U.S. patent application number 10/312189 was filed with the patent office on 2005-07-21 for polymeric, fiber matrix delivery systems for bioactive compounds.
Invention is credited to Benjelloun, Meriem, Dhoot, Nikhil, El-Sherif, Dalia, Han, Baohua, Kanakasabai, Saravanan, Ko, Frank K., Wheatley, Margaret A..
Application Number | 20050158362 10/312189 |
Document ID | / |
Family ID | 22797516 |
Filed Date | 2005-07-21 |
United States Patent
Application |
20050158362 |
Kind Code |
A1 |
Wheatley, Margaret A. ; et
al. |
July 21, 2005 |
Polymeric, fiber matrix delivery systems for bioactive
compounds
Abstract
Multifunctional systems for delivery of bioactive compounds
incorporated within or between polymeric fibers in a matrix are
provided. Also provided are methods of delivering bioactive
compounds via implementation, coating and/or wrapping of these
systems and methods for modulating the rate of release of bioactive
compounds from these delivery systems.
Inventors: |
Wheatley, Margaret A.;
(Media, PA) ; Ko, Frank K.; (Philadelphia, PA)
; El-Sherif, Dalia; (King of Prussia, PA) ; Dhoot,
Nikhil; (Philadelphia, PA) ; Kanakasabai,
Saravanan; (King of Prussia, PA) ; Benjelloun,
Meriem; (Philadelphia, PA) ; Han, Baohua;
(Lake Hiawatha, NJ) |
Correspondence
Address: |
LICATLA & TYRRELL P.C.
66 E. MAIN STREET
MARLTON
NJ
08053
US
|
Family ID: |
22797516 |
Appl. No.: |
10/312189 |
Filed: |
February 28, 2005 |
PCT Filed: |
June 25, 2001 |
PCT NO: |
PCT/US01/41133 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60214034 |
Jun 23, 2000 |
|
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|
Current U.S.
Class: |
424/426 ;
427/2.21 |
Current CPC
Class: |
A61K 9/0009 20130101;
A61K 38/39 20130101; Y10T 442/2525 20150401; A61K 9/0024 20130101;
A61K 9/70 20130101 |
Class at
Publication: |
424/426 ;
427/002.21 |
International
Class: |
A61F 002/00 |
Claims
What is claimed is:
1. A system for delivery of bioactive compounds comprising a
bioactive compound incorporated within or between polymeric
fibers.
2. The system of claim 1 which is biodegradable.
3. The system of claim 1 which is nondegradable.
4. The system of claim 1 wherein the fibers are arranged as a
matrix or linear assembly, a film coating on a device, or a braided
or woven structure.
5. The system of claim 1 wherein particles of the bioactive
compound are suspended in a polymer solution prior to
electrospinning of the polymeric fibers so that the bioactive
compound is incorporated between the polymeric fibers.
6. The system of claim 1 wherein the bioactive compound is
dissolved into a polymer solution prior to electrospinning of the
polymeric fibers so that the bioactive compound is incorporated
within the polymeric fibers.
7. The system of claim 1 comprising more than one bioactive
compound incorporated into a single or multiple layers of polymeric
fibers for delivery of the bioactive compounds sequentially or in
concert.
8. A method for delivering bioactive compounds to a patient
comprising incorporating a bioactive compound into a polymeric
fiber matrix or linear assembly or a braided or woven structure and
implanting the polymer fiber matrix or linear assembly or braided
or woven structure into the patient.
9. The method of claim 8 further comprising coating a device with
the polymeric fiber matrix or linear assembly or braided or
nonwoven structure and implanting the coated device into the
patient for delivery of the bioactive compounds.
10. The method of claim 9 wherein the device comprises a tissue
engineering device and the bioactive compound enhances cell
attachment and growth to the device.
11. The method of claim 8 wherein the polymeric fiber matrix or
linear assembly or a braided or woven structure is implanted
directly on a wound of the patient to deliver the bioactive
compound to the wound of the patient.
12. The method of claim 8 wherein the polymeric fiber matrix or
linear assembly or a braided or woven structure is implanted on the
surface of an organ, tissue or vessel of the patient to deliver the
bioactive compound to the organ, tissue or vessel of the
patient.
13. The method of claim 12 wherein the polymeric fiber matrix or
linear assembly or a braided or woven structure is wrapped around
the surface of an organ, tissue or vessel of the patient.
