U.S. patent application number 10/865636 was filed with the patent office on 2004-11-18 for anti-inflammatory and antimicrobial uses for bioactive glass compositions.
Invention is credited to Diamond, Mason, Greenspan, David C., Lee, Sean, Meyers, James L., West, Jon K..
Application Number | 20040228905 10/865636 |
Document ID | / |
Family ID | 32512506 |
Filed Date | 2004-11-18 |
United States Patent
Application |
20040228905 |
Kind Code |
A1 |
Greenspan, David C. ; et
al. |
November 18, 2004 |
Anti-inflammatory and antimicrobial uses for bioactive glass
compositions
Abstract
Compositions and methods for treating wounds to significantly
reduce the healing time, reduce the incidence of scar formation,
improve the success of skin grafts, reduce the inflammatory
response and providing anti-bacterial treatments to a patient in
need thereof, that include small non-interlinked particles of
bioactive glass or highly porous bioactive glass, are disclosed.
Anti-bacterial solutions derived from bioactive glass, and methods
of preparation and use thereof, are also disclosed. The
compositions include non-interlinked particles of bioactive glass,
alone or in combination with anti-bacterial agents and/or
anti-inflammatory agents. The compositions can include an
appropriate carrier for topical administration. Anti-bacterial
properties can be imparted to implanted materials, such as
prosthetic implants, sutures, stents, screws, plates, tubes, and
the like, by incorporating small bioactive glass particles or
porous bioactive glass into or onto the implanted materials.
Anti-bacterial properties can also be imparted to devices used for
in vitro and ex vivo cell culture by incorporating non-interlinked
particles of bioactive glass into the devices. Anti-bacterial
compositions derived from aqueous extracts of bioactive glass are
also disclosed. These compositions can be used, for example, in
food preparation, solutions used for cell culture, and buffer
solutions, such as i.v. solutions.
Inventors: |
Greenspan, David C.;
(Gainesville, FL) ; West, Jon K.; (Gainesville,
FL) ; Lee, Sean; (Karlsruhe, DE) ; Meyers,
James L.; (Gainesville, FL) ; Diamond, Mason;
(Gainesville, FL) |
Correspondence
Address: |
BURNS DOANE SWECKER & MATHIS L L P
POST OFFICE BOX 1404
ALEXANDRIA
VA
22313-1404
US
|
Family ID: |
32512506 |
Appl. No.: |
10/865636 |
Filed: |
June 10, 2004 |
Related U.S. Patent Documents
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10865636 |
Jun 10, 2004 |
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09560046 |
Apr 27, 2000 |
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6756060 |
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09560046 |
Apr 27, 2000 |
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09164293 |
Oct 1, 1998 |
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6428800 |
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09164293 |
Oct 1, 1998 |
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08715911 |
Sep 19, 1996 |
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09560046 |
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09392516 |
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Current U.S.
Class: |
424/445 ;
424/617; 514/152; 514/35 |
Current CPC
Class: |
Y10S 514/886 20130101;
Y10S 514/951 20130101; Y10S 514/864 20130101; C03C 4/0007 20130101;
Y10S 514/887 20130101; Y10S 514/862 20130101; Y10S 424/13 20130101;
A61K 8/25 20130101; A61L 15/18 20130101; A61Q 17/005 20130101; Y10S
514/831 20130101; A61L 15/44 20130101; Y10S 514/965 20130101; Y10S
514/859 20130101; A61L 15/46 20130101; Y10S 514/863 20130101; A61Q
19/00 20130101; A61K 45/06 20130101; A61Q 1/02 20130101; Y10S
514/83 20130101; A61Q 5/00 20130101; Y10S 514/861 20130101; Y10S
514/829 20130101 |
Class at
Publication: |
424/445 ;
424/617; 514/035; 514/152 |
International
Class: |
A61K 033/24; A61K
009/14; A61K 031/65 |
Claims
What is claimed is:
1. A composition for the accelerated healing of wounds and burns
and/or for improving the appearance of scar tissue resulting from
such wounds and burns comprising non-linked, small particles of
bioactive glass in a carrier.
2. The composition of claim 1, further comprising one or more
therapeutic agents.
3. The composition of claim 2, wherein therapeutic agent(s) are
selected from the group consisting of healing promotion agents,
growth factors, anti-inflammatory agents and topical
anesthetics.
4. The composition of claim 2, wherein the therapeutic agent is a
topical antibiotic.
5. The composition of claim 4, wherein the topical antibiotic is
selected from the group consisting of chloramphenicol,
chlortetracycline, clyndamycin, clioquinol, erythromycin,
framycetin, gramicidin, fusidic acid, gentamicin, mafenide,
mupiroicin, neomycin, polymyxin B, bacitracin, silver sulfadiazine,
tetracycline, chlortetracycline and combinations thereof.
6. The composition of claim 1, wherein the pharmaceutically
acceptable carrier is a cream base, high moisture gel, white
petrolatum, light mineral oil, or mixture thereof.
7. The composition of claim 1, wherein the bioactive glass has a
composition by weight percentage:
1 Component Percent SiO.sub.2 40-86 CaO 10-46 Na.sub.2O 0-35
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
8. The composition of claim 1, wherein the bioactive glass has a
composition by weight percentage:
2 Component Percent SiO.sub.2 45 CaO 24.5 Na.sub.2O 24.5
P.sub.2O.sub.5 6
9. The composition of claim 1, wherein the bioactive glass has a
particle size range less than about 90 microns as measured by SEM
or laser light scattering techniques.
10. The composition of claim 1, wherein the bioactive glass has a
particle size range less than about 20 microns as measured by SEM
or laser light scattering techniques.
11. The composition of claim 1, wherein the bioactive glass has a
particle size range less than about 2 microns as measured by SEM or
laser light scattering techniques.
12. A method for treating wounds and burns comprising the
contacting of a wound with an effective wound healing amount of
bioactive glass.
13. A method for grafting skin comprising applying bioactive
particulate glass to a graft site, the donor tissue, or both.
14. The method of claim 13, further comprising the application of a
topical antibiotic to the graft site, the donor tissue, or
both.
15. A wound or burn dressing comprising a bandage, a topical
antibiotic and non-linked particles of bioactive glass.
16. The wound or burn dressing of claim 15 wherein the bandage is
cotton, gauze, fiberglass, or synthetic material.
17. The dressing of claim 16 wherein the fiberglass is made from
bioactive glass
18. A wound or burn treatment applicator apparatus comprising a
topical carrier in a first chamber, a non-linked particles of
bioactive glass in a second chamber and a mixing means for mixing
the topical antibiotic and the bioactive glass.
19. The apparatus of claim 18, wherein the wound or burn treatment
apparatus is a multi chamber syringe.
20. A method for accelerating the healing of wounds or burns
comprising contacting a wound or burn with an effective wound or
burn healing accelerating amount of a particulate bioactive
glass.
