U.S. patent application number 13/663050 was filed with the patent office on 2013-10-31 for non-aqueous compositions and methods for bone hemostasis.
The applicant listed for this patent is Baxter Healthcare S.A., Baxter International Inc.. Invention is credited to Andreas Goessl, Katarzyna I. Gorna, Heinz Gulle.
Application Number | 20130287818 13/663050 |
Document ID | / |
Family ID | 48168649 |
Filed Date | 2013-10-31 |
United States Patent
Application |
20130287818 |
Kind Code |
A1 |
Gorna; Katarzyna I. ; et
al. |
October 31, 2013 |
NON-AQUEOUS COMPOSITIONS AND METHODS FOR BONE HEMOSTASIS
Abstract
Bone hemostat compositions, and methods for their use and
manufacture are provided. Exemplary hemostatic compositions include
polymeric components such as random and non-random copolymers,
natural polymers, ceramics, reactive group polymers, and
combinations thereof. Bone compositions may be used during surgical
procedures, and may be applied to bone to inhibit or prevent
bleeding from bone.
Inventors: |
Gorna; Katarzyna I.;
(Vienna, AT) ; Goessl; Andreas; (Vienna, AT)
; Gulle; Heinz; (Gross-Enzersdorf, AT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Baxter Healthcare S.A.
Baxter International Inc. |
Glattpark (Opfikon)
Deerfield |
IL |
CH
US |
|
|
Family ID: |
48168649 |
Appl. No.: |
13/663050 |
Filed: |
October 29, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61553032 |
Oct 28, 2011 |
|
|
|
Current U.S.
Class: |
424/400 ;
514/772.1; 525/524 |
Current CPC
Class: |
A61L 24/043 20130101;
A61B 2017/00933 20130101; A61L 2430/02 20130101; A61P 19/08
20180101; A61B 17/56 20130101; A61K 31/765 20130101; A61L 24/046
20130101; C08G 81/00 20130101; A61L 2400/04 20130101; C08L 71/02
20130101; C08L 71/02 20130101; A61L 24/046 20130101; A61L 24/043
20130101 |
Class at
Publication: |
424/400 ;
525/524; 514/772.1 |
International
Class: |
C08G 81/00 20060101
C08G081/00 |
Claims
1. A biocompatible composition for use as a bone hemostat, the
composition comprising: a polyoxyethylene-polyoxypropylene block
copolymer having a molecular weight (Mw) within a range from about
9800 Mw to about 16300 Mw, wherein the biocompatible composition is
present in a nonaqueous form.
2. The biocompatible composition according to claim 1, wherein the
polyoxyethylene-polyoxypropylene block copolymer is a triblock
copolymer.
3. The biocompatible composition according to claim 1, wherein the
polyoxyethylene-polyoxypropylene block copolymer has a molecular
weight (Mw) within a range from about 9800 Mw to about 14600
Mw.
4. The biocompatible composition according to claim 1, wherein the
block copolymer comprises a percentage of polyethylene oxide within
a range from about 60% to about 80%.
5. The biocompatible composition according to claim 1, wherein the
block copolymer comprises a percentage of polypropylene oxide
within a range from about 20% to about 40%.
6. The biocompatible composition according to claim 1, wherein the
polyoxyethylene-polyoxypropylene block copolymer comprises 202
ethylene oxide units and 56 propylene oxide units.
7. The biocompatible composition according to claim 1, further
comprising a random alkylene oxide copolymer, wherein: the
polyoxyethylene-polyoxypropylene block copolymer is present within
a range from about 45% to about 80% by weight of the composition,
and the random alkylene oxide copolymer is present within a range
from about 20% to about 55% by weight of the composition.
8. The biocompatible composition according to claim 1, further
comprising a random alkylene oxide copolymer, and ceramic
particles, wherein: the polyoxyethylene-polyoxypropylene block
copolymer is present within a range from about 40% to about 80% by
weight of the composition, the random alkylene oxide copolymer is
present within a range from about 20% to about 50% by weight of the
composition, and the ceramic particles are present within a range
from about 5% to about 20% by weight of the composition.
9. The biocompatible composition according to claim 8, wherein the
ceramic particles comprise a member selected from the group
consisting of Si-substituted ceramic particles and Sr-substituted
ceramic particles.
10. The biocompatible composition according to claim 8, wherein the
ceramic particles have a particle size less than about 150
.mu.m.
11. The biocompatible composition according to claim 1, further
comprising a random alkylene oxide copolymer, and a second
polyoxyethylene-polyoxypropylene block copolymer, wherein: the
polyoxyethylene-polyoxypropylene block copolymer is present within
a range from about 40% to about 70% by weight of the composition,
the random alkylene oxide copolymer is present within a range from
about 5% to about 40% by weight of the composition, and the second
polyoxyethylene-polyoxypropylene block copolymer is present within
a range from about 5% to about 30% by weight of the
composition.
12. The biocompatible composition according to claim 11, wherein
the second polyoxyethylene-polyoxypropylene block copolymer
comprises 4 ethylene oxide units and 16 propylene oxide units.
13. The biocompatible composition according to claim 1, further
comprising a random alkylene oxide copolymer, a second
polyoxyethylene-polyoxypropylene block copolymer, and ceramic
particles, wherein: the polyoxyethylene-polyoxypropylene block
copolymer is present at about 44.4% weight of the composition, the
random alkylene oxide copolymer is present at about 22.2% by weight
of the composition, the second polyoxyethylene-polyoxypropylene
block copolymer is present at about 22.2% weight of the
composition, and the ceramic particles are present at about 11.2%
weight of the composition.
14. The biocompatible composition according to claim 1, further
comprising a random alkylene oxide copolymer, and a second
polyoxyethylene-polyoxypropylene block copolymer, wherein: the
polyoxyethylene-polyoxypropylene block copolymer is present at
about 57.1% weight of the composition, the random alkylene oxide
copolymer is present at about 14.3% by weight of the composition,
and the second polyoxyethylene-polyoxypropylene block copolymer is
present at about 28.6% weight of the composition.
15. The biocompatible composition according to claim 14, wherein
the second polyoxyethylene-polyoxypropylene block copolymer
comprises 4 ethylene oxide units and 32 propylene oxide units.
16. The biocompatible composition according to claim 1, further
comprising a random alkylene oxide copolymer, and a second
polyoxyethylene-polyoxypropylene block copolymer, wherein: the
polyoxyethylene-polyoxypropylene block copolymer is present at
about 50% weight of the composition, the random alkylene oxide
copolymer is present at about 25% by weight of the composition, and
the second polyoxyethylene-polyoxypropylene block copolymer is
present at about 25% weight of the composition.
17. The biocompatible composition according to claim 16, wherein
the second polyoxyethylene-polyoxypropylene block copolymer
comprises 4 ethylene oxide units and 32 propylene oxide units.
18. The biocompatible composition according to claim 1, further
comprising a random alkylene oxide copolymer, a second
polyoxyethylene-polyoxypropylene block copolymer, and ceramic
particles, wherein: the polyoxyethylene-polyoxypropylene block
copolymer is present at about 50.7% weight of the composition, the
random alkylene oxide copolymer is present at about 12.7% by weight
of the composition, the second polyoxyethylene-polyoxypropylene
block copolymer is present at about 25.4% weight of the
composition, and the ceramic particles are present at about 11.2%
weight of the composition.
