U.S. patent application number 16/863775 was filed with the patent office on 2020-10-08 for multiphase gel.
The applicant listed for this patent is BVW Holding AG. Invention is credited to Lukas Bluecher, Michael Milbocker.
Application Number | 20200316265 16/863775 |
Document ID | / |
Family ID | 1000004914966 |
Filed Date | 2020-10-08 |
United States Patent
Application |
20200316265 |
Kind Code |
A1 |
Bluecher; Lukas ; et
al. |
October 8, 2020 |
MULTIPHASE GEL
Abstract
Disclosed are hydrogels polymerized with or around a solid
biofunctional moiety, biodegradable or permanent, designed to be
implantable in a mammalian body, intended to block or mitigate the
formation of tissue adhesions, and intended to aid in functional
healing. The hydrogels of the present invention are characterized
by comprising multiphasic structural elements: a) at least one gel
phase, b) at least one solid phase, c) optional polymeric chains
connecting gel and solid phases, d) optional shape designs that
provide for an interpenetrating geometry between gels and solids,
e) optional shape designs that enhance a tissue-hydrogel interface,
and f) optional shape designs that provide a biofunctional aspect.
The hydrophobicity of the various phases is chosen to reduce tissue
adhesion and enhance tissue healing. The morphology of the polymers
comprising the gel phase is typically of high molecular weight and
has morphology that encourages entanglement. Useful polymeric
structures include branching chains, comb or brush, and dendritic
morphologies.
Inventors: |
Bluecher; Lukas; (Eurasberg,
DE) ; Milbocker; Michael; (Holliston, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BVW Holding AG |
Cham |
|
CH |
|
|
Family ID: |
1000004914966 |
Appl. No.: |
16/863775 |
Filed: |
April 30, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15586114 |
May 3, 2017 |
10668190 |
|
|
16863775 |
|
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62331286 |
May 3, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C08L 2201/06 20130101;
A61L 31/041 20130101; A61L 2300/41 20130101; A61L 31/145 20130101;
A61L 31/129 20130101; A61L 2300/412 20130101; C08L 75/08 20130101;
A61L 31/148 20130101; A61L 2300/424 20130101; C08L 2203/02
20130101; A61L 31/16 20130101; A61L 2300/30 20130101; A61L 2300/802
20130101; A61L 2400/18 20130101; C08L 75/06 20130101 |
International
Class: |
A61L 31/04 20060101
A61L031/04; A61L 31/12 20060101 A61L031/12; A61L 31/14 20060101
A61L031/14; A61L 31/16 20060101 A61L031/16; C08L 75/06 20060101
C08L075/06; C08L 75/08 20060101 C08L075/08 |
Claims
1-14. (canceled)
15. A composition comprising: a solid phase including a
microstructured substrate, the microstructured substrate being
comprised of a plurality of microfeatures having a distance between
adjacent microfeatures, wherein at least one of the plurality of
microfeatures is configured to transition to a gel phase, wherein
the at least one microfeature increases in volume in the gel phase
such that the increase in volume decreases the distance between the
at least one microfeature and at least one adjacent
microfeature.
16. The composition of claim 15, wherein the composition is
configured to form an interface with a target surface.
17. The composition of claim 16, wherein the composition is further
configured to restrain at least a portion of the target surface
between the at least one microfeature and the at least one adjacent
microfeature when in the gel phase.
18. The composition of claim 17, wherein the composition is
configured to localize the target surface to the composition via
the restraining of at least a portion of the target surface.
19. The composition of claim 16, wherein the target surface
comprises living tissue.
20. The composition of claim 15, wherein the solid phase and gel
phase are temporally discrete from each other.
21. The composition of claim 15, wherein the at least one of the
plurality of microfeatures is configured to transition to the gel
phase when in contact with water.
22. A composition comprising: a solid phase including a
hierarchical microstructured substrate, the hierarchical
microstructured substrate being comprised of a plurality of
hierarchical microfeatures having a distance between adjacent
hierarchical microfeatures along the substrate, wherein at least
one of the plurality of hierarchical microfeatures is configured to
transition to a gel phase, wherein the at least one hierarchical
microfeature increases in volume in the gel phase such that the
increase in volume decreases the distance between the at least one
hierarchical microfeature and at least one adjacent hierarchical
microfeature.
21. The composition of claim 20, wherein the plurality of
hierarchical microfeatures comprise a first structure and a second
structure, the first structure being of a larger scale than the
second structure, and the second structure being disposed about the
first structure.
22. The composition of claim 21, wherein the hierarchically
arranged first and second structures are configured such that a
hydrophilic and a hydrophobic domain are formed along the
hierarchical arrangement.
23. The composition of claim 22, wherein the composition is
configured to form an interface with a target surface, such that
when the interface is formed, at least a portion of the interface
forms a Wenzel-Cassie interface.
24. The composition of claim 23, wherein the composition is
configured to localize a target surface by forming a Wenzel-Cassie
interface, and then further restrain at least a portion of the
target surface between the at least one microfeature and the at
least one adjacent microfeature when in the gel phase.
25. The composition of claim 23, wherein the target surface
comprises living tissue.
26. The composition of claim 22, wherein the solid phase and gel
phase are temporally discrete from each other.
27. The composition of claim 22, wherein the at least one of the
plurality of microfeatures is configured to transition to the gel
phase when in contact with water.
28. The composition of claim 22, wherein the composition is
disposed about an implantable device.
29. The composition of claim 22, wherein the composition is
configured to form an adhesion barrier.
30. The composition of claim 22, wherein the composition is
disposed about a soft-tissue reinforcement prosthetic.
31. The composition of claim 22, wherein the composition is
disposed about a stent.
32. The composition of claim 22, wherein the composition is
disposed about an implant.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims benefit of U.S. provisional
application No. 62/331,286 filed on May 3, 2016 and is a
continuation of U.S. patent application Ser. No. 15/586,114 filed
May 3, 2017, the contents of which are hereby incorporated by
reference in their entirety.
TECHNICAL FIELD
[0002] The present disclosure relates generally to biomedical and
pharmaceutical applications of absorbable or biodegradable
multiphasic hydrogels, where optionally one or more phases are not
absorbable in situ. More particularly, the present invention
relates to systems of multiphase hydrogels comprising both gel and
nongel phases, wherein these phases may be coupled mechanically,
hydrophobically, by metal ions, or by covalent bonds.
BACKGROUND OF THE INVENTION
[0003] In connective tissue, the term "ground substance" is the
non-cellular components of extracellular matrix. Cells are
surrounded by extracellular matrix in tissues, which acts as a
support for the cells. Ground substance traditionally does not
include collagen but does include all the other proteinaceous
components, including proteoglycans, matrix proteins and water.
Ground substance is amorphous, gel-like, and is primarily composed
of glycosaminoglycans (most notably hyaluronan), proteoglycans, and
glycoproteins. The formation of tissue adhesions can best be
described as a process of denaturation, and more specifically
protein denaturation.
[0004] Denaturation is a process in which proteins or nucleic acids
lose the tertiary structure and secondary structure which is
present in their native state, by application of some external
stress or compound such as an acid or base, a concentrated
inorganic salt, an organic solvent, exposure to air, or temperature
change.
[0005] When a surgical procedure is performed external stress is
applied to tissue, which can be oxidative, change the ionic
equilibrium, create necrotic byproducts, or otherwise increase the
entropy of the tissue. If proteins in a living cell are denatured,
this results in disruption of cell activity and possibly cell death
(which occurs in all surgical procedures). Denatured proteins can
exhibit a wide range of characteristics, from loss of solubility to
communal aggregation. These two effects tend to create scaffolds on
which bridges between living tissues are formed.
[0006] Denaturation occurs at different levels of the protein
structure. In the quaternary structure denaturation, protein
subunits are dissociated and/or the spatial arrangement of protein
subunits is disrupted. This can lead to cell death, which promote
upregulation of reaction oxygen species as well as providing an
environment for microbial proliferation. The tertiary structure
denaturation involves the disruption of covalent interactions
between amino acid sidechains (such as disulfide bridges between
cysteine groups), noncovalent dipoledipole interactions between
polar amino acid sidechains, and Van der Waals (induced dipole)
interactions between nonpolar amino acid sidechains. In the
secondary structure denaturation, proteins lose all regular
repeating patterns such as alphahelices and betapleated sheets, and
adopt a random coil configuration. This contributes to the higher
entropic state associated with chronic inflammation and thick
capsule formation.
[0007] Primary structure denaturation, such as a sequence of amino
acids held together by covalent peptide bonds, is not directly
disrupted by denaturation. But the high entropy environment
associated with global protein denaturation has been associated
with primary structure disruption and pathologies such as
cancer.
[0008] Most biological substrates lose their biological function
when denatured. For example, enzymes lose their activity, because
the substrates can no longer bind to the intended active site, and
because amino acid residues involved in stabilizing the substrates'
transition states are no longer positioned to be able to do so. The
denaturing process and the associated loss of activity can be
measured using techniques such as dual polarization
interferometry.
[0009] Unfortunately, almost all antiadhesive materials (gel or
sheet) used surgically at present are chaotropic agents. These
devices disrupt the structure of macromolecules, and denature
macromolecules such as proteins and nucleic acids (e.g. DNA and
RNA). Chaotropic solutes increase the entropy of the system by
interfering with intramolecular interactions mediated by
noncovalent forces such as hydrogen bonds, van der Waals forces,
and hydrophobic effects. Hydrophobic effects are primary in
establishing the boundaries between tissue layers. When the
equilibrium of these forces that are established in vital tissue is
disrupted, the "healing" stimulus leads to macroscopic cellular
structures that are deleterious to clinical success.
[0010] For these reasons it is important that antiadhesion
barriers, that are, by their current construction, absorbable, not
degrade into byproducts that are chaotropic. Macromolecular
structure and function is dependent on the net effect of these
forces (for example, protein folding), therefore it follows that an
increase in chaotropic solutes precipitated by an implant in a
biological system will denature macromolecules, reduce enzymatic
activity and induce stress on cells. In particular, tertiary
protein folding is dependent on hydrophobic forces from amino acids
throughout the sequence of proteins. Chaotropic solutes decrease
the net hydrophobic effect of hydrophobic regions because of a
disordering of water molecules adjacent to the protein. This
solubilizes the hydrophobic region in the solution, thereby
denaturing the protein. This is also directly applicable to the
hydrophobic region in lipid bilayers; if a critical concentration
of a chaotropic solute is reached (in the hydrophobic region of the
bilayer) then membrane integrity will be compromised, and the cell
(tissue layer) will lyse.
[0011] Many implants that degrade into acids form chaotropic salts
that are water soluble and exert chaotropic effects via a variety
of mechanisms. Whereas chaotropic compounds such as hydroxyl
compounds, for example polyethylene glycol, interfere with
noncovalent intramolecular forces, salts can have chaotropic
properties by shielding charges and preventing the stabilization of
salt bridges. Hydrogen bonding is stronger in nonpolar media, so
salts, which increase the chemical polarity of the solvent, can
also destabilize hydrogen bonding. The loss of hydrogen bonding
disassociates the delimiters of tissue layers, promoting translayer
bridge formation. In terms of intersurface dynamics, the formation
of adhesions is promoted due to insufficient water molecules to
effectively solvate the ions resulting from surgical tissue
disruption. This can result in iondipole interactions between the
salts and hydrogen bonding species which are more favorable than
normal hydrogen bonds, which accordingly promote bridging between
tissue layers over promotion of tissue layer boundaries.
[0012] Accordingly, it is important that an antiadhesion prosthetic
that is absorbable not contribute to a chaotropic effect. Granted
much of the denaturation due to surgical intervention is due to
disruption of tissue layers, cell death and perturbation of the
ionic and hydrophobic equilibrium established in living tissue.
Thus, a barrier material should be chemically neutral and
reestablish the structural aspects of the tissue perturbed by
surgical intervention. Since this intervention is intended to be
temporary, then the elimination of the barrier material itself must
not be chaotropic. This is where most absorbable materials fail. In
cases where an implant is intended to disappear to minimize site
colonization by endogenous bacteria, and the implant serves a
mechanical function, then such chaotropic effects may be acceptable
in a risk/benefit analysis. But where a material is specifically
implanted for the purpose of reestablishing normal tissue
structure, such chemotropic effects may not be ignored.
[0013] Additional background information includes the
following:
[0014] U.S. Pat. No. 6,312,725 discloses compositions suited for
use in a variety of tissue related applications when rapid adhesion
to the tissue and gel formation is desired
[0015] U.S. Pat. No. 6,399,700 discloses comb copolymers comprising
hydrophobic polymer backbones and hydrophilic noncell binding side
chains which can be endcapped with cell-signaling ligands that
guide cellular response.
[0016] U.S. Pat. No. 6,413,539 discloses hydrogelforming,
selfsolvating, absorbable polyester copolymers capable of
selective, segmental association into compliant hydrogels upon
contacting an aqueous environment.
[0017] U.S. Pat. No. 6,465,513 discloses compounds useful in the
treatment of inflammatory diseases.
[0018] U.S. Pat. No. 6,486,140 discloses the use of chitosan and a
polysaccharide immobilized thereto selected from heparin, heparin
sulphate and dextran sulphate for the manufacture of an agent
capable of preventing or substantially reducing undesirable
adhesion of damaged tissue with adjacent or surrounding tissues in
connection with wound healing; and a process for the use of such
agent.
[0019] U.S. Pat. No. 6,486,285 discloses a water-swellable polymer
gel prepared by reacting an ester of a carboxyl group containing
polysaccharide with a compound having at least two.alpha.amino
groups, which is derived from a natural amino acid, and a foamed
article thereof.
[0020] U.S. Pat. No. 6,514,522 discloses polysaccharide polymers,
for example, chitosanarabinogalactan and polysaccharide amine
polymers are disclosed. The polymers can be used to prevent wound
adhesion, to provide scaffolds for tissue transplantation and
carriers for cell culture.
[0021] U.S. Pat. No. 6,642,363 discloses materials which contain
polysaccharide chains, particularly alginate or modified alginate
chains. The polysaccharide chains may be included as side chains or
auxiliary chains from a backbone polymer chain, which may also be a
polysaccharide. Further, the polysaccharide chains may be
crosslinked between side chains, auxiliary chains and/or backbone
chains.
[0022] U.S. Pat. No. 6,903,199 discloses waterinsoluble,
crosslinked amide derivatives of hyaluronic acid and manufacturing
method thereof, where the amide derivatives of hyaluronic acid are
characterized by crosslinking, of polymer or oligomer having two or
more amine groups, with hyaluronic acid or its hyaluronate salts
through amidation reaction.
[0023] U.S. Pat. No. 6,923,961 discloses carboxypolysaccharides
including carboxymethyl cellulose and their derivatives are
provided that can be made into sponges, gels, membranes,
particulates and other forms, for a variety of antiadhesion,
antithrombogenic, drug delivery and/or hemostatic applications
during surgery and pharmacological therapeutics.
[0024] U.S. Pat. No. 7,026,284 discloses a polyphenol useful as a
gene complex, cell adhesion inhibitor or immune tolerogen. The
polyphenol of forming the agent is selected from catechin group
consisting of epigallocatechingallate, tannic acids, or
proantodianisidine, a protein of the protein complex is selected
from proteins consisting of animal proteins composed of polypeptide
chain of peptidecombined amino acids, vegetative proteins, nucleus
proteins, glycogen proteins, lipoproteins and metal proteins, the
gene complex comprises by compositing genes by polyphenol catechins
in order to introduce genes to cells of animals or human bodies, a
cell composed of the cell adhesion inhibitor is selected from cells
consisting of an animal cell including a stem cell, skin cell,
mucosa cell, hepatocyte, islet cell, neural cell, cartilage cell,
endothelial cell, or epidermal cell.
[0025] U.S. Pat. No. 7,265,098 discloses methods for delivering
bioadhesive, bioresorbable, antiadhesion compositions. Antiadhesion
compositions can be made of intermacromolecular complexes of
carboxylcontaining polysaccharides, polyethers, polyacids,
polyalkylene oxides, multivalent cations and/or polycations.
[0026] U.S. Pat. No. 7,316,845 discloses compositions for coating
biological and nonbiological surfaces, which minimize or prevent
cell-cell contact and tissue adhesion, and methods of preparation
and use thereof, are disclosed. Embodiments include polyethylene
glycol/polylysine block or comb-type copolymers with high molecular
weight PLL (greater than 1000, more preferably greater than
100,000); PEG/PLL copolymers in which the PLL is a dendrimer which
is attached to one end of the PEG; and multilayer compositions
including alternating layers of polycationic and polyanionic
materials.
[0027] U.S. Pat. No. 7,569,643 discloses novel polymeric
compositions based upon A.sub.n(BCB)A.sub.n polyester/polyether
multiblocks.
[0028] U.S. Pat. No. 7,879,356 discloses novel bioabsorbable
polymeric compositions based upon AB polyester polyether or related
diblocks and triblocks.
[0029] U.S. Pat. No. 7,883,694 discloses crosslinked polymer
compositions that include a first synthetic polymer containing
multiple nucleophilic groups covalently bound to a second synthetic
polymer containing multiple electrophilic groups. The first
synthetic polymer is preferably a synthetic polypeptide or a
polyethylene glycol that has been modified to contain multiple
nucleophilic groups, such as primary amino (NH.sub.2) or thiol (SH)
groups. The second synthetic polymer may be a hydrophilic or
hydrophobic synthetic polymer, which contains or has been
derivatized to contain, two or more electrophilic groups, such as
succinimidyl groups.
[0030] U.S. Pat. No. 7,994,116 discloses to a method for prevention
or reduction of scar tissue and/or adhesion formation wherein a
therapeutically effective amount of a substance that inhibits a
proinflammatory cytokine.
[0031] U.S. Pat. No. 8,003,782 discloses that a pharmaceutical
composition containing complex carbohydrates with or without
natural or synthetic essential oils can work effectively as a
topical, oral or mucosal pharmaceutical composition.
[0032] U.S. Pat. No. 8,048,444 discloses an implant introduced into
a surgical site of a patient to prevent postsurgical adhesions.
[0033] U.S. Pub. No. 20090208589 discloses new biopolymers which
mimic the properties of natural polysaccharides found in vivo. The
inventive polysaccharides can be used as viscosupplements,
viscoelastics, tissue space fillers, and/or antiadhesive
agents.
[0034] U.S. Pub. No. 20100160960 discloses hydrogel tissue adhesive
is formed by reacting an oxidized polysaccharide with a
waterdispersible, multiarm amine in the presence of a polyol
additive, which retards the degradation of the hydrogel.
[0035] U.S. Pub. No. 20110166089 discloses provide a solution for
tissue adhesion prevention and a method for tissue adhesion
prevention that are applicable to general surgery and in which
covering condition during surgery is stable and convenient. The
invention is the solution for tissue adhesion prevention of which
the active ingredient is trehalose.
[0036] U.S. Pub.No. 20110237542 discloses to a composition for
preventing tissue adhesion which comprises a biocompatible
hyaluronic acid and a polymer compound. More specifically, the
invention is a composition containing hyaluronic acid which has not
been modified by a chemical crosslinking agent.
[0037] U.S. Pub.No. 20110243883 discloses provides branched
polymers which can be used as lubricants or shock absorbers in
vivo. For example, the inventive polymers can be used as
viscosupplements, viscoelastics, tissue space fillers, and/or
antiadhesive agents.