21. A method for improving the appearance of the scar formed during
the healing of wounds or burns comprising contacting a wound or
burn with an effective scar appearance improving amount of a
non-linked, particulate bioactive glass.
22. The method of claim 21 wherein the bioactive glass is present
in a composition comprising the bioactive glass in the form of
non-linked, small particles of bioactive glass and a suitable
carrier.
23. The composition of claim 1, wherein the bioactive glass
particles have been combined with a biocompatible, biodegradable
material to form a composite material.
24. A method of reducing the level of inflammation in a wound by
contacting the wound with an effective inflammation reducing amount
of a bioactive glass.
25. The method of claim 24 wherein the inflammation is chronic
inflammation.
26. A method of reducing the level of bacterial infection in a
wound comprising contacting the wound with an effective
antibacterial amount of a bioactive glass.
27. The method of claim 26, wherein the bioactive glass has a
composition by weight percentage:
3 Component Percent SiO.sub.2 40-86 CaO 10-46 Na.sub.2O 0-35
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
28. The method of claim 26, wherein the bioactive glass has a
composition by weight percentage:
4 Component Percent SiO.sub.2 45 CaO 24.5 Na.sub.2O 24.5
P.sub.2O.sub.5 6
29. The method of claim 26, wherein the bioactive glass has a
particle size range less than about 90 microns as measured by SEM
or laser light scattering techniques.
30. The method of claim 26, wherein the bioactive glass has a
particle size range less than about 20 microns as measured by SEM
or laser light scattering techniques.
31. The method of claim 26, wherein the bioactive glass has a
particle size range less than about 2 microns as measured by SEM or
laser light scattering techniques.
32. An antibacterial composition comprising non-linked, small
particles of bioactive glass.
33 The composition of claim 32, wherein the bioactive glass has a
composition by weight percentage:
5 Component Percent SiO.sub.2 40-86 CaO 10-46 Na.sub.2O 0-35
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
34. The composition of claim 32, wherein the bioactive glass has a
composition by weight percentage:
6 Component Percent SiO.sub.2 45 CaO 24.5 Na.sub.2O 24.5
P.sub.2O.sub.5 6
35. The composition of claim 32, wherein the bioactive glass has a
particle size range less than about 90 microns as measured by SEM
or laser light scattering techniques.
36. The composition of claim 32, wherein the bioactive glass has a
particle size range less than about 20 microns as measured by SEM
or laser light scattering techniques.
37. The composition of claim 32, wherein the bioactive glass has a
particle size range less than about 2 microns as measured by SEM or
laser light scattering techniques.
38. An antibacterial composition comprising an aqueous extract of
small particles of bioactive glass.
39. The composition of claim 38, wherein the bioactive glass has a
composition by weight percentage:
7 Component Percent SiO.sub.2 40-86 CaO 10-46 Na.sub.2O 0-35
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
40. The composition of claim 38, wherein the bioactive glass has a
composition by weight percentage:
8 Component Percent SiO.sub.2 45 CaO 24.5 Na.sub.2O 24.5
P.sub.2O.sub.5 6
41. Cosmetic products comprising non-interlinked particles of
bioactive glass and/or an aqueous extract thereof in combination
with a liquid cosmetic base containing water.
42. The cosmetic products of claim 41, wherein the cosmetic base
comprises a liquid material selected from the group consisting of
liquid foundation, skin lotion, milky lotion, shampoo, hair rinse
and cream.
43 The cosmetic products of claim 41, wherein the bioactive glass
has a composition by weight percentage:
9 Component Percent SiO.sub.2 40-86 CaO 10-46 Na.sub.2O 0-35
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
44. The cosmetic products of claim 41, wherein the bioactive glass
has a composition by weight percentage:
10 Component Percent SiO.sub.2 45 CaO 24.5 Na.sub.2O 24.5
P.sub.2O.sub.5 6
45. The cosmetic products of claim 41, wherein the bioactive glass
has a particle size range less than about 90 microns as measured by
SEM or laser light scattering techniques.
46. The cosmetic products of claim 41, wherein the bioactive glass
has a particle size range less than about 20 microns as measured by
SEM or laser light scattering techniques.
47. The cosmetic products of claim 41, wherein the bioactive glass
has a particle size range less than about 2 microns as measured by
SEM or laser light scattering techniques.
48. Prosthetic implants, sutures, stents, screws, plates and tubes
comprising the composition of claim 1.
49. Devices used for in vitro cell culture comprising the
composition of claim 1.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to bioactive glass-containing
compositions, aqueous extracts derived from such compositions,
cosmetics including these compositions, implants including the
compositions, and methods of using the compositions to accelerate
healing, reduce inflammation and reduce bacterial infection. More
specifically, the present invention relates to compositions
including particles of bioactive glass, optionally including one or
more agents which aid in the delivery and distribution of the
particles and which may also have other therapeutic effects, and
methods of use thereof.
BACKGROUND OF THE INVENTION
[0002] When an injury occurs, cell damage initially comes from the
precipitating event, such as a cut, resulting in ruptured cells and
severed or crushed capillaries and other blood vessels. However,
later damage can occur due to bacterial growth or to an
inflammatory response.
[0003] The healing process involves several steps, including
coagulation, inflammation, repair (or fibroplasia) of the damaged
tissue, angiogenesis (or revascularization), re-epithelialization
and remodeling. Several of these steps, while necessary to promote
normal healing, can cause excessive scarring and other health
related problems if unchecked.
[0004] For example, unchecked inflammation can have harmful
consequences. For example, many chronic and even life-threatening
disorders, such as asthma, rheumatoid arthritis, lung fibrosis,
peritoneal adhesions, hypersensitivity and autoimmune diseases are
a result of an uncontrolled inflammatory response. An unresolved
inflammation in the lung resulting from bacterial infection (i.e.,
pneumonia) may eventually lead to extensive tissue damage and a
chronic lung abscess. Inflammation of the peritoneal cavity and the
resulting adhesions following abdominal surgery is a major cause of
infertility in women. Asthma is an often life-threatening disorder
which results from an inadvertently stimulated inflammatory
response in the lungs.
[0005] An excessive inflammatory response can cause extensive
swelling, which can lead to additional injury as a result of
anoxia. Pain results from a combination of kinins and the effect of
lysozymes and pressure from the swelling on nerve endings.
Unchecked, the inflammatory response can set off a neural feedback
loop and cause hyperalgesia, a phenomenon in which the surrounding
area of injury remains painful. Accordingly, there is a great
interest in the medical community to develop anti-inflammatory
agents.
[0006] The amount of bacterial burden in a wound bed is an
important factor in the healing of wounds, especially dermal
ulcers. Some bacterial colonization is inevitable, and may even be
beneficial in stimulating the body's natural immune response.
