U.S. patent application number 11/439680 was filed with the patent office on 2006-09-21 for processes for manufacturing polymeric microspheres.
This patent application is currently assigned to Scimed Life systems, Inc. a Minnesota corporation. Invention is credited to Samuel P. Baldwin, Marcia Buiser.
Application Number | 20060210710 11/439680 |
Document ID | / |
Family ID | 28453206 |
Filed Date | 2006-09-21 |
United States Patent
Application |
20060210710 |
Kind Code |
A1 |
Buiser; Marcia ; et
al. |
September 21, 2006 |
Processes for manufacturing polymeric microspheres
Abstract
Processes of manufacturing polymeric microspheres facilitate the
generation of polymeric microspheres of size ranges smaller than
600 microns diameter by forming beads of a predetermined size from
a starting material which may include a template polymer, and
subsequently contacting the beads with a structural polymer. After
crosslinking of the structural polymer has taken place, the
template polymer may be removed to form the finished
microspheres.
Inventors: |
Buiser; Marcia; (Watertown,
MA) ; Baldwin; Samuel P.; (Newton, MA) |
Correspondence
Address: |
FISH & RICHARDSON PC
P.O. BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Assignee: |
Scimed Life systems, Inc. a
Minnesota corporation
|
Family ID: |
28453206 |
Appl. No.: |
11/439680 |
Filed: |
May 24, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10109966 |
Mar 29, 2002 |
|
|
|
11439680 |
May 24, 2006 |
|
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Current U.S.
Class: |
427/212 |
Current CPC
Class: |
C08J 3/12 20130101; C08L
29/04 20130101; C08L 29/04 20130101; A61L 24/06 20130101; A61F
2/0036 20130101; A61L 31/048 20130101; C08L 29/04 20130101; B29B
2009/125 20130101; C08J 3/24 20130101; A61L 27/16 20130101; A61L
24/001 20130101; B29B 9/16 20130101; A61L 2430/36 20130101; Y10T
428/2985 20150115; A61L 27/16 20130101; A61L 24/06 20130101; A61K
9/1635 20130101; B29B 2009/166 20130101; A61K 49/0452 20130101;
C08J 2329/04 20130101; A61L 24/0036 20130101; A61L 31/048 20130101;
A61L 27/50 20130101 |
Class at
Publication: |
427/212 |
International
Class: |
B05D 7/00 20060101
B05D007/00 |
Claims
1.-36. (canceled)
37. A particle comprising a polymer and having a core region and an
exterior region, wherein the core region includes first pores
having a first average pore size and the exterior region includes
second pores having a second average pore size that is smaller than
the first average pore size.
38. The particle of claim 37, wherein the polymer is
crosslinked.
39. The particle of claim 37, wherein the polymer is selected from
the group consisting of vinyl polymers, polyacrylamides,
polyethylene glycol, polyamides, polyureas, polyurethanes, and
derivatives thereof.
40. The particle of claim 37, wherein the polymer comprises a
hydrophilic polymer.
41. The particle of claim 37, wherein the polymer comprises
polyvinyl alcohol.
42. The particle of claim 37, wherein the first pores have a first
average pore size of up to about 50 microns.
43. The particle of claim 42, wherein the second pores have a
second average pore size of 10 microns or less.
44. The particle of claim 37, wherein the second pores have a
second average pore size of 10 microns or less.
45. The particle of claim 37, wherein the particle has a diameter
of smaller than 600 microns.
46. The particle of claim 37, wherein the particle has a diameter
of from one micron to 50 microns.
47. The particle of claim 37, wherein the particle has a diameter
of from 50 microns to 100 microns.
48. The particle of claim 37, wherein the particle has a diameter
of from 100 microns to 600 microns.
49. The particle of claim 37, wherein the particle has a diameter
of from 600 microns to 1000 microns.
50. A particle comprising a polymer comprising polyvinyl alcohol,
the particle having a core region and an exterior region, wherein
the core region includes first pores having a first average pore
size of up to about 50 microns and the exterior region includes
second pores having a second average pore size of 10 microns or
less.
51. The particle of claim 50, wherein the particle has a diameter
of smaller than 600 microns.
52. The particle of claim 50, wherein the particle has a diameter
of from 600 microns to 1000 microns.
Description
TECHNICAL FIELD
[0001] This invention generally relates to polymeric microspheres
and processes of manufacturing polymeric microspheres.