BRIEF SUMMARY OF THE INVENTION
[0038] In view of the limitations inherent in the above cited
patents and status of the art, it is an object of the present
invention to provide a gel optionally comprising at least one solid
phase and optionally comprising a biologically active aspect. The
bioactive aspect can be geometrical, chemical, or mechanical.
[0039] Yet another object of the present invention is to provide a
gel polymer optionally terminated with a biologically active
agent.
[0040] A further object of the present invention, is to provide a
gel polymer capable of the controlledrelease or presentation at an
implant surface of a biologically active agent/drug for modulating
cellular events, such as, wound healing and tissue
regeneration.
[0041] A further object of the present invention, is to provide a
gel polymer capable of the controlledrelease or presentation at an
implant surface of a biologically active agent/drug for therapeutic
treatment of diseases.
[0042] A further object of the present invention, is to provide a
gel polymer which is capable of being extruded onto or injected
into living tissue for providing a protective barrier with or
without an anti-inflammatory agent or an agent which inhibits
fibrotic tissue production for treating conditions, such as,
postsurgical adhesion.
[0043] A further object of the present invention, is to provide a
gel polymer which is capable of being extruded onto or injected
into living tissue for providing a protective barrier with or
[0044] without a wound healing agent or an agent which promotes
vascularization for treating conditions, such as, repairing a soft
tissue defect.
[0045] A further object of the present invention, is to provide a
gel polymer which is capable of being extruded onto or injected
into living tissue for providing a first protective barrier aspect
and a second tissue scaffold aspect, wherein each aspect comprises
a separate phase.
[0046] A further object of this invention is to provide a gel
polymer for delivering a botanical extract possessing
anti-inflammatory or wound healing properties, for example extracts
derived from the genus Boswellia.
[0047] A further object of the present invention is to provide a
gel polymer comprising distinct phases, each of the phases designed
to a specific absorption rate to achieve a specific functional
aspect.
[0048] A further object of the present invention is to provide a
gel polymer comprising distinct phases wherein the gel phase is
tissue adhesive to achieve localization and prevent migration of
the gel after implantation at an intended site. A further object of
the present invention, is to provide a gel polymer comprising
distinct phases wherein the gel phase is lubricious, and minimizes
the irritation associated between adjacent layers of tissue created
during a surgical operation that involves tissue dissection.
[0049] A further object of the present invention is to provide a
gel polymer comprising distinct phases wherein the different phases
are temporarily linked such that as the ionic linker is solvated in
vivo, the linking strength is diminished.
[0050] A further object of the present invention is to provide a
gel polymer comprising distinct phases wherein the solid phase
binds the gel phase, such that the gel phase is not free to spread
or swell without limit.
[0051] A further object of the present invention is to provide a
gel polymer comprising distinct phases wherein the solid phase and
gel phase possess shape memory and the shape achieved during
manufacturing and formation of the gel system is a low energy state
of the gel system.
[0052] A further object of the present invention is to provide a
gel polymer comprising distinct phases wherein the combination of
phases
[0053] This present disclosure generally addresses methods of
treating tissue defects and modulating cell to cell interactions
and tissue to tissue interactions by administration of a polymeric
gel material incorporating nongel phases which optionally may
contain bioactive molecules to facilitate the repair of a tissue
surface.
[0054] The present disclosure further provides biomedical and
pharmaceutical applications of absorbable or biodegradable
multiphasic hydrogels, where optionally one or more phases are not
absorbable in situ. More particularly, the present invention
relates to multiphasic systems of hydrogels comprising gel and
non-gel phases, wherein these phases may be coupled mechanically,
hydrophobically, by metal ions, or by covalent bonds. The
disclosure further provides methods of using multiphasic gels in
humans for providing: a) a protective barrier to prevent
postsurgical adhesion, b) a carrier of tissue scaffolding, c) a
sealant for isolating layers of tissue chemically, d) a lubricious
aspect to ameliorate or reduce tissue inflammation, e) an ordering
aspect to reduce the entropy of the healing process, and f) a
controlled composition for delivery of biologically active agents
for modulating cellular signaling such as wound healing and tissue
regeneration or therapeutic treatment of diseases such as cancer
and infection.
[0055] The disclosure relates to materials that contain
polysaccharide chains or polyester chains, particularly hyaluronan
or galactomannan chains, but includes modified cellulose, alginate,
polylactic acid, polyurethane, and ethylene or propylene
moieties.
[0056] The polysaccharide, particularly hyaluronan or galactomannan
chains may be included as side chains or auxiliary chains linking
phases, and in particular gel and solid phases.
[0057] The gel phase backbone is typically an ether, containing
ethylene and/or propylene structure. For example, a backbone can
comprise a poloxamer. In other embodiments, the backbone may also
be a polysaccharide, such as hyaluronan associated with
galactomannan.
[0058] Hyaluronan is a polymer of disaccharides, themselves
composed of Dglucuronic acid and D-Nacetylglucosamine, linked via
alternating beta1,4 and beta1,3 glycosidic bonds. Galactomannans
are polysaccharides consisting of a mannose backbone with galactose
side groups (more specifically, a (14) linked betaDmannopyranose
backbone with branch points from the 6positions linked to
alphaDgalactose. Any combination of these subunits comprising
hyaluronan and galactomannan are contemplated by the present
disclosure.
[0059] Further, the polysaccharide chains may be crosslinked
between side chains, auxiliary chains and/or backbone chains. These
materials are advantageously modified by covalent bonding thereto
of biologically active molecules for cell adhesion signaling or
other cellular messaging.
[0060] This disclosure relates also to derivatized
carboxypolysaccharides (CPS). Specifically, the disclosure relates
to derivatized carboxypolysaccharides and uses in manufacturing
gels incorporating polyethylene oxide (PEO) or polypropylene oxide
(PPO) for drug delivery and for antiadhesion preparations. More
specifically, this invention relates to antiadhesion and healing
compositions comprising composites of biofunctionalized CPS, PEO
and PPO.
[0061] One embodiment is directed to a multiphasic gel, whererin
the gel phase comprises a poloxamer polymer backbone to which is
linked polysaccharide groups, particularly of hyaluronan or
galactomannan. The polysaccharide groups are present as side chains
or alternating with the poloxamer in a chain configuration. The
chains may be polymerized into rings, thus eliminating any
endgroups. The gel polymers provide synthetically modified
polysaccharides exhibiting controllable mechanical and charge
distribution properties to which an organic moiety may be
attached.
[0062] Further, the idisclosure is directed to processes for
preparing such polymers including an organic moiety and to the use
of such polymers, for example, as cell transplantation matrices,
preformed hydrogels for cell transplantation, nondegradable
matrices for immunoisolated cell transplantation, vehicles for drug
delivery, wound dressings and antiadhesion prosthetics.
[0063] Another embodiment is directed to polysaccharides,
particularly hyaluronan, which are modified by being crosslinked
with an organic bioactive moiety. The hyaluronan may further be
modified by covalent bonding thereto of a biologically active
molecule for cell adhesion, cell repulsion, or other cellular
interaction. Crosslinking of the hyaluronan with a poloxamer can
particularly provide polysaccharide/polyether materials with
controlled mechanical properties and shape memory properties which
greatly expand their range of use.
[0064] In many applications, such as tissue engineering, size and
shape of the matrix is of importance. The modification of the
crosslinked polysaccharides with the biologically active molecules
can provide a further threedimensional environment. Then finally
the addition of a solid phase, with a particular geometry tuned to
the healing process, provides essentially a four-dimensional
environment. For example, a gel tends to take the shape of the
vessel which contains it, but a system of solid torus, polymerized
into the gel matrix so as to form a chainmaillike configuration,
can internally constrain a gel dimensionally to prevent gel
thinning, clumping, or partitioning.
[0065] Another embodiment is directed to modified polysaccharides,
such as polymers containing a poloxamer backbone with the above
described side chain hyaluronan or crosslinked hyaluronan, modified
by covalent bonding thereto of a biologically active molecule for
mitigation of cell adhesion or other cellular interaction, which is
particularly advantageous for maintenance, viability and directed
expression of desirable patterns of gene expression. For example, a
terminal group that stimulates nitric oxide production and promotes
angiogenesis. Alternatively, a terminal group that comprises a
constituent of a botanical extract with healing or antiaging
properties.
[0066] In particular, a biofunctional molecules optionally could be
those obtained from various extracts and purification of Boswellia
genus botanicals. More particularly, the extracts have a polycyclic
structure with one or more pendant hydroxyl groups. These
biofunctional molecules are covalently bonded, using the hydroxyl
group, to join a polymeric backbone or side chain to the
biofunctional molecules. Preferably, the biofunctional molecule is
chiral. The chirality can be due to an odd number of cyclic
structures, or an asymmetric terminal chain. The biofunctional
molecules may include synthetic analogues of naturally occurring
structures.
[0067] The present compositions are preferably advantageously used,
for example, in the reduction or prevention of adhesion formation
subsequent to medical procedures such as surgery and as lubricants
and sealants. In addition, compositions according to the present
invention may be used as coatings and transient barriers in the
body, for materials which control the release of bioactive agents
in the body (drug delivery applications), for wound and burn
dressings and for producing biodegradable and nonbiodegradable
articles, among numerous others.
[0068] The present disclosure includes a multiphasic structure;
each of the phases may be directed to a different cellular response
or purpose. In particular, a gel aspect may provide an antiadhesive
functionality which resorbs in the body. Secondly, a solid phase
can provide a tissue scaffold aspect, which aids in the ordering of
tissue repair and rejuvenation, such that metabolic functionality
is encouraged over fibrosis and walling off of the repair site.
[0069] Lastly, the present disclosure incorporates a solid phase
that provides a lubricious aspect unattainable with a homogenous
gel phase. The solid phase acts as a mechanical analogue to ball
bearings, and the gel phase acts as a lubricant. In combination,
freshly excised tissue surfaces are both sealed and hydrated while
the solid phase prevents tissue bridging by contact and a
dimensional rolling aspect, which serves to separate as well as
facilitate differential motion, which is common between dissected
layers of tissue.
[0070] The chemical structures and methods of the disclosure
concern gels, more particularly hydrogels, comprising hydrophilic
blocks, hydrophobic blocks and biofunctional moiety. The hydrogels
of the present invention are intended for implantation in a
mammalian body and may be absorbable or alternatively relatively
persistent. These hydrogels are characterized by possessing at
least two distinct phases, be they liquid, solid, gas, or
distinctly a gel.
[0071] A hydrogel is a polymeric material with a high tendency for
water absorption and/or association, which maintains mechanical
integrity through physical crosslinks or polymeric entanglements
which are reversible or degradable in vivo. The hydrophobic blocks
may be absorbable polyester chain blocks, polyoxypropylene blocks,
urethane segments and botanical extract molecules. Of particular
interest are cyclic lactones, for example glycolide, Ilactide,
dllactide, epsilon.caprolactone, and p dioxanone. With respect to
botanical extracts, polycyclic structures are of particular
interest, for example boswellic acid derived from Boswellia.
Examples include, boswellic acids, tirucalic acids, thujenes,
champhenes, and the like, or their synthetic analogs.
[0072] The hydrophilic blocks may be polyoxyethylene blocks,
polysaccharides, or derivatives hereof. The length of the
hydrophilic block and its weight fractions can be varied to
modulate the in situ volume equilibrium of the gel, its modulus,
its water content, diffusivity of bioactive drug through it, its
adhesiveness to surrounding tissue, and bioabsorbability.
[0073] The polymers constructed from these constituents are
typically long chains with multiple pendant end groups, commonly
referred to as comb or brushtype copolymers that elicit controlled
cellular response. Examples of brush type polymers are hyaluronan
and galactomannan. The backbone or chain portion of the polymer can
be biodegradable or nonbiodegradable, depending on the intended
application. Biodegradable backbones are preferred for most tissue
engineering, drug delivery and wound healing device applications,
while nonbiodegradable backbones are desirable for permanent
implant applications. A portion of the side chains can be endcapped
with cellsignaling polycyclic structures functionalized with
ligands to control the degree of cell adhesion and tissue healing.
The cellsignaling can be elicited at a phasic polymer surface or
released into the surrounding tissue through degradation of a
portion of the polymer.
[0074] In the preferred embodiment, the overall comb copolymer
should have a molecular weight sufficiently high as to confer good
mechanical properties to the polymer in the hydrated state through
chain entanglement. That is, its molecular weight should be above
the entanglement molecular weight, as defined by one of ordinary
skill in the art.
[0075] The overall molecular weight of the comb copolymer should
thus be above about 30,000 Daltons, more preferably above 100,000
Daltons, and more preferably still above 1 million Daltons. The
side chains are preferably hydrophilic and degradable, and the
polymer backbone contains a multiplicity of hydrophilic, degradable
blocks. The density of the hydrophilic side chains along the
backbone of the polymers depends on the length of the side chains
and the watersolubility characteristics of the final polymer. The
total percentage by weight of the hydrophilic side chains is
between 10 and 50 percent of the total copolymer composition,
preferably around 30 percent by weight. Preferably, the hydrophilic
side chains associate with water and form a hydrated layer which
repels proteins and hence resists cellular adhesion.
[0076] The side chains of the comb polymer can be endcapped with
cellsignaling
[0077] Molecules modified by chemical ligands in order to elicit
controlled cell responses. Ligands capable of bonding to hydroxyl
groups, for example diisocyanates, can be covalently attached to
the hydroxyls of biofunctional molecules and in turn attached to
the hydroxyl groups of the polymer side chains.
[0078] A defined fraction of biofunctionalized side chains can be
obtained by using appropriate stoichiometric control during the
coupling of the ligands to the polymers, by protecting the
endgroups on those side chains which are not to be endcapped with
the biofunctional molecule, or by combinations of these approaches.
Generally, the ligands are attached to the biofunctional molecule
first, which then enables the biofunctional molecules to link to
the polymer side chains without leaving exposed ligands which may
promote protein attachment and subsequently adhesions.
[0079] Typically the number of phases in a gel system are two,
comprising a gel fraction and a solid fraction. However, the number
of phases is unlimited, and may include phases of different
degradation rates. While the gel aspects of the present invention
possess a characteristic viscosity, that viscosity can change with
temperature and pH. Typically, the gel systems of the present
invention are nonNewtonian, and more typically are thixotropic.
Alternatively, the gels can be constituted to be antithixotropic,
as in starch suspensions.
[0080] In the case of solid particles suspended, polymerized, or
encapsulated within a gel phase, the particulate fraction is
typically longer lasting and structural. In a structural aspect,
tori are of particular utility since they possess high symmetry and
can act as pivots in a gel system. Also importantly, they can act
as chainmail, linking gel domains while providing both
translational and rotational freedom. They are particularly useful
when the gel is surface polymerized to the solid.
[0081] Alternatively, the solid aspect can be a sphere, wherein
there is no interpenetration of he gel through the solid, and all
the coupling, if any, is surface mediated. In this configuration,
the spheres act as stress reliever, allowing for rotational freedom
in a gel where stresses may develop differentially between
surfaces.
[0082] Additionally, the solid surfaces may be polyhedral, wherein
at a certain compressional density or thinning as a result of
forces between adjacent tissue layers, the solid particle lock
together, providing a step function resistant to further thinning
or mobilization of the gel phase.
[0083] In refined aspects, any of the above basic geometric
considerations can be further enhanced by texturing a solid phase
surface. For example, several micron sized solids can be texturized
with nanometer scale structure. Such surface nanoscale structures
could be in the shape protrusions. Examples of protrusions are
pyramids, hooks, bumps, or undulations. Alternatively, the surface
features could be in the shape of indentations. Examples of
indentations include recessions of every geometric shape, in
particular cylindrical depressions, conical depressions and the
like. Clearly, a hybrid of protrusions and depressions are
considered. In particular, a reference plane may be established,
wherein there are alternating depressions and protrusions separated
by a flat planar surface of relatively small total surface
area.
[0084] Regarding tori and related structures, structures of the
present invention may be of any genus. Long strands of many tori
contacting at an edge may be considered, as well as closed forms
such as loops and even three dimensional forms such as
icosahedrons, and the like. Any platonic solid is contemplated.
[0085] The solid phase may be composite, that is, coated or
comprising layers. The coating may facilitate a short term bonding
between solid and gel phases. The surface may provide an initial
interaction with the gel phase that dissipates by absorption. The
surface may achieve a mechanical aspect that upon absorption
transitions to a tissue reactive aspect. In particular, a
monofilament torus may degrade into a multifilament torus, wherein
once the outer coating is resorbed the loosely toroid
multifilamentous structure facilitates tissue association. The
coating itself may comprise yet smaller solid phase structures that
absorb or disperse within the gel component. These smaller
dimensional structure may carry a chemically active moiety. The
solid phase may be principally responsible for an adhesive aspect,
and this aspect may be modified by time. In particular, the
particles may be first adhesive and later antiadhesive.
[0086] The particles may be structure such that they migrate toward
high energy surfaces, for example the interface between the gel
system and a tissue surface. It may be advantageous that the solid
phase and the gel phase be constituted of essentially the same
chemical constituents, and only differing in the crosslink density
or degree of association with water.
[0087] Accordingly, aspects such as resorption time, viscosity,
hydrophobicity, etc. can be modified in a layered approach, and by
the selection of multiple phasic elements. The total gel system of
the present invention can be designed for resorption times on the
order of hours to several months. The gel system of the present
invention is preferably resorbed in an amorphous state, in
particular crystalline states are explicitly to be avoided. For
example, design considerations such as considerations of chirality
are preferably employed, as known in the art, to avoid a fracture
degradation pathway. Whenever possible, the formation of hard
particulate matter, except when intended, is to be avoided. For
example, it is preferred that the degradation products of a gel
system do not form numerous, spherical, highly fibrotic centers.
And in particular, it is especially to be avoided, the formation of
said centers wherein the implant matter is sequestered from normal
degradation processes, and persist for an extended period. Such
centers have been associated with late stage endogenous
infection.
[0088] In one embodiment, the disclosure provides a backbone of
polyoxyethylene, polyoxypropylene, or combinations of these in
chain form with multiple hydroxyl groups to which are covalently
attached side chains of polysaccharides. It is not necessary tha
the polysaccharides exhibit the gelling behavior of alginates,
since the backbone can alternatively form a hydrogel. In this case
the main function of the polysaccharide would be to control the
degradation rate, provide a tissue adhesive functionality and
modify the hydrophobicity of biofunctional end groups.
[0089] Another embodiment provides a polymeric backbone section to
which is bonded a side chain, preferably multiple side chains, of
polymerized, optionally modified hyaluronan and galactomannan. The
modified polysaccharides preferably maintain the mild gelling
behavior of conventional hyaluronan sulfate. The linkage between
the polymeric backbone section and the side chains may be provided
by difunctional or multifunctional linker compounds, for example
diisocyanates, or by groups incorporated within the polymeric
backbone section reactive with the polysaccharide units or by
groups on the polysaccharide units or derivatives thereof reactive
with groups on the polymeric backbone section. The polymers may
advantageously further comprise biologically active molecules
bonded to the side chains, particularly preferably bonded through
the hydroxyl groups on hyaluronan and galactomannan.
[0090] In a particularly preferred embodiment, the side chains are
hyaluronan, the biologically active molecules exhibit cell
antiadhesion properties and the polymers provide a mucoadhesivity
for localizing the hydrogel in vivo without forming tissue
adhesions.
[0091] In a yet more preferred embodiment, the side chains are
hyaluronan, the biologically active molecules are of two types,
some of which exhibit cell antiadhesion properties and others
exhibit angiogenic properties, and the polymers provide a
mucoadhesivity for localizing the hydrogel in vivo to repair a
wound site and protect the healing wound site from tissue
adhesions.