14. A method for modulating rate of release of a bioactive compound
from a delivery system for bioactive compounds comprising a
bioactive compound incorporated within or between polymeric fibers,
said method comprising modulating loading of the bioactive compound
incorporated with or between polymeric fiber, selecting polymers to
produce polymeric fibers which degrade at varying rates, varying
diameter of the polymeric fibers, or varying polymeric
concentration of the polymeric fibers.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to delivery systems comprising
polymeric fiber matrices, film coatings or braided/woven structures
for the controlled release of bioactive compounds. The delivery
systems of the present invention may be comprised of either
biodegradable or nondegrading polymeric fibers. In one embodiment,
these fibers have submicron and/or micron diameters. Bioactive
compounds are included in the delivery system either by suspending
the compound particles or dissolving the compound in the polymer
solution used to produce the fibers.
BACKGROUND OF THE INVENTION
[0002] A number of polymer matrices for use in the controlled
release and/or delivery of bioactive compounds, and for particular
drugs, have been described.
[0003] U.S. Pat. No. 3,991,766 describes a medicament repository
consisting of a surgical element in the form of tubes, sheets,
sponges, gauzes or prosthetic devices of polyglycolic acid having
incorporated therein an effective amount of a medicament.
[0004] U.S. Pat. No. 4,655,777 describes a method for producing a
biodegradable prothesis or implant by encasing an effective amount
of fibers of calcium phosphate or calcium aluminate in a matrix of
polymer selected from the group consisting of polyglycolide,
poly(DL-lactide), poly(L-lactide), polycaprolactone, polydioxanone,
polyesteramides, copolyoxalates, polycarbonates,
poly(glutamic-co-leucine) and blends, copolymers and terpolymers
thereof to form a composite.
[0005] U.S. Pat. No. 4,818,542 discloses a method for preparing a
spherical microporous polymeric network with interconnecting
channels having a drug distributed within the channels.
[0006] U.S. Pat. No. 5,128,170 discloses a medical device and
methods for manufacturing medical devices with a highly
biocompatible surface wherein hydrophillic polymer is bonded onto
the surface of the medical device covalently through a nitrogen
atom.
[0007] U.S. Pat. No. 5,545,409 discloses a composition and method
for controlled release of water-soluble proteins comprising a
surface-eroding polymer matrix and water-soluble bioactive growth
factors.
[0008] U.S. Pat. No. 5,769,830 discloses synthetic, biocompatible,
biodegradable polymer fiber scaffolds for cell growth. Fibers are
spaced apart by a distance of about 100 to 300 microns for
diffusion and may comprise polyanhydrides, polyorthoesters,
polyglycolic acid or polymethacrylate. The scaffolds may be coated
withe materials such as agar, agarons, gelatin, gum arabic,
basement membrane material, collagen type I, II, III, IV or V,
fibronectin, laminin, glycosaminoglycans, and mixtures thereof.
[0009] U.S. Pat. No. 5,898,040 discloses a polymeric article for
use in drug delivery systems which comprises a polymeric substrate
with a highly uniform microporous polymeric surface layer on at
least part of the substrate.
[0010] Encapsulation of a bioactive compound within a polymer
matrix has also been described. For example, WO 93/07861 discloses
polymer microspheres of 50 to 100 microns comprising a compound
contained in a fixed oil within the polymer microsphere. U.S. Pat.
No. 5,969,020 discloses a foam precursor comprising a crystalline
thermoplastic polymer and solid crystalline additive for use in
preparation of drug delivery systems.
[0011] Recently, it has been shown that polymer fibers of nanometer
diameter can be electrospun from sulfuric acid into a coagulation
bath (Reneker, D. H. and Chun, I. Nanotechnology 1996 7:216). In
these studies more than 20 polymers including polyethylene oxide,
nylon, polyimide, DNA, polyaramide and polyaniline were electrospun
into electrically charged fibers which were then collected in
sheets or other useful geometrical forms. Electrospinning
techniques have also been applied to the production of high
performance filters (Doshi, J. and Reneker, D. H. Journal of
Electrostatics 1995 35:151; Gibson et al. AIChE Journal 1999
45:190) and for scaffolds in tissue engineering (Doshi, J. and
Reneker, D. H. Journal of Electrostatics 1995 35:151; Ko et al.
"The Dynamics of Cell-Fiber Architecture Interaction," Proceedings,
Annual Meeting, Biomaterials Research Society, San Diego, Calif.,
April 1998; and WO 99/18893). WO 99/18893 describes a method for
preparing nanofibrils from both nondegrading and biodegradable
polymers for use as tissue engineering scaffolds.