19. A method of treating a patient, the method comprising:
administering a biocompatible composition to a bone of the patient,
wherein the biocompatible composition comprises a
polyoxyethylene-polyoxypropylene block copolymer having a molecular
weight (Mw) within a range from about 9800 Mw to about 16300 Mw,
and wherein the biocompatible composition is present in a
nonaqueous form.
20. A method of manufacturing a biocompatible compositions for use
in treating a bone of a patient, the method comprising: preparing a
mixture containing a polyoxyethylene-polyoxypropylene block
copolymer having a molecular weight (Mw) within a range from about
9800 Mw to about 16300 Mw; melting the mixture; solidifying the
melted mixture; and packaging the solidified mixture.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 61/553,032 filed Oct. 28, 2011, the content
of which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Embodiments of the present invention relate generally to
biocompatible materials, and more particularly to compositions for
use in biomedical applications and methods of their
manufacture.
[0003] Bones are living vascular organs which form part of the
body's skeleton. Bones may include a variety of tissue types,
including marrow, endosteum, periosteum, blood vessels, epithelium,
nerves, cartilage, and mineralized osseous tissue. Bleeding from
cut or disrupted bone is a common occurrence in many operative
procedures. Excessive bleeding from bone during surgery may impair
the surgeon's view of the operative field, may result in the need
for blood transfusions, and may be associated with post-operative
complications.
[0004] Cauterization techniques are used to control bleeding in
soft tissue, but are ineffective for controlling bleeding in bone.
Hence, bleeding in bone has traditionally been treated by using
bone wax, a beeswax-based product that can be smeared across the
cut surface to plug the holes in the bone, so as to reduce or stop
the bleeding. More recently, synthetic bone hemostasis materials
have been proposed, including Ostene (Ceremed Inc.) and HemaSorb
(Orthocon Inc.).
[0005] Although bone hemostasis materials are currently available
and provide real benefits to patients in need thereof, many
advances may still be made to provide improved compositions for
bone hemostasis. Embodiments of the present invention provide
solutions to at least some of these outstanding needs.
BRIEF SUMMARY OF THE INVENTION
[0006] It is an object to provide a biocompatible material for use
in biomedical applications which overcomes at least some of the
problems or limitations associated with currently available bone
hemostat products. Another object is to provide a biocompatible
material which is a commercially acceptable alternative to
currently available bone hemostat products.
[0007] Embodiments of the present invention encompass bone hemostat
compositions, and methods for their use and manufacture. Bone
hemostat compositions as disclosed herein can be administered to
cut or damaged bone of a patient, for controlling, inhibiting, or
preventing bleeding from the bone. Exemplary compositions for use
in bone hemostasis include synthetic, resorbable, or soluble (e.g.
water soluble) polymers that after application to a bleeding bone
surface or site will remain in place temporarily to provide the
desired effect of controlling blood flow, and will then disappear
or disperse away from the treatment area within a few days, thus
leaving space for new bone to grow. In some instances, a bone
hemostat composition may be provided in a paste or paste-like form.
In some instances, a bone hemostat composition may be provided in a
doughy or dough-like form. According to some embodiments, a bone
hemostat composition may be provided in a nonaqueous form that is a
very viscous paste and dough-like.
[0008] Exemplary bone hemostat compositions may include granules,
flakes, powders, or various combinations thereof, of any hemostatic
and biodegradable components, and may be provided as molding
compounds for bone or bone tissue. Exemplary bone hemostat
compositions may optionally include natural polymer components,
such as cross-linked gelatin particles, chitosan particles, or
collagen particles, alone or in combination with ceramic particles
such as particles of hydroxyapatite, Si-hydroxyapatite or Sr
substituted biphasic ceramic, in a moldable, malleable carrier
based on polymer compositions or blends.
[0009] Various formulations based on non-random and random
copolymer compositions, including without limitation Poloxamer 407,
Pluronics with hydrophobic properties (e.g. L-31, L61), and Pluriol
V-10, along with other polymer components such as polyethylene
glycol of various molecular weights, can be used in the preparation
of polymer compositions or blends for a bone hemostat or bone
hemostat with enhanced hemostatic and osteogenic properties. Bone
hemostat compositions with enhanced hemostatic properties may also
include natural polymer components such as gelatin and cross-linked
derivatives thereof, chitosan, or collagen, such as, for example,
cross-linked gelatin particles, chitosan particles, or collagen
particles, as a filler. In some embodiments, inorganic particles
based on nanosize hydroxyapatite, siliconated hydroxyapatite
biphasic ceramic, Sr substituted biphasic ceramic, and the like,
are used as an osteogenic filler for bone hemostat.
[0010] Exemplary bone hemostat compositions may be provided as a
malleable paste. For example, embodiments encompass a malleable,
ready-to use hemostat for application in bone. Exemplary bone
hemostat compositions may include a synthetic polymeric matrix,
optionally combined with hemostatic agents, antibiotics, or ceramic
particles or powders. Bone hemostat paste compositions disclosed
herein may be provide in a ready-to-use form for bone hemostasis,
that does not require any preparation such as pre-warming or
kneading. Exemplary bone hemostat compositions exhibit a reasonably
short dissolution time. Exemplary bone hemostat compositions
disclosed herein can be formulated so as not to change their
handling characteristics upon kneading or application to a bone
site, which may be bleeding, damaged, or otherwise compromised.
[0011] Embodiments of the present invention encompass bone hemostat
compositions that stop or inhibit bone bleeding upon application,
resist irrigation, and remain in place for a duration sufficient to
achieve stable hemostasis. Exemplary bone hemostat compositions are
formulated to offer controlled, precise application, and to conform
to the site of care. In some embodiments, bone hemostat
compositions may be ready for use directly out of the package, and
do not require warming or kneading prior to application to the
patient's bone. In some instances, bone hemostat compositions as
disclosed herein are absorbed in the patient's body within 30 days.
Exemplary bone hemostat compositions can permit normal bone healing
and promote bone regeneration. In some instances, bone hemostat
compositions can reduce hematoma formation. What is more, exemplary
bone hemostats can be used as carriers for medications including
anti-inflammatory drugs which may be used to reduce inflammation at
the surgery site. Embodiments of the present invention provide
polymeric formulations with superior handling properties for bone
hemostasis.
[0012] In one aspect, embodiments of the present invention
encompass biocompatible compositions for use as a bone hemostat.
Exemplary compositions include any of the compositions disclosed
herein. For example, a bone hemostat composition may include a
polyoxyethylene-polyoxypropylene block copolymer. In some cases,
such a block copolymer may have a molecular weight (Mw) within a
range from about 9800 Mw to about 16300 Mw. Embodiments of the
present invention also encompass methods of treating an individual
or patient, which may include administering a biocompatible
composition as disclosed herein to a bone of the patient, for
example for the purpose of inhibiting or controlling bleeding from
the bone. What is more, embodiments of the present invention
encompass kits for the treatment of a bone of an individual or
patient. In some instances, kits may include a biocompatible
composition as disclosed herein, and instructions for use.
