications for bioactive
agents, the devices and coated articles produced herein are useful
in releasing non-bioactive agents as well. Examples of
non-bioactive agents include, but are not limited to, an adhesive,
a pesticide, a fragrance, an antifoulant, a dye, a salt, an oil, an
ink, a cosmetic, a catalyst, a detergent, a curing agent, a flavor,
a fuel, a herbicide, a metal, a paint, a photographic agent, a
biocide, a pigment, a plasticizer, a propellant, a stabilizer, a
polymer additive, or any combination thereof.
[0069] The polymers useful herein are biocompatible and either
biodegradable or non-biodegradable. In a further aspect, polymers
useful in the methods described herein include, but are not limited
to, a silicone, a poly(diene) such as poly(butadiene) and the like;
a poly(alkene) such as polyethylene, polypropylene, and the like; a
poly(acrylic) such as poly(acrylic acid) and the like; a
poly(methacrylic) such as poly(methyl methacrylate) or a
poly(hydroxyethyl methacrylate), and the like; a poly(vinyl ether);
a poly(vinyl alcohol); a poly(vinyl ketone); a poly(vinyl halide)
such as poly(vinyl chloride) and the like; a poly(vinyl nitrile), a
poly(vinyl ester) such as poly(vinyl acetate) and the like; a
poly(vinyl pyridine) such as poly(2-vinyl pyridine) or
poly(5-methyl-2-vinyl pyridine) and the like; a poly(styrene); a
poly(carbonate); a poly(ester); a poly(orthoester) including a
copolymer; a poly(esteramide); a poly(anhydride); a poly(urethane);
a poly(amide); a cellulose ether such as methyl cellulose,
hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and the
like; a cellulose ester such as cellulose acetate, cellulose
acetate phthalate, cellulose acetate butyrate, and the like; a
poly(saccharide), a protein, gelatin, starch, gum, a resin, and the
like. These materials may be used alone, as physical mixtures
(blends), combinations, or as copolymers. Derivatives of any of the
polymers listed above can also be used.
[0070] In a specific aspect, the polymer comprises a silicone, a
poly(diene), a poly(alkene), a poly(acrylic), a poly(methacrylic),
poly(vinyl ether), a poly(vinyl alcohol), a poly(vinyl ketone), a
poly(vinyl halide), a poly(vinyl nitrile), a poly(vinyl ester), a
poly(vinyl pyridine), a poly(styrene), a poly(carbonate), a
poly(ester), a poly(orthoester), a poly(esteramide), a
poly(anhydride), a poly(urethane), a poly(amide), a cellulose
ether, a cellulose ester, a poly(saccharide), a protein, gelatin,
starch, a gum, a resin, or any combination, blend, or copolymer
thereof.
[0071] In a further aspect, the polymer of the device or coated
article includes a biocompatible, non-biodegradable polymer such
as, for example, a polyacrylate; a polymer of ethylene-vinyl
acetate; an acyl substituted cellulose acetate; a non-degradable
polyurethane; a polystyrene; a polyvinyl chloride; a polyvinyl
fluoride; a poly(vinyl imidazole); a chlorosulphonate polyolefin; a
polyethylene oxide; or a blend, combination, or copolymer
thereof.
[0072] In another aspect, the polymer of the device or coated
article includes a biocompatible, biodegradable polymer such as,
but limited to, a poly(lactide), a poly(glycolide), a
poly(lactide-co-glycolide), a poly(lactic acid), a poly(glycolic
acid), a poly(lactic acid-co-glycolic acid), a poly(caprolactone),
a poly(orthoester), a poly(phosphazene), a poly(hydroxybutyrate) or
a copolymer containing a poly(hydroxybutarate); a
poly(lactide-co-caprolactone); a polycarbonate; a polyesteramide; a
polyanhydride; a poly(dioxanone), a poly(alkylene alkylate); a
copolymer of polyethylene glycol and a polyorthoester, a
biodegradable polyurethane, a poly(amino acid), a polyamide, a
polyesteramide, a polyetherester, a polyacetal, a
polycyanoacrylate, a poly(oxyethylene)/poly(oxypropylene)
copolymer, polyacetals, polyketals, polyphosphoesters,
polyhydroxyvalerates or a copolymer containing a
polyhydroxyvalerate, polyalkylene oxalates, polyalkylene
succinates, poly(maleic acid), and copolymers, terpolymers,
combinations, or blends thereof.