[0012] The present invention relates to delivery systems for the
controlled release of bioactive compounds which comprise polymeric
fibers and the bioactive compound.
SUMMARY OF THE INVENTION
[0013] An object of the present invention is to provide a system
for delivery of bioactive compounds comprising a bioactive compound
incorporated within or between a polymeric fiber matrix or linear
assembly, film coating or braided/woven structure.
[0014] Another object of the present invention is to provide a
method for delivering a bioactive compound to a patient for
controlled release of the bioactive compound in the patient. In one
embodiment of this method of the present invention, the bioactive
compound is incorporated into a polymeric fiber matrix or linear
assembly or a braided or woven structure and implanted into the
patient. In another embodiment, the bioactive compound is
incorporated into a polymeric fiber film used to coat implants,
tissue engineering scaffolds and other devices such as pumps and
pacemakers which are then implanted into the patient. In yet
another embodiment, the bioactive compound is incorporated into a
polymeric fiber film used to wrap organs, tissues or vessels in a
patient.
[0015] Another object of the present invention is to provide
methods for modulating the rate of release of a bioactive compound
from a delivery system for bioactive compounds comprising a
bioactive compound incorporated within or between polymeric fibers.
These methods include modulating loading of the bioactive compound
incorporated with or between polymeric fiber, selecting polymers to
produce the polymeric fibers which degrade at varying rates,
varying polymeric concentration of the polymeric fibers and varying
polymeric fiber diameter.
DETAILED DESCRIPTION OF THE INVENTION
[0016] Electrospinning is a simple and low cost electrostatic
self-assembly method capable of fabricating a large variety of
long, meter-length, organic polymer fibers with micron or submicron
diameters, in linear, 2-D and 3-D architecture. Electrospinning
techniques have been available since the 1930's (U.S. Pat. No.
1,975,504). In the electrospinning process, a high voltage electric
field is generated between oppositely charged polymer fluid
contained in a glass syringe with a capillary tip and a metallic
collection screen. As the voltage is increased, the charged polymer
solution is attracted to the screen. Once the voltage reaches a
critical value, the charge overcomes the surface tension of the
suspended polymer cone formed on the capillary tip of the syringe
and a jet of ultrafine fibers is produced. As the charged fibers
are splayed, the solvent quickly evaporates and the fibers are
accumulated randomly on the surface of the collection screen. This
results in a nonwoven mesh of nano and micron scale fibers. Varying
the charge density (applied voltage), polymer solution
concentration, solvent used, and the duration of electrospinning
can control the fiber diameter and mesh thickness. Other
electrospinning parameters which may be varied routinely to effect
the fiber matrix properties include distance between the needle and
collection plate, the angle of syringe with respect to the
collection plate, and the applied voltage.
[0017] In the present invention, electrospinning is used to produce
polymeric fiber matrices with the capability of releasing bioactive
compounds in a controlled manner over a selected period of time. In
one embodiment, the delivery system of the present invention is
used to maintain delivery of a steady concentration of bioactive
compound. In another embodiment, the delivery system is used in
pulsed delivery of the bioactive compound wherein the compound is
released in multiple phases in accordance with either rapid or slow
degradation of the polymer fibers or diffusion of the bioactive
compound from the polymer fibers. In yet another embodiment, the
delivery system is used to obtain a delayed release of a bioactive
compound. For example, the bioactive compound-containing fiber
polymer matrix can be coated with a layer of nonwoven polymer fiber
matrix with no bioactive compound. In this embodiment, different
polymers with different degradation times can be used to obtain the
desired time delays.
[0018] The delivery systems of the present invention can be used to
deliver a single bioactive compound, more than one Ibioactive
compound at the same time, or more than one bioactive compound in
sequence. Thus, as used herein, the phrases "a bioactive compound"
and "the bioactive compound", are meant to be inclusive of one or
more bioactive compounds.
[0019] For purposes of the present invention by "fiber" it is meant
to include fibrils ranging in diameter from submicron, i.e.
approximately 1 to 100 nanometers (10.sup.-9 to 10.sup.-7 meters)
to micron, i.e. approximately 1-1000 micrometers. The bioactive
compound is incorporated within the polymeric fibers either by
suspension of compound particles or dissolution of the compound in
the solvent used to dissolve the polymer prior to electrospinning
of the polymeric fibers. For purposes of the present invention, by
"incorporated within" it is meant to include embodiments wherein
the bioactive compound is inside the fiber as well as embodiments
wherein the bioactive compound is dispersed between the fibers. The
polymeric fibers comprising the bioactive compound can be arranged
as matrices, linear assemblies, or braided or woven structures. In
addition, the fibers which release a bioactive compound can serve
as film coatings for devices such as implants, tissue engineering
scaffolds, pumps, pacemakers and other composites.