However, excessive bacterial colonization is clearly detrimental
and can lead to high levels of bacterial waste products, chronic
inflammation, heavy exudate, increased tissue necrosis and
eventually, full infection. Wounds typically will not heal when the
bacterial burden is above about 10.sup.5 microorganisms per gram of
tissue.
[0007] Topical anti-microbial agents, including organism specific
antibiotics such as bacitracin and silver sulfadiazine are
typically used in wound care. However, these agents are generally
regarded as relatively weak in action. More importantly, the recent
rise of strains of microorganisms resistant to these agents has led
to many intractable cases of infection. Other typically used
antimicrobial agents, such as iodine and alcohol, damage native
tissue and repair cells, and retard the healing process of dermal
wounds.
[0008] Many treatments have been proposed for treating wounds and
accelerating wound healing. Often, such treatments involve the use
of growth factors, such as platelet derived growth factor (PDGF) or
the use of cultured cells derived from the wounded patient's own
skin. These methods are limited by the difficulty of preparing the
growth factors, the time spent in preparing the cell cultures, and
the high costs of such treatments. Further, potential side effects
associated with such therapies are unknown at this time. For
example, the prolonged use of corticosteroids is associated with
untoward secondary effects.
[0009] It would be advantageous to provide compositions and methods
for treating wounds, and, in particular, for treating bacterial
infection and inflammatory response in patients. The present
invention provides such compositions and methods.
SUMMARY OF THE INVENTION
[0010] Compositions and methods for treating wounds to
significantly reduce the healing time and prevent the body's
natural defenses from proceeding unchecked are disclosed. The
compositions and methods allow wounds to heal in significantly less
time than would otherwise occur. Inflammation is greatly reduced
around the wound site. The incidence of scar formation following a
wound or burn is reduced. The presence of bacteria is also reduced.
The success of skin grafts is increased.
[0011] The compositions include non-interlinked particles of
bioactive glass, alone or in combination with an additional
anti-bacterial and/or anti-inflammatory agent, and optionally
include other therapeutic agents. Formulations including the
compositions, alone or in combination with a suitable carrier,
preferably for topical administration, are also disclosed. Also
disclosed are anti-bacterial solutions derived from bioactive
glass, and methods of preparation and use thereof.
[0012] The compositions can be incorporated into implanted
materials, such as prosthetic implants, sutures, stents, screws,
plates, tubes, and the like, to impart anti-bacterial and
anti-inflammatory properties to the materials. Anti-bacterial
properties can also be imparted to devices used for in vitro and ex
vivo cell culture by incorporating the composition into the
devices.
[0013] Anti-bacterial and anti-inflammatory compositions derived
from aqueous extracts of bioactive glass can be formed by placing
bioactive glass in an aqueous solution, allowing the glass to
dissolve over a suitable period of time, for example, a week or
more, and filtering out the undissolved glass particles. The
solvent can also be evaporated to provide a solid material with
anti-bacterial properties. These compositions can be used in
situations where prevention or reduction of bacterial infections
would be advantageous, for example, food preparation, cosmetics,
media used for cell culture, and buffer solutions.
[0014] When used topically to treat a wound or burn, the wound or
burn is contacted with an effective amount of the composition for
the intended application. When used for skin grafting, the
bioactive glass-containing composition is applied to either the
graft site prior to placing the donor tissue, or to the donor
tissue itself.
[0015] The compositions can be administered to the pulmonary
system, for example, via an inhaler, as an adjunct therapy for
treating pneumonia or chronic sinus infections. The compositions
can also be co-administered to the pulmonary system with
therapeutic agents which are themselves inflammatory, to minimize
the inflammatory response to these agents. The compositions can be
applied directly to a surgical site to minimize post-surgical
adhesions, minimize inflammation around the site, and prevent or
minimize infection at the site. In one embodiment, the compositions
are included in a polymeric material, preferably a biodegradable
polymeric material, which is then applied to a surgical site to
minimize post-surgical adhesions.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0016] Compositions and methods for treating wounds to
significantly reduce the healing time and prevent the body's
natural defenses from proceeding unchecked are disclosed. The
compositions and methods allow wounds to heal in significantly less
time than would otherwise occur. Inflammation is greatly reduced
around the wound site. The incidence of scar formation following a
wound or burn is reduced. The presence of bacteria is also reduced.
The success of skin grafts is increased.
[0017] The compositions include non-interlinked particles of
bioactive glass, alone or in combination with an additional
anti-bacterial and/or anti-inflammatory agent, and optionally
include other therapeutic agents. Formulations including the
composition and a suitable carrier, preferably for topical
administration, are also disclosed. Also disclosed are
anti-bacterial solutions derived from bioactive glass, and methods
of preparation and use thereof.
[0018] Not being bound to any particular theory or mechanism, it is
believed that the surface area and reactivity of particulate
bioactive glass provides an adsorption of hydronium ions from a
solution and a release of sodium that increases the pH of the
environment. Through the pH-dependent binding of hemoglobin, the
amount of oxygen in the wound or burn is thereby increased.
[0019] These reactions also 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 fibrin, 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 phosphate layer
that may incorporate collagen, fibrin and fibronectin to stabilize
the wound quickly and effectively. In addition, the bioactive glass
is believed to strongly inhibit the overactive inflammatory
response present in chronic wounds. In some cases, wounds or burns
healed with the compositions and methods disclosed herein heal
without the necessity of eschar formation. That is, new epithelial
tissue can be directly formed. The bioactive glass-containing
compositions described herein have been shown to increase the IL-6
concentration when injected into the peritoneal cavity of mice,
without a concomitant increase in other cytolines, such as
TNF-.alpha., IL-1 and IL-10. The absence of the other cytokines
indicates that the overall response is anti-inflammatory rather
than pro-inflammatory.
[0020] The terms "wound" and "burn," collective referred to herein
as "injury" have their usual meanings. "Normal" is used in the
sense it is usually used in the medical arts. The terms
"anti-bacterial agents" and "antibiotics" as used herein mean
pharmacologically acceptable synthetic or natural agents which
destroy or inhibit microorganisms and includes both antibacterial
and antiviral agents. "Medical practitioner" means one of ordinary
skill in the art wound and burn treatment. Typically this person is
a physician, nurse, dentist, or paramedic.
[0021] I. Compositions Including Bioactive Glass
[0022] Compositions including non-interlinked particles of
bioactive glass, alone or in combination with anti-bacterial agents
and/or anti-inflammatory agents, can be used for a variety of
purposes.
[0023] As used herein the terms "bioactive glass" or "biologically
active glass" mean an inorganic glass material having an oxide of
silicon as its major component and which is capable of bonding with
growing tissue when reacted with physiological fluids.
[0024] Bioactive glasses are well known to those skilled in the
art, and are disclosed, for example, in An Introduction to
Bioceramics, L. Hench and J. Wilson, eds. World Scientific, New
Jersey (1993), the contents of which are hereby incorporated by
reference.