[0092] When a linker group or ligand is used, such linker groups
may be selected from any divalent moieties which are compatible
with the ultimate use of the polymer and which provide for covalent
bonding between the polymeric backbone section and the
polysaccharide side chains and additionally any biofunctional end
groups. Additionally, the liner groups may link to the other phasic
fractions, in particular, a solid phase of absorbable
polyurethane.
[0093] When polysaccharides are used, it is conventional for the
polysaccharide to be bonded through a carboxylate group. In this
case, the linker group may be selected to significantly affect the
biodegradability of the polymer depending upon the extent of
hydrolyzability of groups in the linker chain. For example, amino
acid linkers are frequently used due to the controllability of the
degradation interval. For example, amino acid linker groups, such
as glycine, will provide ester linkages which are readily
hydrolyzable and, thus, facilitate degradation of the polymer in an
aqueous environment, whereas, amino alcohols provide an ether
linkage which is significantly less degradable. Amino aldehydes are
also useful linker groups. The substituent groups on the amino
acids will also affect the rate of degradability of the
linkage.
[0094] The linker group may also be varied in chain length
depending upon the desired properties. Linkages providing, for
example, from 10 to 20 atoms between the backbone and side chain,
are typical, although longer linkage chains are possible.
Additionally, the linker may be branched to provide for clustering
of multiple side chains. These structures are typically referred to
as dendritic in structure because they may provide a multiplicity
of branching points.
[0095] The polymeric backbone section, linkages, side chains and
biofunctional end groups may be provided in a number of hydrophilic
and hydrophobic configurations which will largely determine the
stability of the resulting hydrogel. The polymeric backbone itself
may comprise Iternating hydrophobic and hydrophilic blocks. Since
the biofunctional endgroups are typically hydrophobic, it is
generally useful to modify their hydrophobicity by attaching them
to hydrophilic side chains.
BRIEF DESCRIPTION OF THE DRAWINGS
[0096] FIG. 1 depicts a multiphase gel polymer system 100 of the
present disclosure.
[0097] FIG. 2 depicts a bifurcating sequence 200.
[0098] FIG. 3, depicts mixtures 300 of dendritic 302 and comb 304
polymers.
[0099] FIG. 4 is an image of a toroid multiphase gel structure
according to the present disclosure.
DETAILED DESCRIPTION OF THE INVENTION
[0100] Homogenous adhesion barrier gels should not admit tissue
in-growth initially upon implantation, otherwise their efficacy
relating to establishing separate tissue layers would be obviated.
Thus, as the homogenous gel portion resorbs, there may be need for
a tissue scaffold, in particular a tissue scaffold that has an
appreciably longer duration than the gel barrier, such that when
the gel has been resorbed, or nearly so, the second scaffold aspect
come increasingly more dominant.
[0101] For example, the gel in the initial time course may be
highly absorbable, and correspondingly chaotropic, due to release
of byproducts that disrupt local equilibrium. However, at this
early stage, when tissues are far from normal equilibrium states, a
barrier layer may be more important than chaotropic considerations.
However, as the surgical intervention aspect is resolved, it is
desirable that the antiadhesion barrier not contribute to chronic
inflammation and any aspect of entropy increase. Furthermore, it is
advantageous that the gel aspect transition to a tissue scaffold
aspect, wherein order is presented or reestablished to the tissue
surface, wherein normal barrier layers may be stabilized or
promoted.
[0102] Naturally, this consideration calls for a two stage repair,
in which first a barrier aspect is temporarily presented and
subsequently replaced by an ordering and chemically neutral aspect.
It should be appreciated that by chemically neutral we do not mean
that the second ordering aspect is strictly permanent, but rather
that its degradation byproducts are either sufficiently chemically
neutral or that the degradation period sufficiently long, such that
normal tissue structures are reestablished without interlayer
bridging.
[0103] Compounds useful in the present disclosure are generally
classified as complex carbohydrates. For purposes of this invention
complex carbohydrates are defined as any polymer comprising more
than two sugar moieties including such classes of compounds as
polysaccharides and oligosaccharides. Polysaccharides include
mucopolysaccharides and mannans whereas oligosaccharides comprise
branched polysaccharides such as sialylated sugars including milk
sugars.
[0104] Mucopolysaccharides are glycosaminoglycans, which can be
obtained from numerous sources (e.g. rooster combs, trachea,
umbilical cords, skin, articular fluids and certain bacteria such
as Streptococci). Most glycosaminoglycans (hyaluronic acid,
chondroiti sulfates A, B, and C, heparin sulfate, heparin, keratan
sulfate, dermatan sulfate, etc.) are composed of repeating sugars
such as nacetylglucosamine glucuronic acid and nacetyl
galactosamine (these are known as nonsulfated glycosaminoglycans).
If such glycosaminoglycans contain sulfur groups they are known as
sulfated glycosaminoglycans. All of these can be combined with
other polysaccharides or with alkane groups.
[0105] The present application combines bioactive groups with
biocompatible groups to address wound healing through a positive
physiological reaction that may restore anatomy and function of
various tissues after trauma without inflammatory interference. The
trauma may be accidental, the result of surgical intervention or
the effect of a disease or genetic condition. The ideal end result
of wound healing is restoration of tissues morphology. Restoration
of tissue morphology requires directing a functional aspect as well
as reducing high entropy responses, such as scar formation.
[0106] One prevalent part of the wound healing process is to form
connective tissues or scar tissue that may support the healing
tissues during wound healing and regeneration. However, in many
cases during wound healing, the newly formed connective tissues
(scar tissue) may interfere negatively with the normal function of
the tissue intended to be healed. In general, such tissue responses
are characterized by a high degree of disorder, and
characteristically lack a metabolic component, wherein the tissue
formed is primarily avascular. Wound healing, with the formation of
connective tissues may also induce adhesions that may induce
pathological conditions. For example, scar tissue may induce
cosmetically undesirable results such as cheloid formation.
Examples of adhesions and scarring may be found virtually in any
organ or tissue undergoing wound healing after trauma or surgery.
Following abdominal surgery and following gynecological surgery it
is not uncommon that the surgical procedure may induce adhesions
that may both make later surgery more difficult and induce
pathological conditions such as ileus.
[0107] In spinal surgery it is common to have a situation with a
dense scar formation called epidural fibrosis. This may in certain
cases induce significant difficulties for repeated surgery and can
induce compression of the adjacent nerve tissue. In other organs
excessive wound healing may induce unwanted fixation of tissues and
structures that may reduce function and induce pathological
conditions.
[0108] In general, a method for controlling wound healing,
particularly the reduction of cellular random scar tissue and
adhesions, would be of a great value in most cases of posttraumatic
or postsurgical wound healing. Thus, it is insufficient to merely
reduce the stimulus to the formation of scar and adhesions by
blocking such formation or providing an ameliorative coating, but
also a repair of the surgically corrected defect must be
facilitated or directed which includes a metabolic aspect such that
repeated resorption and modification of the repair site is
reduced.
[0109] Intercellular adhesion mediated by VLA4 and other cell
surface receptors is associated with a number of inflammatory
responses. At the site of an injury or other inflammatory stimulus,
activated vascular endothelial cells express molecules that are
adhesive for leukocytes. The mechanics of leukocyte adhesion to
endothelial cells involves, in part, the recognition and binding of
cell surface receptors on leukocytes to the corresponding cell
surface molecules on endothelial cells. Once bound, the leukocytes
migrate across the blood vessel wall to enter the injured site and
release chemical mediators to combat infection. A polymer that
mitigates fibrosis, while promoting endothelial and leukocyte
infiltration, can be promotional to wound healing and
antimicrobial.Surprising, it has been discovered that a single
phase antiadhesion substance can be insufficient in several
aspects. In particular, an aspect that is distinct from the
mechanical characteristics of a gel barrier can serve as a
structural impetus, encouraging avenues of repair not realized in
homogenous materials.
[0110] In intraorgan systems, tissue damage occurs that elicits an
adhesion mechanism that results in migration or activation of
leukocytes that can be damaging. For example, the initial insult
following myocardial ischemia to heart tissue is complicated by
leukocyte entry to the injured tissue causing still further insult.
Inflammatory conditions mediated by adhesion mechanisms are almost
always deleterious, for example, asthma, Alzheimer's disease,
atherosclerosis, AIDS dementia, diabetes, inflammatory bowel
disease (including ulcerative colitis and Crohn's disease),
multiple sclerosis, rheumatoid arthritis, tissue transplantation,
tumor metastasis, meningitis, encephalitis, stroke, and other
cerebral traumas, nephritis, retinitis, atopic dermatitis,
psoriasis, myocardial ischemia and acute leukocytemediated lung
injury such as that which occurs in adult respiratory distress
syndrome. Therefore, it is desirable to develop a hydrogel which
combines a barrier aspect with a structural biofunctional aspect
and optionally a chemical biofunctional aspect which also affects
cellular adhesion and prevents clinically adverse tissue
adhesions.
[0111] One difficulty associated with implantable hydrogel
compositions is that optimizing the composition to relative to gel
mechanical characteristics, in particular the absorbability may
worsen tissue inflammation at the site of administration. A
possible explanation for this effect is that highly reductive
compositions are capable of promoting rapid leukocyte infiltration
which may adversely affect tissue responses.
[0112] Accordingly, the hydrogel aspect of the present disclosure
is hydrophilic and avoids the adverse events of polymers currently
in use for biomedical applications which are generally hydrophobic.
However, a relatively more hydrophobic component with a structural
aspect, such as tori polymerized within a gel matrix, may provide a
tissue regenerative response associated with the reformation of
functional and metabolic tissue.
[0113] As defined herein, hydrophobic refers to a material that
repels water and exhibits a static contact angle with water greater
than 60 degrees at 20 degrees C., and has a water permeability less
than 3.times.10 10 cm 3 (STP) cm/(cm 2 s Pa). Hydrophobicity can
give rise to uncontrolled interactions between cells and adsorbed
proteins at the surface of an implanted material, which can result
in a chronic inflammatory response that can lead to failure of
implants and even promote tumorigenicity. Therefore, it is
advantageous to encapsulate such materials, even mildly hydrophobic
materials, within a gel matrix which provides initial
sequestration, until normal cellular responses are reestablished,
and radical foreign body responses are minimized, and a normal
regenerative function characterized by a low degree of entropy can
be established.
[0114] On the other hand, for tissue healing applications, it is
desirable that the polymeric material used to form a biodegradable
scaffold for cells, promote cell adhesion, migration, growth and
differentiation while providing adequate morphological stimulus;
and without promoting an inflammatory response. Though commonly
used synthetic scaffold materials such as polylactide,
polyglycolide, etc., and copolymers thereof, have suitable
mechanical, processing and biodegradation properties, their
hydrophobic nature and acid byproducts leads to protein adsorption
and denaturing of proteins attached to the material surface which
elicits uncontrolled inflammatory response.
[0115] The present disclosure couples tissue directing materials
with hydrophilic moieties to reduce protein adhesion to the implant
during the first highly reactive phase, and additionally may
contain a selective bioactive material which can down regulate
inflammation and promote tissue migration into a tissue defect to
heal the defect rather than promote aggressive cellular response to
the implant. The ideal antiadhesive surface for many biomaterials
applications resists protein adsorption while providing molecules
with specific chemical signals to guide tissue regeneration,
survival, growth, migration and differentiation in an adjacent
tissue defect.
[0116] As used herein, the term "biomaterial" refers to a material
used in a medical device intended to interact with a biological
system. Such biomaterial with biofunctionality may be chemical in
nature, or structural, wherein the shape promotes a desired
cellular response. For example, a typical biomaterial is modified
with polyethylene oxide, which has been studied in recent years for
the reduction of protein adsorption at the surface of biomaterials.
The objective of these surface modification schemes is the
elimination of nonspecific interactions of cells with implant
materials. Polyethers can be combined with hydrophobic biomaterials
to shield the hydrophobic biomaterials from the foreign body
response, and thus provide them to the body directly rather than
through a fibrotic capsule. Reduction of a fibrotic capsule is
paramount, since these capsules are avascular, and serve to
sequester implants from normal protective functions of the body.
Implants associated with thick capsules are also associate many
years after implantation. Thus, the teachings of the present
disclosure are instructive regarding absorbable implants as well as
permanent implants.
[0117] Regarding the chemical aspect of biofunctionalization of an
implant, activation-specific chemical signals can be relayed to
cells at a surface through tethered ligands of cell surface
receptors. These signals are presented in a localized manner at a
controlled dose without diffusive loss. The mimicry of tethered
ligands through the addition of bioactive moieties may provide more
constant stimulation to cells by avoiding the downregulation
present when soluble ligands are internalized by cells. Control
over spatial distribution of ligands on surfaces may also be key to
guiding cell behavior. Thus systems which will allow spatial
control of local ligand density through multiphasic architectures,
or the creation of clusters of ligands on select surfaces, in
addition to providing control over the average surface density of
ligands on said surfaces, are highly desirable. In the present
invention these ligands may be associated with a chemical
biofunctional moiety or with a structural biofunctional phase.
[0118] Additionally, molecules with dimeric adhesion receptors are
particularly useful as ligands and include approximately ten known
alpha chains paired with one of approximately six known beta
chains, which are known to mediate a wide range of interactions
between cells and extracellular matrix and control cell behaviors
as diverse as migration, growth, and differentiation, providing a
permissive environment for the action of growth factors. Thus, such
molecules are particularly useful in facilitating a healing
response, especially when deployed in a multiphasic system.
[0119] An important aspect of healing involves cross-communication
between adhesion and growth factor receptors, and it is
hypothesized that these factors work competitively at a site of
wound healing. Therefore, by favoring growth factor expression over
adhesion formation a wound may be repaired prior to significant
adhesion formation, thus shutting down significantly or entirely
the stimulus for adhesion formation. The favoring of growth factor
expression can be achieved chemically as well as structurally.
Therefore, a biofunctional geometry delivered in close proximity to
adhesion and growth factor receptors in the focal healing complex
can modulate the flow of both positive and negative regulatory
signals between the two. In particular, a hierarchical
hydrophobichydrophilic domain structured polymer endcapped with a
biofunctional molecule can beneficially undergo morphological
changes which are associated with the hydration of the hydrophilic
domains and formation of pseudocrosslinks via the hydrophobic
component of the system. Such polymeric structures form
biocompatible gels in vivo with extended persistence by virtue of
the pseudocrosslinks. Domain separation can be enhanced by the
inclusion of multiphasic domains, with and without structural
aspects.
[0120] Hydrophobichydrophilic polymer morphology has been reported
to be responsible for enhanced biocompatibility and superior
mechanical strength due to formation of twophase structure
comprising hydrophilic and hydrophobic domains. Such domains are a
generic feature of many polyurethane systems, where the twophase
structure is commonly referred to as amorphous and crystalline
segments. This molecular structure can be mimicked in a macroscopic
way, by incorporating solid hydrophobic structural elements in a
hydrophilic gel phase.
[0121] Hydrophobic-hydrophilic polymer morphology can be affected
by temperature and pH, especially for extended and hydrated
systems, and is responsible for thermoreversible gels. In order for
these gels to maintain their shortterm structure in vivo,
regardless of their longerterm biodegradability, involves covalent
bonds between watersoluble and waterinsoluble blocks. Some of the
gels of the present invention are responsive to temperature and pH
changes. For example, those containing poloxamers will shrink in
size in a base environment and expand in an acidic environment.
Similarly, higher temperature tends to cause the gels of the
present invention to contracts, whereas lower temperature causes
them to become more diffuse. In some instances, a low enough
temperature causes them to solubilize and lose their thixotropic
aspect. These considerations can be important in conditioning gel
systems for implantation, since typically a hysteresis is
associated with certain pH and thermal modifications, and some of
these modifications can be considered irreversible below a certain
energy threshold. Alternatively, such reversible modifications can
be useful in manufacturing aspects in terms of purification,
removal of residual monomeric components, and the preparation of
gel precursors suitable for shelflife stability. In this later
aspect, ionic constituents, such as salts, can achieve a similar
effect.
[0122] In the case where the hydrophilic blocks and hydrophobic
blocks are a mixture or blend and not polymerized together, the
desired structural aspects are not achieved since the hydrophilic
component rapidly disperses in tissue. Polymers comprising
covalently bonded hydrophilic and hydrophobic domains exhibit a
hydrationdehydration equilibrium which can be altered by changes in
temperature or pH. The equilibrium structures are characteristic of
hydrogels. Thus, hydrogels of the present invention, in the absence
of hydrophobic/hydrophilic covalent bonding, the hydrophilic blocks
undergo intermolecular segmental mixing with the neighboring
hydrophobic blocks to produce a viscous liquid. With
hydrophobic/hydrophilic covalent bonding, competition between the
water as an extrinsic solvent and the hydrophilic block forces the
hydration of the hydrophobic block, and results in aggregation or
association of the hydrophobic blocks to establish pseudocrosslinks
which maintain a 3-dimensional integrity.
[0123] Three-dimensional stability can also be achieved by the use
of metal ionic crosslinks, as is common in the preparation of
alginates, and similar polysaccharides. The mechanism of gel
formation for in vivo administration is associated with orientation
of the hydrophobic blocks toward the exterior of the gel and the
interface with the adjoining tissues can be used to establish an
adhesive joint, which prevents gel migration from target site and
sustains its intended efficacy. In some cases, a mucoadhesive
functionality is desirable and achieved with most polysaccharide
copolymerizations. Additionally, this effect can be enhanced by the
insertion of a biofunctional structural form which is relatively
more hydrophobic than the remaining gel portion of a polymeric
chain of hydrophobic and hydrophilic blocks. Thus, the
biofunctional moiety is presented preferentially at the phase
discontinuities within the hydrogel and is predisposed to
segmentation within the tissue.
[0124] Chemical bonding between phasic components can be carried
out by a chemical reaction, e.g. gelation with a polyfunctional
reagent; crosslinking using a coordinate bond, e.g. gelation by
calcium ions of alginic acid; crosslinking using a hydrophobic
bond, e.g. gelation by heating methyl cellulose or hydroxypropyl
cellulose; crosslinking using intermolecular association, e.g.
cooling of agar or carrageenan to cause the gelation, or the like.
The density of crosslinking can impact water absorbability and
strength of the resulting gel as well as rate of degradation in
vivo. Such crosslinks can be important in associating several
phasic constituents of a gel.
[0125] However, multiphasic hydrogels can be formed without the use
of crosslinking at all and which rely on entanglement. Entanglement
and the formation of pseudobonds between hydrophobic segments
require the hydrophobic and hydrophilic segments to be covalently
bonded together in long structures. The covalent bonding prevents
the separation of the hydrophobic and hydrophilic components. The
following are patents descriptive of the above background
information.
[0126] The term "poloxamer" refers to nonionic triblock copolymers
composed of a central hydrophobic chain of polyoxypropylene
(poly(propylene oxide)) flanked by two hydrophilic chains of
polyoxyethylene (poly(ethylene oxide)). Poloxamers are also known
by the trade names Pluronics and Kolliphor.
[0127] The term "thixotropy" is the property of certain gels or
fluids that are viscous under normal conditions, but flow (become
less viscous) under shear stress. Some thixotropi gels exhibit a
nonNewtonian pseudoplastic flow and a timedependent change in
viscosity. A thixotropic fluid is a fluid which takes a finite time
to attain equilibrium viscosity when introduced to a step change in
shear rate.