[0073] In another aspect, the polymer comprises a biodegradable
polymer, wherein the biodegradable polymer comprises a
poly(caprolactone), a poly(orthoester), a poly(phosphazene), a
poly(hydroxybutyrate) or a copolymer containing
poly(hydroxybutarate), a poly(lactide-co-caprolactone), a
polycarbonate, a polyesteramide, a polyanhydride, a
poly(dioxanone), a poly(alkylene alkylate), a copolymer of
polyethylene glycol and polyorthoester, a biodegradable
polyurethane, a poly(amino acid), a polyetherester, a polyacetal, a
polycyanoacrylate, poly(oxyethylene)/poly(oxypropylene) copolymer,
or a combination, blend, or copolymer thereof.
[0074] In a further aspect, the device is an implant or rod
comprising a biodegradable polymer, wherein the bioactive agent is
imbedded within the implant. In a further aspect, the bioactive
agent is encapsulated in an implant or rod composed of
poly(lactide-co-glycolide), poly(lactide), poly(glycolide), or a
mixture thereof. Lactide/glycolide polymers for drug-delivery
formulations are typically made by melt polymerization through the
ring opening of lactide and glycolide monomers. Some polymers are
available with or without carboxylic acid end groups. When the end
group of the poly(lactide-co-glycolide), poly(lactide), or
poly(glycolide) is not a carboxylic acid, for example, an ester,
then the resultant polymer is referred to herein as blocked or
capped. The unblocked polymer, conversely, has a terminal
carboxylic group. The biodegradable polymers herein can be blocked
or unblocked. In a further aspect, linear lactide/glycolide
polymers are used; however star polymers can be used as well. In
certain aspects, high molecular weight polymers can be used for
medical devices, for example, to meet strength requirements. In
other aspects, low or medium molecular weight polymers can be used
for drug-delivery and vaccine delivery products where resorption
time of the polymer and not material strength is as important. The
lactide portion of the polymer has an asymmetric carbon.
Commercially racemic DL-, L-, and D-polymers are available. The
L-polymers are more crystalline and resorb slower than DL-polymers.
In addition to copolymers comprising glycolide and DL-lactide or
L-lactide, copolymers of L-lactide and DL-lactide are available.
Additionally, homopolymers of lactide or glycolide are
available.
[0075] In the case when the biodegradable polymer is
poly(lactide-co-glycolide), poly(lactide), or poly(glycolide), the
amount of lactide and glycolide in the polymer can vary. In a
further aspect, the biodegradable polymer contains 0 to 100 mole %,
40 to 100 mole %, 50 to 100 mole %, 60 to 100 mole %, 70 to 100
mole %, or 80 to 100 mole % lactide and from 0 to 100 mole %, 0 to
60 mole %, 10 to 40 mole %, 20 to 40 mole %, or 30 to 40 mole %
glycolide, wherein the amount of lactide and glycolide is 100 mole
%. In a further aspect, the biodegradable polymer can be
poly(lactide), 95:5 poly(lactide-co-glycolide) 85:15
poly(lactide-co-glycolide), 75:25 poly(lactide-co-glycolide), 65:35
poly(lactide-co-glycolide), or 50:50 poly(lactide-co-glycolide)
where the ratios are mole ratios.
[0076] Polymers that are useful for the present invention are those
having an intrinsic viscosity of from 0.15 to 2.0, 0.15 to 1.5
dL/g, 0.25 to 1.5 dL/g, 0.25 to 1.0 dL/g, 0.25 to 0.8 dL/g, 0.25 to
0.6 dL/g, or 0.25 to 0.4 dL/g as measured in chloroform at a
concentration of 0.5 g/dL at 30.degree. C. In a further aspect,
when the biodegradable polymer is poly(lactide-co-glycolide),
poly(lactide), or poly(glycolide), the polymer has an intrinsic
viscosity of from 0.15 to 2.0, 0.15 to 1.5 dL/g, 0.25 to 1.5 dL/g,
0.25 to 1.0 dL/g, 0.25 to 0.8 dL/g, 0.25 to 0.6 dL/g, or 0.25 to
0.4 dL/g as measured in chloroform at a concentration of 0.5 g/dL
at 30.degree. C.
