| United States Patent Application |
20040005364
|
| Kind Code
|
A1
|
|
Klein, Barbara K.
; et al.
|
January 8, 2004
|
Antimicrobial and immunostimulating composition
Abstract
A medical composition comprising an antimicrobially effective and
immunostimulating amount of a combination of a .beta.-glucan component
and a silver-containing component is disclosed. The medical composition
may be adapted for use topically or incorporated with a mesh material
which may be further adapted for use as a wound dressing or as a surgical
mesh. Methods for manufacturing the medical compositions described herein
are also provided. The invention further provides methods for treating
tissue damaged by wound or burn, and methods for treating or repairing
tissue at a surgical site.
| Inventors: |
Klein, Barbara K.; (North Oaks, MN)
; Katzner, Leo D.; (Shakopee, MN)
|
| Correspondence Name and Address:
|
FAEGRE & BENSON LLP
2200 WELLS FARGO CENTER
90 SOUTH 7TH STREET
MINNEAPOLIS
MN
55402
US
|
| Serial No.:
|
460760 |
| Series Code:
|
10
|
| Filed:
|
June 12, 2003 |
| U.S. Current Class: |
424/618; 514/54 |
| U.S. Class at Publication: |
424/618; 514/54 |
| Intern'l Class: |
A61K 033/38; A61K 031/715 |
Claims
What is claimed is:
1. A medical composition for topical application, the composition
comprising an antimicrobially effective and immunostimulating amount of a
combination of a .beta.-glucan component and a silver-containing
component.
2. The medical composition of claim 1, wherein the .beta.-glucan component
is a cereal-derived .beta.-glucan compound.
3. The medical composition of claim 2, wherein the .beta.-glucan compound
is derived from wheat, oats, barley, or a combination thereof.
4. The medical composition of claim 2, wherein the .beta.-glucan compound
has a molecular weight in the range of about 1 kDa to about 1500 kDa.
5. The medical composition of claim 2, wherein the .beta.-glucan compound
has a molecular weight in the range of about 200 kDa to about 700 kDa.
6. The medical composition of claim 2, wherein the .beta.-glucan compound
includes (1-3)(1-4) .beta.-D-glucan.
7. The medical composition of claim 6, wherein the .beta.-glucan compound
includes (1-3) linkages and (1-4) linkages in a proportion of about 30%
(1-3) linkages and about 70% (1-4) linkages.
8. The medical composition of claim 1, wherein the .beta.-glucan component
is derived from bacteria, yeast, fungi, or a combination thereof.
9. The medical composition of claim 1, wherein the silver-containing
component includes elemental silver.
10. The medical composition of claim 1, wherein the silver-containing
component includes a silver compound selected from the group consisting
of inorganic silver salts and organic silver salts.
11. The medical composition of claim 1, wherein the silver-containing
component includes a silver compound selected from the group consisting
of silver nitrate, silver bromide, silver sulfate, silver fluoride,
silver iodide, silver chloride, silver oxides, silver protein, silver
lactate, silver citrate, and silver sulfadiazine.
12. The medical composition of claim 1, wherein the silver-containing
component is silver nitrate.
13. The medical composition of claim 1, wherein the composition is a gel,
a cream, a lotion, or an unguent.
14. The medical composition of claim 13, wherein the composition is a
cream or lotion comprising: a cereal-derived .beta.-glucan compound; a
solvent; an emulsifying/solubilizing agent; a suspending/viscosity-increa-
sing agent; and a preservative.
15. The medical composition of claim 1, wherein the composition comprises:
about 0.05% to about 15% by weight of the .beta.-glucan component; and
about 0.05% to about 70% by weight of the silver-containing component.
16. The medical composition of claim 1, wherein the composition comprises:
about 0.05% to about 15% by weight of the .beta.-glucan component; and
about 0.05% to about 15% by weight of the silver-containing component.
17. The medical composition of claim 16, wherein the composition
comprises: about 0.05% to about 15% by weight of (1-3)(1-4)
.beta.-D-glucan; and about 0.05% to about 15% by weight of silver
nitrate.
18. The medical composition of claim 16, wherein the composition is an
ointment comprising about 50% to about 99.5% by weight of petrolatum.
19. The medical composition of claim 16, wherein the composition is a gel
comprising at least about 50% by weight of water and about 0.5% to about
15% by weight of a suspending/viscosity-increasing agent.
20. The medical composition of claim 16, wherein the composition is a
lotion comprising about 20% to about 90% by weight water and about 3% to
about 60% by weight petrolatum.
21. The medical composition of claim 16, wherein the composition is a
lotion comprising, by weight: about 0.05% to about 15% oat-derived
.beta.-glucan; about 0.05% to about 15% silver nitrate; about 20% to
about 90% water; about 3% to about 60% petrolatum; about 2% to about 30%
glycerol stearate; and about 2% to about 20% PEG 100 stearate.
22. The medical composition of claim 16, wherein the composition is a
lotion comprising, by weight: about 1% oat-derived .beta.-glucan; about
1.5% silver nitrate; about 82.5% water; about 10% petrolatum; about 2.5%
glycerol stearate; and about 2.5% PEG 100 stearate.
23. A wound dressing comprising a mesh material; and a composition
comprising an antimicrobially effective and immunostimulating amount of a
combination of a .beta.-glucan component and a silver-containing
component.
24. The wound dressing of claim 23, wherein the wound dressing includes a
first layer comprising the mesh material, and a second layer comprising
the composition.
25. The wound dressing of claim 23, wherein the mesh material comprises a
synthetic material.
26. The wound dressing of claim 23, wherein the mesh material comprises a
synthetic material selected from the group consisting of polyester,
polypropylene, polytetrafluoroethylene, expanded polytetrafluoroethylene,
polyurethane, polyethylene terephthalate, polyglycolic acid, polyglactin,
and silicone.
