U.S. patent application number 09/164293 was filed with the patent office on 2001-11-15 for composition and method for acceleration of wound and burn healing.
Invention is credited to GREENSPAN, DAVID C., WEST, JON K..
Application Number | 20010041186 09/164293 |
Document ID | / |
Family ID | 24875977 |
Filed Date | 2001-11-15 |
United States Patent
Application |
20010041186 |
Kind Code |
A1 |
GREENSPAN, DAVID C. ; et
al. |
November 15, 2001 |
COMPOSITION AND METHOD FOR ACCELERATION OF WOUND AND BURN
HEALING
Abstract
A method for treating wounds including contacting a wound with
an effective wound healing amount of bioactive glass and topical
antibiotic and composition for the accelerated healing of wounds
and burns including particulates of bioactive glass and at least
one topical antibiotic.
Inventors: |
GREENSPAN, DAVID C.;
(GAINESVILLE, FL) ; WEST, JON K.; (GAINESVILLE,
FL) |
Correspondence
Address: |
BURNS DOANE SWECKER & MATHIS L L P
POST OFFICE BOX 1404
ALEXANDRIA
VA
22313-1404
US
|
Family ID: |
24875977 |
Appl. No.: |
09/164293 |
Filed: |
October 1, 1998 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09164293 |
Oct 1, 1998 |
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08715911 |
Sep 19, 1996 |
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5834008 |
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Current U.S.
Class: |
424/405 ; 424/43;
424/443; 424/445; 424/446 |
Current CPC
Class: |
A61L 15/18 20130101;
A61K 33/00 20130101; A61L 15/44 20130101; A61L 15/46 20130101; A61P
41/00 20180101; A61K 31/00 20130101; A61K 45/06 20130101; C03C
4/0007 20130101 |
Class at
Publication: |
424/405 ;
424/443; 424/445; 424/446; 424/43 |
International
Class: |
A61L 009/04; A61K
009/00 |
Claims
What is claimed is:
1. A composition for the accelerated healing of wounds and burns
comprising particulates of bioactive glass and at least one topical
antibiotic.
2. The composition of claim 1, wherein said bioactive glass has a
composition by weight percentage: SiO.sub.2 40-60 CaO 10-30
Na.sub.2O 10-35 P.sub.2O.sub.5 2-8 CaF.sub.2 0-25 B.sub.2O.sub.3
0-10 K.sub.2O 0-8 MgO 0-5
3. The composition claim 1, wherein said bioactive glass has a
particle size range less than 90 microns.
4. The composition of claim 1, wherein said bioactive glass has a
particle size range less than 10 microns.
5. The composition of claim 1, wherein said bioactive glass has a
particle size range less than 2 microns.
6. The composition of claim 1, wherein said topical antibiotic is
chloramphenicol, chlortetracycline, clyndamycin, clioquinol,
erythromycin, framycetin, gramicidin, fusidic acid, gentamicin,
mafenide, mupiroicin, neomycin, polymyxin B, bacitracin, silver
sulfadiazine, tetracycline, chlortetracycline, or combinations
thereof.
7. The composition of claim 1, further comprising a
pharmaceutically acceptable carrier.
8. The composition of claim 7, wherein said pharmaceutically
acceptable carrier is an ointment, gel, white petrolatum, light
mineral oil, or mixtures thereof.
9. A method for treating wounds and burns comprising contacting a
wound with an effective wound healing amount of bioactive glass and
topical antibiotic.
10. A method for grafting skin comprising applying bioactive
particulate glass to a graft of skin and then placing the
graft.
11. The method of claim 10, further comprising applying a topical
antibiotic to the graft.
12. A wound or burn dressing comprising a bandage, a topical
antibiotic and particulate bioactive glass.
13. The wound or burn dressing of claim 12 wherein said bandage is
cotton, gauze, fiberglass, fiberglass made from bioactive glass or
synthetic material.
14. A wound or burn treatment apparatus comprising a topical
antibiotic in a first chamber, a particulate bioactive glass in a
second chamber and a mixing means for mixing the topical antibiotic
and the particulate bioactive glass.
15. The apparatus of claim 14, wherein said wound or burn treatment
apparatus is a multi chamber syringe.
16. A method for accelerating the healing of wounds or burns
comprising contacting a wound or bum with an effective wound or
burn healing accelerating amount of a particulate bioactive glass.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a treatment composition and
method for the accelerated healing of wounds and burns. More
specifically, the present invention relates to the combination and
use of particles of bioactive glass and one or more topical
antibiotics. The present invention also relates to a treatment
composition and method for the accelerated healing of wounds and
burns including the combination of bioactive glass, one or more
topical antibiotics and wound or burn dressings.