[0077] When the device or coated article is used to deliver a
bioactive agent, other pharmaceutically-acceptable components can
be incorporated in the delivery system in combination with the
bioactive agent. For example, the pharmaceutically-acceptable
component can include, but is not limited to, a fatty acid, a
sugar, a salt, a water-soluble polymer such as polyethylene glycol,
a protein, polysaccharide, or carboxmethyl cellulose, a surfactant,
a plasticizer, a high- or low-molecular-weight porosigen such as
polymer or a salt or sugar, or a hydrophobic low-molecular-weight
compound such as cholesterol or a wax.
[0078] In further aspects of the invention, the invention includes
devices and coated articles made by the methods described
herein.
[0079] In a further aspect, described herein are devices comprising
at least one polymer and at least one agent, wherein the agent is
dispersed in the polymer, wherein the device comprises at least two
exposed surfaces of the same polymer, wherein at least one of the
exposed surfaces or at least one part of at least one exposed
surface has surface morphology different than the other exposed
surface or surfaces. The device can be composed of one polymer or a
mixture of two or more polymers. Regardless if one or more polymers
are used, the polymer or polymers are evenly distributed throughout
the device. Thus, in various aspects, when two or more polymers are
used to produce the device, the polymers are not two distinct
polymer phases (e.g., co-extrusion of two polymers) but a mixture
of the polymers.
[0080] Using the techniques described herein, it is possible to
change the surface morphology of one or more exposed surfaces of
the delivery system so that the delivery system has varying (i.e.,
different) surface morphologies. This is desirable for a number of
different applications. For example, when the delivery system is a
rod used as an implant, wherein the ends of the rod are not
contacted with a fluid but the longitudinal surface is contacted
with the fluid, the longitudinal surface has a surface morphology
that is different than that of the ends of the rod. In this aspect,
the rate of release and the direction of release can be better
controlled. The delivery systems produced by the methods described
herein also have the added benefit of containing more of the agent
(i.e., higher loading). In a further aspect, the agent is greater
than 30%, greater than 40%, or greater than 50% by weight of the
device or coating on the coated article. In the case when the
delivery system is to be implanted into a subject, the greater
loading capacity results in higher doses of the agent that can
released over a longer period of time as well as the use of smaller
implants.
[0081] In another aspect, described herein is a polymer coated
article that has been treated with a fluid of this invention. In a
specific aspect, the article comprises at least one first exposed
surface and a polymer coating comprising a second exposed surface,
wherein the polymer coating is connected to the first exposed
surface of the article, wherein the morphology near the second
exposed surface of at least part of the polymer coating is
different than the morphology of the remaining polymer coating. The
term "connected" as used herein includes when the polymer is
adjacent to (i.e., intimate contact with) the article or is
indirectly attached to the article by way of one or more
intermediate layers. As described above, the agent can be present
in the article prior to the application of the polymer coating, the
agent can be incorporated into the polymer prior to coating, or a
combination thereof. The morphology near the second exposed surface
of at least part of the polymer coating is different than the
morphology of the remaining polymer coating. The term "near" is
defined herein to include the exposed surface of the polymer
coating and a predetermined distance below the exposed surface of
the coating. The distance below the surface can vary and will
depend upon the selection of the fluid, the contacting time with
the fluid, and the desired release pattern. At least part of or the
entire polymer surface can be fluid treated, and thus have a
different morphology than the underlying polymer surface.
EXAMPLES
[0082] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how the compounds, compositions, and methods
described and claimed herein are made and evaluated, and are
intended to be purely exemplary and are not intended to limit the
scope of what the inventors regard as their invention. Efforts have
been made to ensure accuracy with respect to numbers (e.g.,
amounts, temperature, etc.) but some errors and deviations should
be accounted for. Unless indicated otherwise, parts are parts by
weight, temperature is in degrees Centigrade (.degree. C.) or is at
ambient temperature, and pressure is at or near atmospheric. There
are numerous variations and combinations of reaction conditions,
e.g., component concentrations, component mixtures, desired
solvents, solvent mixtures, temperatures, pressures and other
reaction ranges and conditions that can be used to optimize the
product purity and yield obtained from the described process. Only
reasonable and routine experimentation will be required to optimize
such process conditions.