[0013] In another aspect, embodiments of the present invention
encompass compositions for use as a bone hemostat, and methods of
their manufacture. In some instances, biocompatible bone hemostat
compositions may be provided as an aqueous solution. In some
instances, biocompatible bone hemostat compositions may be provided
as a nonaqueous solution. Exemplary biocompatible bone hemostat
compositions may include water, such that the composition is
hydrated or present as an aqueous composition. In some cases,
compositions include a polyoxyethylene-polyoxypropylene block
copolymer having a molecular weight (Mw) within a range from about
9800 Mw to about 16300 Mw. In some instances, the
polyoxyethylene-polyoxypropylene block copolymer is a triblock
copolymer. In some instances, the polyoxyethylene-polyoxypropylene
block copolymer has a molecular weight (Mw) within a range from
about 9800 Mw to about 14600 Mw. In some cases, the block copolymer
has a percentage of polyethylene oxide within a range from about
60% to about 80%. In some cases, the block copolymer has a
percentage of polypropylene oxide within a range from about 20% to
about 40%. In some cases, the polyoxyethylene-polyoxypropylene
block copolymer has 202 ethylene oxide units and 56 propylene oxide
units. In some cases, the composition includes water and is
hydrated. In some cases, water is present in the composition within
a range from about 20% to about 45% by weight of the composition,
and a polyoxyethylene-polyoxypropylene block copolymer is present
in the composition within a range from about 20% to about 80% by
weight of the composition. According to some embodiments,
compositions may include natural polymers such as gelatin,
chitosan, or collagen. For example, compositions may include
natural polymer particles such as gelatin particles, chitosan
particles, or collagen particles. In some cases, a biocompatible
composition may include water and cross linked gelatin particles,
where the water is present at about 44.4% by weight of the
composition, a polyoxyethylene-polyoxypropylene block copolymer is
present at about 33.3% weight of the composition, and the cross
linked gelatin particles are present at about 22.2% weight of the
composition. In some cases, a biocompatible composition may include
water and cross linked gelatin particles, where the water is
present within a range from about 20% to about 50% by weight of the
composition, a polyoxyethylene-polyoxypropylene block copolymer is
present within a range from about 20% to about 40% weight of the
composition, and the cross linked gelatin particles are present
within a range from about 20% to about 40% weight of the
composition. In some cases, a biocompatible composition may include
an ethylene glycol polymer and an oxazoline polymer. For example,
the oxazoline polymer may be present within range from about 2% to
about 10% by weight of the composition. In some instances, a
biocompatible composition may include water, an ethylene glycol
polymer, an oxazoline polymer, and cross linked gelatin particles
or other natural polymer particles. For example, the water can be
present at about 24.4% by weight of the composition, the
polyoxyethylene-polyoxypropylene block copolymer can be present at
about 26.7% weight of the composition, the ethylene glycol polymer
can be present at about 13.3% by weight of the composition, the
oxazoline polymer can be present at about 2.7% by weight of the
composition, and the cross linked gelatin particles can be present
at about 33.3% weight of the composition. In some cases, a
biocompatible composition may include an ethylene glycol polymer, a
random alkylene oxide copolymer, and an oxazoline polymer. In some
cases, a biocompatible composition may include water, an ethylene
glycol polymer, a random alkylene oxide copolymer, an oxazoline
polymer, and cross linked gelatin particles or other natural
polymer particles such as chitosan or collagen particles. For
example, water can be present at about 27% by weight of the
composition, a polyoxyethylene-polyoxypropylene block copolymer can
be present at about 20% weight of the composition, the ethylene
glycol polymer can be present at about 10% by weight of the
composition, the random alkylene oxide copolymer can be present at
about 5% by weight of the composition, the oxazoline polymer can be
present at about 3% by weight of the composition, and the cross
linked gelatin or other natural polymer particles can be present at
about 35% weight of the composition. In some cases, a biocompatible
composition may include an ethylene glycol polymer, a random
alkylene oxide copolymer, an oxazoline polymer, and ceramic
particles. In some instances, a biocompatible composition may
include water, an ethylene glycol polymer, a random alkylene oxide
copolymer, an oxazoline polymer, cross linked gelatin or other
natural polymer particles, and ceramic particles. For example,
water can be present at about 27% by weight of the composition, the
polyoxyethylene-polyoxypropylene block copolymer can be present at
about 20% weight of the composition, the ethylene glycol polymer
can be present at about 10% by weight of the composition, the
random alkylene oxide copolymer can be present at about 5% by
weight of the composition, the oxazoline polymer can be present at
about 3% by weight of the composition, the cross linked gelatin
particles or other natural polymer components can be present at
about 30% weight of the composition, and the ceramic particles can
be present at about 5% weight of the composition. In some
instances, ceramic particles may include Si-substituted
hydroxyapatite particles. In some instances, ceramic particles may
include Sr-substituted hydroxyapatite particles or Sr-substituted
biphasic ceramic particles. In some instances, the ceramic
particles include Si-substituted hydroxyapatite particles having
particle size less than about 150 .mu.m. In some instances, a
random alkylene oxide copolymer of the composition has an ethylene
oxide to propylene oxide ratio of about 1:1.
[0014] In yet another aspect, embodiments of the present invention
encompass compositions for use as a bone hemostat, and methods of
their manufacture. Exemplary biocompatible bone hemostat
compositions may contain little or no water, and thus may be
present as an anhydrous composition, an unhydrated composition, or
a nonaqueous composition. In some cases, compositions include a
polyoxyethylene-polyoxypropylene block copolymer having a molecular
weight (Mw) within a range from about 9800 Mw to about 16300 Mw. In
some instances, the polyoxyethylene-polyoxypropylene block
copolymer is a triblock copolymer. In some instances, the
polyoxyethylene-polyoxypropylene block copolymer has a molecular
weight (Mw) within a range from about 9800 Mw to about 14600 Mw. In
some cases, the block copolymer has a percentage of polyethylene
oxide within a range from about 60% to about 80%. In some cases,
the block copolymer has a percentage of polypropylene oxide within
a range from about 20% to about 40%. In some cases, the
polyoxyethylene-polyoxypropylene block copolymer has 202 ethylene
oxide units and 56 propylene oxide units. In some instances,
compositions may include a random alkylene oxide copolymer. For
example, compositions may include a
polyoxyethylene-polyoxypropylene block copolymer that is present at
about 57.1% weight of the composition, and a random alkylene oxide
copolymer that is present at about 42.9% by weight of the
composition. In some cases, a biocompatible composition includes a
random alkylene oxide copolymer, where a
polyoxyethylene-polyoxypropylene block copolymer is present within
a range from about 45% to about 80% by weight of the composition,
and the random alkylene oxide copolymer is present within a range
from about 20% to about 55% by weight of the composition. In some
cases, a biocompatible composition includes a random alkylene oxide
copolymer and ceramic particles. For example, a biocompatible
composition may include a polyoxyethylene-polyoxypropylene block
copolymer that is present at about 44.4% weight of the composition,
a random alkylene oxide copolymer that is present at about 44.4% by
weight of the composition, and ceramic particles that are present
at about 11.2% weight of the composition. In some cases, a
biocompatible composition may include a
polyoxyethylene-polyoxypropylene block copolymer that is present
within a range from about 40% to about 80% by weight of the
composition, a random alkylene oxide copolymer that is present
within a range from about 20% to about 50% by weight of the
composition, and ceramic particles that are present within a range
from about 5% to about 20% by weight of the composition. In some
instances, a biocompatible composition may include a random
alkylene oxide copolymer and a second
polyoxyethylene-polyoxypropylene block copolymer. For example, a
biocompatible composition may include a
polyoxyethylene-polyoxypropylene block copolymer that is present at
about 50% weight of the composition, a random alkylene oxide
copolymer that is present at about 25% by weight of the
composition, and a second polyoxyethylene-polyoxypropylene block
copolymer that is present at about 25% weight of the composition.