[0025] The glass preferably includes between 40 and 86% by weight
of silicon dioxide oxide (SiO), between about 0 and 35% by weight
of sodium oxide (Na.sub.2O), between about 4 and 46% by weight
calcium oxide (CaO), and between about 1 and 15% by weight
phosphorus oxide (P.sub.2O.sub.5). More preferably, the glass
includes between 40 and 60% by weight of silicon dioxide oxide
(SiO.sub.2), between about 5-30% by weight of sodium oxide
(Na.sub.2O), between about 10 and 35% by weight calcium oxide
(CaO), and between about 1 and 12% by weight phosphorus oxide
(P.sub.2O.sub.5). The oxides can be present as solid solutions or
mixed oxides, or as mixtures of oxides.
[0026] CaF.sub.2, B.sub.2O.sub.3, Al.sub.2O.sub.3, MgO and K.sub.2O
may be included in the composition in addition to silicon, sodium,
phosphorus and calcium oxides. The preferred range for
B.sub.2O.sub.3 is between 0 and 10% by weight. The preferred range
for K.sub.2O is between 0 and 8% by weight. The preferred range for
MgO is between 0 and 5% by weight.
[0027] Anti-microbial salts such as AgNO.sub.3, CuO, and ZnO, or
other antimicrobial salts of the silver, copper and zinc ions, such
as nitrates, acetates, etc., can be added. The preferred range for
these salts is between 0 and 5% by weight.
[0028] The most preferred glass is Bioglass.RTM..TM. (a trademark
of University of Florida), which has a composition including about
45% by weight silicon dioxide, about 24.5% by weight sodium oxide,
about 6% by weight phosphorus oxide, and about 24.5% by weight
calcium oxide. Another preferred material is hydroxyapatite.
[0029] Particulate, non-interlinked bioactive glass is preferred in
the present invention. That is, the glass is in the form of small,
discrete particles, rather than a fused matrix of particles or a
mesh or fabric (woven or non-woven) of glass fibers. Note that
under some conditions the discrete particles of the present
invention may tend to cling together because of electrostatic or
other forces but are still considered to be non-interlinked.
Preferably the particle size is less than about 90 microns; more
preferably, less than about 20 microns; even more preferably, less
than about 5 microns, and ideally, less than about 2 microns, as
measured by SEM or laser light scattering techniques.
[0030] Highly porous bioactive glass has similar anti-bacterial and
anti-inflammatory properties to small particles of bioactive glass,
due to its relatively fast degradation rate and high surface area,
in comparison to non-porous bioactive glass compositions. When
highly porous bioactive glass is used in place or in addition to
small particles of bioactive glass, the pore size is between about
0 and 500 .mu.m, preferably between about 10 and 150 .mu.m, and
more preferably, between about 50 and 100 .mu.m. The degree of
porosity of the glass is between about 0 and 85%, preferably
between about 30 and 80%, and more preferably, between about 40 and
60%. Porous bioactive glass can be prepared, for example, by
incorporating a leachable substance into the bioactive glass
composition, and leaching the substance out of the glass. Suitable
leachable substances are well known to those of skill in the art,
and include, for example, sodium chloride and other water-soluble
salts. The particle size of the leachable substance is roughly the
size of the resulting pore. The relative amount and size of the
leachable substance gives rise to the degree of porosity. Also, as
described herein, porosity can be achieved using sintering and/or
by controlling the treatment cycle of glass gels to control the
pores and interpores of the material.
[0031] The glass composition can be prepared in several ways, to
provide melt-derived glass, sol-gel derived glass, and sintered
glass particles. The sintered particles may be in sol-gel derived,
or pre-reacted melt derived form. Sol-gel derived glass is
generally prepared by synthesizing an inorganic network by mixing
metal alkoxides in solution, followed by hydrolysis, gelation, and
low temperature (around 200-900.degree. C.) firing to produce a
glass. Sol-gel derived glasses produced this way are known to have
an initial high specific surface area compared with either
melt-derived glass or porous melt-derived glass. The surface area
of the sol-gel derived glasses is at least about 50 m.sup.2/g. Melt
derived glass is generally prepared by mixing grains of oxides or
carbonates, melting and homogenizing the mixtures at high
temperatures, typically between about 1250 and 1400.degree. C. The
molten glass can be fritted and milled to produce a small
particulate material.
[0032] The glass composition is preferably melt-derived. In each
preparation, it is preferred to use reagent grade glass, especially
since the glass is used to prepare materials which ultimately may
be administered to a patient.
[0033] A. Melt Derived Glass
[0034] A melt-derived glass composition can be prepared, for
example, by preparing an admixture of the individual metal oxides
and other components used to prepare the glass composition,
blending the admixture, melting the admixture, and cooling the
mixture. The melting temperature is determined in large part by the
glass composition, and ranges, for example, from about
900-1500.degree. C., preferably between about 1250 and 1450.degree.
C. The melt is preferably mixed, for example, by oxygen bubbling,
to ensure a thorough homogenation of the individual components.
[0035] The mixture can be cooled, for example, by adding the molten
admixture to a suitable liquid, such as deionized water, to produce
a glass frit. Porosity can be introduced by grinding the glass into
a powder, admixing the powder with a foaming agent, and hot
pressing the mixture under vacuum and elevated temperature. The
particle size of the glass powder is between about 2 and 70 .mu.m,
the vacuum is preferably less than 50 MPa, and the hot pressing is
preferably performed at a temperature above 400.degree. C.,
preferably between about 400 and 500.degree. C. Suitable foaming
agents include compounds which evolve carbon dioxide and/or water
at elevated temperatures, for example, metal hydroxides, metal
carbonates, and peroxides, such as hydrogen peroxide. Preferred
metal carbonates are sodium bicarbonate, sodium carbonate and
calcium carbonate. The foaming agents are preferably added in a
range of between about 1-5, more preferably 2-3 percent by weight
of the glass powder. The preparation of melt-derived porous glass
is described, for example, in U.S. Pat. No. 5,648,301 to Ducheyne
and El Ghannam, the contents of which are hereby incorporated by
reference.
[0036] B. Sintered Glass Particles
[0037] Glass can be sintered using known methodology. In one
embodiment, an aqueous slurry of the glass powder and a foaming
agent with a suitable binder, such as polyvinyl alcohol, is formed.
The slurry is then poured into a mold, allowed to dry, and sintered
at high temperatures. These temperature may range, depending on the
glass composition and foaming agent used, between about 500 and
1000.degree. C., more preferably between about 600 and 800.degree.
C.
[0038] C. Spun Fibers of Sol-Gel Derived Glass
[0039] It is known in the art to control the heat treatment cycle
of glass gels to control the pores and interpores of the material
to create a porous glass material. However, since a pore diameter
larger than 0.1 microns is difficult to achieve using this method,
the sintering and foaming processes described herein are generally
more preferred.