Example 1
Fabrication of Implants Containing 45 Wt % Vitamin B.sub.12
[0083] An implant formulation was made with vitamin B.sub.12 and
poly(DL-lactide). The poly(DL-lactide) was ester capped and had an
inherent viscosity of 0.37 dL/g. The inherent viscosity was
measured at 30.degree. C. with 0.5 gm/dL polymer concentration in
chloroform.
[0084] The desired vitamin B.sub.12 content in the implant was 45
wt % vitamin B.sub.12. First vitamin B.sub.12 (2.25 gm) and the
poly(DL-lactide) (2.75 gm) were dry blended using a mortar and
pestle to form a blended powder. Next a Tinius Olsen Model UE-4-78
melt plastometer was used to extrude the blended powder. The Tinius
Olsen is a solid block of steel about 80 mm in diameter and about
160 mm high/long with a hollow core about 13 mm in diameter. The
discharge of the core has a shoulder that allows different size
"dies" to be used based on the desired diameter of extruded rod.
For this run, a 1.5-mm die was used, meaning that the core of the
die was 1.5 mm in diameter. The main block of the Tinius Olsen has
heater bands encased by insulation and a shroud that allow the
Tinius Olsen to be heated to a desired temperature. A thermocouple
was used to measure the temperature of the block. The control
system then uses the thermocouple values to either turn the heater
bands on or off. Throughout the extrusion process, the heater bands
will switch off and on to maintain the desired temperature. The
blend, approximately 5 gm, was loaded into the Tinius Olsen which
had been equilibrated to 90.degree. C. A charging rod was placed in
the core of the Tinius Olsen to compress the blend and a weight of
3.7 kg was placed on the end of the charging rod to aid in the
compaction of the blend. The equilibration time for the blend to
melt lasted for about 15 minutes. After an extrusion load of 10,400
gm was placed on the charging rod, the plug was removed from the
discharge area to begin the extrusion run. The 5-gm charge afforded
5 segments of extruded rod each having a length of about 20 cm.
[0085] Next ethyl acetate was placed in a graduated cylinder and
one end of the rod was held with forceps and dipped in the ethyl
acetate for about 5 seconds. The implants were then dried at
ambient temperature. Once the implants were dry, the ends of the
extruded rod segments were cut and discarded. The remaining treated
segment was cut into implants that had the cylindrical portion
treated with ethyl acetate and the ends left untreated. The only
treated part was thus that portion of the implant that came into
contact with the cylindrical wall of the implant. The vitamin
B.sub.12 content was 45 wt %. The in vitro release characteristics
of the vitamin B.sub.12 implants made with poly(DL-lactide) by the
above-described manufacturing process (with and without ethyl
acetate exposure) are shown in FIG. 1. These release data showed
that the ethyl acetate treated implants released vitamin B.sub.12
with less burst of vitamin B.sub.12 and at a slower rate of release
as compared to implants not treated with ethyl acetate.
Example 2
Fabrication of Implants Containing 30 wt % of Leuprolide a
9-Amino-Acid Peptide (PROPHETIC)
[0086] An implant formulation can be made with small peptides (3 to
12 amino acids) or large peptides (13 to 50 amino acids) with
poly(DL-lactide) or poly(lactide-co-glycolide).
[0087] Leuprolide is a 9-amino-acid peptide that is an LHRH agonist
indicated for the treatment of prostate cancer. The desired
leuprolide content in the implant is 35 wt % peptide. To prepare a
depot formulation of luprolide, leuprolide and poly(DL-lactide) or
poly(lactide-co-glycolide) can be dry blended in a variety of ways
including the use of a mortar and pestle to form a blended powder.
Next this blend or admixture is added to a twin-screw extruder
having a 2-mm die. An extruded rod of is then made. The rod is
subsequently cut to form implants. Each implant is dipped in ethyl
acetate for about one time for about 5 seconds. The implants are
then dried at ambient temperature.
Example 3
Fabrication of Implants Containing 10 wt % of Octreotide a
14-Amino-Acid Peptide (PROPHETIC)
[0088] An implant formulation can be made with small peptides (3 to
12 amino acids) or large peptides (13 to 50 amino acids) with
poly(DL-lactide) or poly(lactide-co-glycolide).