Relatedly, a biocompatible composition may include a
polyoxyethylene-polyoxypropylene block copolymer that is present
within a range from about 40% to about 70% by weight of the
composition, a random alkylene oxide copolymer that is present
within a range from about 5% to about 40% by weight of the
composition, and a second polyoxyethylene-polyoxypropylene block
copolymer that is present within a range from about 5% to about 30%
by weight of the composition. In some instances, a second
polyoxyethylene-polyoxypropylene block copolymer may include 4
ethylene oxide units and 16 propylene oxide units. In some cases, a
biocompatible composition may include a random alkylene oxide
copolymer, a second polyoxyethylene-polyoxypropylene block
copolymer, and ceramic particles. For example, a biocompatible
composition may include a polyoxyethylene-polyoxypropylene block
copolymer that is present at about 44.4% weight of the composition,
a random alkylene oxide copolymer that is present at about 22.2% by
weight of the composition, a second
polyoxyethylene-polyoxypropylene block copolymer that is present at
about 22.2% weight of the composition, and ceramic particles that
are present at about 11.2% weight of the composition. In some
instances, a biocompatible composition may include a
polyoxyethylene-polyoxypropylene block copolymer that is present at
about 57.1% weight of the composition, a random alkylene oxide
copolymer that is present at about 14.3% by weight of the
composition, and a second polyoxyethylene-polyoxypropylene block
copolymer that is present at about 28.6% weight of the composition.
A second polyoxyethylene-polyoxypropylene block copolymer may
include 4 ethylene oxide units and 32 propylene oxide units. In
some cases, a biocompatible composition may include a
polyoxyethylene-polyoxypropylene block copolymer that is present at
about 50% weight of the composition, a random alkylene oxide
copolymer that is present at about 25% by weight of the
composition, and a second polyoxyethylene-polyoxypropylene block
copolymer that is present at about 25% weight of the composition. A
second polyoxyethylene-polyoxypropylene block copolymer may include
4 ethylene oxide units and 32 propylene oxide units. In some cases,
a biocompatible composition may include a random alkylene oxide
copolymer, a second polyoxyethylene-polyoxypropylene block
copolymer, and ceramic particles. For example, a biocompatible
composition may include a polyoxyethylene-polyoxypropylene block
copolymer that is present at about 50.7% weight of the composition,
a random alkylene oxide copolymer that is present at about 12.7% by
weight of the composition, a second
polyoxyethylene-polyoxypropylene block copolymer that is present at
about 25.4% weight of the composition, and ceramic particles that
are present at about 11.2% weight of the composition. In some
instances, ceramic particles may include Si-substituted
hydroxyapatite particles. In some instances, ceramic particles may
include Si-substituted hydroxyapatite particles having particle
size less than about 150 .mu.m. In some instances, ceramic
particles may include Sr-substituted biphasic ceramic
particles.
[0015] In another aspect, embodiments of the present invention
encompass methods of treating a patient, which include
administering a biocompatible composition as disclosed herein to a
bone of the patient. Relatedly, embodiments of the present
invention encompass kits for the treatment of a bone of a patient.
Exemplary kits may include a biocompatible composition as disclosed
herein, and instructions for using the composition to treat a bone
of a patient.
[0016] In another aspect, embodiments of the present invention
encompass methods of manufacturing an aqueous or hydrated
biocompatible composition as disclosed herein. For example, methods
may include combining water with one or more polymers, which may
include a polyoxyethylene-polyoxypropylene block copolymer having a
molecular weight (Mw) within a range from about 9800 Mw to about
16300 Mw, to obtain a homogeneous paste. Methods may also include
combining natural polymer components, such as gelatin, chitosan, or
collagen with the paste. Relatedly, methods may also include
combining ceramic particles with the paste. The components can be
further mixed to obtain a homogeneous product.
[0017] In yet another aspect, embodiments of the present invention
encompass methods of manufacturing a nonaqueous biocompatible
composition as disclosed herein. For example, methods may include
combining one or more polymers, which may include a
polyoxyethylene-polyoxypropylene block copolymer having a molecular
weight (Mw) within a range from about 9800 Mw to about 16300 Mw,
optionally with ceramic and/or natural polymer particles, to obtain
a homogenous material. Further, methods may include heating the
combined material above a melting point, or otherwise bringing the
composition to a molten state. Methods may also include allowing
air bubbles to escape from the melted material, and allowing the
melted material to solidify. Additional mixing and homogenization
of the material can be performed.
[0018] The terms "invention," "the invention," "this invention" and
"the present invention" used in this patent are intended to refer
broadly to all of the subject matter of this patent and the patent
claims below. Statements containing these terms should be
understood not to limit the subject matter described herein or to
limit the meaning or scope of the patent claims below. Embodiments
of the invention covered by this patent are defined by the claims
below, not this summary. This summary is a high-level overview of
various aspects of the invention and introduces some of the
concepts that are further described in the Detailed Description
section below. This summary is not intended to identify key or
essential features of the claimed subject matter, nor is it
intended to be used in isolation to determine the scope of the
claimed subject matter. The subject matter should be understood by
reference to appropriate portions of the entire specification of
this patent, any or all drawings, and each claim.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Illustrative embodiments of the present invention are
described in detail below with reference to the following drawing
figures:
[0020] FIG. 1 shows an aqueous bone hemostat composition according
to embodiments of the present invention.
[0021] FIG. 2 shows a non-aqueous bone hemostat composition
according to embodiments of the present invention.
[0022] FIG. 3 shows a non-aqueous bone hemostat composition
according to embodiments of the present invention.
[0023] FIG. 4 depicts use of non-aqueous bone hemostat compositions
according to embodiments of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0024] Embodiments of the present invention encompass biocompatible
compositions for use in bone hemostasis. In some cases, bone
hemostat compositions may include polyoxyethylene-polyoxypropylene
block copolymers, natural polymers, ceramic particles, ethylene
glycol polymers, oxazoline polymers, and various combinations or
blends thereof. Optionally, bone hemostat compositions may be
formulated as aqueous compositions or as nonaqueous
compositions.
[0025] Definitions of a number of terms used throughout the
specification are provided below.