BACKGROUND OF THE INVENTION
[0002] When an injury occurs, cell damage comes from the
precipitating event, such as a cut, resulting in ruptured cells and
severed or crushed capillaries and other blood vessels. The
interruption of blood flow produces anoxia, causing the death of
additional cells. Within 15 minutes of injury the wound is filled
with dead and dying cells, extracellular substances (collagen,
elastic fibers, fat and ground substances), extravasated blood, and
possibly bacteria and viruses introduced by the injurious agent.
Tissue damage is not restricted to the initial area of injury. it
may increase over the next several hours or days as a result of the
release of lysomal enzymes from the injured cells or as a
consequence of swelling and infection. (See Reese et al., Role of
Fibronectin in Wound Healing, the subject matter of which is hereby
incorporated by reference.
[0003] Coagulation, the first phase of the healing process, bridges
the gap between the injury and the inflammatory response, the
second phase of wound healing. It stops the loss of blood and
restores some of the mechanical and physical integrity to the
damaged tissue. The proteins of the coagulation cascade are
normally confined to the intravascular space but are released into
the tissues after blood vessel disruption. Coagulation is initiated
by either the intrinsic or extrinsic pathway, both of which must be
activated for maximum fibrin formation. The result of the
activation of either of the two coagulation pathways is the
generation of thrombin, which in turn catalyzes the conversion of
fibrinogen to fibrin monomer. Fibrin monomer spontaneously
polymerizes to form the clot. Just after polymerization, the fibrin
fibers are held together by hydrophobic and ionic forces and are
relatively unstable. Fibrin stabilizing factor, which is generated
from its proenzyme by thrombin, covalently cross-links the fibrin
fibrils by catalyzing a transamination reaction between glutamine
and lysine residues in adjacent fibers. The cross-linking of fibers
greatly increases the mechanical strength of the clot. Platelets,
along with other blood cells, are trapped in the fibrin mesh as the
clot forms by fibronectin. The platelet surfaces are heavily
coated, and each looks like a nexus with the fibrin fibers
radiating out from it.
[0004] The second phase of wound repair is the inflammatory
response, which is necessary for subsequent phases of healing. It
is initiated by the release of histamine and serotonin from
platelets and mast cells and by kinins. Histamine and kinins act to
increase capillary dilation, opening previously closed capillaries
in the area of injury. The increased blood flow through the
capillary beds produces two of the characteristics of the
inflammatory response: redness and heat. Prostaglandin release
within a few hours of injury results in the full development of the
inflammatory response, which may last from 3 to 5 days depending on
the extent of the injury. The extreme vasodilation produced by the
factors just discussed causes a widening of the endothelial cell
junctions lining the capillaries. Fluid and macromolecular
components of blood escape into the tissues through the gaps,
producing swelling, the third characteristic of the inflammatory
response. If the swelling is extensive, it may interrupt blood
flow, increasing the extent of injury as a result of anoxia. Pain,
the final characteristic of inflammation, results form a
combination of the kinins as well as the direct effect of lysosomal
enzymes and pressure from the swelling on nerve endings.
[0005] Control of infection at the wound site is of critical
importance in successful wound repair. Infections delay healing,
enlarge the wound lesion, may lead to systemic infection, and
greatly increase the likelihood of disfiguring and physically
debilitating scars. Vasodilation of the capillary beds reduces the
velocity of blood through the capillaries. This, along with the
production of potent chemotactic factors from the complement
fixation and the release of chemotactic agents from the damaged
tissue, cause the accumulation of polymorphonuclear leukocytes
("PMN's") along the walls of the capillaries which are the host's
major cellular defense against infection. The PMN's subsequently
pass through the endothelial junctions of the capillary wall into
the site of the injury. If bacteria are present in the wound, they
may release soluble chemotactic factors and/or activate complement
with the subsequent generation of chemotactic fragments. PMN's at
the site of an infection or injury release substance that affect
the PMNs' mobility, keeping them at the site. Fibronectin
facilitates the attachment of the bacterium to the membrane of the
phagocyte.