27. The wound dressing of claim 23, wherein the mesh material comprises a
material derived from a human source, an animal source, or a cadaveric
source.
28. The wound dressing of claim 23, wherein the mesh material is
impregnated with the composition.
29. The wound dressing of claim 23, wherein the composition is coated onto
the mesh material.
30. The wound dressing of claim 23, wherein about 0.01% to about 50% by
weight of the wound dressing is the .beta.-glucan component, and about
0.01% to about 15% by weight of the wound dressing is the
silver-containing component.
31. The wound dressing of claim 23, wherein the composition includes about
10 parts by weight of cereal-derived .beta.-glucan to about 3 parts by
weight silver nitrate.
32. The wound dressing of claim 23, wherein the composition further
comprises collagenic protein.
33. The wound dressing of claim 32, wherein about 0.1% to about 20% by
weight of the wound dressing is the collagenic protein.
34. The wound dressing of claim 23, and further comprising, as an exterior
surface, a polymeric vapor-permeable film in contact with the mesh
material.
35. A biocompatible mesh device for treating or repairing tissue at a
surgical site, comprising: a mesh matrix; and a composition comprising an
antimicrobially effective and immunostimulating amount of a combination
of a .beta.-glucan component and a silver-containing component.
36. The biocompatible mesh device of claim 35, wherein the mesh matrix
comprises a biocompatible synthetic material.
37. The biocompatible mesh device of claim 35, wherein the mesh matrix
comprises a biocompatible synthetic material selected from the group
consisting of polyester, polypropylene, polytetrafluoroethylene, expanded
polytetrafluoroethylene, polyurethane, polyethylene terephthalate,
polyglycolic acid, polyglactin, and silicone.
38. The biocompatible mesh device of claim 35, wherein the mesh matrix
comprises a material derived from a human source, an animal source, or a
cadaveric source.
39. The biocompatible mesh device of claim 35, wherein the mesh matrix is
impregnated with the composition.
40. The biocompatible mesh device of claim 35, wherein the composition is
coated onto the mesh matrix.
41. The biocompatible mesh device of claim 35, wherein the .beta.-glucan
component is a cereal-derived .beta.-glucan compound.
42. The biocompatible mesh device of claim 41, wherein the .beta.-glucan
compound is derived from wheat, oats, barley, or a combination thereof.
43. The biocompatible mesh device of claim 41, wherein the .beta.-glucan
compound has a molecular weight in the range of about 1 kDa to about 1500
kDa.
44. The biocompatible mesh device of claim 41, wherein the .beta.-glucan
compound has a molecular weight in the range of about 200 kDa to about
700 kDa.
45. The biocompatible mesh device of claim 41, wherein the .beta.-glucan
compound includes (1-3)(1-4) .beta.-D-glucan.
46. The biocompatible mesh device of claim 41, wherein the .beta.-glucan
compound includes (1-3) linkages and (1-4) linkages in a proportion of
about 30% (1-3) linkages and about 70% (1-4) linkages.
47. The biocompatible mesh device of claim 35, wherein the
silver-containing component includes elemental silver.
48. The biocompatible mesh device of claim 35, wherein the
silver-containing component includes a silver compound selected from the
group consisting of inorganic silver salts and organic silver salts.
49. The biocompatible mesh device of claim 35, wherein the
silver-containing component includes a silver compound selected from the
group consisting of silver nitrate, silver bromide, silver sulfate,
silver fluoride, silver iodide, silver chloride, silver oxides, silver
protein, silver lactate, silver citrate, and silver sulfadiazine.
50. The biocompatible mesh device of claim 35, wherein the
silver-containing component is silver nitrate.
51. A method for treating tissue damaged by wound or burn, comprising the
steps of: cleaning a site of damaged tissue; and applying topically to
the site an antimicrobial and immunostimulating composition comprising a
combination of a .beta.-glucan component and a silver-containing
component.
52. The method of claim 51, and including repeating application of the
composition intermittently until healing of the damaged tissue is
complete.
53. A method for treating tissue damaged by wound or burn, comprising the
steps of: a) cleaning a site of damaged tissue; and b) covering the site
with a wound dressing comprising a mesh material; and a composition
comprising an antimicrobially effective and immunostimulating amount of a
combination of a .beta.-glucan component and a silver-containing
component.
54. A method for treating or repairing tissue at a surgical site
comprising the step of applying to the surgical site a biocompatible mesh
device, the mesh device comprising: a mesh matrix; and a composition
comprising an antimicrobially effective and immunostimulating amount of a
combination of a .beta.-glucan component and a silver-containing
component.
55. A method for manufacturing a medical composition, comprising the step
of combining, in an appropriate solvent, a .beta.-glucan component and a
silver-containing component in appropriate portions to provide an
antimicrobial and immunostimulating composition.
56. The method of claim 55, wherein the composition is suitable for
topical application.
57. The method of claim 55, further comprising the step of coating or
impregnating a mesh material to provide a wound dressing.
58. The method of claim 55, further comprising the step of impregnating a
mesh matrix to provide a biocompatible mesh device suitable for treating
or repairing tissue at a surgical site.
Description
REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 09/538,655 filed Mar. 30, 2000, and entitled
"Anti-microbial and Immunostimulating Composition" the entire disclosure
of which is hereby incorporated by reference.
TECHNICAL FIELD
[0002] This invention relates generally to an antimicrobial and
immunostimulating medical composition which may be adapted for use
topically or as part of a mesh matrix which may be further adapted for
use as a wound dressing or as a surgical mesh.