BACKGROUND INFORMATION
[0002] Microparticles, microcapsules and microspheres have
important applications in the medical, pharmaceutical,
agricultural, textile and cosmetics industries as delivery
vehicles, cell culture substrates or as embolization agents.
[0003] Polymeric microspheres, i.e., microspheres formed (at least
in part) from a crosslinkable polymer, have found a variety of uses
in the medical and industrial areas. They may be employed, for
example, as drug delivery agents, tissue bulking agents, tissue
engineering agents, and embolization agents. Accordingly, there are
numerous methods directed toward preparing polymeric microspheres.
These methods include dispersion polymerization of the monomer,
potentiometric dispersion of a dissolved crosslinkable polymer
within an emulsifying solution followed by solvent evaporation,
electrostatically controlled extrusion, and injection of a
dissolved crosslinkable polymer into an emulsifying solution
through a porous membrane followed by solvent evaporation.
[0004] Additional methods include vibratory excitation of a laminar
jet of monomeric material flowing in a continuous liquid medium
containing a suitable suspending agent, irradiation of slowly
thawing frozen monomer drops, and continuous injection of a
dissolved crosslinkable polymer into a flowing non-solvent through
a needle oriented in parallel to the direction of flow of the
non-solvent.
[0005] These methods known in the art have shortcomings that may
curtail the formation of uniformly sized microspheres of small
diameter ranges (e.g., in the range of 100-600 microns) for various
applications, particularly when the base material has a high
viscosity.
SUMMARY OF THE INVENTION
[0006] The present invention facilitates production of small,
uniformly sized polymeric microspheres in a manner not limited, in
terms of obtainable size range, by the viscosity or density of the
structural polymer.
[0007] In one aspect, a process of the invention includes
generating spherical beads or particles of a desired or
predetermined size from a suitable template polymer, contacting the
beads or particles with a structural polymer, such as polyvinyl
alcohol, and crosslinking the structural polymer into the beads or
particles. The template polymeric material may subsequently be
removed, resulting in polymeric microspheres.
[0008] As used herein, the term "template" polymer refers to a
soluble polymer that is used to create temporary particle forms
(i.e., beads), which may be porous or non-porous depending on the
template polymer that is selected. A "structural" polymer invades
or surrounds the temporary form and, following crosslinking,
creates the permanent structure of the particle. Structural
polymers are generally chemically crosslinkable, i.e., crosslink
through the formation of covalent bonds. Chemically crosslinkable
polymers may be crosslinked through, for example, photoinitiation
or other application of actinic radiation, by exposure to a
chemical crosslinking agent or thermal energy or through
freeze-thaw cycles.
[0009] In a preferred embodiment, a process of the invention
includes generating spherical beads of a desired size from a
starting material including a porous template polymer and a
solvent; diffusing the structural polymer into the beads; and
crosslinking at least the structural polymer. The solidified
template polymer may exhibit a porosity gradient, from the outside
to the inside of the beads, which determines the manner and extent
to which the structural polymer diffuses into the beads.
Alternatively, the template may have homogeneous porosity. The
template polymer is subsequently removed, leaving behind a
microsphere composed of only the structural polymer. In this way,
the process of the invention overcomes the problem associated with
generation of smaller-sized polymeric microspheres from viscous
polymer solutions, by starting with particles of a desired size and
subsequently contacting the particles with a structural
polymer.
[0010] In an alternative embodiment of the diffusion method,
spherical beads of a desired size are generated from starting
material including a template polymer and a crosslinking agent. The
structural polymer is diffused into the beads. The inclusion of a
crosslinking agent in the starting material causes the structural
polymer to crosslink into the beads upon contact therewith. The
template polymer is subsequently removed, resulting in the
formation of polymeric microspheres.
[0011] In another preferred embodiment, a process of the invention
includes generating spherical particles or beads of a desired
predetermined size from a starting material including a generally
non-porous template polymer, such as methyacrylate, and contacting
the beads with a structural polymer. To prevent premature damage to
the beads, the template polymer in this case should not dissolve in
the carrier of the structural polymer. The latter polymer is
subsequently crosslinked and the template polymeric material is
removed, leaving behind intact hollow polymeric spherical
particles. In this embodiment the beads are coated on the outside
surface with a generally uniform layer of the structural polymer,
as opposed to the structural polymer diffusing within the beads.