[0026] The term "biocompatible material" used herein encompasses a
material that does not threaten, impede, or adversely affect living
tissue.
[0027] The term "resorbable polymer matrix" used herein encompasses
a polymer composition which can be gradually dissolved and
eliminated from the body.
[0028] The term "copolymer" used herein (also known as a
heteropolymer) encompasses a polymer derived from two or more types
of monomeric species. This is in contrast to a homopolymer where
only one type of monomer is used.
[0029] The term "non-random" used herein encompasses an intra-chain
distribution of co-monomers having a particular pattern that is
segmented. It is a unique structural feature of a block
copolymer.
[0030] The term "poloxamer" used herein encompasses a nonionic
triblock copolymer composed of a central hydrophobic chain of
polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic
chains of polyoxyethylene (poly(ethylene oxide)). In some
instances, a poloxamer may be referred to as a
polyoxyethylene-polyoxypropylene (POE-POP) block copolymer.
[0031] The term "number average molecular weight" used herein is
calculated as follows:
M w = i N i M i 2 i N i M i ##EQU00001##
where N.sub.i is the number of molecules of molecular weight
M.sub.i.
[0032] The term "bone hemostasis" refers to a process of
inhibiting, preventing, or otherwise modulating or controlling
bleeding in bone. Relatedly, the terms "bone hemostat" encompasses
compositions that can be applied or administered to bone, for the
intended purpose of achieving or facilitating bone hemostasis.
[0033] Each aspect or embodiment described herein may be combined
with any other aspect(s) or embodiment(s) unless clearly indicated
to the contrary. In particular any feature indicated as being
preferred or advantageous may be combined with any other feature or
features indicated as being preferred or advantageous.
[0034] The biocompatible material described herein is suitable for
use in therapy. Such therapy includes, but is not restricted to,
medicine, dentistry and surgery. More specific applications include
use of the polymer composition as a hemostatic agent or a carrier
for medication.
[0035] In exemplary biocompatible materials, a resorbable polymer
matrix can provide a continuous phase, and additives or particles
can provide a non-continuous, dispersed phase.
[0036] Primary Non-Random Copolymer Components
[0037] Embodiments of the present invention encompass compositions
having one or more primary non-random copolymer components. For
example, bone hemostat compositions may include at least one
non-random copolymer of poly(alkylene oxide)s or derivatives
thereof. A non-random copolymer of poly(alkylene oxide)s can be
linear or branched. Exemplary poly(alkylene oxide)s may include
polyoxyethylene-polyoxypropylene (POE-POP) block copolymers or
poloxamers, and may contain poly(ethylene oxide) (EO) and
polypropylene oxide) (PO) units with the molecular formula
(EO).sub.x(PO).sub.y(EO).sub.x. Often, a non-random copolymer will
include at least two poly(alkylene oxide)s. In some embodiments, a
non-random copolymer of poly(alkylene oxide)s has a number average
molecular weight within a range from about 9,840 to about 14,600
g/mol. In some embodiments, a non-random copolymer of poly(alkylene
oxide)s has a number average molecular weight within a range from
about 6,500 to about 16,300 g/mol. Relatedly, in some cases, the
molecular weight may be determined based on an end group analysis
approach. The number average molecular weight of the poly(alkylene
oxide) may be selected so as to confer certain handling properties,
such as a desired deformation force or working window, to the bone
hemostat composition. As further discussed elsewhere herein, a
non-random copolymer, for example in conjunction with other
components of the bone hemostat composition, can operate to
facilitate blood wicking and clotting.
[0038] In some embodiments, the polyoxypropylene core of a
poloxamer has an average molecular weight in the range from about
3200 to about 4100 g/mol. Relatedly, a poloxamer may have a
polyoxypropylene core of 56 units (e.g. 3248 g/mol) or 70 units
(e.g. 4060 g/mol). In some embodiments, a poloxamer has a
polyoxyethylene content of from about 25% to about 30%. In some
embodiments, the bone hemostat composition may include poloxamer
407 (Pluronic F127), which is a commercially available
polyoxyethylene-polyoxypropylene triblock copolymer of the formula
(EO).sub.101(PO).sub.56(EO).sub.101. In some embodiments, a bone
hemostat composition may include a polyoxyethylene-polyoxypropylene
triblock copolymer of the formula
(EO).sub.106(PO).sub.70(EO).sub.106, or for example
(EO).sub.106(PO).sub.69(EO).sub.106. Depending on the values of x
and y in the formula (EO).sub.x(PO).sub.y(EO).sub.x, the molecular
weight and/or the PO percentage of the poloxamer may vary. It has
been observed that bone hemostat compositions containing poloxamer
407 have excellent handling properties.
[0039] Exemplary compositions may incorporate poloxamers that are
present in solid form, as compared to, for example, a wax form. In
some instances, a poloxamer may include a percentage of PO of
between about 20% and about 40%. In some instances, the percentage
of PO in a poloxamer may be about 30%. By adjusting the amount or
percentage of PO block or polyoxypropylene core, it may be possible
to control or modulate the solubility of the composition. For
example, use of a poloxamer having a relatively higher PO
concentration or amount may provide a bone hemostat composition
that dissolves in the body at a relatively lower rate, as compared
to that of a poloxamer having a lower PO concentration or amount.
If, however, the amount of PO in the poloxamer is excessively high,
the resulting bone hemostat composition may be highly hydrophobic,
and may not dissolve quickly enough to provide a desired
therapeutic or treatment effect. Other poloxamers which may be used
include Pluronic F77/poloxamer 217 (30% PO), Pluronic F87/poloxamer
237 (30% PO), Pluronic F88/poloxamer 238 (20% PO), Pluronic
F98/poloxamer 288 (20% PO), Pluronic F108/poloxamer 388 (20% PO),
and Pluronic F68/poloxamer188 (20% PO).
[0040] According to embodiments of the present invention, one or
more primary non-random copolymer components may be used,
optionally in combination with other components as described
elsewhere herein, to prepare a matrix for a bone hemostat paste.
The solubility of non-random copolymer components, optionally in
combination with other components as described elsewhere herein,
can be tailored to obtain a bone hemostat composition with desired
dissolution kinetics, for example by blending polymers with
different hydrophilic-hydrophobic properties or by blending soluble
and poorly soluble polymers.
[0041] Secondary Non-Random Copolymer Components
[0042] Embodiments of the present invention encompass compositions
having one or more secondary non-random copolymer components. For
example, bone hemostat compositions may include at least one
secondary non-random copolymer of poly(alkylene oxide)s or
derivatives thereof, in addition to a primary non-random copolymer.
Exemplary poly(alkylene oxide)s may include
polyoxyethylene-polyoxypropylene (POE-POP) block copolymers or
poloxamers, and may contain poly(ethylene oxide) (EO) and
poly(propylene oxide) (PO) units with the molecular formula
(EO).sub.x(PO).sub.y(EO).sub.x. Often, a non-random copolymer will
include at least two poly(alkylene oxide)s. In some instances, a
secondary non-random copolymer component may be more hydrophobic,
or less water miscible, than a primary non-random copolymer
component. The presence of such secondary non-random copolymer
components in addition to a primary non-random copolymer can
operate to reduce, slow down, or modulate dissolution of the bone
hemostat composition.