[0006] Dead cells, cellular debris, and extracellular proteins must
then be removed or readsorbed to allow revascularization and repair
to continue. Macrophages are primarily responsible for the
clearance of wound debris. Wound macrophages, like wound PMN's are
actively phagocytic. They migrate into the wound using the fibers
of the fibrin clot as a scaffold to move within the clot, attaching
to the fibers through fibronectin. The macrophages encounter,
engulf, and destroy the dead cells trapped in the clot matrix, as
well as the damaged cells from the wound margin. The fibrin clot
itself is resolved primarily by the activation of the plasminogen
that was incorporated into the fibers during their formation. Some
of the fibrin fragments are engulfed by macrophages in the area.
Since most of the clot fragments are released away from the area of
the most intense macrophage activity, many of the fragments are
removed by lymphatic drainage and thus enter the circulation. These
soluble complexes are removed by the sessile cells of the RES,
primarily those of the spleen and liver. Also, PMN's trapped in the
clot die as a result of anoxia, releasing their lysosomal contents.
These enzymes attack the surrounding clot and dissolve it. Although
the release of lysosomal enzymes by PMN's may be considered
beneficial to the host in most cases, they may also increase tissue
destruction and delay healing. If the PMN's accumulate rapidly
within the wound and remain there (as in an infection), their
lysosomal enzymes dissolve significant portions of the clot,
removing the framework used by the macrophages and fibroblasts to
move into the wound and recolonize it. These areas of destruction
must eventually be drained or slowly removed by the macrophages.
The dissolved portion of the clot is then replaced as part of the
chronic inflammatory response.
[0007] Repair, or fibroplasia, of the damaged tissue occurs during
some of the above stages. Within 12 to 24 hours of injury,
fibroblasts, including those at some distance from the wound
margins, begin to move toward the area of injury and to
proliferate. This response is apparently due to factors released by
the injured tissue and platelets and possibly to factors released
by the kinin, complement or coagulation cascades. The proliferating
fibroblasts derive part of their nutrients from the components of
tissue debris and cells released by macrophages. The fibroblast
phase may last 2 to 4 weeks in a skin wound, whereas it may persist
several months in an injury to the stomach or intestines.
Fibroblasts, as the macrophages did, use the fibers of the fibrin
clot as a scaffold to move into and within the damages area. The
Fibroblasts synthesize and secrete sufficient quantities of
fibronectin to promote their own attachment to fibronectin
deficient substrates.
[0008] Angiogenesis, or revascularization, begins with the growth
of capillary buds into the area directly behind the fibroblasts. In
the early phases of wound repair, the capillaries are much more
numerous than in normal tissue, which probably reflects the high
oxygen and nutrient requirements of the rapidly regenerating
tissue. The capillaries are very leaky, which facilitates the
movement of cells and macromolecule into the wound site.
Eventually, the capillaries originating from one side of the wound
grow into contact with capillaries originating from the other sides
and fuse, reestablishing complete circulation within the wound.
[0009] By the end of the fifth day after the injury, fibroblasts
begin laying down large quantities of collagen. The collagen
molecule is synthesized on the membrane of the endoplastic
reticulum. It then undergoes extensive postranslational
modification, hydroxylation, glycosylation, and further steps to
form the procollagen molecule. The procollagen molecule is then
secreted and is further modified to tropocollagen by specific serum
peptidasees. These activated tropocollagen molecules quickly
polymerize to form increasingly large collagen fibers. Thereafter,
crosslinking among the collagen fibers occurs. The collagen network
in effect replaces the fibrin clot as the major structural element
of the wound. This becomes particularly important during the
remodeling phase of wound healing.
[0010] Reepithelialization begins to occur within a few hours of
injury as the attachment of the epithelial cells to the dermis
loosened near the margin of the wound, and the cells begin to
migrate over the defect, always maintaining contact with the
mesenchymal tissue. By 48 hours after the injury, the cells are
also beginning to proliferate to replace the lost cells. The
epithelial cells continue to divide after the bridge is complete to
form a thicker epithelium. Wound contracture aids
reepithelialization insofar as it reduces the size of the defect to
be reepithelialized by as much as 50%. Contracture is believed to
occur as a result of the cellular element of the granulation tissue
in the wound--the fibroblasts and myofibroblasts.
[0011] Remodeling is the last step of wound healing. Scar tissue
continues to gain tensile strength for several months after
collagen content stabilizes. This gain in strength comes from the
rearrangement of the collagen in the wound and perhaps form
increased crosslink of the collagen. Collagen accumulation is the
sum of synthesis and destruction, and both occur simultaneously
during the wound healing process. After about 14 days, a balance
between collagen synthesis and degradation is reached. The
collagenase involved in the remodeling comes from epithelial cells,
from fibroblasts encountering new epithelium, and from macrophages
that contain collagenase in their lysosomes.