[0003] It is known to utilize immunostimulating agents as components of
topical compositions, wound dressings, and surgical meshes. Examples of
these uses are given in U.S. Pat. No. 5,980,918 to Klein, U.S. Pat. No.
5,676,967 to Williams et al., and U.S. patent application Ser. No.
09/406,551 also to Klein, respectively. U.S. Pat. Nos. 5,980,918 and
5,676,967, and U.S. patent application Ser. No. 09/406,551 are all
assigned jointly with the present application and are hereby incorporated
by reference.
[0004] There is a need with respect to all topical compositions, wound
dressings and surgical meshes to provide an effective antimicrobial
function in addition to the immunostimulating function described above.
[0005] This and other objectives and advantages of the invention will
appear more fully from the following description, made in conjunction
with the accompanying drawings wherein like reference characters refer to
the same or similar parts throughout the several views.
SUMMARY OF THE INVENTION
[0006] The present invention provides a medical composition that has the
immunostimulating properties common to the topical compositions, wound
dressings, and surgical meshes described in the aforementioned patents
and patent application, along with antimicrobial properties that aid in
preventing or alleviating infection. Consequently, a medical composition
according to the present invention comprises an antimicrobially effective
and immunostimulating amount of a combination of a .beta.-glucan
component and a silver-containing component.
[0007] The .beta.-glucan component is suitably derived from a cereal such
as oats, wheat or barley, but may also be derived from yeast, bacteria,
and fungus. The medical composition of the present invention may suitably
include a cereal-derived .beta.-D-glucan derived from one of wheat, oats,
and barley. An especially beneficial form of .beta.-D-glucan is
characterized as (1-3)(1-4) .beta.-D-glucan derived from oats, wheat, or
barley.
[0008] The silver component of the medical composition is suitably chosen
from a group comprising elemental silver, silver nitrate, silver bromide,
silver sulfate, silver fluoride, silver iodide, silver chloride, silver
oxides, silver protein, silver lactate, silver citrate, and silver
sulfadiazine.
[0009] A topical composition formulated according to the principles of the
present invention may take the form of a an unguent, a cream, a gel, an
emollient, an oil or a lotion.
[0010] The medical composition of the present invention may form a layer
of a biocompatible surgical mesh or may be impregnated into a mesh matrix
of such a surgical mesh.
[0011] Similarly, the medical composition may also form a layer of a wound
dressing or may be impregnated into a mesh material of a wound dressing.
A wound dressing comprising the medical composition of the present
invention may include a mesh material that has a coating that includes a
.beta.-glucan compound and elemental silver or a silver compound. The
wound dressing may include a polymeric film of vapor-permeable material
bonded to one side of the coated mesh material, as an exterior surface of
the wound dressing.
[0012] Methods for manufacturing the medical compositions described herein
are also provided. The invention further provides methods for treating
tissue damaged by wound or burn, and methods for treating or repairing
tissue at a surgical site.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 is a side view of a wound dressing incorporating the medical
composition of the present invention.
[0014] FIG. 2 is a side view of a surgical mesh incorporating the medical
composition of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Medical Composition
[0016] Each of the components of the medical composition described herein
serves a particular function or functions, and is available in purities
conducive for use in the particular applications. Thus, a component may
comprise United States Pharmacia (USP), National Formulary (NF), or other
purified grade appropriate for topical use on burns and wounds on the
skin, or for internal use when required.
[0017] The medical compositions of the invention may be prepared from the
stated components, and any other additives, using conventional methods.
[0018] The preferred active ingredients of the medical composition of the
present invention are a .beta.-glucan compound and a silver compound.
[0019] .beta.-Glucan Component
[0020] Compounds classified as .beta.-glucans comprise a large group of
higher molecular weight polymers containing glucopyranosyl units in
.beta.-linked chains. .beta.-glucans are found in essentially all living
cells that are enclosed by cell walls and have considerable structural
variation depending on the source. .beta.-glucans are highly unbranched
homopolysaccharides and are isomerically disposed to .alpha.-D-glucan
(e.g., starch), which is typically non-functional as a structural support
component of the cell. .beta.-glucans generally comprise a large number
of glucopyranosyl units linked primarily by (1-3) and (1-4) linkages.
Various types of .beta.-glucans are described in U.S. Pat. No. 5,980,918
to Klein, which was incorporated by reference above.
[0021] As described in U.S. Pat. No. 5,980,918, .beta.-glucans have a
strong immunostimulating property, which makes them ideal for use in
medical compositions applied to wounds and surgical sites. The
.beta.-glucans actually stimulate the immune response of the tissues at
the wound or surgical site, which has the effect of improving tissue
regeneration and speeding recovery.
[0022] The primary source of .beta.-glucan compounds has historically been
yeast and bacterial cells. The most readily available types of
.beta.-glucans presently are those derived from yeast, bacteria, fungi
and from cereal grains such as wheat, barley, and oats. All of these
.beta.-glucans may be used to formulate the medical composition of the
present invention.
[0023] Cereal-derived .beta.-D-glucan is significantly different from
.beta.-glucans obtained from other sources, including .beta.-D-glucans
derived from yeast such as Saccharomyces cerevisiae and bacteria such as
Cellulomonas flavigena. The cereal-derived (1-3)(1-4) .beta.-D-glucan is
distinctive from microbial-derived glucans, which have all (1-3) linkages
or primarily (1-3) linkages with a few (1-6) linkages.
[0024] The molecular weight of the mixed-linkage cereal-derived
.beta.-glucan suitable for use in this invention is generally much
greater than that of microbial-derived glucans. Suitable cereal-derived
.beta.-glucan compounds may span a fairly broad range of molecular
weights, i.e., from about 1 kDa to about 1,500 kDa, and preferably from
200 kDa to 700 kDa.