[0020] These fiber assemblies can be spun from any polymer which
can be dissolved in a solvent. The solvent can be either organic or
aqueous depending upon the selected polymer. Examples of polymers
which can be used in production of the polymeric fibers of the
present invention include, but are not limited to, nondegradable
polymers such as polyethylenes, polyurethanes, and EVA, and
biodegradable polymers such as poly(lactic acid-glycolic acid),
poly(lactic acid), poly(glycolic acid), poly(glaxanone),
poly(orthoesters), poly(pyrolic acid) and poly(phosphazenes).
[0021] Examples of bioactive compounds which can be incorporated
into the polymeric fibers include any drug for which controlled
release in a patient is desired. Some examples include, but are not
limited to, steroids, antifungal agents, and anticancer agents.
Other bioactive compounds of particular use in the present
invention include tissue growth factors, angiogenesis factors, and
anti-clotting factors.
[0022] If the bioactive compound is to reside within or inside the
polymer fiber, selection of the polymer should be based upon the
solubility of the bioactive compound within the polymer solution.
Water soluble polymers such as polyethylene oxide can be used if
the bioactive compound also dissolves in water. Alternatively,
hydrophobic bioactive compounds which are soluble in organic
solvent such as steroids can be dissolved in an organic solvent
together with a hydrophobic polymer such as polylactic glycolic
acid (PLAGA).
[0023] If the bioactive compound is to reside between the polymer
fibers, dissolution of the bioactive compound in the polymer
solution is not required. Instead, the bioactive compound can be
suspended in the polymer solution prior to electrospinning of the
fibers.
[0024] In one embodiment of the present invention, the bioactive
compound-containing fibers can be splayed directly onto devices
such as implants, tissue engineering scaffolds, pumps and
pacemakers as a film coating. For implants and tissue engineering
scaffolds, examples of preferred bioactive compounds include tissue
growth factors and angiogenesis factors. For pumps or pacemakers,
the bioactive compound may comprise an anti-clotting factor. The
coated device is then implanted into a patient wherein the
bioactive compound or compounds are released upon degradation of or
by diffusion from, or combinations thereof, the polymeric fiber
film.
[0025] In another embodiment, a matrix or linear assembly of the
bioactive compound-containing fibers is prepared. In this
embodiment, the matrix or linear assembly of bioactive
compound-containing fibers can be sandwiched between layers of
polymer which contain no bioactive compound to decrease any burst
effect and/or to obtain a delayed release. Alternatively, the
matrix may comprise layers of fibers containing different bioactive
compounds. The matrix or linear assembly is then implanted into a
patient for controlled release of the bioactive compound as the
polymeric fibers degrade or as the bioactive compound diffuses from
the polymeric fibers. The time delay can be controlled by varying
the choice of polymer used in the fibers, the concentration of
polymer used in the fiber, the diameter of the polymeric fibers,
and/or the amount of bioactive compound loaded in the fiber.
[0026] For purposes of the present invention, by "implanting" or
"implanted" as used herein, it is meant to be inclusive of
placement of the delivery systems of the present invention into a
patient to achieve systemic delivery of the bioactive compound, as
well as placement of the delivery system into a patient to achieve
local delivery. For example, the delivery systems of the present
invention may be placed on the wound of a patient to enhance
healing via release of the bioactive compound. Delivery systems may
also be placed on the surface or wrapped around an organ, tissue or
vessel for delivery of the bioactive compound to the organ tissue
or vessel.
[0027] In another embodiment of the present invention, a braided,
knitted or woven structure of bioactive compound-containing fibers
is prepared. These structures are prepared using an extension of
the traditional 2-dimensional braiding technology in which fabric
is constructed by the intertwining or orthogonal interlacing of
yarns to form an integral structure through position displacement.