[0089] Octreotide is a 14-amino-acid peptide indicated for the
treatment of agromegaly. The desired octreotide content in the
implant is 10 wt % peptide. To prepare a depot formulation of
octreotide, octreotide and poly(DL-lactide) or
poly(lactide-co-glycolide) can be dry blended in a variety of ways
including the use of a mortar/pestle or by mixing preformed polymer
and peptide particles in a V-blender to form a blended powder. Next
this blend or admixture is added to a twin-screw extruder having a
2-mm die. An extruded rod of is then made. The rod is subsequently
cut to form implants. Each implant is dipped in ethyl acetate for
about one time for about 5 seconds or can be dipped for 2 seconds
for three times. The implants are then dried at ambient
temperature.
Example 4
Fabrication of Implants Containing 44 wt % Deslorelin
[0090] An implant formulation was made with Deslorelin and
poly(DL-lactide). The poly(DL-lactide) was ester capped and had an
inherent viscosity of 0.37 dL/g. The inherent viscosity was
measured at 30.degree. C. with 0.5 gm/dL polymer concentration in
chloroform.
[0091] The desired Deslorelin content in the implant was 44 wt %
Deslorelin. First Deslorelin (1.6 gm) and the poly(DL-lactide) (1.6
gm) were dry blended using a mortar and pestle to form a blended
powder. Next a Tinius Olsen Model UE-4-78 melt plastometer was used
to extrude the blended powder. The Tinius Olsen is a solid block of
steel about 80 mm in diameter and about 160 mm high/long with a
hollow core about 13 mm in diameter. The discharge of the core has
a shoulder that allows different size "dies" to be used based on
the desired diameter of extruded rod. For this run, a 3.9-mm die
was used, meaning that the core of the die was 3.9 mm in diameter.
The main block of the Tinius Olsen has heater bands encased by
insulation and a shroud that allow the Tinius Olsen to be heated to
a desired temperature. A thermocouple was used to measure the
temperature of the block. The control system then uses the
thermocouple values to either turn the heater bands on or off.
Throughout the extrusion process, the heater bands will switch off
and on to maintain the desired temperature. The blend,
approximately 3.2 gm, was loaded into the Tinius Olsen which had
been equilibrated to 90.degree. C. A charging rod was placed in the
core of the Tinius Olsen to compress the blend and a weight of 6.6
kg was placed on the end of the charging rod to aid in the
compaction of the blend. The equilibration time for the blend to
melt lasted for about 15 minutes. After an extrusion load of 10,400
gm was placed on the charging rod, the plug was removed from the
discharge area to begin the extrusion run. The 3.2-gm charge
afforded 3 segments of extruded rod each having a length of about
20 cm.
[0092] The batch was then segregated into four sections. The first
section was not surface treated. The second was treated with ethyl
acetate. The third was treated with methylene chloride. The fourth
was treated with acetone.
[0093] The second section was cut into implants approximately 4 mm
in length. The entire implant was then surface treated with ethyl
acetate by first mounting the implant on a needle and then dipping
into a vial of ethyl acetate. Rod sections three and four were
likewise handled, treating their respective surfaces with methylene
chloride and acetone. The implants were then dried at ambient
temperature. The Deslorelin content was 44 wt %. The in vitro
release characteristics of the Deslorelin implants made with
poly(DL-lactide) by the above-described manufacturing process (with
and without solvent exposure) are shown in FIG. 2. These release
data showed that the solvent treated implants released Deslorelin
with less burst of Deslorelin (10-33% of the non-treated
formulation) and at a slower rate of release as compared to
implants not treated with solvent.
Example 5
Fabrication of Implants Containing 50 wt % Risperidone
[0094] An implant formulation was made with Risperidone and
poly(DL-lactide). The poly(DL-lactide) was ester capped and had an
inherent viscosity of 0.37 dL/g. The inherent viscosity was
measured at 30.degree. C. with 0.5 gm/dL polymer concentration in
chloroform.