[0040] D. Leaching of the Porous Material
[0041] To aid in preparing glass compositions with high porosity,
the glass composition can include a material which can be
preferably leached out of the glass composition, and, in doing so,
provide the composition with high porosity. For example, minute
particles of a material capable of being dissolved in a suitable
solvent, acid, or base can be mixed with or melted into the glass,
and subsequently leached out. The resulting voids have roughly the
same size as the particle that was leached out. In the case of a
material which is part of a melt-derived glass composition, the
size of the pores and degree of porosity depends on the amount of
added material relative to the amount of glass. For example, if the
leached material constituted about 80% of the glass, then the glass
would be approximately 80% porous when the material was leached
out. When leaching the glass composition, care should be taken not
to leach out those components which add to the bioactivity of the
glass, i.e., the calcium and phosphorus oxides.
[0042] II. Formulations Including Bioactive Glass
[0043] The bioactive glass may be administered to the wound in a
topical, pharmaceutical formulation, such as in the form of a
suspension, lotion, cream, ointment, or gel. Those skilled in the
art will appreciate that there are other appropriate topical
carriers such as those listed in U.S.P.D.
[0044] Other Therapeutic Agents
[0045] In addition to bioactive glass, the formulations can include
other therapeutic agents such as antibiotics, antivirals, healing
promotion agents, anti-inflammatory agents, immunosuppressants,
growth factors, anti-metabolites, cell adhesion molecules (CAMs),
bone morphogenic proteins (BMPs), vascularizing agents,
anti-coagulants, and topical anesthetics/analgesics.
[0046] The antibiotics can be topical antibiotics suitable for skin
treatment. Examples of such antibiotics include but are not limited
to: chloramphenicol, chlortetracycline, clyndamycin, clioquinol,
erythromycin, framycetin, gramicidin, fusidic acid, gentamicin,
mafenide, mupiroicin, neomycin, polymyxin B, bacitracin, silver
sulfadiazine, tetracycline and chlortetracycline.
[0047] Suitable antivirals include topical antivirals, such as
acyclovir, and gancyclovir. Suitable anti-inflammatory agents
include corticosteroids, hydrocortisone and nonsteroidal
antinflammatory drugs. Suitable growth factors include basic
fibroblast growth factor (bFGF), epithelial growth factor (EGF),
transforming growth factors .alpha. and .beta. (TGF .alpha. and
.beta.), platelet-derived growth factor (PDGF), and vascular
endothelial growth factor/vascular permeability factor (VEGF/VPF)).
Suitable topical anesthetics include benzocaine and lidocaine.
[0048] In one embodiment, the therapeutic agent is one which would
otherwise cause an inflammation at the site at which it is
delivered, and the bioactive glass particles reduce the associated
inflammation. For example, a number of compounds, for example,
amine compounds, result in inflammation when administered
topically, i.e., in a transdermal patch. A number of other
compounds result in inflammation when administered via pulmonary
administration, i.e., via an inhaler.
[0049] It is acceptable to place particulate bioactive glass
directly into a wounded area or on a burn with no carrier or
excipient. However, preferably bioactive glass alone or in
combination with one or more other therapeutic agents is combined
in any pharmaceutically acceptable carrier for topical use, such as
a suspension, ointment, cream, or gel to facilitate application to
the wound. For example, the composition of the present invention
can be blended with white petrolatum to form an ointment, with
mineral oil to form a suspension, with a commercially available,
cream cosmetic base to form a non-greasy cream, or with a
commercially available water soluble, lubricating gel, e.g., K Y
Gel (trademark), to form a high moisture gel.
[0050] The bioactive glass and other therapeutic agents can be
combined with other wound and burn treatments or dressings such as,
but not limited to, collagen, fibrin, fibronectin, various growth
factors, such as PDGF, TGF-.beta., vitamin E, gauze, cotton,
cellulose, synthetic wound or burn dressings and other wound or
burn dressings/treatments known to those of ordinary skill in the
art. Dressings of fiberglass, including fiberglass made from fibers
of bioactive glass, can also be used. In addition, the bioactive
glass may be combined with any biocompatible material, such as
biodegradable polymer like polylactic/glycolic acid to form a
composite material for accelerating would healing
[0051] While the ratio of bioactive glass to carrier is not
critical, preferably the blend of bioactive glass, other
therapeutic agents, and carrier contains about 20% to about 80%
bioactive glass. The preferred particle size range for the
bioactive glass not greater than about 90 microns is recommended.
Particle sizes specifically less than about 10 microns as well as
less than about 2 microns can also be used, where the particle
sizes are measured by SEM or laser light scattering techniques.
Particles of such a small size range generally provide for the
advantages of the present invention but do not illicit any
undesirable immune response. This phenomenon is an unanticipated
result, given the general history found in the literature on the
biological response to small synthetic particles. The proportion
other therapeutic agents varies according to the agent and the
nature of the application. However, the preferred proportions are
such that the amount of the agent administered to the wound or burn
is in the dosage range accepted within standard medical care.
[0052] If the bioactive glass is to mixed with a topical carrier
such as an ointment, then it is preferable that the glass not be
significantly pre-reacted prior to application. This can be
achieved, for example, by applying the composition immediately
after mixing. Alternately, the topical carrier may be of such a
nature as to not pre-react the glass, such as, for example
glycerin. The bioactive particulate glass and topical carrier can
be separate components in a two part system wherein the bioactive
glass and topical carrier 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 carrier 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.
[0053] III. Articles of Manufacture Including Bioactive Glass
[0054] The compositions can be incorporated into implanted
materials, such as prosthetic implants, sheets, pins, valves,
sutures, stents, screws, plates, tubes, and the like, by
incorporating bioactive glass particles into the implanted
materials. The compositions can be moldable or machinable.
[0055] In another embodiment, anti-bacterial properties are
imparted to devices used for in vitro and ex vivo cell culture by
incorporating non-interlinked particles of bioactive glass into the
devices.
[0056] The articles of manufacture are imparted with anti-bacterial
properties via the incorporation of the bioactive glass, which will
allow the articles to be implanted, or used to culture cells, with
a reduced likelihood of bacteriological contamination.
[0057] IV. Aqueous Solutions Derived from Bioactive Glass
[0058] The anti-bacterial (and anti-fungal) compositions derived
from aqueous extracts of bioactive glass are formed by placing
bioactive glass in an aqueous solution, allowing the glass to
dissolve over a suitable period of time, and filtering out the
un-dissolved glass particles. The solvent can be evaporated to
provide a solid material with anti-bacterial properties. The
compositions can be used in situations where bacteria are present,
for example, food preparation, solutions used for cell culture, and
buffer solutions.