[0128] The terms "multiphase" and "multiphasic" refer to a gel
composition comprise of at least one gel phase and at least one
solid phase, and optionally a liquid phase and/or a ga phase. The
various phases may be interpenetrating such that mechanically one
or more of the phases cannot be separated without altering the gel
composition.
[0129] The term "cytophylactic polymer" refers to a polymeric
system able to direct cellular activity in such a way as to augment
the natural cellular processes. These polymers are denominated
stimuliresponsive or environmentally sensitive polymers in the
sense that they elicit a biologically appropriate response to a
wide variety of cellular environments. Temperature, pH, ionic
strength and electric field are among the most important stimuli,
causing phase or shape changes which dramatically affects the
optical, mechanical or transport properties of the present
compositions. A number of molecular mechanisms exist which can
cause sharp transitions and water plays a crucial role in most of
them. These include: ionization, ion exchange, release or formation
of hydrophobically bound water and helixcoil transition.
[0130] Additionally, diamine groups such a biocompatible lysine can
be used at polymerizing links in isocyanate functionalized
polymeric backbones, side chains, and biofunctional end groups.
Alternatively, the reactive monomer can include a leaving group
that can be displaced with a nucleophilic group on a hydrophilic
polymer. For example, epichlorohydrin can be used during the
polymerization step. The monomer is incorporated into the polymer
backbone, and the chloride group is present on the backbone for
subsequent reaction with nucleophiles. An example of a suitable
hydrophilic polymer containing a nucleophilic group is a
polyethylene glycol with a terminal amine group. PEGNH.sub.2 can
react with the chloride groups on the polymer backbone to provide a
desired density of PEGylation on the polymer backbone. Pegylation,
in general, is suitable to the botanical extracts of the present
invention, since many of them are poorly incorporated in biological
tissue, and can be toxic in the absence of hydrophilic
modification.
[0131] Using the chemistry described herein, along with the general
knowledge of those of skill in the art, one can prepare polymer
backbones which include suitable leaving groups or nucleophiles for
subsequent coupling reactions with suitably functionalized
hydrophilicpolymers.
[0132] Examples of useful configurations between solid and gel
phase gel systems are shown in FIG. 1 although the invention is not
limited to such configurations and further configurations using the
basic structural units can be provided according to the
invention.
[0133] FIG. 1 depicts a multiphase gel polymer system 100 of the
present invention comprising: a polymeric backbone 102 which
defines the overall polymeric morphology of the gel 103 (not drawn
to scale), linkage groups 104, side chains 106, and biofunctional
end groups 108. The backbone 102 generally comrpises hydrophobic
110 and hydrophilic 112 group segments, some or all of which can be
biodegradable. Solid phase polymer 113 is depicted as a torus, and
comprising pendant hydroxyl groups 115. Linkage groups 104 form
bridges 114 between the backbones 102 and solid phase polymer 113,
and the solid phase may be of an entirely different composition
than the backbone. Typically the bridges comprise linkage groups
104 and side chains 106, wherein the backbones 102 are joined to
side chains 106 through linkage groups 104. The biofunctional group
108 may optionally be located on the ends 116 of the backbone 102,
on the ends 118 of pendant side chains 120, sandwiched 121 between
linkage groups 104 which in turn links to a side chain 106.
Biofunctional groups 108 may be located at the junction of two side
chains 106 connected by linkage groups 104. It is important to note
gel polymer 103 is formed during manufacturing in the presence of
solid polymer 113 such that gel 103 passes through, as illustrated
at 124, the toroidal opening 126 of solid polymer 113. Thus, the
gel fraction 103 is a contiguous macromolecule that interpenetrates
the solid polymer 113.
[0134] One preferred embodiment is polymers wherein the backbone
itself is a polysaccharide, for example hyaluronan. The side
chains, for example, may be galactomannan. A particular example
involves chains comprising hyaluronan units to which are attached
galactomannan side chains functionalized with a diisocyanate
linker. Dendritic polymers and comb polymer backbones can be
provided by the polymerization product of difunctional and higher
functional prepolymers. For example linear chains of polysaccharide
pendant hydroxyl groups can be polymerized with triol endcapped
with isocyanate groups. These structures can provide a highly
crosslinked polymer which would rapidly degrade to low molecular
weight components and readily be cleared by the body.
[0135] For example, FIG. 2 illustrates a bifurcating sequence 200
wherein a polymer backbone 202 has a 3-armed structure 204
comprising two side chains 206. The terminus of each arm of the
3-armed structure 204 is linked to another 3armed structure 204
through linkage group 208. At the final terminus of the bifurcating
structure are located pendant biofunctional groups 210, optionally
linked to a solid phase 212. Structures are not drawn to scale.
[0136] Dendrimers are of particular interest due to their
propensity for entanglement and the formation of hydrogels that are
relatively stable in the implant environment. Referring to FIG. 3,
mixtures 300 of dendritic 302 and comb 304 polymers are possible
wherein the dendritic portion serves as a scaffold to the more
mobile comb structures. Therefore, the dendritic fraction may be
principally endcapped with antiadhesion end groups 306 and the comb
fraction may be coupled to a solid phase 308. Alternatively, the
comb fraction may be a hyaluronan based gel and the dendritic
fraction a poloxamer gel. Polymers containing hyaluronan are known
to act as tissue scaffolds, mimicking their biological function in
living extracellular matrix.
[0137] A further useful backbone structure is comb polymers which
contain many side chains extending from a polymer backbone.
Polyvinyl alcohol provides a particularly useful backbone for comb
polymers. The alcohol groups of polyvinyl alcohol can be esterified
and subjected to a carbodiimide linkage chemistry to provide the
side chain linkages.
Ligands and Linking Groups Coupled to Biofunctional End Groups
[0138] Although the principle interest of the present invention is
the attachment of biofunctional solid phase to a gel phase, the gel
phase may be terminated at least partially with biofunctional
molecules. For example, extracts derived from genus Boswellia can
be bound to the terminal ends of hydrogel structures, other
botanical extracts are contemplated. Useful botanicals include,
camphenes, camphor, coneole and eucal (derived from eucalyptus),
moronic acid (derived from pistachio), and like structures.
[0139] In particular, polycyclic structures with an odd number of
cycles is useful in the present invention. More particularly,
chiral polycyclic structures of 3 or 5 rings are of interest. The
5cyclic structures include, .beta.Boswellic acid, 3O
Acetyl.beta.boswellic acid, 11Keto.beta.boswellic acid, 30
Acetyl11keto.beta.boswellic acid, 11Hydroxy.beta.boswellic acid, 3O
Acetoxy11methoxy.beta.boswellic acid, 3O
Acetyl11hydroxy.beta.boswellic acid, 9,11Dehydro.beta.boswellic
acid, 3O Acetyl9,11dehydro.beta.boswellic acid, aBoswellic acid, 3O
Acetylaboswellic acid, Oleanolic acid, Ursolic acid, Baurenol,
Lupeol, 11Hydroxyaboswellic acid, 9,11Dehydroaboswellic acid, 3O
Acetyl9,11dehydroaboswellic acid,
3Hydroxy8,9,24,25tetradehydrotirucallic acid, 3O
Acetyl8,9,24,25tetradehydrotirucallic acid, and
3Oxo8,9,24,25tetradehydrotirucallic acid.
Ratio Considerations in the Gel Phase
[0140] The density of the hydrophilic side chains along the polymer
backbone depends in part on the molecular weight of the side
chains. The total percent of the hydrophilic units to the
hydrophobic units in the present polymers is between 10 and 50
percent by weight, preferably around 30 percent by weight.
[0141] One relevant consideration when determining an appropriate
ratio of hydrophilic to hydrophobic units is that the overall
polymer, when the hydrophilic side chains are not endcapped with
cellsignaling moieties, has some noncell binding properties and
preferably incorporates a hallo of water around the polymeric
construct when implanted in a mammalian body. A relatively high
density of 500 Dalton or less hydrophilic side chains can provide
the same degree of resistance to cellular adhesion as a lower
density of higher molecular weight side chains. Those of skill in
the art can adjust the molecular weight and density of the polymers
taking these factors into consideration.
Density of Tethered Biofunctional Solid Phase
[0142] The side chains of the present invention can be optionally
bonded to the solid phases, or polymerized around the solid phases.
The solid phase can be cellsignaling regarding its geometrical
shape. Chemical ligands can be added to the solid phase in order to
elicit specific cell responses. Ligands such as adhesion peptides
or growth factors can be covalently or ionically attached to the
solid phase or mixed within. A defined fraction of ligandbearing
solid phases can be obtained by using appropriate stoichiometric
control during the coupling of the ligands to the solid phase, by
protecting one or more constituents of the solid phase from
reaction with ligands, or by a combination of these approaches.
Polymeric Mixtures (Both Solid and Gel Phase)
[0143] Comb and dendritic polymers can comprise the solid phase as
well as the gel phase. When hyaluronan is coupled to a comb or
dendritic polymer morphology, cells attach and spread readily on
the polymer surface. Accordingly, the solid phase may be coated
with these structures. Preferably, cellular proliferation due to
the solid is delayed, typically by about 14 days postimplant, so as
not to promote tissue adhesion. Adhesion in biological systems is
primarily an acute response to a significant disruption of
biological structure. Such disruption is associated with release of
cytokines that trigger a multiplicity of cellular responses. Given
that the gel system is designed to repair or correct the condition
responsible for initiation of the acute cellular response, there is
a need to down regulate that response, particularly because it
tends to be counter to organized cellular repair and healing. Thus,
there is a need for a first palliative interval associated with the
gel fraction wherein affected tissue surfaces are physically
separated, and where the usual cellular communications are
disrupted. The requirement is nonspecific, and usually a crude
physical barrier is sufficient. However, this deprives the
underlying damaged tissue from important nutrient and oxygenation
associated with tissue formation. Thus the purpose of the present
invention is to initially block using relatively convention gel
approaches coupled with a solid aspect that is released in delayed
fashion by degradation of the gel fraction or encounter only
subsequently by infiltrating tissue, such that a healing response
is promoted.
[0144] An important aspect in healing is angiogenesis which
provides the metabolic capacity for repair. With respect to this
second interval of tissue interaction, the degree of cell spreading
and proliferation on the surface of the polymeric implant or the
release of constituents that induce such a response within the
surrounding tissue can be controlled by mixing within the solid
phase, relatively hydrophobic copolymers with strongly hydrophilic
dendritic or comb polymers.
[0145] The size of the biofunctional solid phase and the spatial
density of the biofunctional solid phase within the gel is dictated
by the rate of absorption of the gel phase.
[0146] The copolymers described herein can be blended with other
polymers that do not elicit controlled cell responses. In
applications where it is desirable to use a biofunctionalized
copolymer to modify the surface of a second polymer, the polymers
may be processed to achieve segregation of bioactive moieties.
Avoiding a Crystalline State
[0147] Returning to the original thesis, wherein a gel system
provides order to the healing process and avoids chaotropic effect,
it is important to consider the degradation and resorption process
of the gel/biological system as a whole. It is recognized that
certain clinically useful functionalities, such as the blocking of
adhesion formation either by chemotactic sequestration or by
physical barrier, are desired; it is important to consider the
system as a whole. Many absorbable implants degrade by forming
numerous particulate, other absorbables degrade by a surface
reaction wherein the tissue exposed surface decreases in molecular
weight and forms a diffuse cloud of degradation byproducts. Ideally
neither outcome is achieved. A biodegradable implant is preferably
dismantled either at the surface or volumetrically in discrete
small molecular weight units. In particular, the macroscopic
appearance of the implant does not change, but rather its volume
decreases. One can imagine the analogy to a hard candy sweet,
wherein the candy transitions from a hard solid without a
peripheral boundary of diffuse structure. This desired effect can
be achieved volumetrically as well, wherein the shape of the
implant does not change appreciably, but the tensile strength and
molecular weight of the implant diminishes. However, even if this
desired result is achieved initially, it is not desirable for the
implant to ultimately fractionate. It is more desirable for the
tensile strength to decrease and the final product to be in a
gellike state and highly tenuous without fractionation.
[0148] Accordingly, the solid phase should not contribute to the
ultimate fractionation of the gel system in vivo. More
particularly, the solid phase should not act as a nidus for
fractionation of the implant. If the implant should ultimately
fractionate, the resulting particulate formation should have a
modulus substantially below that of tissue. There are two ways to
achieve this endpoint. Firstly, the solid phase transforms into the
gel phase, and the resulting gel phase resorbs in a homogeneous
fashion analogous to the original gel phase. Secondly, the solid
phase becomes a structural element of the healing tissue. For
example, solid fibrils within the gel are comprising a cellular
constituent, for example hyaluronan, wherein they are directly
incorporated into the tissue structure. In other aspects, the solid
phase is fed upon by cells, providing both a directional stimulus
and a nutrient or chemical advantage to local cells. Thus, the soli
phase can be considered a nutrient or chemical supplement that aids
in regenerative processes. Such supplemental effects may include
cellular signaling, both at the energetic level and at the amino
acid instructional level.
[0149] In consideration of the above, if the solid phase is small
enough, fractionation of the implant by release of a solid phase is
not necessarily disadvantageous, especially when such release in
original form or a degraded form, stimulates a path that results in
reduced disorder of the regenerating tissue.
[0150] In particular, the desired function of an implant is not to
create boundaries between tissues, since essentially the human body
is a freely intercommunication structure. Processes leading to
formation of fibrotic encapsulation, especially encapsulants that
are devoid of blood vessels, create zones that are segregated from
the normal immunological protections of the body. Such zones have
been shown clinically to be sites of endogenous infection,
sometimes many years after implantation.
[0151] Large scale crystalline structures within the body are
nonbiologic, generally. Any process that results in the formation
of atomically dense polyhedral molecular structures is to be
avoided. These structures can be individual, or comprise a
macroscopic volume. However, their density and strong internal
binding, resulting in the regular geometric shape, are inhibitory
to cellular processes. They are identified as foreign, and incite a
strong foreign body response which creates a multiplicity of
avascular tissue encapsulations. These encapsulations are benign at
the time of their formation, but are problematic in the long term
since they are not connected to the protective and restorative
processes of living tissue.
[0152] In the case of amorphous degradation, generally this mode of
resorption is preferred since the low density at the periphery
allows for some degree of cellular infiltration. In the late stage
of degradation, this cellular infiltration is associated with a low
degree of inflammation, primarily due to the absence of a
welldefined implant border. While it is preferred that the solid
phase contribute positively to the ordered regeneration of the
affected tissue, in absence of this ideal, a reduced foreign body
reaction and a low levelof inflammatory activity is much preferred
to usual modes of implant resorption.
Long-Term Lubricants in the Body
[0153] There are many clinical applications where a long term
lubricant, especially at joint surfaces would be beneficial.
Unfortunately, no implantable gel, whether comprises absorbable or
nonabsorbable chemical units, is permanent. The body is essentially
self-maintaining. There is not biologic locus where a lubricating
substance persists for the life of the individual. It is
unrealistic to expect a longterm synthetic material to exceed the
capabilities of the regenerative biologic system. The best outcome
is the restoration of functionality to the site, and in many cases
this entails reduction of an inflammatory response that in most
cases results in separation of tissue volumes and the inhibition of
restorative processes.
[0154] However, the repair process can be of long duration,
especially in those situations where blood supply is low. For
example, tendons are a classic example of high stress low metabolic
activity. In this situation, the tendon can actually be compromised
further by the addition of fibrotic tissue, resulting in an
increasingly more painful situation.
[0155] Accordingly, it may be useful, but not necessarily
physiologic, to provide a lubricant that may act beyond organic
moieties to reduce stressrelated degradation of an already
compromised biologic tissue. In these situations the
pressures/stresses may be extreme for short durations. There is
need for a shock absorber functionality. For example, consider a
gel phase that serves the purpose of providing lubricity and a
degree of separation between injured tissue, which without
separation may be joined by tissue and compromised further. In this
case, even if the addition of solid particulate to the gel
construct does not aid in maximum freedom of movement, its function
as a solid, and not easily deformed from its designed shape, makes
it ideal as a shock absorber. Thus in those situation where stress
is extreme and local, and normal gels would be thinned to the point
of being ineffective, a residual solid particulate fraction would
provide a high modulus layer of protection, wherein surfaces do not
abrade or impart their maximum kinetic energy. In this situation,
the particulate fraction serves only an auxiliary function, they do
not contribute to wound repair but rather provide a safeguard,
wherein when forces exceed a certain threshold they prevent a
bottoming action that may result in further tissue degradation. In
the case where the gel is quickly resorbed in one fraction, a
second gel fraction can be of longer duration of small volume, and
principally serving as a coupling mechanism between particles,
where in the final stages there is remaining only a thin layer of
less resorbable gel coupling a solid phase with a clinically useful
modulus not achieved in the bulk gel implantation.
Adherent Gel Systems
[0156] The primary dislocation of gels implanted in the body for a
specific function is the effect of gravitational slumping. Stated
simply, the lower energy state of any sufficiently dense implant,
is for the implant to migrate to lower elevations within the body.
This slumping effect can be exacerbated by the presence of defects
or voids between tissue layers. In many cases, the slumping of an
implanted gel results in the gel being displaced to a location
where pressures are low and where the gel is essentially not
needed. Furthermore, in cases where the gel pools into generally
spherical volumes, the implant can result in regions where
microbial growth is sequestrated from normal cellular protective
mechanism. Thus, there is a need for a gel implant to retain its
shape, and more importantly adhere to the tissue surfaces
designated by a surgeon.
[0157] Gravitational slumping can be avoided to a considerable
degree by engineering a preferred shape into the gel construct.
However, that shape is not always a priori known, and a surgeon
would like the implant to assume the shape of the tissue to which
it is applied. In this case, an in situ polymerizing gel construct
offers several advantages. Given the extremely challenging
regulatory environment for in situ polymerizing products, other
avenues are commercially more viable.
[0158] For example, mucoadhesive systems have been considered. They
offer good initial localization of an implant. However, longer
term, the fluids present in the body equilibrate with the van der
Waals forces essential to the mucoadhesive functionality and
eventually render mucoadhesivity ineffective. In many cases a
shortterm adhesive functionality is clinically useful, and many
polysaccharide compositions of the present invention fulfill this
need.
[0159] However, there is a need for an implant localizing mechanism
which is not rendered ineffective by the body. Such methodologies,
in the absence of chemical bonding, constitute high energy
surfaces, which precipitate a protein denaturation, and
consequently a permanent localization of a surface with respect to
tissue.
[0160] Generally, as described previously, denaturation of proteins
is not a desired outcome. However, when it is surface specific, and
of limited volume its utility exceeds is disadvantages. To this
end, it is instructive to consider the biological world, and in
particular superhydrophobic surfaces. For example, in the case of a
rose petal, a droplet is immobilized on the rose petal surface.
This effect, known as the CassieWenzel effect relies on a three
phase juxtaposition between the solid of the petal surface, the
liquid in a spherical geometry, and the air which serves to
localized the liquid/solid interface my means of a
nanostructure.
[0161] In the body we do not have three phases available, gases are
absent. However, there is a distinction to be made between polar
water and hydrophobic substances such as oils and fats. In the
body, there is an abundance of segregated hydrophobic and
hydrophilic domains. These substances behave similarly to the
relationship between gas and solids. They essentially do not
interact. Thus when a structure is juxtaposed between two
nonreacting media, such as water between as solid/gas interface,
the results can be localization of the water. In the case of living
tissue, a substance can be interposed between the hydrophilic and
hydrophobic constituents of the body. That substance must possess a
hierarchy of structural surfaces, some of which are predisposed to
attracting the hydrophilic fraction and other which is predisposed
to attracting the hydrophobic fraction. Thus we define a
liquidliquid analogue to the CassieWenzel effect, wherein the
essential geometry remains the same.