A wide range of 3-dimensional structures comprising the bioactive
compound-containing fibers can be fabricated in a circular or
rectangular loom. In this embodiment, the structure may comprise
only bioactive compound-containing fibers, bioactive
compound-containing fibers sandwiched between polymeric fibers
which contain no bioactive compound, or a mixtures of fibers
containing different bioactive compounds. Like the matrix or linear
assembly, this structure can be implanted into a patient for
controlled release of the bioactive compound or compounds as the
polymeric fibers degrade or as the bioactive compound diffuses from
the polymeric fibers. Again, delivery rate of the bioactive
compound can be controlled by varying the choice of polymer used in
the fibers, the concentration of polymer used in the fiber, the
diameter of the polymeric fibers, and/or the amount of bioactive
compound loaded in the fiber.
[0028] Accordingly, the present invention also relates to methods
for modulating the rate of release of a bioactive compound from a
delivery system for bioactive compounds comprising a bioactive
compound incorporated within or between polymeric fibers. By
"modulate" or "modulating", it is meant that the rate or release of
the bioactive compound incorporated within of between the polymeric
fibers of the delivery system is increased or decreased. Methods
for modulating the rate of release include increasing or decreasing
loading of the bioactive compound incorporated within or between
the polymeric fibers, selecting polymers to produce the polymeric
fibers which degrade at varying rates, varying polymeric
concentration of the polymeric fibers and/or varying diameter of
the polymeric fibers varying one or more of these parameters can be
performed routinely by those of skill in the art based upon
teachings provided herein.
[0029] The ability of systems of the present invention to release a
bioactive compound in a controlled manner was demonstrated using
polymeric fiber matrices containing fluorescently labeled bovine
serum albumin (FITC-BSA) dispersed between the fibers of the
matrix. To construct the bioactive compound-loaded matrices,
various concentrations of finely ground FITC-BSA were suspended in
biodegradable polymer polylactic glycolic acid in 50:50 dimethyl
formamide:tetrahydrofuran. Suspensions contained in a glass syringe
with a capillary tip were electrospun into approximately 500 nm
diameter fibers via an electrostatic based self-assembly process in
which a high voltage electric field was generated between the
oppositely charged polymer and a metallic collection screen. At a
critical voltage the charge overcomes the surface tension of the
deformed polymer drop at the needle tip, producing an ultrafine
jet. The similarly charged fibers are splayed and during their
passage to the screen, the solvent quickly evaporates so that dry
fibers accumulate randomly on the screen forming a mesh matrix.
[0030] The material properties of this mesh matrix of bioactive
compound-containing fibers were examined via standard electron
microscopy and tensile testing. It was found that tensile strength
and the release profiles were a function of protein loading.
[0031] In vitro release of the FITC-BSA into an infinite sink of
37.degree. C. phosphate buffered saline was also measured. This
sink mimics in vivo conditions. While release in the first 24 hours
after initiation was dominant, release to over 120 hours was
observed with an increase in release at the point where the fibers
started to breakdown.
[0032] The following nonlimiting examples are provided to further
illustrate the present invention.
EXAMPLES
Example 1
Preparation of Fiber Matrix Containing BSA-FITC
[0033] A 25% (w/v) solution of polylactic glycolic acid was
prepared in a 50:50 mixture of dimethylformamide and
tetrahydrofuran. A mixture of FITC-BSA and BSA in the ratio of 1:5
was added to the solution in order to obtain 2% protein loading. A
syringe containing 5 ml of the polymer plus bioactive compound
mixture was placed at an angle of 45.degree.. The syringe was
fitted with a 16G needle with the tip of the needle at a distance
of 24 cm from the metallic collection screen. A piece of nonwoven
mat was placed on the metallic screen. A voltage of 20 kV was
applied between the collection screen and the needle tip which
resulted in fibers being sprayed into a nonwoven matrix on the
metallic screen. The spraying was complete in about 4 hours.
[0034] It was found that with this specific polymer solvent system,
polymer concentrations lower than 25% resulted in fibers with beads
of polymers. These beads were eliminated when the polymer
concentration was increased to 25% or greater. However, as will be
understood by the skilled artisan upon reading this disclosure,
this concentration will vary for different polymer/solvent systems
and different bioactive compounds.
Example 2
In Vitro Release of Protein
[0035] In vitro release of the FITC-BSA into an infinite sink of
37.degree. C. phosphate buffered saline was measured. Pre-weighed
pieces from different regions of the mat were placed into
scintillation vials and 10 ml of phosphate buffered saline were
added and the capped vials were placed on a rotary shaker at
37.degree. C. The buffer was exchanged at different points in time
in order to mimic infinite sink conditions. The amount of protein
released was measured in the form of fluorescence of the FITC-BSA
on a spectrophotofluorometer at an excitation wavelength of 495 nm
and an emission wavelength of 513 nm.
* * * * *