[0043] In some embodiments, a non-random copolymer of poly(alkylene
oxide)s has a weight average molecular weight within a range from
about 1,100 to about 5,000 g/mol, and a percentage of
polyoxypropylene from about 60% to about 90%, or higher. For
example, an exemplary secondary non-random copolymer may include
Pluronic L31, which is a commercially available
polyoxyethylene-polyoxypropylene triblock copolymer of the formula
(EO).sub.2(PO).sub.16(EO).sub.2. Another exemplary secondary
non-random copolymer may include Pluronic L61, which is a
commercially available polyoxyethylene-polyoxypropylene triblock
copolymer of the formula (EO).sub.3(PO).sub.30(EO).sub.3. Pluronic
L62 with the formula (EO).sub.5(PO).sub.30(EO).sub.5, Pluronic L63
with the formula (EO).sub.9(PO).sub.30(EO).sub.9, Pluronic L72 with
the formula (EO).sub.6(PO).sub.35(EO).sub.6, Pluronic L81 with the
formula (EO).sub.3(PO).sub.39(EO).sub.3, Pluronic L92 with the
formula (EO).sub.8(PO).sub.47(EO).sub.8, Pluronic L101 with the
formula (EO).sub.4(PO).sub.56(EO).sub.4, Pluronic L122 with the
formula (EO).sub.11(PO).sub.69(EO).sub.11 are other block
copolymers which may be used as a secondary non-random copolymer
component.
[0044] According to embodiments of the present invention, one or
more secondary non-random copolymer components may be used,
optionally in combination with other components as described
elsewhere herein, to prepare a matrix for a bone hemostat paste.
The solubility of non-random copolymer components, optionally in
combination with other components as described elsewhere herein,
can be tailored to obtain a bone hemostat composition with desired
dissolution kinetics, for example by blending polymers with
different hydrophilic-hydrophobic properties or by blending soluble
and poorly soluble polymers.
[0045] In some cases, a secondary non-random copolymer component
may be provided as a liquid, or as a viscous liquid. In some cases,
a secondary non-random copolymer component may be more hydrophobic
that the primary non-random copolymer component.
[0046] Random Copolymer Components
[0047] Embodiments of the present invention encompass compositions
having one or more random copolymer components. For example, bone
hemostat compositions may include at least one random copolymer of
poly(alkylene oxide)s or derivatives thereof. Exemplary
poly(alkylene oxide)s may include polyoxyethylene-polyoxypropylene
(POE-POP) copolymers, and may contain random arrangements of
poly(ethylene oxide) (EO) and poly(propylene oxide) (PO) units.
[0048] Random copolymers of poly(alkylene oxide)s are commercially
available from a variety of manufacturers including BASF, Dow
Chemical, and Sigma/Aldrich under the trade names PLURADOT.RTM.,
PLURACOL.RTM., SYNALOX.RTM. EPB, and EMKAROX.RTM. among others.
They are available in a range of EO:PO ratios and molecular weights
(e.g., 1000 to 22,000 g/mol) and in linear and branched geometries,
and are commonly characterized by their viscosity rather than
molecular weight. Dow Chemical provides a number of random
copolymers of poly(alkylene oxide)s with molecular weights in the
range of 1,500 to 4,900 including those with the following codes:
EP 530, EP 1730, EP 435, EP 1660, 15-200, 112-2, UCON 50-HB-5100,
and UCON 50-HB-660. Sigma/Aldrich provides a number of random
copolymers of poly(alkylene oxide)s with molecular weights in the
range of 2,500 to 12,000 including those with the following codes:
43,819-7, 43,820-0, 43,818-9, 40,918-9.
[0049] According to some embodiments, an exemplary random copolymer
component includes a random alkylene oxide copolymer having a
weight average molecular weight of about 22,000 g/mol and an EO:PO
mass ratio of about 50:50. Such a compound is commercially
available from BASF Corporation as PLURACOL.RTM. V-10 or
PLURIOL.RTM. V-10. Often, a random copolymer will include at least
two poly(alkylene oxide)s. In some cases, random copolymer
components may operate to improve cohesiveness and moldability of a
bone hemostat compositions. In some cases, bone hemostat
compositions may be present as an aqueous paste that includes a
random copolymer component within a range from about 2% to about
10% by weight of the composition.
[0050] Basic Matrix for Soluble Bone Hemostat
[0051] Embodiments of the present invention encompass the use of
various polymeric compositions to provide a basic matrix for
soluble bone hemostat composition. In some embodiments, one or more
primary non-random copolymer components can be used to prepare such
a basic matrix. Relatedly, a one or more primary non-random
copolymer components, optionally in combination with one or more
secondary non-random copolymer components, and/or one or more
random copolymer components, can be mixed at various ratios to
provide a basic matrix for soluble bone hemostat. For example, it
is possible to prepare a basic matrix for soluble bone hemostat by
mixing Pluronic F127, Pluronic L-61, Pluronic L-31, and Pluriol V10
at selected ratios, as discussed elsewhere herein.
[0052] A primary non-random copolymer component (e.g. Pluronic
F127) may be a solid polymer that after melting will form a hard
and brittle material. A secondary non-random copolymer component
(e.g. Pluronic L-61 or Pluronic L-31) may be a liquid polymer that
is hydrophobic. When blended, the combined primary and secondary
non-random copolymer component may provide a material with soft,
malleable properties. A random copolymer component (e.g. Pluriol
V10) may be a very viscous polymer with hydrophobic properties, and
when blended with a primary non-random copolymer component (e.g.
Pluronic F127) may provide a resulting material with good handling
properties. Some random copolymer components may high molecular
weights, strong hydrophobic properties, and low miscibility in
water. In some embodiments, compositions containing random
copolymer components may also include secondary non-random
copolymer components of low molecular weight (e.g. Pluronic L-31 or
Pluronic L-61). Such secondary non-random copolymer components may
operate as a kind of plasticizer for a primary non-random copolymer
component (e.g. Pluronic F127), and in some situations may allow
for a reduction in the amount of random copolymer component (e.g.
Pluriol V10) in a bone hemostat composition. According to some
embodiments, bone hemostat compositions containing certain
combinations of primary and secondary non-random copolymer
components and random copolymer components in ready-to-use paste
with superior handling properties. The presence or ratios of such
components can affect the handling properties of a bone hemostat
composition. Similarly, the presence or ratios of such components
can affect the dissolution kinetic of a bone hemostat
composition.
[0053] The presence of hemostatic additives in poloxamer
compositions can improve or provide blood wicking and clotting at
the local defect site. Poloxamers may operate as a mechanical
barrier, by obstructing the bleeding vessels. Polymeric
compositions or blends can be used alone, or in some instances as a
carrier or a matrix for antibiotics, blood coagulants or related
materials including natural polymer components such as gelatin and
cross-linked derivatives, for example cross-linked gelatin
particles, or osteoconductive ceramics.