[0162] The present invention discloses an novel tissue adherent
mechanism, analogous to the CassieWenzel effect in air, whereby the
differences in surface energy between the two constituents creates
a localization of the implant in vivo which is not saturated in the
body.
[0163] Additionally, wherein the localization is maintained for an
extended period, the surface texture may additionally serve as a
tissue scaffolding technology. Accordingly, not all of the solid
phase surface need be devoted to a localization effect, other
surface elements or other surface particulates may be devoted to
the scaffolding aspect.
[0164] In summary, there are three ways to localize a gel in situ:
1) sticky, e.g., mucoadhesive, 2) frictional, the opposite of
lubricious, and 3) in situ polymerizing, where bonds are formed
between implant and living tissue.
Entropic Considerations
[0165] Any system liberating heat increases the entropy of that
system. In the body, the healing process liberates large amount of
heat, both in the reparative process and in the degradation of
failed cellular constituents. It is a challenge in the medical
sciences to enhance the healing process without increasing it
entropy.
[0166] Historically, the case of mesh augmented soft tissue repair
is instructive. Initially it was thought that placing an
antagonistic material in the body, such as polypropylene, would
enhance the healing process by increasing the energy dissipation at
the wound site by an upregulated foreign body response. While
increase heat output and increased cellular activity were achieved,
these endpoints did not result in product wound healing.
[0167] In the case where dense encapsulation occurred due to the
antagonistic nature of the implant material, blood supply was
eliminated or severely curtailed to the implant site. As a result,
bacteria which preferentially adhere to such high energy sites,
proliferated, whether they be there as a result of the initial
implantation or by an endogenous source.
[0168] It is noteworthy to recognize that in such environments,
bacterial counts too low to exceed the normal bodily responses
exceed them in such a high energy environment. The combination of
high surface energy, necrotic tissue debris, and the inhibit of
regular antimicrobial cellular processes, results in a highly
disorder wound repair, as well as possible systemic adverse
events.
[0169] This clinical experience has resulted in the generally
accepted belief that less is more, and that mesh prosthetics
intended to strengthen soft tissue defects are beneficially
constructed when they contain less material, leading to the now
generally accepted criterion of areal density. Reduced areal
density is considered a positive, although this results in a vastly
decreased tensile strength. Thus the original intension of soft
tissue augmentation prosthetics has be supplanted by the desire for
a more normal and ordered repair. The reason for this is that
disordered repairs often fail since they are not metabolically
viable. Common to both concerns is the avoidance of dense,
avascular tissue that shields the implant from antimicrobial
processes and also prevents an ordered repair of the tissue
site.
[0170] While the gels of the present invention are not intended to
provide a reinforcing benefit initially, they can achieve this
result in the longer term. There is presently no successful
replacement for tissue to correct a tissue defect. Synthetics
undergo encapsulation, shrinkage, and ultimately provide no support
to the affect region. Biologics degrade quickly, and provide only
minimal support during their short tenure within the body. In fact,
these approaches have been fundamentally misdirected in that they
seek to provide a mechanical enhancement, while neglecting the fact
that such mechanical enhancement is fundamentally opposed to normal
tissue restoration. These repairs have certainly found utility in
extremely pathologic cases or in individuals where normal healing
is compromised. But far too often, these mesh are implanted in
individuals where a simple suture repair of the defect would
suffice; and this is especially true in women of childbearing age
where regenerative processes are naturally elevated.
[0171] One can appreciate the truth in the concept of "less is
more", if that concept means no mechanical support is more. In
essence, what is needed in healthy individuals is a support for
normal healing, and not a replacement. Necessarily, to support a
site means to be present at a site, and one of the main
disadvantages of current gel technologies is that they
gravitationally migrate from the site needing support. The support
is not one of reducing forces or bridging tissue layers. The
support is one of correcting the abiological instance of surgical
intervention. While the actual treatment of the defective tissue
site may be beneficial, surgically getting to that site initiates a
cascade of cellular responses that are, at least in the short term,
deleterious. For example, infection is never a concern for
individuals that rejuvenate without the need for surgical
intervention. Similarly remodeling of tissue, and the ballingup of
surgical implants never occurs in injured tissue without the
presence of a prosthetic. These observations indicate that
promoting healing is more beneficial to a patient that mechanically
reinforcing a softtissue defect.
[0172] In short, there is no methodology at present that supersedes
the effectiveness of normal tissue repair. In considering this
observation, what differentiates normal tissue repair from
synthetic tissue augmentation? If one looks at the tissue site 3
months after the initial insult in any repair where normal healing
occurs and synthetic augmentation was instituted, it is always the
case that in the normal healing instance the entropic state or the
ordered appearance of the tissue is always greater in the normal
healing case. This is not to say that there are not cases where the
tissue defect is so extreme that it can be repaired by normal
processes. Thus, whether one advocates for minimal surgical
intervention or otherwise, the main criteria for success are not
how strong the repair methodology is, but rather the orderliness of
the repair, and this is supported by the recent popularity in using
reduced areal density mesh, even though these mesh are insufficient
in cases where the normal reparative mechanism is insufficient.
[0173] It is not sufficient to not interfere in the normal healing
process, if that was sufficient surgeons would never have opted for
the various tissue augmentation methodologies available on the
market. Thus, beyond the need to block adverse tissue layer to
tissue layer adhesion, there is a greater need to promote and
accelerate normal tissue healing mechanism. Chief among these
criteria are the need for blood supply, because without blood
supply no metabolic mechanism can be employed in tissue repair. In
fact, it is likely in all situations that a prosthetic that
promotes blood delivery to a region accomplishes more than any
other therapeutic treatment regarding optimal repair of soft tissue
defects Clinically the industry has concentrated on pain, and not
surprisingly, since all synthetic interventions provide a short
term mechanical benefit at the cost of long term insufficiency on
many levels. Long term risk/benefit is just now being realized. To
avoid the long term adverse events one must minimize the synthetic
intervention, even if it means compromising tissue repair in the
short term and this is essentially the program currently in vogue
concerning light weight mesh. However, merely reducing the
chaotropic effect is not in itself a benefit.
[0174] To be clinically useful, the implant must provide an
ordering effect, not in terms of setting things identically, but in
terms of providing continuity to the surrounding tissue structure.
Thus, establishing order in a biologic system does not mean
simplifying, or minimizing variability, it simply means matching
the dimensional aspects of the surrounding tissue. The dimensional
aspects being the number and range of hierarchical structures
present in tissue, understanding the energetic and fluid mechanical
needs of living cells, and stemming the short term needs without
disrupting the normal cellular repair process. There are clearly
enhancements over these essential needs, many of which are
currently under study, and therefore we include in this largely
physical set of considerations the biological considerations
regarding the chemical signaling of cells.
Drug Delivery Aspect
[0175] In another aspect of the invention, the multiphasic gel
comprises a biofunctional molecule at a concentration from about 5%
to about 50% of the implant by weight. The molecule may be
incorporated in the gel fraction if it is water soluble, and in the
solid fraction if not water soluble. The gel phase may be loaded
with excipients to control drug release both from the soli phase
and the gel phase. Excipients useful in the present invention are
tocopherol isomers and/or their esters; tocotrienols and/or their
esters; benzyl alcohol; benzyl benzoate; those dibenzoate esters of
poly(oxyethylene) diols having low water solubility; dimethyl
sulfone; poly(oxypropylene) diols having low water solubility; the
mono, di, and triesters of Oacetylcitric acid with straight and
branched chain aliphatic alcohols; and liquid and semisolid
polycarbonate oligomers.
[0176] The biofunctional agent of the present invention is selected
from the group consisting of analgesics, anesthetics, narcotics,
angiostatic steroids, anti-inflammatory steroids, angiogenesis
inhibitors, nonsteroidal antiinflammatories, antiinfective agents,
antifungals, antimalarials, antitublerculosis agents, antivirals,
alpha androgenergic agonists, beta adrenergic blocking agents,
carbonic anhydrase inhibitors, mast cell stabilizers, miotics,
prostaglandins, antihistamines, antimicrotubule agents,
antineoplastic agents, antipoptotics, aldose reductase inhibitors,
antihypertensives, antioxidants, growth hormone agonists and
antagonists, vitrectomy agents, adenosine receptor antagonists,
adenosine deaminase inhibitor, glycosylation antagonists, anti
aging peptides, topoisemerase inhibitors, antimetabolites,
alkylating agents, antiandrigens, antioestogens, oncogene
activation inhibitors, telomerase inhibitors, antibodies or
portions thereof, antisense oligonucleotides, fusion proteins,
luteinizing hormone releasing hormones agonists, gonadotropin
releasing hormone agonists, tyrosine kinase inhibitors, epidermal
growth factor inhibitors, ribonucleotide reductase inhibitors,
cytotoxins, IL2 therapeutics, neurotensin antagonists, peripheral
sigma ligands, endothelin ETA/receptor antagonists,
antihyperglycemics, antiglaucoma agents, antichromatin modifying
enzymes, insulins, glucagonlikepeptides, obesity management agents,
anemia therapeutics, emesis therapeutics, neutropaenia
therapeutics, tumorinduced hypercalcaemia therapeutics, blood
anticoagulants, immunosuppressive agents, tissue repair agents,
psychotherapeutic agents, botulinum toxins (Botox, Allergan), and
nucleic acids such as siRNA and RNAi.
[0177] Specific areas of the human or animal body to be targeted
for injection or implantation or topical applications of these
multiphasic gel system include, but are not limited to: heart,
brain, spinal nerves, vertebral column, skull, neck, head, eye, ear
organs of hearing and balance, nose, throat, skin, viscara, hair,
shoulder, elbow, hand, wrist, hip, knee, ankle, foot, teeth, gums,
liver, kidney, pancreas, prostate, testicles, ovaries, thymus,
adrenal glands, pharynx, larynx, bones, bone marrow, stomach,
bowel, upper and lower intestines, bladder, lungs, mammaries.
[0178] The multiphasic gel system according to the present
invention has particular applicability in providing a controlled
and sustained release of active agents effective in obtaining a
desired local or systemic physiological or pharmacological effect
relating at least to the following areas: treatment of cancerous
primary tumors, chronic pain, arthritis, rheumatic conditions,
hormonal deficiencies such as diabetes and dwarfism, modification
of the immune response such as in the prevention and treatment of
transplant rejection and in cancer therapy.
[0179] The system is also suitable for use in treating HIV and HIV
related opportunistic infections such as CMV, toxoplasmosis,
Pneumocystis carinii and Mycobacterium avium intercellular. The
system may be used to create layers between tissue, in particular
between layers of tissue modified by surgical intervention in order
to direct or stimulate healing and the separate adjacent tissue
layers that would be compromised by the formation of adhesions.
[0180] Other uses of the formulations include, for example,
mediating homograft rejection with formulations comprising
surolimus or cyclosporine. Local cancer therapy may be delivered
to, for example, the kidney or liver, using in formulations
comprising, for example, adriamycin or small epidermal growth
factors. Prostate cancer may be treated with formulations including
fenasteride. Cardiac stents implants, central nervous system
implants (e.g., spinal implants), orthopedic implants, etc., may be
coated with formulations including growth or differentiation
factors, anti-inflammatory agents, or antibiotics. In particular,
botanical extracts known to possess antimicrobial or healing
stimulative properties are useful.
[0181] Suitable classes of active agents for use in the system of
the present invention include, but are not limited to the
following: peptides and proteins such as cyclosporin, insulins,
glucagon-like peptides, growth hormones, insulin related growth
factor, botulinum toxins, and heat shock proteins; anesthetics and
pain killing agents such as lidocaine and related compounds, and
benzodiazepam and related compounds; anticancer agents such as
5-fluorouracil, methotrexate and related compounds;
anti-inflammatory agents such as 6-mannose phosphate; Antifungal
agents such as fluconazole and related compounds; antiviral agents
such as trisodium phosphomonoformate, trifluorothymidine,
acyclovir, cidofovir, ganciclovir, DDI and AZT; cell
transport/mobility impending agents such as colchicines,
vincristine, cytochalasin B and related compounds; anti-glaucoma
drugs such as beta-blockers: timolol, betaxolol atenolol;
immunological response modifiers such as muramyl dipeptide and
related compounds; steroidal compounds such as dexamethasone,
prednisolone, and related compounds; and carbonic anhydrase
inhibitors.
[0182] It is also contemplated that these multiphasic gel
formulations can be coatings on implanted surfaces, such as but not
limited to, those on catheters, stents (cardiac, CNS, urinary,
etc.), prothesis (artificial joints, cosmetic reconstructions, and
the like), tissue growth scaffolding fabrics, or bones and teeth to
provide a wide variety of therapeutic properties (such as but not
limited to, anti-infection, anticoagulation, anti-inflammation,
improved adhesion, improved tissue growth, improved
biocompatibility).
[0183] These surfaces can be from a wide variety of materials, such
as but not limited to, metals, polyethylene, polypropylene,
polyurethanes, polycarbonates, polyesters, poly(vinyl actetates),
poly(vinyl alcohols), poly(oxyethylenes), poly(oxypropylenes),
cellulosics, polypeptides, polyacrylates, polymethacrylates,
polycarbonates and the like.
[0184] Active agents, or active ingredients, that may be useful in
the present invention, as determined by one of ordinary skill in
the art in light of this specification without undue
experimentation, include but are not limited to:
[0185] Analgesics, Anesthetics, Narcotics such as acetaminophen;
clonidine (Duraclon Roxane) and its hydrochloride, sulfate and
phosphate salts; oxycodene (Percolone, Endo) and its hydrochloride,
sulfate, phosphate salts; benzodiazepine; benzodiazepine
antagonist, flumazenil (Romazicon, Roche); lidocaine; tramadol;
carbamazepine (Tegretol, Novartis); meperidine (Demerol,
SanofiSynthelabo) and its hydrochloride, sulfate, phosphate salts;
zaleplon (Sonata, WyethAyerst); trimipramine maleate (Surmontil,
WyethAyerst); buprenorphine (Buprenex, Reckitt Benckiser);
nalbuphine (Nubain, Endo) and its hydrochloride, sulfate, phosphate
salts; pentazocain and hydrochloride, sulfate, phosphate salts
thereof; fentanyl and its citrate, hydrochloride, sulfate,
phosphate salts; propoxyphene and its hydrochloride and napsylate
salts (Darvocet, Eli Lilly& Co.); hydromorphone (Dilaudid,
Abbott) and its hydrochloride, sulfate, and phosphate salts;
methadone (Dolophine, Roxane) and its hydrochloride, sulfate,
phosphate salts; morphine and its hydrochloride, sulfate, phosphate
salts; levorphanol (Levodromoran, ICN) and its tartrate,
hydrochloride, sulfate, and phosphate salts; hydrocodone and its
bitartrate, hydrochloride, sulfate, phosphate salts;
[0186] Angiostatic and/or Antiinflammatory Steroids such as
anecortive acetate (Retaane.RTM., Alcon, Inc., Fort Worth, Tex.);
tetrahydrocortiso; 4,9(11)-pregnadien-17-.alpha.-21-diol-3,20-dione
(Anecortave) and its 21-acetate salt; 11-epicortisol;
17-.alpha.-hydroxyprogesterone; tetrahydrocortexolone; cortisone;
cortisone acetate; hydrocortisone; hydrocortisone acetate;
fludrocortisone; fludrocortisone acetate; fludrocortisone
phosphate; prednisone; prednisolone; prednisolone sodium phosphate;
methylprednisolone; methylprednisolone acetate; methylprednisolone,
sodium succinate; triamcinolone; triamcinolone-16,21-diacetate;
triamcinolone acetonide and its 21-acetate, 21-disodium phosphate,
and 21-hemisuccinate forms; triamcinolone benetonide; triamcinolone
hexacetonide; fluocinolone and fluocinolone acetate; dexamethasone
and its 21-acetate, 21-(3,3dimethylbutyrate), 21-phosphate disodium
salt, 21-diethylaminoacetate, 21-isonicotinate, 21-dipropionate,
and 21-palmitate forms; betamethasone and its 21-acetate,
21-adamantoate, 17-benzoate, 17,21-dipropionate, 17-valerate, and
21-phosphate disodium salts; beclomethasone; beclomethasone
dipropionate; diflorasone; diflorasone diacetate; mometasone
furoate; and acetazolamide (Diamox.RTM. Lederle Parenterals, Inc.,
Carolina, Puerto Rico; several other manufacturers);
21-nor-5-.beta.-pregnan 3-.alpha.-17-.alpha.-20-triol-3-acetate;
21-nor-.beta.-pregnan-3-.alpha.-17-.alpha.-20-triol-3-phosphate;
21-nor-5-.beta.-pregn-17-20)en-3-.alpha.-,16-diol;
21-nor-5-.beta.-pregnan-3-.alpha.-,17-.beta.-,20-triol;
20-acetamide-21-nor-5-.beta.-pregnan
3-.alpha.-,17-.alpha.-diol-3-acetate;
3-.beta.-acetamido-5-.beta.-pregnan-11-.beta.-,17-.alpha.-,21-triol-20-on-
e-21-acetate,
21-nor-5-.alpha.-pregnan-3-.alpha.-17-.beta.-20-triol;
21-.alpha.-methyl-.beta.-pregnan-3-.alpha.-,11-.beta.-17-.alpha.-21-tetro-
l-20-one-21-methyl ether;
20-azido-21-nor-5-.beta.-pregnan-3-.alpha.-,17-.alpha.-diol;
20-(carbethoxymethyl)-thio-21-nor-5-.beta.-pregnan-3-.alpha.-.,17-.alpha.-
-diol;
20-(4-fluorophenyl)-thio-21-nor-5-.beta.-pregnan-3-.alpha.-17.alpha-
.diol;
16-.alpha.-(2-hydroxyethyl)-17-.beta.-methyl-5-.beta.-androstan-3-.-
alpha.-,17-.alpha.-diol;
20-cyano-21-nor-5-.omega.-pregnan-3-.alpha.-,17-.alpha.-diol;
17-.alpha.-methyl-5-.beta.-androstan-3-.alpha.-.,17-.beta.-diol;
21-nor-5-.beta.-pregn-17(-20)en-3-.alpha.-ol; 21or
5-.beta.-pregn-17(20)en-3-.alpha.-ol-3-acetate;
21-nor-5-pregn-17(20)-en-3-.alpha.-ol-16-acetic acid 3-acetate;
3-.beta.-azido-5-.beta.-pregnan-11-.beta.-,17-.alpha.-,21-triol-20-one-21-
-acetate; an
5-.beta.-pregnan-11-.beta.-17-.alpha.-,21-triol-20-one;
4-androsten-3one-17-.beta.-carboxylic acid;
17-.alpha.-ethynyl5(10)estren17-.beta.-ol3one; and
17-.alpha.-ethynyl1,3,5(10)estratrien3,17-.beta.-diol.
[0187] Nonsteroidal Antiinflammatories such as naproxin;
diclofenac; celecoxib; sulindac; diflunisal; piroxicam;
indomethacin; etodolac; meloxicam; ibuprofen; ketoprofen;
rflurbiprofen (Myriad); mefenamic; nabumetone; tolmetin, and sodium
salts of each of the foregoing; ketorolac bromethamine; ketorolac
bromethamine tromethamine (Acular.RTM., Allergan, Inc.); choline
magnesium trisalicylate; rofecoxib; valdecoxib; lumiracoxib;
etoricoxib; aspirin; salicylic acid and its sodium salt; salicylate
esters ofalpha, beta, gammatocopherols and tocotrienols (and all
their d, l, and racemic isomers); methyl, ethyl, propyl, isopropyl,
nbutyl, secbutyl, tbutyl, esters of acetylsalicylic acid.