The beads can be either soaked in a solution containing the
structural polymer, or the structural polymer can be sprayed or
otherwise applied onto the outer surfaces of the beads. The
structural polymer can be crosslinked, whether diffused within or
applied onto the outer surface of the particles or beads, by a
chemical crosslinking agent such as formaldehyde or glutaraldehyde,
or by exposure to actinic or thermal energy.
[0012] The size of the beads can be determined or influenced by
passing the mixture including a template polymer through a droplet
generator with a nozzle adapted to generate droplets of a
predetermined size, and subsequently depositing the droplets into a
gelling solution to solidify the droplets, resulting in spherical
beads. The size distribution of the beads can be improved by
sieving.
[0013] Alternatively, a generally non-porous template polymer, such
as methacrylate, can be used for generation of beads using
spheronization technology known in the art.
[0014] In a preferred embodiment of the invention, a desired size
for the resulting polymeric microspheres is in the range 1-50
microns diameter. Other desirable size ranges for the polymeric
microspheres include microspheres in the size range 50-100 microns
diameter, microspheres in the size range 100-600 microns diameter
and microspheres in the size range 600-1000 microns diameter.
[0015] The foregoing and other objects, aspects, features and
advantages of the invention will become more apparent from the
following description and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The foregoing and other objects of the invention and the
various features thereof may be more fully understood from the
following description when read together with the accompanying
illustrative flowcharts in which like reference characters
generally refer to the same parts throughout the different
illustrations.
[0017] FIG. 1 is an illustrative flow diagram depicting the basic
steps involved in a process of the invention.
[0018] FIG. 2 is an illustrative flow diagram representing the
steps involved in a process of the invention, where the contacting
step is carried out by either diffusion or coating.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The methods of the invention facilitate the generation of
polymeric microspheres of size ranges smaller than 600 microns
diameter by forming template beads or particles of a predetermined
size and subsequently contacting the beads with a structural
polymer. Polymeric microspheres of size ranges smaller than 600
microns can be generated by diffusing a structural polymer, such as
polyvinyl alcohol, within spherical beads of a predetermined size
made from a starting material including a template polymer such as
alginate, chitosan, etc. Diffusion of the structural polymer into
the beads can be achieved by, for example, soaking the beads in a
solution of the structural polymer. The porous nature of the beads
favors the diffusion of the polymer into the beads. Alternatively,
this process may be carried out under conditions that enhance
diffusion, e.g., the addition of a surfactant, elevated temperature
and/or pressure.
[0020] Polymeric microspheres of size ranges smaller than 600
microns diameter can also be generated by coating the outer surface
of prefabricated beads or particles made from a template polymer,
such as methacrylate, with a structural polymer. In this case, the
beads are generally non-porous in morphology and receive a
substantially even coating of the structural polymer either by, for
example, soaking the beads in a solution or suspension of a
structural polymer or by spraying the outer surface of the beads
with such a solution or suspension.
[0021] FIG. 1 shows a flow chart 100 illustrating the basic steps
involved in a process of the invention. The prefabrication or
generation step 102 includes formation of spherical beads or
particles of a predetermined size from a starting material
containing a template polymer. In one embodiment, the starting
material includes a template polymer and a solvent.
[0022] In general, the role of the template polymer is to act as a
removable carrier to encapsulate or support the structural polymer,
which is introduced in a subsequent step. Accordingly, the template
polymer will be soluble in a solvent that does not attack the
crosslinked structural polymer, and may be, for example, an
ionically crosslinkable material. Omission of the structural
polymer at this stage enables the formation of uniformly sized
spherical beads of small size ranges, preferably smaller than 600
microns diameter.
[0023] Suitable porous template polymers include, for example,
alginates, polysaccharides, carrageenans, chitosan, hyaluronic
acid, or other ionically crosslinkable polymers (also known as
"shape-forming agents"), such as the classes of carboxylic-,
sulfate-, or amine-functionalized polymers. The template polymer
can also be generated from a blend of one or more of the above
synthetic or naturally occurring materials, or derivatives thereof.
In one preferred embodiment of the invention, the template polymer
is an alginate, which is ionically crosslinkable.