[0054] Natural Polymer Components
[0055] Exemplary bone hemostat polymeric blends or compositions can
be also formulated with natural polymers such as gelatin or
cross-linked derivatives thereof, for example cross-linked gelatin
particles. Other natural polymer components may chitosan or
collagen. Such natural polymers can be incorporated into bone
hemostat compositions in the form of a fine powder, having small
particles with a diameter of 500 .mu.m or less, or as short fibers
(0.2-2 mm), for example. The presence of such natural polymers may
enhance hemostatic properties of the polymeric blends or
compositions and may enhance process of bone healing or
regeneration. Natural polymer components can be used as an
additive, in combination with a soluble polymer matrix that
includes a triblock copolymer, for example. In bone hemostat
compositions containing gelatin, the relative amounts of water,
block copolymer, and gelatin may be adjusted or selected based on
the ratio of solid to liquid components in the composition. For
example, where more water is used, it is possible to use more
gelatin. Relatedly, where more poloxamer is used, it is possible to
use less gelatin. In bone hemostat compositions containing chitosan
or collagen, the chitosan or collagen can be similarly adjusted or
selected. According to some embodiments, natural polymers for use
with bone hemostat compositions may include cross-linked or
non-cross-linked chitin, chitosan, gelatin, collagen, as well as
cross-linked or non-cross-linked derivatives thereof. Table 1,
discussed elsewhere herein, provides exemplary composition
formulations containing cross-linked gelatin particles. Any wt %
amounts or ranges mentioned with reference to gelatin can also
apply to other natural polymers such as the chitin, chitosan, and
collagen variants disclosed herein.
[0056] Ceramic Particle Components
[0057] Similarly, the presence of ceramic particles can have
positive impact on bone regeneration and can also stimulate
hemostasis by release of calcium ions from ceramic materials. Any
type of ceramic may be used. For example, ceramic particles can be
calcium carbonate, hydroxyapatite, carbonated hydroxyapatite,
tri-calcium phosphate, carbonated hydroxyapatite, biphasic
materials composed from tricalcium phosphate and hydroxyapatite at
various ratios, Si-substituted ceramics, Mg-substituted ceramics,
Sr-substituted ceramics, and the like. For example, ceramic
particles can include Sr-substituted ceramics, such as
Sr-substituted biphasic ceramics, Sr-substituted apatite,
Sr-substituted hydroxyapatite, and the like, or ceramic particles
can include siliconated ceramics, such as siliconated
hydroxyapatite (Actifuse Apatech) and the like. In some instances,
the presence of Si ions on the surface of particles can enhance the
wettability of the particles and provide enhanced interaction with
polymeric compositions and blends. In some instances, ceramic
particles can have a particle size of less than about 150 .mu.m.
Tables 1 and 2, discussed elsewhere herein, provide exemplary
composition formulations containing ceramic components. Any wt %
amounts or ranges, as well as any particle size values or ranges,
mentioned with reference to Si-substituted ceramics can also apply
to other ceramics such as the Sr-substituted ceramic variants
disclosed herein.
[0058] Reactive Group Polymer Components
[0059] Additionally, the polymeric blends can be combined with
polymers having reactive groups, such as e.g., succinimidylesters
(--CON(COCH.sub.2).sub.2), aldehydes (--CHO), especially
succinimidylesters [--N(COCH.sub.2).sub.2 as one of the component
in CoSeal.RTM. (four arm PEG-NHS). In some instances, ethylene
glycol polymers can be provided in a form of 4- or more arm
polymers terminated with specified reactive groups. Handling
properties of a bone hemostat composition may be affected by
incorporating a reactive group polymer components, and in some
instances the molecular weight or the concentration of the reactive
group polymer component may impact such handling properties. In
some cases, a PEG having a low molecular weight (and present as a
liquid form) can be used to enhance or increase flexibility in a
bone hemostat composition.
[0060] Oxazoline Polymer Components
[0061] Exemplary bone hemostat polymeric blends or compositions can
be also formulated to include oxazoline polymers. In some
instances, an oxazoline polymer can be used as a compatibilizer. In
some instances, an oxazoline polymer can be used as a lubricant. In
some instances, an oxazoline polymer can be used as an additive,
enhancing adhesive properties of the hemostat composition, for
example to enhance adhesion to bone. In some instances, an
oxazoline polymer can be used as in either aqueous or nonaqueous
bone hemostat compositions. In some instances, an oxazoline polymer
component can be present in a bone hemostat composition within a
range from about 2% to about 10% by weight of the composition.
EXAMPLES
[0062] The materials and methods of manufacture will now be further
described by reference to the following non-limiting examples.
Hemostatic polymeric compositions or blends can be formulated as an
aqueous or non-aqueous systems.
[0063] Aqueous Systems
[0064] Examples of aqueous bone hemostat compositions are specified
in Table 1.
TABLE-US-00001 TABLE 1 Bone Linear Crosslinked Hemostat
polyethylene Pluriol gelatin aqueous ddH2O Poloxamer oxide (PEG)
V10 Polyoxazoline particles Ceramic formulation (wt %) 407 (wt %)
(wt %) (wt %) (wt %) (wt %) (wt %) 1 44.4 33.3 -- -- -- 22.2 -- 2
24 26.7 13.3* -- 2.7 33.3 -- 3 27 20 10* 5 3 35 -- 4 27 20 10* 5 3
30 5** 5 27 20 10* 5 3 30 5*** *refers to PEG with molecular weight
of 200 Da **refers to Si-substituted hydroxyapatite having a
particle size below 150 .mu.m ***refers to Sr-substituted biphasic
ceramic
[0065] Exemplary formulations such as those presented in Table 1
have been prepared as follows. First, specified amounts of polymers
(e.g. Poloxamer 407, linear PEG, Pluriol V10, and/or polyoxazoline)
were mixed with water to obtain homogenous paste. Next, gelatin
particles and/or ceramic particles were added and again all
components were mixed to obtain homogenous product. After mixing,
the product was stable and could be applied without any further
preparation onto bleeding bone. In order to preserve a moldable
consistency, the aqueous systems should be protected from losing
water. Examples presented in Table 1 contain crosslinked gelatin
particles, but can be also formulated without gelatin. Optionally,
instead of or in addition to gelatin, formulations can be prepared
using chitosan and/or collagen components. Products prepared
according formulations presented in Table 1 were ready-to-use bone
hemostats with excellent handling properties that do not require
any preparation step prior to application.
[0066] In some instances, aqueous hemostat formulations with
desirable handling properties (e.g. paste, viscous paste, or
dough-like consistency) can be produced as disclosed herein. When
preparing a bone hemostat containing poloxamer 407, it may be
possible to achieve a viscous, moldable paste by adding about 10%
by weight of water. Relatedly, it may be possible to achieve a
viscous, moldable paste by adding about 5% by weight of water. In
bone hemostat compositions that include crosslinked gelatin, it may
be desirable to increase the amount of water and decrease the
amount of poloxamer in the composition. For example, both gelatin
and poloxamer may compete for water, and gelatin may swell due to
its swelling capacity. In some instances, it may be possible to
achieve a viscous paste (e.g. dough-like composition) by having the
liquid components (e.g. water, PEG 200 Da, Pluriol V10, and the
like) at about 40% to about 45% by weight of the composition, and
the solid components (e.g. Poloxamer 407, crosslinked gelatin,
polyoxazoline, and the like) at about 55% to about 60% by weight of
the composition. According to some embodiments, the amount of
crosslinked gelatin in a hemostat composition may be within a range
from about 20% to about 40% by weight of the composition. In bone
hemostat compositions containing chitosan or collagen, the chitosan
or collagen can be similarly adjusted or selected.