[0188] Angiogenesis Inhibitors such as squalamine, squalamine
lactate (MS11256F, Genaear) and curcumin; Vascular Endothelial
Growth Factor (VEGF) Inhibitors including pegaptanib (Macugen,
Eyetech/Pfizer); bevacizumab (Avastin, Genentech/generic);
Neovastat (Aeterna); PTK 787 (Schering/Novartis); Angiozyme
(RibozymeChiron); AZD 6474 (AstraZeneca); IMC1C11 (Imclone); NM3
(ILEX Oncology); S6668 (Sugen/Pharmacia); CEP7055 (Cephalon); and
CEP5214 (Cephalon); Integrin Antagonists such as Vitaxin (Applied
Molecular Evolution/Medimmune); S 137 (Pharmacia); S247
(Pharmacia); ST 1646 (Sigma Tau); DPC A803350 (BristolMyers
Squibb); and oguanudines (3D Pharmaceuticals/generic); matrix
metalloproteinase inhibitors such as prinomastat (AG 3340,
Pfizer/generic), (ISV616, InSite Vision), (TIMP3, NIH); S3304
(Shionogi); BMS 275291 (Celltech/BristolMyers Squibb); SC 77964
(Pharmacia); ranibizumab (Lucentis, Genentech); ABT 518 (Abbott);
CV 247 (Ivy Medical); shark cartilage extract (Neovastat, Aeterna);
NX278L antiVEGF aptamer (EyeTech); 2'Omethoxyethyl antisense Craf
oncogene inhibitor (ISIS13650) vitronectin and osteopontin
antagonists (3D Pharm); combretstatin A4 phosphate (CA4P, Oxigene);
fab fragment.alpha.V/beta.1 integrin antagonist (Eos200Protein
Design Labs); .alpha.v/. beta.3 integrin antagonist (Abbott);
urokinase plasminogen activator fragment (A6, Angstrom Pharm.);
VEGF antagonist (AAVPEDF, Chiron); kdr tyrosine kinase inhibitor
(EG3306, Ark Therapeutics); cytochalasin E (NIH);
kallikrininbinding protein (Med. Univ. So. Carolina);
combretastatin analog (MV540, Tulane); pigmentepithelium derived
growth factor (Med. Univ. S.C.); pigmentepithelium derived growth
factor (AdPEDF, GenVec/Diacrin); plasminogen kringle (Med. Univ.
S.C.); rapamycin; cytokine synthesis inhibitor/p38 mitogenactivated
protein kinase inhibitor (SB220025, GlaxoSmithKline); vascular
endothelial growth factor antagonist (SP(V5.2)C, Supratek);
vascular endothelial growth factor antagonist (SU10944,
Sugen/Pfizer); vascular endothelial growth factor antagonist.
[0189] Antiinfective Agents such as Antibacterials including
aztreonam; cefotetan and its disodium salt; loracarbef; cefoxitin
and its sodium salt; cefazolin and its sodium salt; cefaclor;
ceftibuten and its sodium salt; ceftizoxime; ceftizoxime sodium
salt; cefoperazone and its sodium salt; cefuroxime and its sodium
salt; cefuroxime axetil; cefprozil; ceftazidime; cefotaxime and its
sodium salt; cefadroxil; ceftazidime and its sodium salt;
cephalexin; cefamandole nafate; cefepime and its hydrochloride,
sulfate, and phosphate salt; cefdinir and its sodium salt;
ceftriaxone and its sodium salt; cefixime and its sodium salt;
cefpodoxime proxetil; meropenem and its sodium salt; imipenem and
its sodium salt; cilastatin and its sodium salt; azithromycin;
clarithromycin; dirithromycin; erythromycin and hydrochloride,
sulfate, or phosphate salts ethylsuccinate, and stearate forms
thereof; clindamycin; clindamycin hydrochloride, sulfate, or
phosphate salt; lincomycin and hydrochloride, sulfate, or phosphate
salt thereof; tobramycin and its hydrochloride, sulfate, or
phosphate salt; streptomycin and its hydrochloride, sulfate, or
phosphate salt; vancomycin and its hydrochloride, sulfate, or
phosphate salt; neomycin and its hydrochloride, sulfate, or
phosphate salt; acetyl sulfisoxazole; colistimethate and its sodium
salt; quinupristin dalfopristin; amoxicillin; ampicillin and its
sodium salt; clavulanic acid and its sodium or potassium salt;
penicillin G; penicillin G benzathine, or procaine salt; penicillin
G sodium or potassium salt; carbenicillin and its disodium or
indanyl disodium salt; piperacillin and its sodium salt;
ticarcillin and its disodium salt; sulbactam and its sodium salt;
moxifloxacin; ciprofloxacin; ofloxacin; levofloxacins; norfloxacin;
gatifloxacin; trovafloxacin mesylate; alatrofloxacin mesylate;
trimethoprim; sulfamethoxazole; demeclocycline and its
hydrochloride, sulfate, or phosphate salt; doxycycline and its
hydrochloride, sulfate, or phosphate salt; minocycline and its
hydrochloride, sulfate, or phosphate salt; tetracycline and its
hydrochloride, sulfate, or phosphate salt; oxytetracycline and its
hydrochloride, sulfate, or phosphate salt; chlortetracycline and
its hydrochloride, sulfate, or phosphate salt; metronidazole;
rifampin; dapsone atovaquone; rifabutin; linezolide; polymyxin B
and its hydrochloride, sulfate, or phosphate salt; sulfacetamide
and its sodium salt; minocycline; and clarithromycin:
[0190] Antifungals such as amphotericin B; pyrimethamine;
flucytosine; caspofungin acetate; fluconazole; griseofulvin;
terbinafin and its hydrochloride, sulfate, or phosphate salt;
ketoconazole; micronazole; clotrimazole; econazole; ciclopirox;
naftifine; and itraconazole.
[0191] Antimalarials such as chloroquine and its hydrochloride,
sulfate or phosphate salt; hydroxychloroquine and its
hydrochloride, sulfate or phosphate salt; mefloquine and its
hydrochloride, sulfate, or phosphate salt; atovaquone; proguanil
and its hydrochloride, sulfate, or phosphate salt forms.
[0192] Antituberculosis Agents such as ethambutol and its
hydrochloride, sulfate, or phosphate salt forms; aminosalicylic
acid; isoniazid; pyrazinamide'; ethionamide.
[0193] Antivirals such as amprenavir; interferon alfan3; interferon
alfa2b; interferon alfacon1; peginterferon alfa2b; interferon
alfa2a; lamivudine; zidovudine; amadine (Symmetrel, Endo) and its
hydrochloride, sulfate, and phosphate salts; indinavir and its
hydrochloride, sulfate, or phosphate salt; ganciclovir; ganciclovir
sodium salt; famciclovir; rimantadine and its hydrochloride,
sulfate, or phosphate salt; saquinavir; valacyclovir and its
hydrochloride, sulfate, or phosphate salt; zinc ester complexes;
and zin; acetoacetonate or zinc acetoacetic ester complexes.
[0194] Anti HIV/AIDS agents including stavudine, reverset
(Pharmasset), ACH126443 (Achillion), MIV310 (Boehringer Ingelheim),
ZeritlR(d4tT) (BristolMeyers Squibb) Ziagen (GlaxoSmithKline),
Viroad (Glead), hivid (Roche), Emtriva (Gilead), delavirdine
(Pfizer), AG1549 (Pfizer), DPC083 (BristolMyers Squibb), NSC675451
(Advanced Life Sciences), IMC125 (Tibitec), azidicarbonamide,
GPGNH2 (Tripep), immunitin (Colthurst), cytolin (Cytodyn), HRG21
(Virionyx), MDX010 (Gilead), TXUPAP (Wayne Hughes Inst), proleukin
(Chiron), BAY 504798 (Bayer), BG777 (Virocell), Crixivan (Merck),
Fuzeon (HoffLaRoche), WF10 (Oxo Chemie), Ad5 Gag vaccine (Merck),
APIA00003 and 047 (Wyeth), Remunex (Immune Response Corp.), MVABN
Nef (Bavarian Nordic), GTU MultyHIV vaccine (FIT Biotech).
[0195] Insulins such as Novolog (aspart), Novolin R, Novolin N,
Novolin L, Novolin 70/30, and Novolog 70/30 (Novo Nordisk); Humalog
(lispro) Humulin R, Humulin N, Humulin L, Humulin 50/50 and 70/30,
and Humalog Mix 75/25 and 70/30 (Eli Lilly); Ultralente (Eli
Lilly); Lantus (glargine, Aventis); porcine; and bovine
insulins.
[0196] Glucagonlike Peptidel (Glp1) and analogs (for diabetes
therapy and appetite suppression, cardiac protection) (see Keiffer
et al., 20 Endocr Rev., 876913 (1999) Glp1 Receptor stimulators
such as exendin4, Exenatide and Exenatide LAR (Amylin Pharma);
Liraglutide (Novo Nordisk); ZP10 (Zealand Pharma); Glp1albumin
(Conjuchem); and DpplV inhibitors (which inhibit enzyme attack on
Glp1) such as LAF237 (Novartis); MK0431 (Merck); BMS477188
(BristolMyers Squibb); and GSK23A (GlaxoSmithKline);
[0197] Alpha Androgenergic Agonist such as brimonidine tartrate;
Beta Adrenergic Blocking Agents such as betaxolol and its
hydrochloride, sulfate, or phosphate salt; levobetaxolol and its
hydrochloride, sulfate, or phosphate salt; and timolol maleate.
[0198] Carbonic Anhydrase Inhibitors such as brinzolamide;
dorzolamide and its drochloride, sulfate, or phosphate salt; and
dichlorphenamide.
[0199] Mast Cell Stabilizers such as pemirolast and its potassium
salt; nedocromil and its sodium salt; cromolyn and its sodium
salt.
[0200] Miotics (Cholinesterase Inhibitors) such as demecarium
bromide.
[0201] Prostaglandins such as bimatoprost; travoprost; and
latanoprost.
[0202] Antihistamines such as olopatadine and its hydrochloride,
sulfate, or phosphate salt forms; fexofenadine and its
hydrochloride, sulfate, or phosphate salt; azelastine and its
hydrochloride, sulfate, or phosphate forms; diphenhydramine and its
hydrochloride, sulfate, or phosphate forms; and promethazine and
its hydrochloride, sulfate, or phosphate forms.
[0203] Antimicrotubule Agents such as Taxoids including paclitaxel
(Taxol, BristolMyers Squibb); vincristine (Oncovin, Eli Lilly &
Co.) and its hydrochloride, sulfate, or phosphate salt forms;
vinblastine (Velbe, Eli Lilly & Co.) and its hydrochloride,
sulfate, or phosphate salt; vinorelbine (Novelbinr, Fabre/GSK);
colchicines; docetaxel (Taxotere, Aventis); 109881 (Aventis); LIT
976 (Aventis); BMS 188797 (BristolMyers Squibb); BMS 184476
(BristolMyers Squibb); DJ 927 (Daiichi); DHA paclitaxel
(Taxoprexin, Protarga); Epothilones including epothiloneB (EPO 906,
Novartis/generic); BMS 247550 (BristolMyers Squibb); BMS 310705
(BristolMyers Squibb); epothilone D (KOS 862, Kosan/generic); and
ZK EPO (Schering AG).
[0204] Antineoplastic agents such as doxorubicin and its
hydrochloride, sulfate, or phosphate salt; idarubicin and its
hydrochloride, sulfate, or phosphate salt; daunorubicin and its
hydrochloride, sulfate, or phosphate salt; dactinomycin; epirubicin
and its hydrochloride, sulfate, or phosphate salt; dacarbazine;
plicamycin; mitoxantrone (Novantrone, OSI Pharmaceuticals) and its
hydrochloride, sulfate, or phosphate salt; valrubicin; cytarabine;
nilutamide; bicalutamide; flutamide; anastrozole; exemestane;
toremifene; femara; tamoxifen and tamoxifen citrate; temozolimide
(Temador); gemcitabine and its hydrochloride, sulfate, or phosphate
salt; topotecan and its hydrochloride, sulfate, or phosphate salt;
vincristine and its hydrochloride, sulfate, or phosphate salt;
liposomal vincristine (OncoTCS, Inex/Elan); methotrexate and
methotrexate sodium salt; cyclophosphamide; estramustine sodium
phosphate; leuprolide and leuprolide acetate; goserelin and
goserelin acetate; estradiol; ethinyl estradiol; Menest esterified
estrogens; Premarin conjugated estrogens; 5flurouracil; bortezamib
(Velcade, Millenium Pharmaceuticals).
[0205] Antiapoptotics such as desmethyldeprenyl (DES,
RetinaPharma).
[0206] Aldose Reductase Inhibitors such as GP1447 (Grelan); NZ314
(parabanic acid derivative, Nippon Zoki); SG210 (Mitsubishi
Pharma/Senju); and SJA705 (Senju).
[0207] Antihypertensives such as candesartan cilexetil
(Atacand/Biopress, Takeda/AstraZeneca/Abbott); losartan (Cozaar,
Merck); and lisinopril (Zestril/Prinivil, Merck/AstraZeneca).
[0208] Antioxidants such as benfotiamine (Albert Einstein Col. Of
Med./WorWag Pharma); ascorbic acid and its esters; tocopherol
isomers and their esters; and raxofelast (IRF1005, Biomedica
Foscama);
[0209] Growth Hormone Antagonists such as octreotide (Sandostatin,
Novartis); and pegvisomant (Somavert, Pfizer/Genentech); Vitrectomy
Agents such as hyaluronidase (Vitrase, ISTA Pharm./Allergan);
[0210] Adenosine Receptor Antagonist such as A2B adenosine receptor
antagonist (754, Adenosine Therapeutics);
[0211] Adenosine Deaminase Inhibitor such s pentostatin (Nipent,
Supergen);
[0212] Glycosylation Antagonists such as pyridoxamine (Pyridorin,
Biostratum);
[0213] Anti-Ageing Peptides, such as AlaGluAspGly (Epitalon, St
Petersburg Inst. Bioreg. and Geron).
[0214] Topoisomerase Inhibitors such as doxorubicin
(Adriamycin/Caelyx, Pharmacia/generics); daunorubicin (DaunoXome,
Gilead/generics); etoposide (Vepecid/Etopophos, BristolMyers
Squibb/generics; idarubicin (Idamycin, Pharmacia); irinotecan
(Camptosar, Pharmacia); topotecan (Hycamtin, GlaxoSmithKline);
epirubicin (Ellence, Phamacia); and raltitrexed (Tomudex,
AstraZeneca).
[0215] Antimetabolites such as methotrexate (generic) and its
sodium salt; 5fluorouracil (Adrucil, ICN Pharmacia); cytarabine
(Cytosar, Pharmacia/generic); fludarabine (Fludara, Schering) and
its forms as salts with acids; gemcitabine (Gemsar, Eli Lilly&
Co.); capecitabine (Xeloda, Roche); and perillyl alcohol (POH,
Endorex).
[0216] Alkylating Agents such as chlorambucil (Leukeran,
GlaxoSmithKline); cyclophosphamide (Cytoxan,
Pharmacia/BristolMeyers Squibb); methchlorethanine (generic);
cisplatin (Platinal, Pharmacia/BristolMeyers Squibb); carboplatin
(Paraplatin, BristolMyers Squibb); temozolominde (Temodar) and
oxaliplatin (SanofiSynthelabs).
[0217] Antiandrogens such as flutamide (Eulexin, AstraZeneca);
nilutamide (Anandron, Aventis); bicalutamide (Casodex,
AstraZeneca).
[0218] Antiestrogens such as tamoxifen (Nolvadex, AstraZeneca);
toremofine (Fareston, Orion/Shire); Faslodex (AstraZeneca);
arzoxifene (Eli Lilly & Co.); Arimidex (AstraZeneca); letrozole
(Femera, Novartis); Lentaron (Novartis); Aromasin (Pharmacia);
Zoladex (AstraZeneca); lasoxifene (CP366,156, Pfizer); ERA92
(Ligand/Wyeth); DCP 974 (DuPont/Bristol Myers Squibb); ZK 235253
(Shering AG); ZK1911703 (Shering AG); and ZK 230211 (Shering
AG);
[0219] Oncogene Activation Inhibitors, including for example,
BcrAbl Kinase Inhibition such as Gleevec (Novartis); Her2
Inhibition such as trastuzumab (Herceptin, Genentech); MDX 210
(Medarex); E1A (Targeted Genetics); ME103 (Pharmexa); 2C4
(Genentech); C11033 (Pfizer); PKI 166 (Novartis); GW572016
(GlaxoSmithKline) and ME104 (Pharmexa); EGFr Inhibitors such as
Erbitux (Imclone/BristolMyers Squibb/Merck KgaA); EGFr Tyrosine
Kinase Inhibitors such as gefitinib (Iressa ZD 1839, AstraZeneca);
cetuximab (Erbitux, Imclone/BMS/Merck KGaA); erlotinib (Tarceva,
OSI Pharmaceutical/Genentech/Roche) ABXEGF (Abgenix); C11033
(Pfizer); EMD 72000 (Merck KgaA); GW572016 (GlaxoSmithKline); EKB
569 (Wyeth); PKI 166 (Novartis); and BIBX 1382 (Boehringer
Ingleheim); Farnesyl Transferase Inhibitors such as tipifamib
(Zarnestra, Johnson & Johnson); ionafarnib (Sarasar,
ScheringPlough) BMS214,662 (BristolMyers Squibb); AZ3409
(AstraZeneca); CP609,754 (OSI Pharmaceuticals); CP663,427 (OSI
Pharmaceuticals/Pfizer); Arglabin (NuOncology); RPR130401
(Aventis); A 176120 (Abbott); BIM 46228 (Biomeasure); LB 42708 (LG
Chem); LB 42909 (LG Chem); PD 169451 (Pfizer); and SCH226374
(ScheringPlough); Bcl2 Inhibitors such as BCLX (Isis); ODN 2009
(Novartis); GX 011 (Gemin X); and TAS 301 (Taiho); Cyclin Dependent
Kinase Inhibitors such as flavopiridol (generic, Aventis); CYC202
(Cyciacel); BMS 387032 (BristolMyers Squibb); BMS 239091
(BristolMyers Squibb); BMS 250904 (BristolMyers Squibb); CGP 79807
(Novartis); NP102 (Nicholas Piramal); and NU 6102 (AstraZeneca);
Protein Kinase C Inhibitors such as Affinitac (Isis, Eli Lilly
& Co.); midostaurin (PKC 412, Novartis/generic); bryostatin
(NCl/GPC Biotech/generic); KW 2401 (NCl/Kyowa Hakko); LY 317615
(Eli Lilly & Co.); perifosine (ASIA Medica/Baxter/generic); and
SPC 100840 (Sphinx);
[0220] Telomerase Inhibitors such as GRN163 (Geron/Kyowa Hakko) and
G4T 405 (Aventis); Antibody Therapy including Herceptin
(Genentech/Roche); MDXH210 (Medarex); SGN15 (Seattle Genetics); H11
(Viventia); Therex (Antisoma); rituximan (Rituxan, Genentech);
Campath (ILEX Oncology/Millennium/Shering); Mylotarg
(Celltech/Wyeth); Zevalin (IDEC Pharmaceuticals/Schering);
tositumomab (Bexxar, Corixa/SmithKline Beecham/Coulter);
epratuzumab (Lymphocide, lmmunomedics/Amgen); Oncolym
(Techniclone/Schering AG); Mab Hu1D10 antibody (Protein Design
Laboratories); ABXEGF (Abgenix); infleximab (Remicade.RTM.,
Centocor) and etanercept (Enbrel, WyethAyerst).