[0025] As further described in U.S. Pat. No. 5,980,918, cereal derived
.beta.-glucans have been shown to be the most efficacious in stimulating
the immune response of the tissues at a wound or surgical site.
Therefore, it is preferred to utilize cereal-derived .beta.-glucans such
as those derived from wheat, barley and oats as the .beta.-glucan
component of the medical composition of the present invention.
Cereal-derived glucan (CDG) may be characterized as follows:
[0026] a. CDG is a long chain, unbranched polysaccharide which typically
makes up about 3-4% of oat and barley grains. The CDG concentration is
greater, e.g. 7-10%, in the milled bran fraction of oats.
[0027] b. CDG is found in the endosperm and aleurone cell walls of most
cereal grains. The microbe-derived glucans occur in the cell wall of the
yeast or bacteria.
[0028] c. CDG is a mixed-linkage molecule containing about 70 percent
(1-4)-linkages and about 30 percent (1-3)-linkages. The (1-3)-linked
units mostly occur singly whereas the (1-4)-linked units typically occur
in groups of three or four glucopyranosyl units. Thus, the resultant
structure is a series of short runs of 3 or 4 (1-4)-linked glucopyranosyl
units, adjacent runs connected by (1-3) linkages. The frequencies of the
groups of three (cellotriosyl) and four (cellotetraosyl) glucopyranosyl
units also tend to be characteristic of the source, being affected by
cereal variety, tissue age, and stage of maturity. Oat-derived CDG
typically has more of the groups of three consecutive (1-4)-linked
glucopyranosyl units than does barley-derived CDG. The ratio of
trisaccharide to tetrasaccharide groups is about 2:1 for oats and closer
to 3:1 for barley. CDG differs from microbe-derived glucans, which have
all (1-3)-linkages or mostly (1-3)-linkages with some (1-6)-linkages.
[0029] d. CDG is a linear molecule, while yeast-derived glucan forms a
helical shape.
[0030] e. The degree of polymerization of CDG is in the range of about
1200-1800. On the other hand, yeast-derived .beta.-D-glucan has a much
lower degree of polymerization, i.e. about 60-80. Cellulose, the primary
constituent of plant cell walls, has all .beta. (1-4) linkages and a
degree of polymerization of about 10,000 to 15,000.
[0031] f. CDG forms viscous solutions in warm water. In contrast,
yeast-derived glucan is insoluble in water but dispersible in aqueous
systems.
[0032] g. CDG occurs within the grain with a fairly broad range of
molecular weights, i.e. about 200 kDa to about 700 kDa. The molecular
weight is believed to be dependent upon the grain species, grain source,
glucan extraction conditions and particular laboratory. Microbe-derived
glucan has a much lower molecular weight, in the range of about 10 kDa to
about 14 kDa. Cellulose has a molecular weight of about 700 kDa.
[0033] h. The use of CDG as a food component has been studied extensively
by various researchers; studies have included the use of CDG in
regulation of glucose metabolism, hypoglycemic response, reduction in
serum cholesterol, and the like.
[0034] Thus, in terms of chemical structure and molecular weight, CDG is
much more like cellulose than are the microbial-derived glucans.
[0035] The preferred active agent is .beta.-D-glucan derived from oats,
although the glucans from barley, wheat and/or other cereal grains may be
used for the topical composition, provided the .beta.-D-glucan can be
extracted economically.
[0036] Silver-Containing Component
[0037] The second active ingredient of the medical composition of the
present invention is a silver-containing component providing
antimicrobial properties. The silver-containing component may be a silver
compound or other source of silver that is capable of releasing elemental
silver or silver ion in situ.
[0038] Silver-containing components suitable for use with the medical
composition of the present invention act to kill or inhibit the growth of
bacteria or other infectious agents that may be present at a wound or
surgical site. Silver-containing components suitable for use with the
medical composition of the present invention comprise elemental silver,
or silver compounds including inorganic silver salts such as silver
nitrate, silver bromide, silver sulfate, silver fluoride, silver iodide,
silver chloride and silver oxides, and organic silver salts such as
silver protein (mild and strong), silver lactate, silver citrate, or
silver sulfadiazine. It is to be understood that this is not an
exhaustive list of the silver compounds which may be used with the
medical composition of the present invention and that other silver
compounds may suitably be used. Furthermore, mixtures of silver
compounds, or a silver compound and elemental silver, may also be
suitable. Silver metal, such as silver foil or
colloidal silver, may also
be suitable in some embodiments.
[0039] Topical Compositions
[0040] The medical composition of the present invention may be included as
a component of a topical composition of the type described in U.S. Pat.
No. 5,980,918. In use, such a topical composition is preferably applied
directly to a wound or to a surgical site so that the immunostimulating
and antimicrobial properties of the topical composition may work in
conjunction to stimulate healing. A topical composition which comprises
the medical composition of the present invention may be formulated in
various ways including those topical composition variously known as
unguents, creams, gels, emollients, lotions and oils, each with a
generally characteristic solvent composition and having a form ranging
from liquid to semi-solid. A topical composition may be applied directly
by rubbing the composition onto the desired treatment area, or may be
applied indirectly such as by coating the composition onto an applicator,
a wound dressing, or other means of application.
[0041] A topical composition of the invention may contain, for example,
about 0.05% to about 15% by weight of a .beta.-glucan component, and
about 0.05% to about 70% by weight of a silver-containing component. In
some embodiments, the topical composition contains about 0.05% to about
15% by weight of a .beta.-glucan component, and about 0.05% to about 15%
by weight of a silver-containing component. A particularly suitable
combination is about 0.05% to about 15% by weight of (1-3)(1-4)
.beta.-D-glucan component, and about 0.05% to about 15% by weight of
silver nitrate.