[0012] Typical wound healing takes anywhere from 5 to 21 days. This
time period is of course longer for the immune compromised patient
because such patients are frequently unable to sufficiently
stabilize the wound and ward off infection which prevents the
proper adherence of fibrin, fibronectin or collagen at an
acceptable rate at the locus of the wound. For example, those with
vasculitis or other rheumatic or diabetic diseases frequently
experience wound healing times far in excess of several weeks.
Diabetics frequently develop lesions that take weeks to heal.
Others, such as those with artificial limbs have continuous injury
at the point of contact between the limb and the point of
attachment to the body. Burns also present healing problems insofar
as the burned tissue is incapable of timely production of fibrin.
Accordingly, there is a great need to shorten the duration of time
necessary for wound or burn healing to occur.
[0013] In an attempt to augment soft tissue, it has been previously
suggested in U.S. Pat. No. 4,837,285 to fill and protect a wound
with resorbable collagen matrix beads, the beads having an average
pore size of from 50 to 350 microns, and the collagen comprising
from 1 to 30% by volume of the beads. The collagen matrix is
sufficiently open to stimulate cellular ingrowth therethrough and
yet sufficiently stiff and non-compressible to fill and protect a
wound. The formulation is also sufficiently moisture and gas
permeable to prevent liquid pooling on a wound and to permit
sufficient oxygen diffusion for promoting wound healing. This
patent, however, fails to disclose any method for actually
enhancing the rate of wound healing.
[0014] Accordingly, it is an object of the present invention to
provide a composition and method capable of dramatically enhancing
the time required for wound and burn healing.
[0015] It is further an object of the present invention to provide
a composition and method capable of quickly stabilizing a wound or
bum.
[0016] It is yet another object of the present invention to
increase the likelihood that a skin graft will "take".
SUMMARY OF THE INVENTION
[0017] The present invention is directed to a method for treating
wounds including contacting a wound with an effective wound healing
amount of bioactive glass and topical antibiotic. The present
invention is also directed to a composition for the accelerated
healing of wounds and burns including particulates of bioactive
glass and at least one topical antibiotic. The present invention is
further directed to a method for grafting skin including applying
bioactive glass to a graft and then placing the graft.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a photograph of a wound in patient with vasculitis
taken soon after the wound was inflicted before treatment with a
composition in accordance with the present invention.
[0019] FIG. 2 is a photograph of the same wound of FIG. 1 after
treatment with a composition in accordance with the present
invention taken 4 days after the photograph of FIG. 1.
[0020] FIG. 3 is a photograph of the same wound of FIG. 2 taken 7
days after the photograph of FIG. 2.
[0021] FIG. 4 is a photograph of the same wound of FIG. 2 taken 7
days after the photograph of FIG. 3.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0022] It has unexpectedly been discovered that the combination of
particulate bioactive glass and a topical antibiotic yields a
composition which is capable of dramatically reducing the amount of
time necessary for wound healing to occur. Applicants have found
that the combination of the present invention augments the natural
healing process. The effect of the combination of the present
invention is most dramatically illustrated in the immune
compromised patient whose ability to heal wounds is somewhat
suppressed.
[0023] Particulate bioactive glasses in accordance with the present
invention typically have the following composition by weight
percentage:
[0024] SiO.sub.2 40-60
[0025] CaO 10-30
[0026] Na.sub.2O 10-35
[0027] P.sub.2O.sub.5 2-8
[0028] CaF.sub.2 0-25
[0029] B.sub.2O.sub.3 0-10
[0030] K.sub.2O 0-8
[0031] MgO 0-5
[0032] The preferred composition of the bioactive glass is:
[0033] SiO.sub.2 45
[0034] CaO 24.5
[0035] Na.sub.2O 24.5
[0036] P.sub.2O.sub.5 6
[0037] The preferred particle size range for the bioactive glass is
small and less than 90 microns is recommended. Particle sizes less
than 10 microns as well as less than 2 microns can also be used.
Particles of such a small size range generally provide for the
advantages of the present invention but do not illicit any
undesirable immune response.
[0038] Topical antibiotics are antibiotics suitable for skin
treatment. Examples of such antibiotics include: chloramphenicol,
chlortetracycline, clyndamycin, clioquinol, erythromycin,
framycetin, gramicidin, fusidic acid, gentamicin, mafenide,
mupiroicin, neomycin, polymyxin B, bacitracin, silver sulfadiazine,
tetracycline and chlortetracycline. Those of ordinary skill in the
art will appreciate that there are other appropriate topical
antibiotics such as those listed in U.S.P.D.