[0059] Without being bound to a particular theory, it is believed
that there is a complex relationship between the type of ion being
released from the glass, the amount of that ion, the rate at which
release occurs, the pH of the solution, and the resulting
anti-microbial or anti-inflammatory response. This effect is
observed with respect to the particles of bioactive glass
themselves and also in the ionic solutions derived from the glass
particles. Accordingly, in the uses described below, particles of
bioactive glass can be used in place of or in addition to the
solutions derived from the particles.
[0060] Food Preparation
[0061] Numerous foods are potentially infected with bacteria, such
as E. coli. Ground beef and chicken are particularly susceptible to
bacterial infection. Aqueous solutions including an aqueous extract
from bioactive glass have anti-bacterial properties. As discussed
below in Example 3, the anti-bacterial effect is due, in part, to
the basic nature of the solution (pH greater than about 7,
preferably greater than about 9, more preferably greater than about
10.5). However, sodium hydroxide solutions of relatively high pH
are not as effective at killing bacteria Accordingly, the solutions
have additional antibacterial elements present than merely a
relatively high pH.
[0062] The composition can be sprayed on contaminated surfaces, or
incorporated into food products such as ground beef. Since
bioactive glass has been approved for various uses by the FDA, the
extract of bioactive glass should be harmless to humans.
[0063] Cosmetic Applications
[0064] Liquid-based cosmetics, such as skin lotions, shampoos and
rinses, are directly applied to human skin. While current
manufacturing processes generally control bacterial contamination
when the products are in sealed containers, after unsealing the
package, bacteria, fungi and/or mold may contaminate the cosmetics.
Often, various antibacterial agents are added to the cosmetics to
minimize this process.
[0065] The compositions can be included in cosmetic applications to
minimize contamination by bacteria, fungi and/or mold. The
compositions can be added, for example, to cosmetic bases such as
liquid foundation, shampoo, rinse, lipstick, skin lotion, milky
lotion, creams and the like. The cosmetics can include the ionic
solutions described herein and/or particles of bioactive glass
described herein.
[0066] Solid Compositions
[0067] The aqueous solutions can be dried, for example, by spray
drying or by drying in vacuo to provide an antibacterial
composition. The compositions can be incorporated into other
bacterial solutions, such as Betadine.RTM. solution, to provide an
additional anti-bacterial component to the solutions.
[0068] Cell Growth and Culture
[0069] There are many solutions used for culturing cells. These
include Dulbecco's minimal essential media, Hank's balanced salt
solution, and others. These solutions are essentially isotonic with
the cells to be cultured. A problem associated with cell culture is
often the growth of bacteria in culture along with the desired
cells. Bacterial growth can be minimized by incorporating the
extract of bioactive glass into the cell culture media.
[0070] Buffer Solutions
[0071] Buffer solutions, such as HEPES and TRIS, are often at the
perfect pH to support bacterial growth. Addition of the extract of
bioactive glass to the compositions will impart anti-bacterial
properties to the solutions. While the anti-bacterial effect of the
extract solution is due in part to the relatively high pH, lower
pH's are also somewhat effective. As shown in Example 3, even a pH
of 7.6 was moderately effective as an anti-bacterial solution.
Accordingly, although the buffer solutions will lower the pH
somewhat, the solutions will still exhibit anti-bacterial
properties. In one embodiment, the buffered solution is an i.v.
solution, for example, phosphate buffered saline.
[0072] V. Methods for Improving Wound Healing
[0073] Particulate bioactive glass is capable of dramatically
reducing the amount of time necessary for wound healing to occur.
Further, a composition including non-interlinked particles of
bioactive glass (or an implant including highly porous bioactive
glass) and other anti-bacterial agents augments the natural healing
process. The effectiveness of the composition is most dramatically
illustrated in immune compromised patients whose ability to heal
wounds is somewhat suppressed.
[0074] The compositions can be administered to a wound or burn in a
similar manner as topical formulations currently in clinical use.
The exact amount of application is at the discretion of the medical
practitioner but is typically applied by generously spreading the
composition into the desired area and placing a thin film on the
surrounding area at least once a day. After application of the
composition, the injured area is treated according to accepted
medical practice. For example, after applying the composition, the
injured area is typically covered with a sterile bandage, and the
patient may be given antibiotics, analgesics and/or other
medications systemically. Treatment of the injured area is
continued until, in the judgement of the attending medical
practitioner, the injury has healed and further treatment is not
needed.
[0075] The methods for causing effective wound healing or providing
an anti-bacterial treatment to wounds, involve contacting a wound
with an effective wound healing or anti-bacterial amount of
non-linked particles of bioactive glass, optionally in combination
with an addition anti-bacterial or anti-inflammatory agent.
[0076] In one embodiment, the compounds are used to fill voids,
including voids created during medical procedures. For example,
during a root canal operation, the hollowed-out tooth can be filled
with a composition including bioactive glass. This will help
prevent bacterial infection until the tooth is ultimately filled.
Also, bioactive glass-containing compositions can be used to fill
the pockets that can develop between the teeth and gums.
Compositions including bioactive glass can be used to fill voids
present in aneurysms, and prevent bacterial growth inside the
filled void. Other voids which can be filled include those formed
surgically, such as removal of a spleen, ovary, gall bladder, or
tumor.
[0077] VI. Methods for Grafting Skin
[0078] The methods for grafting skin involve applying non-linked
particles of bioactive glass to either the graft site prior to
placing the donor tissue, or to the donor tissue itself.
[0079] The methods for grafting skin involve applying particulate
bioactive glass to either the graft site or donor tissue before it
is placed in its intended location. Those interested in a detailed
description of skin grafting are referred to "Skin Grafts," in
Selected Readings in Plastic Surgery, vol. 7, No. 2, P. L. Kelton,
MD, Baylor University Medical Center (1992). The graft may also be
further treated with a topical carrier prior to placement. The
application of bioactive glass to grafts is intended to increase
the likelihood that the graft will "take" and incorporate in the
host bed. It is intended that the bioactive glass particulates will
act as an intermediary bond between the host and graft tissue,
suppress the overall inflammatory response which could lead to
rejection, as well accelerate the overall healing process which
will lead to a faster and more successful acceptance.
[0080] VII. Methods for Improving the Appearance and Structure of
Scar Tissue
[0081] The methods for improving the appearance and structure of
scar tissue, especially keloid scar tissue, formed as a wound
heals, involve contacting a wound as it heals with an effective
scar appearance-improving amount of non-linked particles of
bioactive glass. In this method, the particles are preferably
present in a sterile, pharmaceutically acceptable carrier such as
an ointment or gel.