[0024] The solvent utilized in a process of the invention is chosen
based on several considerations. Firstly, the solvent should be
easily removable by evaporation, and should therefore have a
relatively low boiling point. The solvent should be capable of
dissolving the starting material without interfering with the
structural polymer crosslinking. Absence of any environmental
contaminants and ease of disposal are also worthwhile criteria in
the selection of the solvent. Deionized water and saline solution
are preferred as solvents; however, solvents can also be selected
from polar and nonpolar laboratory solvents, such as, for example,
acetone, methane and ethanol (which are polar), or hexane and
benzene (nonpolar).
[0025] The generation step 102 is followed by the contacting step
104, which involves contacting the prefabricated spherical beads or
particles with a structural polymer. The crosslinking step 106
involves crosslinking the structural polymer into the beads or
particles. The last step 108, involves the removal of the template
polymer from the beads, resulting in the formation of polymeric
microspheres. The template polymer is removed by soaking the beads
in a suitable solvent.
[0026] The structural polymer utilized in the contacting step 104
can be selected from a wide variety of generally chemically
crosslinkable polymers such as, for example, vinyl polymers,
polyacrylamides, polyethylene glycol, polyamides, polyureas,
polyurethranes, polyvinyl alcohols, and derivatives thereof. For
some (e.g., embolic) applications, a hydrophilic polymer, such as
polyvinyl alcohol, will be preferred.
[0027] The structural polymer is subsequently crosslinked in step
106 by a crosslinking agent. The crosslinking agent can be a
chemical agent such as, for example, formaldehyde or
glutaraldehyde, or the like thereof. The structural polymer can
also be crosslinked by application of photoinitiation, an ionic
agent or actinic radiation such as, for example, ultraviolet or
gamma radiation, or an electron beam.
[0028] The porosity of the outer polymeric shell can be controlled
by the addition to the polymeric solution of a filler agent, such
as starch, that is not crosslinked in the crosslinking step and can
be removed easily by rinsing the beads.
[0029] The size of the polymeric particles depends on the method
used for generating the spherical beads. Several techniques can be
utilized for the generation of spherical particles or beads from a
suitable starting material. A droplet generator can produce
spherical droplets of a predetermined diameter by forcing a jet
stream of a solution containing a template polymer and a solvent
through a nozzle, which is subjected to a periodic disturbance to
break up the laminar jet stream into droplets. This may involve the
use of a nozzle having, for example, an electrostatic or
piezoelectric element. The size of the droplets depends on the
frequency at which the element is driven. The uniformly sized
droplets fall into a solution containing a positively or a
negatively charged agent, such as calcium or barium, or a charged
polymer, such as polyacrylic acid, resulting in the conversion of
the liquid droplets into solid beads.
[0030] The manner in which liquid droplets are solidified affects
the properties of the particles. Ca.sup.2+, for example, is a
strong gelling ion, so a high concentration of, for example,
CaCl.sub.2 will create an inwardly moving gelling zone as the
droplet solidifies. This creates a high porosity gradient, with the
solidified particle exhibiting a smooth exterior with minimal
porosity (e.g., microporous with an average pore size of 10 microns
or less) and increasing porosity (e.g., up to about 50 microns) at
the particle core. By adding non-gelling ions (e.g., Na.sup.+ in
the form of NaCl) to the solution in order to compete with the
gelling ions, it is possible to limit the porosity gradient,
resulting in a more uniform intermediate porosity throughout the
particle. The porosity of the particle, in turn, affects the
distribution of the structural polymer. A higher porosity gradient
will result in concentration of the structural polymer on the
surface of the particle and, following removal of the template
polymer, a relatively hollow sphere. A lower porosity gradient, by
contrast, will result in a more even distribution of the structural
polymer throughout the particle, and a more densely crosslinked
finished sphere.
[0031] In an alternative embodiment, beads are generated from a
mixture of a template polymer and a crosslinking agent, such as
formaldehyde or glutaraldehyde. The beads are contacted with a
structural polymer and the template polymer is subsequently
removed, resulting in the formation of polymeric spherical
particles. Thus, by inclusion of a crosslinking agent in the
starting material for generating the beads, this embodiment
eliminates the need for a discrete crosslinking step 106.
[0032] FIG. 2 shows a flow chart 200 illustrating the various steps
in particular embodiments of the invention, where the contacting
step 104 includes diffusion 202 or coating 204. The contacting step
employing diffusion 202 is based on diffusing the structural
polymer into the prefabricated beads, generated from a starting
material including a template polymer and a solvent. Diffusion can
be achieved by, for example, soaking the beads in a solution of the
structural polymer.