[0042] In addition to the .beta.-glucan component and silver-containing
component, a topical formulation may include one or more of an ointment
base, a solvent, a suspending/viscosity-increasing agent, an
emulsifying/solubilizing agent, a stiffening agent, an emollient, and a
preservative. Other additives known in the art, such as plasticizers,
humectants, etc. may also be suitable.
[0043] A suitable ointment base may include white petrolatum, cod liver
oil, mineral oil, shark oil, paraffin, lanolin, cetyl alcohol, and/or
cetyl ester wax, and the like.
[0044] In formulations comprising a solvent, the solvent may suitably be
primarily or entirely water. Additional solvents which may be added at
generally lower concentrations include natural oils such as cod liver
oil, mineral oil, etc., and glycerol or propylene glycol. In some
embodiments, the water content of a cream or gel formulation is at least
about 50% by weight.
[0045] A suspending/viscosity-increasing agent, such as carrageenan, may
be suitably included in a topical composition comprising a solvent. Other
possible suspending/viscosity-increasing agents include polyvinyl
alcohol, xanthan gum, agarose, alginate, guar gum, a carbomer such as
CARBOPOL 940 (Noveon, Inc., Cleveland, Ohio), and carboxymethylcellulose,
as well as mixtures thereof. A variation in the concentration of
suspending agents is compensated by varying the solvent concentration.
[0046] A stiffening agent useful in forming a topical composition with the
medical composition of the present invention may comprise cetyl alcohol,
cetyl esters wax, or paraffin.
[0047] A suitable emulsifying/solubilizing agent may suitably include
sodium lauryl sulfate or non-ionic emulsifiers such as glyceryl stearate,
PEG 100 stearate and triethanolamine.
[0048] A suspending/viscosity increasing agent suitable for use with the
medical composition may suitably include polyvinyl alcohol, agarose,
alginate, xanthan gum, guar gum, sodium carboxymethylcelluloses, or
carbomer.
[0049] A preservative such as methyl paraben, ethyl paraben, butyl
paraben, propyl paraben, benzalkonium chloride, benzoic acid, benzoic
alcohol, imidurea, or diazolidinyl urea may also suitably be used in a
topical composition formulated according to the present invention.
[0050] An ointment according to the present invention may comprise about
50% to about 99.5% by weight of petrolatum or alternate ointment base.
[0051] A lotion or cream of the present invention may include, for
example, a cereal-derived .beta.-glucan compound, a solvent, an
emulsifying/solubilizing agent, a suspending/viscosity-increasing agent,
and a preservative.
[0052] A specific formulation of a topical composition comprising the
medical composition of the present invention and taking the form of a
lotion may include 0.05-15 w/w % oat-derived .beta.-D-glucan and 0.05-15
w/w % silver nitrate (AgNO.sub.3). Additional components may include:
20-90 w/w % water, 3-60 w/w % petrolatum, 2-30 w/w % glycerol stearate,
and 2-20 w/w % PEG 100 stearate.
[0053] Another formulation of a topical composition for application to the
skin and mucosa for treating burns and wounds and other skin loss
injuries and conditions comprises 0.05-15 w/w % .beta.-D-glucan and a
silver-containing component as active ingredients in a cream base, gel
base or oil base.
[0054] Another formulation of a topical composition comprising the medical
composition takes the form of a cream and includes .beta.-glucan, a
solvent including water, an ointment base, an emulsifying/solubilizing
agent, a suspending/viscosity increasing agent, and a preservative.
Preferably, at least 20 w/w % of the topical composition of this
formulation will be solvent. The solvent may include an emollient such as
glycerol or propylene glycol. The ointment base typically makes up 3-60
w/w % of the topical composition and may comprise petrolatum, cod liver
oil, mineral oil, shark oil, paraffin, lanolin, cetyl alcohol, and/or
cetyl ester wax.
[0055] A suitable gel formation including the medical composition of the
present invention comprises a gel base generally including water, at
least one suspending/viscosity increasing agent, and optionally a
preservative mixed with the medical composition. The suspending/viscosity
increasing agent(s) is typically chosen from a group that includes
polyvinyl alcohol, sodium carboxymethylcellulose, xanthan gum, agarose,
alginate, guar gum, and carbomer. The suspending/viscosity increasing
agent(s) may include one or more of the aforementioned group. Such a gel
preferably has a water base including at least about 50 w/w % water. More
specifically, such a gel may comprise about 50-98 w/w % water and about
0.5-15 w/w % suspending/viscosity increasing agent(s).
[0056] By way of example, and without limiting the forms that a topical
composition comprising the medical composition of the present invention
may take, a specific formulation of a lotion comprising the medical
composition of the present invention was made as follows: An aqueous
solution of oat derived .beta.-glucan was prepared by dissolving 2 grams
of oat derived .beta.-glucan in 165 grams of water at 95.degree. C. A
separate oil-phase solution was prepared by mixing 20 grams petrolatum
with 10 grams of a (49% glycerol stearate/51% PEG 100 stearate) blend.
This blend may be replaced by equal amounts of the respective
constituents or by an equivalent compound. The oil phase solution was
heated to 65.degree. C. and added to the aqueous solution which had been
cooled to, and held at, 65.degree. C. The mixture of the oil phase and
aqueous solutions was emulsified for two minutes at 27,000 RPM in a
mixer. Three grams of silver nitrate were then added and emulsification
continued for an additional one minute. The weight percentages (w/w %) of
the components of the prepared lotion where as follows:
1
.beta.-D-glucan (oat-derived) 1%
Silver
nitrate 1.5%
Water 82.5%
Petrolatum 10%
Glycerol Stearate 2.5%
PEG 100 Stearate 2.5%
Total
100.0%
[0057] Wound Dressing
[0058] The medical composition of the present invention may be used in
fabricating wound dressings that provide both immunostimulating and
antimicrobial properties. The medical composition of the present
invention may, for example, be added to a mesh wound dressing of the type
disclosed in U.S. Pat. No. 5,676,967 to Williams, et al. incorporated by
reference above. In such a wound dressing, the medical composition
containing a .beta.-glucan component and a silver-containing component
would be used to impregnate a mesh material. The wound dressing may also
include a vapor-permeable layer which is occlusive to moisture and
bacteria.