[0095] The desired Risperidone content in the implant was 50 wt %
Risperidone. First Risperidone (2.0 gm) and the poly(DL-lactide)
(2.0 gm) were dry blended using a mortar and pestle to form a
blended powder. Next a Tinius Olsen Model UE-4-78 melt plastometer
was used to extrude the blended powder. The Tinius Olsen is a solid
block of steel about 80 mm in diameter and about 160 mm high/long
with a hollow core about 13 mm in diameter. The discharge of the
core has a shoulder that allows different size "dies" to be used
based on the desired diameter of extruded rod. For this run, a
3.9-mm die was used, meaning that the core of the die was 3.9 mm in
diameter. The main block of the Tinius Olsen has heater bands
encased by insulation and a shroud that allow the Tinius Olsen to
be heated to a desired temperature. A thermocouple was used to
measure the temperature of the block. The control system then uses
the thermocouple values to either turn the heater bands on or off.
Throughout the extrusion process, the heater bands will switch off
and on to maintain the desired temperature. The blend,
approximately 4 grams, was loaded into the Tinius Olsen which had
been equilibrated to 90.degree. C. A charging rod was placed in the
core of the Tinius Olsen to compress the blend and a weight of 6.6
kg was placed on the end of the charging rod to aid in the
compaction of the blend. The equilibration time for the blend to
melt lasted for about 20 minutes. After an extrusion load of 10,400
grams was placed on the charging rod, the plug was removed from the
discharge area to begin the extrusion run. The 3.2-gm charge
afforded 4 segments of extruded rod each having a length of about
20 cm.
[0096] The batch was then segregated into three sections. The first
section was not surface treated. The second was treated with ethyl
acetate. The third was treated with ethanol.
[0097] The second section was cut into implants approximately 4 mm
in length. The entire implant was then surface treated with ethyl
acetate by first mounting the implant on a needle and then dipping
into a vial of ethyl acetate. The third rod section was likewise
handled, with its surface treated with ethanol. The implants were
then dried at ambient temperature. The Risperidone content was 50
wt %. The in vitro release characteristics of the Risperidone
implants made with poly(DL-lactide) by the above-described
manufacturing process (with and without solvent exposure) are shown
in FIG. 3. These release data showed that the solvent treated
implants released Risperidone with less burst of Risperidone
(<30% of the non-treated formulation for ethyl acetate) and at a
slower rate of release as compared to implants not treated with
solvent. In particular the reduction of cumulative release in
implants treated with ethanol increased over time from a less than
8% reduction at burst to a greater than 14% reduction at Day
14.
Example 6
Fabrication of Implants Containing 50 wt % Vitamin B.sub.12
[0098] An implant formulation was made with vitamin B.sub.12 and
poly(DL-lactide). The poly(DL-lactide) was ester capped and had an
inherent viscosity of 0.37 dL/g. The inherent viscosity was
measured at 30.degree. C. with 0.5 gm/dL polymer concentration in
chloroform.
[0099] The desired vitamin B.sub.12 content in the implant was 50
wt % vitamin B.sub.12. First vitamin B.sub.12 (2 gm) and the
poly(DL-lactide) (2 gm) were dry blended using a mortar and pestle
to form a blended powder. Next a Tinius Olsen Model UE-4-78 melt
plastometer was used to extrude the blended powder. The Tinius
Olsen is a solid block of steel about 80 mm in diameter and about
160 mm high/long with a hollow core about 13 mm in diameter. The
discharge of the core has a shoulder that allows different size
"dies" to be used based on the desired diameter of extruded rod.
For this run, a 3.9-mm die was used, meaning that the core of the
die was 3.9 mm in diameter. The main block of the Tinius Olsen has
heater bands encased by insulation and a shroud that allow the
Tinius Olsen to be heated to a desired temperature. A thermocouple
was used to measure the temperature of the block. The control
system then uses the thermocouple values to either turn the heater
bands on or off. Throughout the extrusion process, the heater bands
will switch off and on to maintain the desired temperature. The
blend, approximately 4 grams, was loaded into the Tinius Olsen
which had been equilibrated to 90.degree. C. A charging rod was
placed in the core of the Tinius Olsen to compress the blend and a
weight of 6.6 kg was placed on the end of the charging rod to aid
in the compaction of the blend. The equilibration time for the
blend to melt lasted for about 20 minutes. After an extrusion load
of 15,245 gm was placed on the charging rod, the plug was removed
from the discharge area to begin the extrusion run. The 4-gm charge
afforded 4 segments of extruded rod each having a length of about
20 cm.