[0033] The contacting step employing coating 204 is based on
application of a uniform layer of the structural polymer on the
outer surface of the beads. The structural polymer can be applied
by, for example, spraying the polymer on the surfaces of
prefabricated beads made from a generally non-porous template
polymer, such as methyacrylate, or soaking such beads in a solution
of a structural polymer. An even spray-coating of the microspheres
can be achieved by, for example, suspending the beads in air while
spraying.
[0034] The structural polymer is crosslinked into the beads in step
106. The template polymer, which generally comprises a porous
polymer in the diffusion embodiment 202, and a non-porous polymer
in the coating embodiment 204, is subsequently removed in step 108.
The end product is microspheres of a desired predetermined size and
composed of the structural polymer. Ionically crosslinkable
materials, such as, for example, shape-forming agents are dissolved
using suitable solvents, such as a solution of sodium
hexametaphosphate or ethylene diamine tetraacetic acid (EDTA), that
leave the structural polymer intact, thereby resulting in polymeric
microspheres. The methyacrylate in the coating embodiment 204 can
be removed by soaking the beads in acetone or another solvent that
removes the methacrylate without dissolving the outer polymeric
shell, resulting in hollow polymeric spheres.
[0035] Formation of porous particles is discussed above. To form
non-porous beads of suitably small diameter, techniques such as
spheronization may be used. Ultimately, the size of the hollow
polymeric microspheres can be controlled by the size of the
preformed beads and the thickness of the polymeric layer.
[0036] Spheronization techniques, which are well-characterized in
the art, generate beads that have low surface to volume ratios and
smooth surfaces, to allow for the application of uniform layer of
the structural polymer. A device called a spheronizer comprises a
rotating frictional plate enclosed within a hollow cylinder with a
slim clearance between the edges of the rotating base plate and the
cylinder wall. Spheronization typically begins with damp extruded
particles, such as particles generated by grinding an agglomerated
mass of a soluble polymer, such as methacrylate. The extruded
particles are broken into uniform lengths and gradually transformed
into spherical shapes while rotating on the base plate of the
spheronizer. The resulting spherical beads have low surface to
volume ratios and smooth surfaces to achieve even coating of the
structural polymer on the surfaces thereof.
[0037] In still another embodiment, the beads are ice crystals. The
ice crystals are removed simply by exposing the microspheres to
elevated temperatures.
[0038] The invention is illustrated further by the following
non-limiting examples.
EXAMPLE 1
[0039] An aqueous solution of 2% sodium alginate was infused
through a droplet generator directly into a 2% CaCl.sub.2 bath. The
parameters used for the droplet generator were a nozzle 300 microns
in diameter; a flow rate of 10 ml/min; and a frequency of 260 Hz.
The CaCl.sub.2 solution was decanted and the resulting calcium
alginate beads were soaked overnight in an 8% polyvinyl alcohol
(PVA) aqueous solution accompanied by slow stirring. The
PVA-infused beads were subsequently recovered using a sieve and
crosslinked by soaking the beads in a mixture of 3%
formaldehyde/20% sulfuric acid at 60.degree. C. for 20 minutes. The
alginate was removed from the beads by soaking the beads in 5%
sodium hexametaphosphate for 1 hour, resulting in PVA microspheres
of 600 microns diameter.
[0040] The absence of non-gelling ions resulted in a heterogeneous
distribution of the PVA within the particle, with a high
concentration at the surface of the particle and a relatively low
concentration at the center, resulting in a hollow microsphere.
EXAMPLE 2
[0041] A solution of 2% alginate was injected through a droplet
generator using a nozzle of 200 micron diameter; a frequency of 660
Hz; and a flow rate of 5 ml/min. The droplets were slowly stirred
into a solution of 2% CaCl.sub.2 solution. The resultant calcium
alginate beads were soaked overnight in an 8% polyvinyl alcohol
solution, sieved and recovered. The polyvinyl alcohol was
crosslinked by soaking the beads in a solution of 4%
formaldehyde/20% sulfuric acid at 60.degree. C. for 25 minutes. The
alginate was removed by soaking the beads in a 5% sodium
hexametaphosphate solution at room temperature, resulting in PVA
microspheres of 400 microns diameter.
[0042] The absence of non-gelling ions resulted in a heterogeneous
distribution of the PVA within the particle, with a high
concentration at the surface of the particle and a relatively low
concentration at the center, resulting in a hollow microsphere.
* * * * *