[0059] As used herein, the term "mesh" and phrase "mesh material" refer to
a woven, non-woven, or film material suitable as a substrate to which the
medical composition of the present invention may be applied. A mesh
material may be of synthetic, animal, human, plant, or mineral origin.
Synthetic materials from which a suitable mesh may be fabricated include
polyester, polypropylene, polytetrafluoroethylene, expanded
polytetrafluoroethylene, polyurethane, polyethylene terephthalate,
polyglycolic acid, polyglactin, and silicone. Other types of meshes may
be used, including but not limited to gauzes and organic meshes, and
polymeric films. Suitable organic surgical meshes that may be combined
with the medical composition of the present invention may be derived from
human sources, animal sources, and cadaveric sources. Homologous mesh
materials may be derived from the tissues of a donor, from animal
tissues, or from cadaveric tissues. Autologous mesh materials are derived
from a patient's own body, and may comprise dermographs, fascia tissues,
and dura mater.
[0060] For the wound dressing, an optional polymeric film may be applied
to the mesh material. The polymeric film is suitably a vapor-permeable
material. Preferably, the film has a moisture-vapor transmission rate
(MVTR) in a range suitable for medical or wound-dressing applications. By
way of example, a MVTR of about 1500 g/m.sup.2/24 hours or greater is
desirable, although a film having a lower MVTR may also be suitable in
some embodiments.
[0061] With reference to the FIG. 1, wound dressing 10 comprises an
impregnated mesh material. The mesh material is preferably a
multifilament woven mesh netting 12 formed of thin polyester fibers 20,
though other types of meshes may be used, including but not being limited
to gauzes, synthetic meshes, and organic meshes (of both autologous and
homologous sources). The mesh netting material 12 has a structure with
holes or openings 14 that permit a solution containing the medical
composition of the present invention to impregnate the mesh netting
material 12.
[0062] The wound dressing 10 may also comprise a vapor-permeable layer 22,
which is occlusive to moisture and bacteria. The vapor-permeable layer 22
may be made, for example, of a film of butylene/poly(alkylene ether)
phthalate plus stabilizer, and joined to surface 18 of the mesh netting
material 12 by a thermal process or other means, and acts to prevent
moisture and bacteria from entering the wound while allowing vapor to
pass through the dressing 10 from the wound site into the air.
[0063] The .beta.-glucan component of the medical composition is applied
to the mesh material of the wound dressing to produce a concentration
equal to about 0.01-50% of the dressing's dry weight, in some
embodiments. The silver-containing component of the medical composition
is applied to the mesh material of the wound dressing to produce a
concentration equal to about 0.01-15% of the dressing's dry weight, in
some embodiments.
[0064] Additional components of the wound dressing may include a coating
of a collagenic protein. The optional collagenic protein component of the
wound dressing may include a mixture of Type I and Type III collagens
that makes up 0.1-20% of the dry weight of the dressing, for example.
Collagen is commercially available in several forms. While other
collagenic protein materials may be used, a readily available material
comprising a mixture of Type I and Type III collagens is a lyophilized,
soluble, collagen fiber-like powder extracted from bovine hides. Type II
and/or Type IV collagens may also be used, but their lower solubility,
higher hydrophobicity makes their controllable application as a
suspension to fibers more difficult, and their subsequent transport into
the wound proceeds at a lower rate.
[0065] Another embodiment of a wound dressing which incorporates the
medical composition of the present invention may comprise a polyester
mesh netting formed of a woven monofilament polyester having a thickness
of about 0.01-0.05 inches. To this netting is applied a coating that
includes a .beta.-glucan compound and a silver compound that are mixed
with a collagenic protein in a ratio of 1:100 to 100:1 on a dry weight
basis.
[0066] By way of example, a wound dressing which comprises the medical
composition of the present invention was made as follows: An aqueous
solution of oat-derived .beta.-glucan and silver nitrate was prepared.
The solution contained 1.0wt.-% .beta.-glucan and 0.3 wt.-% silver
nitrate. This aqueous solution was used to impregnate the mesh netting of
the dressing. The aqueous solution in the mesh netting of the dressing
was then dehydrated at 25.degree. C. Following dehydration, the completed
wound dressing with the impregnated mesh netting was packaged and
sterilized. The weight percentages (w/w %) of the compounds of the
resulting exemplary wound dressing were as follows:
2
.beta.-D-glucan (oat derived) 31.3%
Silver
nitrate 9.8%
Mesh netting 58.9%
Total 100.0%
[0067] Surgical Meshes
[0068] The medical compositions of the present invention may also be used
in producing a biocompatible mesh device for treating or repairing tissue
at a surgical site. Surgical meshes are porous, gauze-like sheet
materials which may be woven or spun from a variety of organic and
synthetic materials. Examples of biocompatible surgical meshes
incorporating .beta.-glucan are given in U.S. patent application Ser. No.
09/406,551 to Klein, incorporated by reference above. The biocompatible
mesh device of the present invention comprises the medical composition
described above, and a mesh matrix.
[0069] The phrase "mesh matrix" is used herein to refer to a biocompatible
woven or non-woven mesh material. The material from which a surgical mesh
is made must be biocompatible, chemically and physically inert, non-toxic
and non-carcinogenic, is preferably mechanically strong, and easily
fabricated and sterilized.