[0039] The bioactive glass and topical antibiotic can be combined
in any pharmaceutically acceptable carrier to facilitate
application to the wound. For example, the composition of the
present invention can be combined with an ointment, white
petrolatum, mineral oil and others known to those of ordinary skill
in the art.
[0040] It is also within the scope of the present invention to
combine the bioactive glass and topical antibiotic of the present
invention with other wound and burn treatments or dressings such as
collagen, fibrin, fibronectin, vitamin E, gauze, cotton,
cellulosic, synthetic wound or burn dressings and other wound or
burn dressings/treatments known to those of ordinary skill in the
art. Dressings of fiberglass and fiberglass made from fibers of
bioactive glass can also be used.
[0041] The present invention is also directed to a method for
grafting skin including the application of particulate bioactive
glass to the graft before it is placed in its intended location.
The graft may also be further treated with a topical antibiotic
prior to placement. The application of bioglass to grafts is
intended to increase the likelihood that the graft will "take" and
incorporate in the host bed.
[0042] While not being bound to any particular theory or mechanism,
it is believed that the high surface area and reactivity of
particulate bioactive glass provides for a release of sodium which
increases pH and increase oxygen in the wound or burn which
otherwise has a lower pH. This has a bacteriostatic effect and
permits the antibiotic to function by activating various growth
factors implicated in tissue repair. These reactions cause a higher
negative surface charge on the glass surface and the development of
a high specific surface area (e.g. from 0.5 m.sup.2/g initially to
over 50 m.sup.2/g by 12 hours) which attracts collagen, fibronectin
and cells. Moreover, the bioactive glass provides for the
precipitation of calcium and phosphorous naturally present in the
wound exudate and blood which cause the rapid formation of a
calcium and phosphate layer that may incorporate collagen, fibrin
and fibronectin to stabilize the wound quickly and effectively. In
some cases, wounds or burns healed with the composition or method
of the present invention heal without the necessity of scab
formation. That is, new epithelial tissue is directly formed.
[0043] It has been determined most preferable to mix the
particulate bioactive glass and the antibiotic of the present
invention just before application to the wound or burn. If the two
are mixed well prior to application, e.g. one week, the ability of
the composition to accelerate would healing is compromised. It is
believed that such early premixing results in a reaction between
the organic in the antibiotic and the bioactive glass thereby
reducing the effectiveness of the particulate bioactive glass.
Accordingly, the present invention is also directed to the
incorporation of the bioactive particulate glass and a topical
antibiotic in a two part system wherein the bioactive glass and
topical antibiotic are mixed and simultaneously applied. For
example, a two part mixing syringe with two separate storage
chambers and a mixing chamber can be used. Other two part systems
could also be used. For example, the particulate bioactive glass
can be incorporated into a bandage and the topical antibiotic can
be applied to the wound or burn which is followed by application of
the bandage. Other two part delivery systems are known to those of
ordinary skill in the art.
EXAMPLE I
[0044] FIG. 1 is a photograph of a wound in patient with vasculitis
taken soon after the wound was inflicted before treatment with a
composition in accordance with the present invention. This wound
was treated with a mixture of particulate bioactive glass of fine
particle size and a topical antibiotic including sulfadiazine. This
type of wound would typically require an overall healing time of
about 3 months. As depicted in FIGS. 2-4, the healing process is
substantially reduced by a composition in accordance with the
present invention.
[0045] For example, as depicted in FIG. 2, after only 4 days,
seepage of the wound is stopped and the surface of the wound
appears dry. If one were to apply only a topical antibiotic to such
a wound in a patient with vasculitis it would normally take about 2
weeks to stop seepage. In FIG. 3, it is shown that the healing
mechanism is well underway and that fatty tissue has covered the
surface of the wound after only 11 days. FIG. 4 shows that after
only 18 days, the wound is 50% healed. In a patient with
vasculitis, it normally takes about 6-8 weeks to reach the 50%
healed stage in a wound of the type pictured in the figures.
EXAMPLE II
[0046] A diabetic suffering from delayed healing lesions was
treated with a mixture of particulate bioactive glass of less than
40.mu. and an equal volume of NEOSPORIN.TM.. The mixture was
applied directly to the delayed healing lesions of about 1/2 cm by
1/2 cm. These lesions normally remain non-healing for over 14 days.
The mixture was applied twice a day. Within 24 hours seepage
ceased. Wound closure and healing was complete within 5 days.
Within 48 hours, scar tissue was apparent around the edges of the
defect.
* * * * *