[0221] Antipsoriasis Agents such as anthralin; vitamin D3;
cyclosporine; methotrexate; etretinate, salicylic acid;
isotretinoin; and corticosteroids; Antiacne Agents such as retinoic
acid; benzoyl peroxide; sulfurresorcinol; azelaic acid;
clendamycin; erythromycin; isotretinoin; tetracycline; minocycline;
Antiskin parasitic Agents such as permethrin and thiabendazole;
Treatments for Alopecia such as minoxidil and finasteride;
Contraceptives such as medroxyprogesterone; norgestimol;
desogestrel; levonorgestrel; norethindrone; norethindrone;
ethynodiol; and ethinyl estradiol; DNAalkyltranferase Agonist
including temozolomide; Metalloproteinase Inhibitor such as
marimastat; Agents for management of wrinkles, bladder, prostatic
and pelvic floor disorders such as botulinum toxin; Agents for
management of uterine fibroids such as pirfenidone, human
interferinalpha, GnRH antagonists, Redoxifene, estrogenreceptor
modulators; Transferrin Agonist including TransMID (Xenova
Biomedix); TfCRM107 (KS Biomedix); Interleukin13 Receptor Agonist
such as IL13PE38QQR (Neopharm); Nucleic acids such as small
interfering RNAs (siRNA) or RNA interference (RNAi), particularly,
for example siRNAs that interfere with VEGF expression; and
Psychotherapeutic Agents including Antianxiety drugs such as
chlordiazepoxide; diazepam; chlorazepate; flurazepam; halazepam;
prazepam; clorazepam; quarzepam; alprazolam; lorazepam; orazepam;
temazepam; and triazolam; and Antipsychotic drugs such as
chlorpromazine; thioridazine; mesoridazine; trifluorperazine;
fluphenazine; loxapine; molindone; thiothixene; haloperidol;
pimozide; and clozapine.
Consideration of Forming Solid Phase within a Gel
[0222] Solid phase can be added to a formed gel or fixed within a
gel during polymerization of the pregel liquid state to a gel
state. Solid phase can be formed within a gel. The present
invention provides a novel process for producing solid materials
based on synthetic polymers and/or biopolymers, in which the
synthetic polymers and/or biopolymers are dissolved or dispersed in
ionic liquids, optionally together with additives, the synthetic
polymers and/or biopolymers are regenerated as solids by contacting
the resulting solution or dispersion with a further liquid or gel
which is miscible with the ionic liquid but is incapable of
dissolving the solid synthetic polymers and/or biopolymers, and
freeing the resulting regenerated solids from the synthetic
polymers and/or biopolymers of the ionic liquids and the further
liquid, which results in the solid materials based on synthetic
polymers and/or biopolymers.
[0223] Accordingly, the present process for producing solid
materials within gels has the following process steps: (1)
solubilizing at least one solid polymer and/or biopolymer (A), or
at least one synthetic polymer and/or biopolymer (A) and at least
one additive (B), in at least one substantially or completely
anhydrous chaotropic liquid (C), (2) contacting the solution or
dispersion (AC) or (ABC) obtained in process step (1) with a gel
(G) which is miscible with the chaotropic liquid (C), but in which
at least the synthetic polymer and/or the biopolymer (A) are
substantially or completely insoluble, which results in a solid
phase (P) which comprises or consists of solid synthetic polymer
and/or biopolymer (A), chaotropic liquid (C) and gel (G), and if
appropriate the at least one additive (B), and a gel phase (G)
which comprises or consists of chaotropic liquid (C) and gel (G),
(3) removing the chaotropic liquid (C) from phase (G), which
results in a multiphasic gel (PG) based on synthetic polymer and/or
biopolymer (A), (5) impregnating the multiphasic gel (PG) with a
liquid (W) which is miscible both with the chaotropic liquid (C)
and with the gel (G), but in which at least the synthetic polymer
and biopolymer (A) are substantially or completely insoluble, and
(6) removing the two liquids (C) and (W) from the multiphasic gel
(PG) by evaporating.
[0224] The solid materials may have a wide variety of different
threedimensional forms, sizes and morphologies. For instance, they
may be pulverulent, in which case the powder particles may have the
form of slabs, spheres, drops, rods, cylinders, needles, flakes, or
irregularly shaped particles, especially pellets and tori. These
bodies may be more or less compact or highly porous, and may have a
high internal surface area.
[0225] The particle size thereof may vary widely. It may be in the
range from a few nanometers up to 1 mm. The particle size
distributions may be monomodal or multimodal and range from very
broad to very narrow, preferably very narrow, distributions.
[0226] The solid materials may, however, also be macroscopic
particles, i.e. particles with a greatest diameter of >1 mm.
They have essentially the same forms as the powder particles.
[0227] In addition, the solid materials may have the form of
fibers. These may have different lengths, for example from about 5
mm to highly entangled and different thicknesses, for example 1
micron to 1 mm.
[0228] The solid materials may also be provided as films. These may
have different thicknesses, for example between 500 nm and 1 mm.
The films may be essentially compact, nanoporous, microporous,
macroporous or in the form of sponge. The films are preferably
essentially compact.
[0229] In particular, the solid materials are powders. The powder
particles preferably have a mean particle size measured by
sedimentation in a gravitational field of 100 microns to 3 mm,
preferably 200 microns to 2.5 mm and especially 300 microns to 2
mm.
[0230] For the performance of the process according to the
invention, basically all synthetic polymers and/or biopolymers (A)
are suitable, provided that they are soluble in one of the
chaotropic liquids (C) described and insoluble in the gel (G) and
liquid (W). In terms of method, the solubilization in the first
process step has no special features, and can be performed with the
aid of the customary and known mixing units, such as stirred tanks,
Ultraturrax, inline dissolvers, homogenization units such as
homogenization nozzles, kneaders or extruders, continuously or in
batchwise mode.
[0231] The content of polymers (A) in the solution or dispersion
(AC) or (ABC) which results in the first process step can likewise
vary widely. In general, the upper limit of the content is fixed in
the individual case by the fact that the viscosity of the solution
or dispersion (AC) or (ABC) in question must not become so high
that it can no longer be processed. The content is preferably 0.1
to 50% by weight, more preferably 0.25 to 30% by weight and
especially 0.5 to 20% by weight, based in each case on (AC) or
(ABC).
[0232] Later in the process according to the invention, in the
second process step, the solution or dispersion (AC) or (ABC)
obtained in the first process step is contacted with a gel (G). The
gel (G) is miscible with the abovedescribed chaotropic liquid (C),
preferably without a miscibility gap, i.e. in any quantitative
ratio. In contrast, the polymer (A) is substantially or completely
insoluble in (G). Any additives (B) present may be soluble or
insoluble in (G).
[0233] The chaotropic liquid (C) used is preferably acetone,
methanol, ethanol, propanol, butanol, ethylene glycol, propylene
glycol, diethylene glycol, 2methoxyethanol, 2ethoxyethanol,
2propoxyethanol and/or 2butoxyethanol, the nitrile used is
preferably acetonitrile and/or propionitrile, the ether used is
preferably diethyl ether, dipropyl ether, tetrahydrofuran and/or
dioxane, the ketone used is preferably acetone and/or methyl ethyl
ketone, the aldehyde used is preferably acetaldehyde and/or
propionaldehyde, the sulfoxide used is preferably dimethyl
sulfoxide, and the amide used is preferably dimethylformamide,
acetamide and/or hexamethylphosphortriamide.
[0234] Particular preference is given to using strongly protic and
aprotic polar organic liquids which already have a comparatively
high vapor pressure or a boiling point below 100 degree C. as the
liquid (C).
[0235] Very particular preference is given to using ethanol and/or
water, but especially water, as the liquid (W)
[0236] The solution or dispersion (AC) or (ABC) can be contacted in
different ways with gel (G), for example by pouring, dripping or
extruding the solution or dispersion (AC) o r (ABC) into the gel
(G), or contacting it in the form of a film with gel (G). This can
be performed continuously or in batchwise mode. The quantitative
ratio of solution or dispersion (AC) or (ABC) to gel (G) may vary
widely from case to case. It is essential that the quantitative
ratio is selected such that the polymer (A) is precipitated or
regenerated quantitatively. The person skilled in the art can
therefore easily determine the quantitative ratio required on the
basis of his or her general technical knowledge, if appropriate
with the aid of a few preliminary tests.
[0237] The temperature at which the second process step is
performed can likewise vary widely. The temperature is guided
primarily by the temperature range within which the gel (G) is in a
fluidlike state. The solution or dispersion (AC) or (ABC) should
also not have excessively high temperatures on contact with (G),
because the result may otherwise be abrupt evaporation and/or
decomposition of the gel (G) or polymer (A). The second process
step is preferably likewise performed at temperatures of 0 to 100
degree C., more preferably 10 to 70 degree C., especially
preferably 15 to 50 degree C. and especially 20 to 30 degree C. In
the second process step, the result is a solid phase which
comprises or consists of solid polymer (A), chaotropic liquid (C)
and gel (G), and if appropriate the at least one additive (B), and
also a liquid phase (W) which comprises or consists of chaotropic
liquid (C) and gel (G).
[0238] Later in the process according to the invention, in the
fourth process step, the chaotropic liquid (C) is removed from
phase (PG) with the aid of the liquid (W), which results in a gel
(PG) based on the polymer (A). Preference is given to removing the
chaotropic liquid (C) by extracting phase (W) by washing at least
once with the liquid (W), and the wash liquid (W) is then removed
from phase (PG). This can be done by employing the abovedescribed
continuous or batchwise method. The washing and removal are
preferably continued until chaotropic liquid (C) can no longer be
detected in the gel (PG) and/or in the wash liquid (W).
[0239] Preferably, the fourth process step is performed at
temperatures at which the resulting gel (PG) is not thermally
damaged, more particularly does not age rapidly. Preference is
given to employing temperatures of 0 to 100 degree C., more
preferably 10 to 70 degree C., especially preferably 15 to 50
degree C. and especially 20 to 30 degree C. The resulting gel (PG)
preferably already essentially has the appropriate threedimensional
form, like the solid material based on polymers (A) to be produced
therefrom.
[0240] Later in the process according to the invention, in the
fifth process step, the gel (PG) is treated with a liquid (W) which
is miscible with the chaotropic liquid (C) and with the gel (G),
but in which at least the polymer (A) is substantially or
completely insoluble.
[0241] When, for example, water is used as the liquid (W)which is
particularly preferred in accordance with the inventionit is
possible to use all of the aboved escribed strongly protic and
aprotic polar organic liquids which have a higher vapor pressure
than water or a boiling point below 100 degree C. at standard
pressure.
[0242] Later in the process according to the invention, in the
sixth process step, the two liquids (C) and (W) are removed from
the gel (PG) by evaporating or fractionation. Preference is given
to fractionation comparatively slowly under gentle conditions at
standard pressure or a slightly reduced pressure between 50 and 100
kPa. Preference is given to employing temperatures between 20 and
50 degree C. More particularly, the fractionation is effected at
room temperature and under standard pressure.
[0243] Apart from the sixth process step, it is possible to perform
at least one of the process steps of the process according to the
invention at a pressure greater than 100 kPa. Preference is given
to performing the process according to the invention at standard
pressure overall. Owing to the exact adjustability of the
dimensions thereof of the solid phase, the resulting solid
materials based on synthetic polymers and/or biopolymers (A),
especially of absorbable polyurethanes (A), can be joined in a
process specific way, in a secure and reliable manner, to give even
more complex threedimensional moldings.
[0244] By virtue of the abovedescribed additives (B), the resulting
solid materials based on synthetic polymers and/or biopolymers,
especially on absorbable polyurethanes (A), can be modified in a
wide variety of different ways for the inventive use. The additives
(B) may be present in more or less homogeneous distribution in the
polymer (A) matrix of the solid materials produced with the aid of
the process according to the invention. For example, it may be
advantageous when fibrous additives (B) have an inhomogeneous
distribution, in order to vary mechanical properties in a desired
manner. The situation is similar for catalytically active additives
(B), the accessibility of which in the polymer (A) matrix can be
improved by an inhomogeneous distribution. In many cases, however,
a very substantially homogeneous distribution in the polymer (A)
matrix is advantageous, for instance when plasticizing additives
(B) are used.
[0245] The additives (B) may be bonded in a more or less fixed
manner to the polymer (A) matrix of the solid materials produced
with the aid of the process according to the invention. For
instance, especially polymeric or particulate additives (B) may be
bonded permanently to the polymer (A) matrix. In contrast,
especially in the case of the low molecular weight additives (B),
it may be advantageous when they are not bonded permanently to the
polymer (A) matrix, and are instead released again in the manner of
a slow release or controlled release.
[0246] The multiphasic gels which are based on synthetic polymers
and/or biopolymers (A), and also on polysaccharides (G), and are
produced in the inventive procedure can therefore be used
advantageously in a wide variety of different technical fields in
the context of the inventive use. For instance, they can be used in
synthetic and analytical chemistry, biochemistry and gene
technology, biology, pharmacology, medical diagnostics, cosmetics,
natural gas and mineral oil extraction technology, process
technology, paper technology, packaging technology, electrical
engineering, magnet technology, communications technology,
broadcasting technology, agricultural technology, aviation and
space technology and textile technology, and also construction,
land and sea transport and mechanical engineering, especially as
construction materials, insulations, fabric, absorbents,
adsorbents, membranes, separating materials, barrier layers,
controlled release materials, catalysts, cultivation media,
catalysts, and also coloring, fluorescent, phosphorescent,
electrically conductive, magnetic, microwaveabsorbing and
flameretardant materials, or for the production thereof.
EXAMPLES
[0247] The following are examples provided to illustrate the method
and multiphasic systems of the present invention. The constituents
of the following examples are available from SigmaAldrich, unless
otherwise indicated. In some cases equivalent weights are used
rather than gram amounts. When equivalent weights are used, the
equivalent is defined with respect to a functional group, for
example hydroxyl groups, isocyanate groups, amine groups and the
like. The relevant functional group should be obvious to one
skilled in the art of the synthesis of polymeric gels. When the
word "equivalent" is used, it is meant equivalent weight.
Coupling Solid and Gel Phases
[0248] Aforementioned, solid phase can be inserted mechanically
into an existing gel phase, the gel state can be formed around a
distribution of solid phase, the solid phase can be formed within
an existing gel state, or in either of these cases the solid phase
and gel phase chemically interact to form bonds.
[0249] The solid and gel phases are typically characterized as
possessing pendant hydroxyl groups. When a desired distribution of
solid phase and gel phase is obtained to form a multiphasic gel,
this state of distribution can be fixed by addition of a
crosslinker, for example a diisocyanate.
[0250] Alternatively, the solid or gel phases can possess a surplus
of terminal NCO groups such that when one of the gel or solid
phases possessing terminal hydroxyl groups is introduced into the
state possessing terminal isocyanate groups that spontaneous
polymerizations occurs. This polymerization can be enhanced by the
addition of catalysts known in the art. The polymerization that
occurs is local, and limited to bonds formed between gel phase
molecules and solid phase molecules. In this situation, it is
preferred that the distribution of solid phase be sufficiently
diffuse that chain extension or polymerization between solid phase
structures does not occur, unless a more complex solid phase
geometry desired.
[0251] The form of macroscopic crosslinking can achieve any degree
desired of constraint on the overall multiphasic gel system. For
example, the coupling can be strictly local between discrete solid
phase and gel domains. Alternatively, and especially with diffusion
of soluble hydroxyl rich monomers in the gel matrix, chain
extension can occur, especially if the isocyanate functionality is
not localized to either the gel phase or the solid phase. If
hydroxyl rich monomers are to be used in the final fixing of solid
state relative to gel state, than any unreacted monomers are to be
washed out by the use of a suitable polar solvent, such as water.
It is important that the resulting multiphasic gel system be
cohesive. In particular, there should be no free small molecule
constituents that are not intended to provide a biofunctional
aspect. Conversely, no fixing of the gel phase to the solid phase,
preferably, alters the functionality or distribution mechanics of a
molecular biofunctional constituent intended to be released into a
mammalian body.
Example 1
Solid Phase A
[0252] In a 3neck flask are placed 400 g of a PLADiol (Mn=1000) and
200 g of Terathane 2000 (Invista, Wichita, Kans.). Toluene is added
in excess, and the mixture gently heated to remove toluene to
obtain a 20% w/w solution. After cooling to room temperature, 650 g
of isophorone diisocyanate was added and mixed under dry nitrogen.
To the mixture was then added 5 g of dibutyltindilaurate (DBTL) and
the mixture was heated to 75.degree.C. After 5 hours, 128.7 g of
1,4butane diol is added and the reaction mixture is diluted with
toluene to get concentration of all components of approximately 15%
Subsequently, the temperature is raised to 80.degree.C. After 10
hours the mixture is allowed to cool to room temperature. The
toluene is driven off under vacuum until a clear solid polyurethane
is obtained.
Example 2
Solid Phase B
[0253] In a 3neck flask are placed 400 g of a PLADiol (Mn=1000) and
400 g of polyethylene glycol (Mn=2000). Toluene is added in excess,
and the mixture gently heated to remove toluene to obtain a 20% w/w
solution. After cooling to room temperature, 650 g of isophorone
diisocyanate was added and mixed under dry nitrogen. To the mixture
was then added 5 g of dibutyltindilaurate (DBTL) and the mixture
was heated to 75 degrees C. After 5 hours, 128.5 g of 1,4butane
diol is added and the reaction mixture is diluted with toluene to
get concentration of all components of approximately 15%
Subsequently, the temperature is raised to 80.degree.C. After 10
hours the mixture is allowed to cool to room temperature. The
toluene is driven off under vacuum until a clear solid polyurethane
is obtained.
Example 3
Solid Phase C
[0254] In a 3neck flask was placed 200 g of a PLADiol (Mn=2000),
200 g of polycaprolactone (Mn=2000) and 400 g of polyethylene
glycol (Mn=2000). Toluene is added in excess, and the mixture
gently heated to remove toluene to obtain a 20% w/w solution. After
cooling to room temperature, 505 g of isophorone diisocyanate was
added and mixed under dry nitrogen. To the mixture was then added 7
g of dibutyltindilaurate (DBTL and the mixture was heated to 75
degrees C. After 5 hours, 128.5 g of 1,4butane diolis added and the
reaction mixture is diluted with toluene to get concentration of
all components of approximately 15%. Subsequently, the temperature
is raised to 80 degrees C. After 10 hours the mixture is allowed to
cool to room temperature. The toluene is driven off under vacuum
until a clear solid polyurethane is obtained.