[0070] Most synthetic surgical meshes are woven from monofilament or
multifilament fibers to form a mesh having pores of varying sizes and
geometries. Other synthetic surgical meshes are formed in a
node-and-fibril arrangement in which the mesh includes larger sections,
or nodes, which are interconnected by fibrils of the mesh material.
[0071] Synthetic materials from which a biocompatible mesh matrix may be
fabricated include polyester, polypropylene, polytetrafluoroethylene,
expanded polytetrafluoroethylene, polyurethane, polyethylene
terephthalate, polyglycolic acid, polyglactin, and silicone. Other types
of meshes may be used, including but not limited to gauzes and organic
meshes. Suitable organic surgical meshes that may be combined with the
medical composition of the present invention may be derived from human
sources, animal sources, and cadaveric sources. Homologous mesh materials
may be derived from the tissues of a donor, from animal tissues, or from
cadaveric tissues. Autologous mesh materials are derived from a patient's
own body, and may comprise dermographs, fascia tissues, and dura mater.
[0072] With reference to FIG. 2, a surgical mesh 28 typically takes the
form of porous, gauze-like sheet of material 30, which may be made from
various organic materials (of both autologous and homologous sources) or
synthetic materials. In general, the surgical mesh will be an implantable
device, and may be suitable for providing reinforcement to a damaged
tissue. The most common use of surgical meshes involves the reinforcement
of herniations. Surgical meshes are also used in gynecological procedures
including abdominal sacrocolopopexy and as suburethral slings. Other
procedures which require surgical meshes include laparosopic retropubic
urethropexy, intraperitoneal placement for adhesion prevention, the
repair of pelvic floor hernias, rectoceles, and cystoceles. It is to be
understood that the aforementioned surgical procedures do not comprise a
complete list of all uses of organic and synthetic surgical meshes. New
and varied uses for surgical meshes are being discovered on an ongoing
basis and the present invention is to be construed to be applicable to
all present and future uses of surgical meshes.
[0073] In many surgical procedures, it is desirable that a surgical mesh
become incorporated into the tissues surrounding a surgical site. One
example of such a surgical procedure is the reinforcement of a
herniation. In the repair of a hernia, and after the hernia has itself
been closed using standard surgical techniques, a surgical mesh of
appropriate size and shape is placed over the newly repaired hernia and
secured in place using sutures, staples, surgical adhesives, or any other
suitable connecting means. As the tissues surrounding the surgical site
heal, granulation tissues growing at and around the surgical site begin
to produce an extracellular matrix which, in a process called fibrosis,
infiltrates and attaches to the material of the surgical mesh secured
over the surgical site. Incorporation of the surgical mesh into the
surgical site by the extracellular matrix strengthens the tissues at the
surgical site and helps prevent re-injury.
[0074] Preferably, the medical composition of the present invention will
be used to impregnate a mesh matrix in the same manner as described above
for the wound dressing of the present invention. However, as illustrated
in FIG. 2, it is also possible that the medical composition may be
constituted as a film that is applied as a discrete layer 32 to one or
both sides of the surgical mesh 28 by a thermal process or by other
means.
[0075] Methods for Treating Tissue Damaged by Wound or Burn
[0076] The present invention further provides methods for treating tissue
damaged by wound or burn.
[0077] In one embodiment, the method comprises the steps of cleaning a
site of damaged tissue, and applying topically to the site an
antimicrobial and immunostimulating composition comprising a combination
of a .beta.-glucan component and a silver-containing component. The
method may further include repeated applications of the composition
intermittently until healing of the damaged tissue is complete. The
topical compositions described above are suitable for use in the method.
[0078] In another embodiment, the method comprises the steps of cleaning a
site of damaged tissue, and covering the site with a wound dressing
comprising a mesh material and a composition comprising an
antimicrobially effective and immunostimulating amount of a combination
of a .beta.-glucan component and a silver-containing component. The wound
dressings described above are suitable for use in the method.
[0079] Method for Treating or Repairing Tissue at a Surgical Site
[0080] The present invention also provides a method for treating or
repairing tissue at a surgical site. The method comprises the step of
applying to the surgical site a biocompatible mesh device, the mesh
device comprising a mesh matrix and a composition comprising an
antimicrobially effective and immunostimulating amount of a combination
of a .beta.-glucan component and a silver-containing component. The mesh
devices described above are suitable for use in the method. The method
may be suitable for treating or repairing tissue at a herniation site, or
for other procedures listed above. In one particular application, the
method may be suitable where the mesh device is required to provide
reinforcement to the tissue. In another application, the method may be
suitable where the mesh device is intended to become incorporated into
the tissues surrounding a surgical site.
[0081] New and varied uses for surgical meshes are being discovered on an
ongoing basis and the present invention is to be construed to be
applicable to all present and future uses of surgical meshes.
[0082] Method for Manufacturing a Medical Composition
[0083] A method for manufacturing a medical composition, comprising the
step of combining, in an appropriate solvent, a .beta.-glucan component
and a silver-containing component in appropriate portions to provide an
antimicrobial and immunostimulating composition. Conventional methods may
be used for combining the components. The method is suitable for
providing the medical compositions described above.
[0084] In one embodiment, the method is suitable to provide a composition
for topical application.
[0085] In another embodiment, the method further comprises the step of
coating or impregnating a mesh material to provide a wound dressing.
[0086] In yet another embodiment, the method further comprising the step
of impregnating a mesh matrix to provide a biocompatible mesh device
suitable for treating or repairing tissue at a surgical site.