[0082] The presence of a bioactive glass particulate within the
healing wound bed may alter the formation of scar tissue by at
least two mechanisms. First, bioactive glasses will act to reduce
the overall inflammatory response in the wound through the
adsorption of inflammatory mediators such as prostaglandins,
TNF-.alpha., IL-1 and a variety of cytokines and the release of
ions that leads to an increase in extracellular osmotic pressure. A
reduced inflammatory response will decrease the number and activity
of macrophages and other inflammatory cells, thereby reducing the
concentration of chemotactic molecules released to recruit
fibroblasts. The end result of decreased fibroblast activity from
otherwise overactive levels is a reduction in the density of scar
tissue.
[0083] Secondly, bioactive glasses attract and bind collagen fibers
to their surface. As fibroblasts infiltrate the wound they migrate
among the glass particulate and lay down collagen among and on the
surface of the particles. The random distribution of bioactive
glass particles to which collagen fibers are attracted and attached
will determine that the fibers themselves are randomly oriented. As
the glass particles resorb, they leave behind a bed of randomly
oriented collagen fibers whose mechanical properties more closely
match those of unwounded tissue.
[0084] An added benefit of using the above methods for treating
wound and grafting skin is that the scar tissue formed upon healing
is more uniform and more closely matches the surrounding skin.
Thus, the scar tissue, the formation of which is generally
unavoidable, has a better appearance. This benefit is particularly
important for treating wound and burns on the face. The
compositions can also be used to improve the appearance and
structure of scar formed as the wound or burn heals.
[0085] VIII. Methods of Reducing Inflammation
[0086] The compositions can be used to reduce inflammation in a
patient. Overly acute or chronic inflammation can result in various
disease states in a patient, for example, arthritis and tendinitis,
pulmonary disorders such as asthma and emphysema, and post-surgical
(peritoneal) adhesions.
[0087] Very small particulate bioactive glass has the property of
exerting an anti-inflammatory effect when in contact with body
tissue. It appears that the bioactive glass suppresses the
production of tissue necrosis factor alpha (TNF-.alpha.) and
interleukin-1 (IL-1) at the earliest stages of administration of
the bioactive glass. This effect is transient and does not induce
any secondary immunologic response. This is very different than the
administration of growth factors, antibiotics or other cytokines
that all show secondary effects on the immune system, even though
they may be small.
[0088] TNF-.alpha. is a powerful pro-inflammatory cytokine that not
only participates in the normal inflammatory response, but is also
implicated in myocardial dysfunction and cardiomyocyte death in
ischemia-reperfusion injury, sepsis, chronic heart failure, viral
myocarditis and cardiac allograft rejection, as well as a host of
other inflammatory disorders. Accordingly, by suppressing the
production of TNF-.alpha., the compositions reduce the likelihood
of these disorders occurring.
[0089] The preferred size range for the bioactive glass, for this
embodiment, is such that the particles do not physically obstruct
vascular, lymph or pulmonary pathways as the particles pass through
the body. Particles less than 20 microns in size, as measured by
SEM or laser light scattering techniques, are particularly
preferred, as immunochemistry results indicate that the body does
not respond to these particles as it would to other particles, for
example, silica particles. Experiments have shown that the body
does not show abnormal or elevated recruitment of macrophages to
the area where Bioglass.RTM. particles have been injected. This is
in stark contrast to small particles of other materials, such as
talcum, asbestos, silicone and metal debris, which are known to be
strongly pro-inflammatory.
[0090] While not intending to be bound to any particular theory or
mechanism, it is believed that the high surface area and reactivity
of the particulate bioactive glass provides for the release of
soluble sodium, calcium, phosphate, silica and other ionic species.
The ionic environment, alone with the increased pH, is believed to
act in such a way as to affect the expression of important cellular
mediators of inflammation. In addition, direct contact of
neutrophils, macrophages and other immune cells with the particle
surface may elicit an unexpected an anti-inflammatory effect on
cell function.
[0091] Incorporation of the anti-inflammatory bioactive glass
particles into compositions intended for pulmonary delivery of
therapeutic agents can be beneficial when those agents cause
inflammation in the lung after delivery.
[0092] Topical inflammatory effects, such as those observed in some
patients using transdermal patches, can be alleviated by
incorporating bioactive glass particles into a topical formulation,
such as a gel, creme, foam, lotion, or transdermal patch.
[0093] Numerous efforts have been made to deliver drugs via the
pulmonary tract. Several therapeutic agents cause local
inflammatory effects when delivered. These effects can be minimized
by incorporating bioactive glass particles into the compositions
for pulmonary administration. In one embodiment, an aqueous extract
of bioactive glass can be used in place of or in addition to the
bioactive glass particles to cause the same anti-inflammatory
effect. The aqueous solution can be used as a pharmaceutical
carrier in an intra-nasal drug delivery device.
[0094] Particles of bioactive glass, and/or solutions including the
extract from bioactive glass, can be delivered by local injection
to sites of inflammation in a patient, for example, at an inflamed
joint or tendon.
[0095] Particles of bioactive glass, and/or solutions including the
extract from bioactive glass, can be delivered by intravenous,
intramuscular, or intra peritoneal injection to provide systemic
anti-inflammatory effects. These effects can be therapeutic and/or
prophylactic. For example, systemic delivery of bioactive glass,
and/or solutions including the extract from bioactive glass, can be
effective in reducing the onset of inflammation brought on by
external challenge.
[0096] Particles of bioactive glass can be administered locally to
a surgical site to minimize post-surgical adhesions. The glass
particles can optionally be incorporated into a polymeric material
which is applied to the surgical site. Preferably, the polymeric
material is biodegradable, and the particles are released as the
polymer degrades. Suitable polymeric materials for this purpose are
disclosed, for example, in U.S. Pat. No. 5,410,016 to Hubbell et
al., the contents of which are hereby incorporated by reference.
Other materials suitable for this purpose, such as Interceed.RTM.,
agarose and crosslinked alginate, are well known to those of skill
in the art.
[0097] Highly porous bioactive glass can have the same
anti-inflammatory effects as the small glass particles, due to its
relatively high surface area.
[0098] Biomedical implants are often associated with inflammation
at the site of implantation. Incorporation of small particles of
bioactive glass and/or highly porous bioactive glass into the
implants, especially on the surface of the implants, can greatly
reduce the inflammation associated with the implants. This can be
especially useful in suture materials to minimize the inflammation
associated with these materials. As discussed below, the
anti-bacterial properties of the compositions also allow the
sutures to minimize the infection surrounding the suture site.
[0099] An "effective, anti-inflammatory amount of bioactive glass"
refers to an amount of bioactive glass, with an appropriate
particle size, which is effective at reducing the inflammation.
Those of skill in the art can readily estimate the actual or
anticipated inflammation associated with a wound site, for example,
caused by an injury, a surgical procedure, arthritis or other
autoimmune disorders, by administration of a therapeutic agent to
the pulmonary system or to the skin, for example, via a transdermal
delivery system, and the like. Those of skill in the art can also
use this estimate to determine an appropriate anti-inflammatory
amount of bioactive glass to administer to the inflamed site, or
site of anticipated inflammation.