[0067] In some instances, it is possible to vary the ratio between
liquid components of a bone hemostat composition. For example, both
PEG 200 and water have similar viscosity, and it may be possible to
use less water when using more PEG 200, and conversely, it may be
possible to use more water when using less PEG 200. In some cases,
bone hemostat compositions may include water without including PEG
200. In some instances, random copolymer components, or
polyoxazoline, may be included in a bone hemostat composition. Such
ingredients may improve cohesiveness and moldability of the
hemostat composition. In some cases, random copolymer components
may be present in a bone hemostat composition within a range from
about 2% to about 10% of the composition. In some cases,
polyoxazoline may be present in a bone hemostat composition within
a range from about 2% to about 10% of the composition. In some
instances, ceramic particles can be included in a bone hemostat
composition within a range from about 5% to about 25% by weight of
the composition. In some instances, ceramic particles can be
included in a bone hemostat composition within a range from about
10% to about 25% by weight of the composition. In some instances,
ceramic particles can be included in a bone hemostat composition at
about 5% by weight of the composition.
[0068] Nonaqueous Systems
[0069] Examples of non-aqueous bone hemostat compositions are
specified in Table 2. In such systems water can still be present
but at lower concentrations, for example lower than 5 wt %.
TABLE-US-00002 TABLE 2 Nonaqueous Poloxamer Pluriol Bone Hemostat
407 V10 Pluronic Pluronic Ceramic formulation (wt %) (wt %) L-31
L-61 (wt %) 1 57.1 42.9 -- -- -- 2 50 25 25 -- -- 3 57.1 14.3 --
28.6 -- 4 50 25 -- 25 -- 5 50.7 12.7 -- 25.4 11.2* 6 44.4 44.4 --
11.2** 7 44.4 22.2 22.2 -- 11.2** *refers to Si-substituted
hydroxyapatite having a particle size below 150 .mu.m **refers to
Sr-substituted biphasic ceramic
[0070] Exemplary formulations such as those presented in Table 2
were prepared as follows. First, all polymeric components and
selected ceramic powders were mixed at specified mass ratios at
room temperature in order to obtain homogenous putty-like material.
Next, this material was heated above the melting point, usually at
80.degree. C., in order to bring all components (despite the
presence of the ceramic) to a molten state. At this stage, molten
material was mixed and left in an oven at 80.degree. C. for about
30 minutes to allow air bubble to escape. Afterward, the material
was removed from the oven, and cooled to room temperature or
quenched in liquid nitrogen, so as to let the molten material
solidify. Next, the solid material was subjected to additional
mixing and homogenization process by kneading, which can also be
achieved by extrusion processes such as those known in polymer
technology (extrusion). After this process, the bone hemostat was
ready to be packed and applied to bleeding bone without any further
preparation required.
[0071] According to some embodiments, if an excessive amount of
liquid components are used, a bone hemostat formulation may not
perform as desired, and may be washed away by bleeding. Relatedly,
if an excessive amount of solid components are used, a bone
hemostat formulation may not perform as desired, and the final
product may be too hard, too brittle, or not sufficiently
malleable.
[0072] Exemplary products such as those prepared according the
formulations presented in Table 1 provided ready-to-use bone
hemostat with good handling properties that do not require any
preparation step prior to application. It was also observed that
exemplary products such as those prepared according to the
formulations presented in Table 2 provided useful bone hemostats,
and in particular, formulations 4 and 5 exhibited excellent
handling properties.
[0073] Turning now to the drawings, FIG. 1 shows an aqueous bone
hemostat composition according to formulation 4 of Table 1. FIG. 2
shows a non-aqueous bone hemostat composition according to
formulation 2 of Table 2. FIG. 3 depicts a non-aqueous bone
hemostat composition according to formulation 5 of Table 2.
Hemostat compositions were also tested in a laboratory. FIG. 4
shows examples of non-aqueous bone hemostat compositions as applied
to bone as part of a sternotomy procedure in heparinized pig.
[0074] Embodiments of the present invention further include methods
of treating a patient or individual, which may involve
administering a biocompatible composition as disclosed herein to a
bone of the patient. For example, methods may include administering
a bone hemostat composition to a damaged or cut bone of a patient,
during a surgical procedure. Embodiments of the present invention
also encompass kits for the treatment of a bone of a patient.
Exemplary kits may include a bone hemostat composition as disclosed
herein, and instructions for use. For example, the instructions for
use may include a description of how to apply a bone hemostat
composition to a bone of a patient. In some cases, the bone
hemostat composition can be packaged in a container suitable for
storage and/or delivery to an end user. The compositions as
disclosed herein may be used in bone healing or regenerations
methods and in kits for use in such methods. For example,
embodiments encompass kits for repairing or treating a bone having
a defect. In some cases, kits may include devices for applying or
fixing the composition to the bone, such as spatulas and the
like.
[0075] Where a range of values is provided, it is understood that
each intervening value between the upper and lower limits of that
range is also specifically disclosed, to the smallest fraction of
the unit or value of the lower limit, unless the context clearly
dictates otherwise. Any encompassed range between any stated value
or intervening value in a stated range and any other stated or
intervening value in that stated range is disclosed. The upper and
lower limits of those smaller ranges may independently be included
or excluded in the range, and each range where either, neither, or
both limits are included in the smaller range is also disclosed and
encompassed within the technology, subject to any specifically
excluded limit, value, or encompassed range in the stated range.
Where the stated range includes one or both of the limits, ranges
excluding either or both of those included limits are also
included. Value ranges may include, for example, integer ranges,
numerical ranges, percentage ranges, and the like.
[0076] The subject matter of embodiments of the present invention
is described herein with specificity to meet statutory
requirements, but this description has been provided by way of
explanation and illustration and is not necessarily intended to
limit the scope of the claims. The claimed subject matter may be
embodied in other ways, may include different elements or steps,
and may be used in conjunction with other existing or future
technologies. This description should not be interpreted as
implying any particular order or arrangement among or between
various steps or elements except when the order of individual steps
or arrangement of elements is explicitly described.
[0077] Different arrangements of the components depicted in the
drawings or described herein, as well as components and steps not
shown or described are possible. Similarly, some features and
subcombinations are useful and may be employed without reference to
other features and subcombinations. Embodiments of the invention
have been described for illustrative and not restrictive purposes,
and alternative embodiments, and many variations in the embodiments
illustrated herein, will become apparent to readers of this patent,
and remain within the scope of the appended claims and their
equivalents. Accordingly, the present invention is not limited to
the embodiments described herein or depicted in the drawings, and
various embodiments and modifications can be made without departing
from the scope of the claims below.
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