[0087] Zone-of-Inhibition Study
[0088] A standard zone-of-inhibition study was performed on the lotion and
wound dressing exemplars described above. The zone-of-inhibition test
involved placing a quantity of the prepared lotion or wound dressing in a
petri dish, which had been cultured with a particular bacterium. The
bacteria used in this test included: B. subtilis, B. vulgatus, C.
albicans, E. coli, P. aeruginosa, and S. aureus. In each of these tests,
the diameter of the prepared lotion or wound dressing placed in the
cultured petri dishes was measured and recorded at the outset of the
test. On the first, second, and fifth days thereafter the diameter of the
zone of inhibition was measured and recorded. The zone of inhibition in
this test was defined as the area surrounding the prepared lotion or
wound dressing on the petri dish which was uninhabited by the bacteria of
the specific culture. Table 1 reports data for the prepared lotion
zone-of-inhibition test and Table 2 reports data for the prepared wound
dressing zone-of-inhibition test.
3TABLE 1
Zone-of-inhibition results using lotion
comprising .beta.-glucan and silver.
Measurement
Bacterium (cm) Day 1 Day 2 Day 5
B. subtilis 1) 2.05 2.93
2.88 2.75
2) 2.20 2.90 2.93 2.90
Mean 2.13 2.92 2.91 2.83
B. vulgatus 1) 2.18 * 3.35 3.38
2) 2.15 * 3.45 3.40
Mean 2.17 * 3.40 3.33
C. albicans 1) 2.35 * 3.70 3.70
2)
2.23 * 3.55 3.65
Mean 2.29 * 3.63 3.68
E. coli 1) 2.05 2.78
2.78 2.68
2) 2.18 2.75 2.70 2.65
Mean 2.12 2.77 2.74 2.67
P. aeruginosa 2.13 3.08 3.03 3.03
1)
2) 2.15 3.00 3.00
3.00
Mean 2.14 3.04 3.02 3.02
S. aureus 1) 2.10 3.08 3.08
3.05
2) 2.25 3.05 3.05 3.03
Mean 2.18 3.07 3.07 3.04
[0089]
4TABLE 2
Zone-of-inhibition results using wound
dressing impregnated with
.beta.-glucan and silver.
Measurement
Bacterium (cm) Day 1 Day 2 Day 5
B.
subtilis 1) 2.30 3.33 3.35 3.30
2) 2.13 3.08 3.03 2.98
Mean
2.22 3.21 3.19 3.14
B. vulgatus 1) 2.43 * 4.13 3.98
2) 2.38
* 4.25 3.93
Mean 2.41 * 4.19 3.96
C. albicans 1) 2.23 *
3.88 3.90
2) 2.20 * 3.88 3.88
Mean 2.22 * 3.88 3.89
E.coli 1) 2.43 3.10 3.10 2.95
2) 2.63 2.98 2.95 2.90
Mean
2.53 3.04 3.03 2.93
P. aeruginosa 2.20 3.33 3.35 3.28
1)
2) 2.23 3.25 3.32 3.33
Mean 2.22 3.29 3.34 3.31
S.
aureus 1) 2.15 3.30 3.30 3.30
2) 2.10 3.25 3.25 3.20
Mean
2.13 3.28 3.28 3.25
[0090] In explaining the results of the zone-of-inhibition tests it is
easiest to refer to a specific example of the tests. Referring first to
Table 1, it can be seen that two separate petri dishes were prepared and
cultured with the B. subtilis bacterium. Into these prepared petri dishes
were placed quantities of the prepared lotion having diameters of 2.05
centimeters and 2.20 centimeters, respectively. After one day, the
diameter of the zone of inhibition for these petri dishes was 2.93
centimeters and 2.90 centimeters, respectively. On day two, the zones of
inhibition for these lotion samples were 2.88 and 2.93 centimeters in
diameter respectively. And on day five, the zones of inhibition for these
lotion samples were 2.75 and 2.90 centimeters, respectively.
[0091] Referring next to Table 2, two petri dishes were prepared and
cultured with the bacterium B. subtilis. Into these prepared petri dishes
were placed portions of a wound dressing treated comprising the medical
composition having respective diameters of 2.30 and 2.13 centimeters.
After one day, the zones of inhibition surrounding the samples of the
wound dressing in each of the petri dishes were 3.33 and 3.08 centimeters
respectively. After two days, the zones of inhibition surrounding the
wound dressing samples were 3.35 centimeters and 3.03 centimeters,
respectively. And, after five days, the zones of inhibition surrounding
the wound dressing samples were 3.30 and 2.98 respectively.
[0092] The results of the zone-of-inhibition tests are indicative of a
strong antimicrobial effect for both the prepared lotion and the prepared
wound dressing. Similar results are observed for a zone-of-inhibition
test when a yeast-derived .beta.-glucan is used in a medical composition
as described herein.
[0093] In contrast, for a zone-of-inhibition test where only .beta.-glucan
is present in either a composition or incorporated into a mesh device, no
inhibition of bacteria is observed. Furthermore, it has been observed
that the presence of .beta.-glucan, as a microbial nutrient, actually
promotes bacterial growth.
[0094] In other words, .beta.-glucan does not provide antimicrobial
activity. The results of the zone-of-inhibition tests described above
indicate that .beta.-glucan does not interfere with the antimicrobial
activity that can be provided by a silver-containing component, even
though .beta.-glucan will promote growth of bacteria. Therefore, the
combination of a silver-containing component and a .beta.-glucan
component can provide antimicrobial and immunostimulating properties to a
medical composition.
[0095] The invention described above may be embodied in other forms
without departing from the spirit or essential characteristics thereof.
The embodiments disclosed in this application are to be considered in all
respects as illustrative and not restrictive. The scope of the invention
is indicated by the appended claims rather than by the foregoing
description and all changes, which come within the meaning and range of
equivalency of the claims, are embraced therein.