[0100] The batch was then segregated into four sections. The first
section was not surface treated. The second was treated with ethyl
acetate. The third was treated with methylene chloride. The fourth
was treated with acetone.
[0101] The second section was cut into implants approximately 4 mm
in length. The entire implant was then surface treated with ethyl
acetate by first mounting the implant on a needle and then dipping
into a vial of ethyl acetate. Rod sections three and four were
likewise handled, treating their respective surfaces with methylene
chloride and acetone. The implants were then dried at ambient
temperature. The vitamin B.sub.12 content was 50 wt %. The in vitro
release characteristics of the vitamin B.sub.12 implants made with
poly(DL-lactide) by the above-described manufacturing process (with
and without solvent exposure) are shown in FIG. 4. The release data
clearly shows a marked reduction of the burst associated with the
non-treated implants when using any of the three solvents. The
smallest burst reduction is 42.6% and the largest is 54.1%. The
most dramatic results are seen in this formulation with the use of
acetone as the solvent.
Example 7
Fabrication of Implants Containing 45 wt % Vitamin B.sub.12
[0102] An implant formulation was made with vitamin B.sub.12 and
EVA (ethyl vinyl acetate). The desired vitamin B.sub.12 content in
the implant was 45 wt % vitamin B.sub.12. First vitamin B.sub.12 (2
gm) and the EVA (2 gm) were dry blended using a mortar and pestle
to form a blended powder. Next a Tinius Olsen Model UE-4-78 melt
plastometer was used to extrude the blended powder. The Tinius
Olsen is a solid block of steel about 80 mm in diameter and about
160 mm high/long with a hollow core about 13 mm in diameter. The
discharge of the core has a shoulder that allows different size
"dies" to be used based on the desired diameter of extruded rod.
For this run, a 3.9-mm die was used, meaning that the core of the
die was 3.9 mm in diameter. The main block of the Tinius Olsen has
heater bands encased by insulation and a shroud that allow the
Tinius Olsen to be heated to a desired temperature. A thermocouple
was used to measure the temperature of the block. The control
system then uses the thermocouple values to either turn the heater
bands on or off. Throughout the extrusion process, the heater bands
will switch off and on to maintain the desired temperature. The
blend, approximately 4 grams, was loaded into the Tinius Olsen
which had been equilibrated to 90.degree. C. A charging rod was
placed in the core of the Tinius Olsen to compress the blend and a
weight of 6.6 kg was placed on the end of the charging rod to aid
in the compaction of the blend. The equilibration time for the
blend to melt lasted for about 20 minutes. After an extrusion load
of 15,245 grams was placed on the charging rod, the plug was
removed from the discharge area to begin the extrusion run. The
4-gm charge afforded 4 segments of extruded rod each having a
length of about 20 cm.
[0103] The batch was then segregated into three sections. The first
section was not surface treated. The second was treated with
methylene chloride for 10 seconds. The third was treated with
methylene chloride for 60 seconds.
[0104] The second section was cut into implants approximately 4 mm
in length. The entire implant was then surface treated with
methylene chloride by first mounting the implant on a needle and
then dipping into a vial of methylene chloride for 10 seconds. Rod
section three was likewise handled, treating the surface with
methylene chloride for 60 seconds. The implants were then dried at
ambient temperature. The vitamin B.sub.12 content was 45 wt %. The
in vitro release characteristics of the vitamin B.sub.12 implants
made with EVA by the above-described manufacturing process (with
and without solvent exposure) are shown in FIG. 5. The release data
clearly shows a drastic reduction of the burst and the release of
the vitamin B.sub.12 from the implants treated with methylene
chloride.
[0105] Throughout this application, various publications are
referenced. The disclosures of these publications in their
entireties are hereby incorporated by reference into this
application in order to more fully describe the compounds,
compositions and methods described herein.
[0106] Various modifications and variations can be made to the
compounds, compositions and methods described herein. Other aspects
of the compounds, compositions and methods described herein will be
apparent from consideration of the specification and practice of
the compounds, compositions and methods disclosed herein. It is
intended that the specification and examples be considered as
exemplary.
* * * * *