[0100] IX. Methods of Reducing Bacterial Infection
[0101] Large particles of bioactive glass and non-porous bioactive
glass do not have appreciable bactericidal properties. However,
small particles of bioactive glass and highly porous bioactive
glass, when present in an aqueous environment, do have appreciable
bactericidal properties. Bactericidal properties have been shown
against Staph. aureus, Staph. epidermidis, and various
streptococci, commonly found in and on the skin. While not being
bound by a specific mechanism of action, it is believed that this
action is a result of the greatly increased bioactivity of the
small particulates, which leads to a sharply increased pH of the
surrounding aqueous environment. The combined properties of being
both broadly bactericidal while at the same time maintaining tissue
biocompatibility make small particles of bioactive glass a suitable
antibacterial treatment, in particular, for skin disorders such as
dermal ulcers.
[0102] The bactericidal action increases with decreasing particle
size. The preferred particle size depends, in part, on the initial
bacterial burden and the desired bacterial kill. For normal
bacterial loads and uninfected wounds, for example, a composition
in the less than 20 micron size range is sufficient. However, for
higher bacterial loads where the danger of infection appears
pressing, the composition should include particles with a size less
than five microns as measured by SEM or laser light scattering
techniques.
[0103] An "effective, antibacterial amount of bioactive glass"
refers to an amount of bioactive glass, with an appropriate
particle size, which is effective at reducing the bacterial
infection. Those of skill in the art can readily estimate the
bacterial load in a wound, and use this estimate to determine an
appropriate particle size and amount of bioactive glass to
administer to the wound. As used herein, the term "antibacterial"
is also used to refer to the ability of the compositions to reduce
infections due to fungi and mold.
[0104] The present invention will be more clearly understood with
reference to the following non-limiting examples.
EXAMPLES
Example 1
Treatment of a Wound with a Particulate Bioactive Glass in a
Carrier
[0105] A photograph was taken of a wound in patient with vasculitis
taken soon after the wound was inflicted. This type of wound would
typically require an overall healing time of about 3 months. The
wound was treated with a mixture of particulate non-interlinked
bioactive glass with a fine particle size, a topical antibiotic
including sulfadiazine, and a petrolatum base carrier.
[0106] A second photograph was taken of the same wound, after
treatment with the bioactive glass composition, 4 days after the
first photograph. A third photograph of the same wound was taken 7
days after the second photograph. A fourth photograph of the same
wound was taken 14 days after the second photograph. These
photographs demonstrate that the wound is healing well. A similar
wound on a patient with vasculitis would not be expected to show a
similar degree of healing for at least about three months, if at
all.
[0107] For example, the second photograph showed that, after only 4
days, seepage of the wound was stopped and the surface of the wound
appeared 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. The third photograph showed that the
healing mechanism was well underway and that fatty tissue had
covered the surface of the wound after only 11 days. The fourth
photograph showed that after only 18 days, the wound was about 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 photographs.
Example 2
Treatment of Delayed Healing in a Diabetic Patient
[0108] A diabetic suffering from delayed healing lesions was
treated with a mixture of particulate bioactive glass with a
particle size less than 40 .mu.m and an equal volume of
NEOSPORIN.TM. antibiotic ointment. This ointment was substantially
a mixture of antibiotic agents in a petrolatum base. 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.
[0109] As the scar tissue continued to develop, its appearance was
much more like that of the surrounding tissue than is typical for
an injury of the type being treated in this patient. After full
development, the appearance of the scar tissue closely approximated
that of the surrounding tissue.
Example 3
Anti-Bacterial Properties of Bioactive Glass
[0110] Small particulate bioactive glasses and highly porous
bioactive glass possess anti-bacterial activity. In aqueous
solutions, bioactive glass with a composition of 45% silicon
dioxide, 24.5% sodium oxide, 24.5% calcium oxide and 6% phosphorous
oxide causes a pH rise in aqueous solutions. The following
experiment was carried out to demonstrate the anti-bacterial
properties of the resulting solution.
[0111] Nutrient broth (10 ml) was added to 5 grams of particulate
bioactive glass with a pore size between 355 and 500 .mu.m, 5 grams
of glass beads (not bioactive glass) with a particle size between
455 and 600 .mu.m, and no glass beads. The resulting solutions were
incubated with rotation for 1 h at 37 C. 950 .mu.l of each
supernatant was removed and added to 50 .mu.l of an overnight
culture of S. sanguis, and incubated for 1 h at 37 C. Survivors
were enumerated by viable counting. A mean reduction in viable
counts of 97% with the bioactive glass supernates was observed,
with little or no kill with the glass bead supernates (13%).
[0112] To determine the contribution made by the pH change, the
experiments were repeated with 50 .mu.l of S. Sanguis added to
unmodified BGS (bioactive glass solution), BGS and HCl (pH around
7.2), BGS and NaCl (pH around 9.8) (a control for chloride ion
addition) and nutrient broth (pH around 7.2). Cultures incubated in
high pH solutions showed reductions of viability of 81% (unmodified
BGS) and 82% (BGS and NaCl), compared to 5% in the HCL treated BGS.
Subsequent experiments with non-bioactive glass derived alkaline
solutions (NaOH, pH 9.8) showed less antibacterial activity, with
kills of 40%. This demonstrates that while decreasing the pH of
bioactive glass supernates reduces their antibacterial activity,
not all of the observed kills can be attributed to their high
pH.
Example 4
Antiinflammatory Effects of Bioactive Glass Particles
[0113] A 1 ml suspension including 25 mg of bioactive glass in a
1:1 solution of fetal bovine serum and phosphate buffered saline
was injected intraperitoneally into a group of five adult male mice
an additional group of five mice received the same solution without
the bioactive glass to serve as a control. At two hours
post-injection, the washed peritoneal fluid was examined for
leukocyte recruitment and inflammatory mediators TNF-.alpha. and
IL-1. Upon microscopic examination it was found that no additional
cells above control levels were recruited. ELISA assays showed that
TNF-.alpha. and IL-1 were not elevated above control levels. There
was a modest increase in IL-6 levels, but in the absence of
observable levels of TNF-.alpha. and IL-1, this indicates a general
anti-inflammatory action. Given the physical presence of
particulate matter that would otherwise induce a strong
inflammatory response in this setting, the lack of recruited cells
and their inflammatory signals represents a direct suppression of
an inflammatory response.
Example 5
Anti-inflammatory Effects of Bioactive Glass Particles
[0114] An adult middle aged male was suffering from two open dermal
lesions on the right forearm. These wounds were non-healing and
highly inflamed, with large amounts of exudate, edema and erythema
resulting from a local inflammatory response to the open, colonized
wound. After two topical treatments with small particulate
bioactive glass, all signs of local inflammation ceased, and the
lesions proceeded to heal normally.
* * * * *