Example 4
Solid Phase D
[0255] Pluronic 31 R1 (molecular weight 3250) (BASF, Mt. Olive,
N.J.) was dried under vacuum at 85.degree. C. for 12 hr. in a
spherical flask, the final water content obtained was below 300
ppm. One equivalent of Pluronic 31 R1 was added to 1/5 equivalent
(I)Lactide and 0.18 grams catalyst (stannous 2ethyl hexanoate)
(0.43%). The reaction was carried out in a sealed flask, under a
dry nitrogen saturated atmosphere, for two and half hours at 145
degrees C. To the above synthesis is added 2 equivalents of toluene
diisocyanate and reacted at 60 degrees C. for 8 hours. To this
result is added 1/2 equivalent of biofunctional molecule, for
example a boswellia extract and reacted at 75 degrees C. for 8
hours.
Example 5
Solid Phase E
[0256] Polyethylene glycol (molecular weight 3000) was dried in
vacuo overnight at 85.degree. C. Thereafter, the PEG was cooled
down to room temperature, and the product capped with dry nitrogen.
One equivalent of PEG was added to 1/5 equivalent (1)Lactide and
0.18 grams catalyst (stannous 2ethyl hexanoate). The mixture of PEG
and lactide is placed in an oil bath under flowing nitrogen at 140
degree C.and mixed for 3 hours. To the above synthesis is added 2
equivalents of toluene diisocyanate and reacted at 60 degrees C.
for 8 hours. To this result is added 1/2 equivalent of
biofunctional molecule, for example a boswellia extract and reacted
at 75 degrees C. for 8 hours.
Example 6
Solid Phase F
[0257] In a reactor equipped with stir rod, place 2 moles of
diisocyanate under nitrogen. Heat the volume to 60.degree.0 and
slowly add 1 mole of poloxamer diol. The poloxamer should be added
at a rate slow enough such that the volume temperature does not
rise above 65.degree.C. If the poloxamer is a solid at 60.degree.C,
then a solvent can be used. When all the poloxamer has been added
to the reaction volume the mixture should be reacted until the
isocyanate content corresponds to two available NCO groups per
poloxamer molecule. Adding the poloxamer slowly ensures each
poloxamer molecule is endcapped with two diisocyanate molecules,
because the majority of the reaction is done in an excess of
diisocyanate, and chain extension of the poloxamer is less
probable. If prevention of chain extension is important a large
excess of diisocyanate can be employed, and the excess diisocyanate
evaporated at the termination of the reaction. Once the poloxamer
diisocyanate is prepared as described above, 1 mole can be loaded
into a reactor under nitrogen, heated to 85.degree.0 and two moles
of dilactide (A) or more generally an ester added slowly, and as
before preventing an excessive exotherm. To this result is added
1/2 equivalent of biofunctional molecule, for example a boswellia
extract and reacted at 75 degrees C. for 8 hours.
Example 7
Gel Phase A
[0258] While poloxamers of many varied combinations of ethylene
oxide (B) and propylene oxide (C) are commercially available, there
are practical limits on constructing these chains with monomeric
ethylene oxide and propylene oxide. Greater control is afforded by
starting with diisocyanates (D) of the monomers, for example DBD or
DCD. To these B or C can be arbitrarily added in any combination by
forming urethane links between the addition monomer and the
diisocyanate end capped chain. Through a stepwise sequence of chain
extensions with monomers and subsequent end capping with
diisocyanate and combination of B and C can be obtained. One
drawback is that the resulting polymer will be more hydrophobic
that a chain obtained by direct polymerization of ethylene oxide
and propylene oxide. However, this drawback can be compensated in
most cases by using less propylene glycol.
[0259] Multiarmed polymers can be constructed without crosslinking
by introducing a triol (T) and linking the triol to poloxamer
chains with diisocyanate. For example, poloxamer chains are
introduced into a reactor and endcapped with diisocyanate. The
resulting poloxamer diisocyanate is then reacted with a low
molecular weight triol such a trimethylolpropane. The result is a
poloxamer triisocyanate which then can be reacted with ester (A).
Preferably, the ester is polylactic acid. This yields a gel
prepolymer. Gels can be made by adding water and stirring
vigorously. Gels comprising up to 95% water can be made.
Example 8
Gel Phase B
[0260] The prepolymer of EXAMPLE 7 wherein the polylactic acid is
substituted with sodium hyaluronan. Gels can be made by adding
water and stirring vigorously. Gels comprising up to 95% water can
be made.
Example 9
Gel Phase C
[0261] The prepolymer of EXAMPLE 7 wherein the polylactic acid is
substituted with any of the above Solid Phases
Example 10
Method of Adding Hyaluronan to a Gel Prepolymer
[0262] Hyaluronan contains repeating segments of
C.sub.14H.sub.21NO.sub.11, each containing 5 hydroxyl groups (OH).
To form a diisocyanate of hyaluronan one reacts a quantity of
diisocyanate containing 2 moles of NCO greater than the number of
moles of OH. Thus, a hyaluronan containing 1 unit of C 14 H 21 NO
11 per molecule, then 1 mole of hyaluronan molecules if to be
reacted with 7 moles of diisocyanate. The reaction is performed in
an organic solvent, where the hyaluronan is altered by ammonia to
make it soluble in an organic solvent, for example tetrahydrofuran.
A small amount of tin catalyst is added to promote urethane link
formation between the hydroxyls of the hyaluronan and the
isocyanate groups of the diisocyanate. To discourage chain
extension, the hyaluronan is first dissolved in organic solvent and
set aside. The reactor is charged with catalyst and diisocyanate
and heated to 80 degrees C. The hyaluronan solution is slowly added
to the reactor and the exotherm monitored. Complete reaction is
indicated when the exotherm subsides. Alternatively, one can
measure the % NCO at each step to verify all the hydroxyl groups on
the hyaluronan are endcapped with isocyanate. When all the
hyaluronan is added to the reactor the reaction is run until the
desired % NCO is reached. % NCO is measured by conventionally by
dibutylamine titration. The reaction is complete when 2 moles of
NCO are measured for every mole of product molecule. Ideally there
is only 1 C 14 H 21 NO 11 unit per product molecule. However,
in
[0263] other applications a spectrum of product molecules
containing a range of C 14 H 21 NO 11 unit per product molecule is
desired. The desired polydispersity can be obtained by adjusting
the amount of NCO used, and verifying with GPC and % NCO
measurements.
[0264] In any one reaction, the dispersity of molecular weights of
product molecules will be Gaussian around a desired mean.
Multimodal distributions can be obtained by mixing the reaction
product of multiple reactions. Hyaluronan isocyanates of higher
isocyanate functionality can be synthesized by adjusting the ratio
of OH groups to isocyanate groups in the reaction mix.
Example 11
Gel Phase D
[0265] In this example a castorderived hydroxylterminated
ricinoleate derivative is used as the triol. One equivalent of
polycin T400 (141 g) is combined with 2 equivalent of toluene
diisocyanate (174 g) at room temperature (22.degree. C.). The
mixture is stirred at 100 revolutions per minute and the
temperature monitored. The mixture will begin to heat up by
exothermic reaction and no heat is to be applied to the reactor
until the temperature in the reactor ceases to rise. Then the
mixture temperature should be increased in 5.degree. C. increments
per 1/2 hour until the mixture reaches 60.degree. C. The reaction
should be continued until the % NCO=13.3%. The target % NCO is
reached when every hydroxyl group in the mixture is reacted with an
NCO group. Ideally, the result is a single diol endcapped with two
diisocyanates. This outcome can be enhanced by slow addition of the
diol to the diisocyanate. The addition should be in 10 g
increments, added when the exotherm from the previous addition has
ceased. However, chain extended variations of the above ideal
outcome are useful, their primary disadvantage being that the
product is slightly higher in viscosity. The ideal % NCO is
calculated by dividing the weight of the functional isocyanate
groups (2.times.42 Dalton) per product molecule by the total weight
of the product molecule (282 Dalton+2.times.174 Dalton) yielding
approximately 13.3%. The above reaction will yield a viscous
product. A less viscous product can be obtained by adding propylene
carbonate to the initial mixture. Additions up to 100% by weight of
propylene carbonate are useful. Adjustment to the target NCO of the
mixture must be performed using standard methods, or the propylene
carbonate may be added after reaching the target % NCO. Propylene
carbonate is available from SigmaAldrich (Milwaukee, Wis.).
Example 12
Gel Phase E
[0266] In this example a polyether hydroxylterminated copolymer of
75% ethylene oxide and 35% propylene oxide is used as the triol.
One equivalent of Multranol 9199 (3066 g) is combined with 3
equivalent of toluene diisocyanate (261 g) at room temperature
(22.degree. C.). The mixture is stirred at 100 revolutions per
minute and the temperature monitored. The mixture will begin to
heat up by exothermic reaction and no heat is to be applied to the
reactor until the temperature in the reactor ceases to rise. Then
the mixture temperature should be increased in 5.degree. C.
increments per 1/2 hour until the mixture reaches 60.degree. C. The
reaction should be continued until the % NCO=1.3%. The target % NCO
is reached when every hydroxyl group in the mixture is reacted with
an NCO group. Ideally, the result is a single diol endcapped with
two diisocyanates. This outcome can be enhanced by slow addition of
the diol to the diisocyanate. The addition should be in 10 g
increments, added when the exotherm from the previous addition has
ceased. However, chain extended variations of the above ideal
outcome are useful, their primary disadvantage being that the
product is slightly higher in viscosity. The ideal % NCO is
calculated by dividing the weight of the functional isocyanate
groups (3.times.42 Dalton) per product molecule by the total weight
of the product molecule (9199 Dalton+3.times.174 Dalton) yielding
approximately 1.3%. Multranol 9199 is available from Bayer
(Pittsburgh, Pa.).
Example 13
Gel Phase F
[0267] Any of the diisocyanates prepared above can be trimerized by
the addition of a low molecular weight triol such as polycin T400
or trimethylolpropane (TMP). In this example TMP is used, but the
method is adaptable to any triol. Complete trimerization of the
diisocyanates of Example 1 and 2 will result in viscous products.
To yield a lower viscosity product propylene carbonate can be
employed or less triol can be used. In the latter case, a mixture
of diisocyanate and triisocyanate is obtained.
[0268] In this example the preceding polyether diisocyanate is
used. One equivalent of polyether diisocyante (682 g) is combined
with 0.1 equivalent TMP (44.7 g) at room temperature (22.degree.
C.). The mixture is stirred at 100 revolutions per minute and the
temperature monitored. The mixture will begin to heat up by
exothermic reaction and no heat is to be applied to the reactor
until the temperature in the reactor ceases to rise. Then the
mixture temperature should be increased in 5.degree. C. increments
per 1/2 hour until the mixture reaches 60.degree. C. The reaction
should be continued until the % NCO=5.8%. The target % NCO is
reached when every hydroxyl group in the mixture is reacted with an
NCO group. The ideal % NCO is calculated by dividing the weight
fraction of the functional isocyanate groups 10%(3.times.42 Dalton)
and 90%(2.times.42) per product molecule by the total weight
fraction of the product molecule (3.times.1364 Dalton+134
Dalton)+1364 yielding approximately 0.3%+5.5%=5.8%. TMP is
available from SigmaAldrich (Milwaukee, Wis.).
Example 14
Preparation of a Modified Boswellia Extract Using a
Triisocyanate
[0269] The hydroxyl number of Boswellia extract will vary depending
on extraction method, species of Boswellia extracted, and even
variations within species. The goal is to obtain a product with no
NCO functionality, so all reaction mixtures should be reacted until
the final % NCO=0.
[0270] One hundred grams of the preceding polyether triisocyanate
is combined with 1 g of Boswellia extract at room temperature
(22.degree. C.) under 90% nitrogen and 10% nitric oxide atmosphere.
The mixture is stirred at 100 revolutions per minute and the
temperature monitored. The mixture will begin to heat up by
exothermic reaction. When the temperature ceases to rise, a % NCO
reading is taken. If % NCO>0 than an additional 1 g of Boswellia
extract is to be added. By a series of Boswellia addition one
calculates the change in % NCO as a function of 1 g additions of
Boswellia extract, a linear plot is obtained from which the total
amount of Boswellia extract addition necessary to bring the % NCO
to zero is obtained. This amount of Boswellia extract is added to
the mixture and the mixture is reacted so that % NCO=0 is
obtained.
Example 15
Preparation of Modified Boswellia Extract Using a Triisocyanate
[0271] Preparation of a modified Boswellia extract using the
triisocyanate/diisocyanate of Example 14.
[0272] The hydroxyl number of Boswellia extract will vary depending
on extraction method, species of Boswellia extracted, and even
variations within species. The goal is to obtain a product with no
NCO functionality, so all reaction mixtures should be reacted until
the final % NCO=0. In this example the product of Example 14 is
used as the polyether diisocyanate/triisocyanate mixture. One
hundred grams of Example 29 is combined with 1 g of Boswellia
extract at room temperature (22.degree. C.) under 90% nitrogen and
10% nitric oxide atmosphere. The mixture is stirred at 100
revolutions per minute and the temperature monitored. The mixture
will begin to heat up by exothermic reaction. When the temperature
ceases to rise, a % NCO reading is taken. If % NCO>0 than an
additional 1 g of Boswellia extract is to be added. By a series of
Boswellia addition one calculates the change in % NCO as a function
of 1 g additions of Boswellia extract, a linear plot is obtained
from which the total amount of Boswellia extract addition necessary
to bring the % NCO to zero is obtained. This amount of Boswellia
extract is added to the mixture and the mixture is reacted so that
% NCO=0 is obtained.
Example 16: Preparation of Modified Boswellia Extract Using
Multibranched Isocyanate
Preparation of a Polyether Triisocyanate
[0273] In this example a polyether hydroxylterminated copolymer of
75% ethylene oxide and 35% propylene oxide is used as the triol.
One equivalent of Multranol 9199 (3066 g) is combined with 3
equivalent of toluene diisocyanate (261 g) at room temperature
(22.degree. C.). The mixture is stirred at 100 revolutions per
minute and the temperature monitored.
[0274] The mixture will begin to heat up by exothermic reaction and
no heat is to be applied to the reactor until the temperature in
the reactor ceases to rise. Then the mixture temperature should be
increased in 5.degree. C. increments per 1/2 hour until the mixture
reaches 60.degree. C. The reaction should be continued until the %
NCO=1.3%. The target % NCO is reached when every hydroxyl group in
the mixture is reacted with an NCO group. Ideally, the result is a
single diol endcapped with two diisocyanates. This outcome can be
enhanced by slow addition of the diol to the diisocyanate. The
addition should be in 10 g increments, added when the exotherm from
the previous addition has ceased. However, chain extended
variations of the above ideal outcome are useful, their primary
disadvantage being that the product is slightly higher in
viscosity. The ideal % NCO is calculated by dividing the weight of
the functional isocyanate groups (3.times.42 Dalton) per product
molecule by the total weight of the product molecule (9199
Dalton+3.times.174 Dalton) yielding approximately 1.3%. Multranol
9199 is available from Bayer (Pittsburgh, Pa.).
Preparation of a Modified Boswellia Extract Using the Above
Triisocyanate.
[0275] The hydroxyl number of Boswellia extract will vary depending
on extraction method, species of Boswellia extracted, and even
variations within species. The goal is to obtain a product with no
NCO functionality, so all reaction mixtures should be reacted until
the final % NCO=0.
[0276] One hundred grams of above triisocyanate is combined with 1
g of Boswellia extract at room temperature (22.degree. C.) under
90% nitrogen and 10% nitric oxide atmosphere. The mixture is
stirred at 100 revolutions per minute and the temperature
monitored. The mixture will begin to heat up by exothermic
reaction. When the temperature ceases to rise, a % NCO reading is
taken. If % NCO>0 than an additional 1 g of Boswellia extract is
to be added. By a series of Boswellia addition one calculates the
change in % NCO as a function of 1 g additions of Boswellia
extract, a linear plot is obtained from which the total amount of
Boswellia extract addition necessary to bring the % NCO to zero is
obtained. This amount of Boswellia extract is added to the mixture
and the mixture is reacted so that % NCO=0 is obtained.
Example 17
Preparation of Genus 1 Solid Phase
[0277] Any of the above solid phase absorbable polyurethanes may be
used. The polyurethane is dissolved in acetone in a 20% by weight
ratio of polymer to acetone to form a polyurethane solution. A
beaker is filled with distilled water and placed on a magnetic
stirrer. The stir rate is selected to create a vortex in the water.
A 3 ml syringe with an 18G needle is loaded with polyurethane
solution. The tip of the needle is placed in the water and the
polyurethane solution is introduced into the water at a rate of 1
ml/minute.
[0278] The polyurethane instantly becomes a solid on contact with
the water. The lamellar flow of the polyurethane solution through
the inner diameter of the needle induces a rolling motion at the
exit of the needle. The solidifying polyurethane forms into tori
upon exit of the needle. The rate of introduction of the
polyurethane solution to the water can be used to control the
thickness of the formed tori. Other variables that can be adjusted
are the temperature of the water, the dilution of the polyurethane
solution, and the selection of solvents other than acetone. The
diameter of the formed tori can be controlled by selecting needles
of different inner diameter. Small inner diameter results in small
diameter tori.
[0279] After each introduction of 3 ml of polyurethane solution to
100 ml of water, the stirring of the water is halted. The water at
this point appears milky with homogenously distributed microtori.
During this standing period the acetone is drawn out of the
polyurethane by the water. A period of approximately 1 hour is
allocated for the acetone to leave the polyurethane sufficiently to
prevent clumping and adhesion of the tori. The tori may be filter
from the water suspension, or another bolus of polyurethane
solution may be administered. Up to approximately 15 ml of
polyurethane solution can be introduced into the water if single
tori are desired. Higher genus solid phase can be obtained by
allowing the tori density to increase to the point where newly
formed tori have a high probability of joining with an existing
torus in solution while the introduced polyurethane is still in a
relatively solvated state.
[0280] Tori can be harvested from solution using standard filter
paper, wherein the tori are captured on the filter paper and dried
in an oven at 40.degree. C. The result is dry, flowable tori. An
image of a torus 400 prepared according to the present methods is
shown in FIG. 4. Torus 400 has a diameter of about 500 micron.
Example 18
Formation of a Multiphase Gel
[0281] Any of the above gel prepolymers can be used. A beaker of
water is charged with adesired density of solid phase tori and
stirred at a rate sufficient to obtain a uniform distribution of
tori in the water. A solution of gel prepolymer is prepared by
making a solution of prepolymer and a solvent. Solvents can be
acetone, toluene or an inert addition such as propylene carbonate
or a water miscible diol. The solution is introduced to the water
mixture at 1 cc/minute at 10 minute intervals. Between intervals
the pH of the solution is maintained between 6.5 and 7.5 pH using a
suitable base, for example sodium hydroxide. This process is
continued until a desired viscosity is achieved. Slower additions
are successful, but faster additions may result in the formation of
inhomogeneities in the forming gel. The formed gel is then washed
in distilled water several time to remove the solvent and sodium
ions. If a volatile solvent is used, vacuum can be used to remove
solvent. It is important that the gel does not desiccate, since
many gels will not rehydrate fully.
Example 19
Formation of a Rehydrating Multiphase Gel
[0282] In some instances it is desirable to obtain a multiphase gel
which can have all the water removed and be rehydrating to its
originally formed ratio of water to polymer. To achieve this
result, the water fraction of the gel can be loaded with salt ions,
in particular sodium chloride. Under rehydration, reintroduction of
the dehydrated gel to distilled water in a ratio of polymer weight
to water volume that will result in 0.9% salt (physiologic saline)
is useful in implantable applications.
[0283] Although there have been described particular embodiments of
the present invention of a new and useful MULTIPHASE GEL it is not
intended that such references be construed as limitations upon the
scope of this invention except as set forth in the following
claims.
* * * * *