U.S. patent application number 15/218756 was filed with the patent office on 2016-11-17 for wound gel containing antimicrobial composition.
The applicant listed for this patent is Next Science, LLC. Invention is credited to Matthew Franco Myntti.
Application Number | 20160331703 15/218756 |
Document ID | / |
Family ID | 48044439 |
Filed Date | 2016-11-17 |
United States Patent
Application |
20160331703 |
Kind Code |
A1 |
Myntti; Matthew Franco |
November 17, 2016 |
WOUND GEL CONTAINING ANTIMICROBIAL COMPOSITION
Abstract
A gel useful in reducing bacterial colonization in or around the
area of a wound includes at least one PEG and an aqueous
composition having a pH of from 2 to 4, a total solute
concentration of from 1.8 to 4.0 Osm/L, and from 0.9 to 1.7 g/L of
at least one cationic surfactant. The aqueous composition can
include a buffer system that includes an organic acid and a salt of
an organic acid. The gel is effective even when free of materials
having antimicrobial properties other than those provided by the
aqueous composition such as sporicides, antifungals and
antibiotics.
Inventors: |
Myntti; Matthew Franco; (St.
Augustine, FL) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Next Science, LLC |
Jacksonville |
FL |
US |
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|
Family ID: |
48044439 |
Appl. No.: |
15/218756 |
Filed: |
July 25, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15075147 |
Mar 19, 2016 |
9427417 |
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15218756 |
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13684456 |
Nov 23, 2012 |
9314017 |
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15075147 |
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PCT/US2012/059263 |
Oct 8, 2012 |
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13684456 |
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61545108 |
Oct 8, 2011 |
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61660649 |
Jun 15, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 8/466 20130101;
A61K 31/194 20130101; A61K 8/347 20130101; A61K 47/02 20130101;
A01N 59/26 20130101; A61K 47/10 20130101; A61L 26/0066 20130101;
A61K 33/20 20130101; A61K 33/04 20130101; A61K 8/55 20130101; A01N
59/00 20130101; A61K 47/12 20130101; A61K 47/34 20130101; A61K
8/365 20130101; A61K 8/463 20130101; A61K 8/4926 20130101; A61K
9/0063 20130101; A61P 31/04 20180101; A01N 37/36 20130101; A01N
25/08 20130101; A01N 61/00 20130101; A61K 9/08 20130101; A61K 8/498
20130101; A61K 8/86 20130101; A61L 2300/404 20130101; A61K 8/416
20130101; A01N 25/02 20130101; A61K 8/34 20130101; A61K 33/42
20130101; A01N 41/04 20130101; A61P 17/02 20180101; A61K 9/06
20130101; A61K 33/00 20130101; A61K 8/602 20130101; A61K 33/24
20130101; A61K 8/19 20130101; A61K 8/44 20130101; A61K 9/0014
20130101; A61Q 17/005 20130101; A61K 8/41 20130101; A61K 33/02
20130101; A01N 25/30 20130101; A61K 8/37 20130101; A61K 8/4973
20130101; A61K 31/14 20130101; A61K 33/32 20130101; A61K 31/19
20130101; A61Q 11/00 20130101; A61K 8/39 20130101; A01N 37/36
20130101; A01N 59/26 20130101; A01N 2300/00 20130101; A01N 25/02
20130101; A01N 25/30 20130101; A01N 59/00 20130101; A01N 61/00
20130101; A01N 25/08 20130101; A01N 25/30 20130101; A01N 59/00
20130101; A01N 61/00 20130101 |
International
Class: |
A61K 31/14 20060101
A61K031/14; A61K 9/00 20060101 A61K009/00; A61K 31/194 20060101
A61K031/194; A61K 31/19 20060101 A61K031/19; A61K 9/06 20060101
A61K009/06; A61K 47/10 20060101 A61K047/10 |
Claims
1. A gel useful in reducing bacterial colonization in or around the
area of a wound, said gel comprising at least one PEG and an
aqueous composition having a pH of from 2 to 4, a total solute
concentration of from 1.8 to 4.0 Osm/L, and from 0.9 to 1.7 g/L of
at least one cationic surfactant, said gel being free of
sporicides, antifungals and antibiotics.
2. The gel of claim 1 wherein said aqueous composition has a total
solute concentration of from 1.8 to 2.8 Osm/L.
3. The gel of claim 1 wherein said at least one cationic surfactant
comprises benzalkonium chloride.
4. The gel of claim 1 wherein said at least one cationic surfactant
is benzalkonium chloride.
5. A gel useful in reducing bacterial colonization in or around the
area of a wound, said gel consisting essentially of at least one
PEG, an aqueous composition having a pH of from 2 to 4, a total
solute concentration of from 1.8 to 4.0 Osm/L, and from 0.9 to 1.7
g/L of at least one cationic surfactant, and optionally one or more
of an emollient, a lotion, a humectant, a glycosaminoglycan, an
analgesic, colloidal silver and a coalescent.
6. The gel of claim 5 wherein said aqueous composition has a total
solute concentration of from 1.8 to 2.8 Osm/L.
7. The gel of claim 5 wherein said at least one cationic surfactant
comprises benzalkonium chloride.
8. The gel of claim 5 wherein said at least one cationic surfactant
is benzalkonium chloride.
9. A gel useful in reducing bacterial colonization in or around the
area of a wound, said gel comprising: a) at least one PEG and b) a
composition having a pH of from 2 to 4 and a total solute
concentration of from 1.8 to 4.0 Osm/L that consists essentially of
(1) water, (2) a buffer system that comprises of one or more
organic acids and at least one salt of one or more organic acids,
and (3) from 0.9 to 1.7 g/L of at least one cationic surfactant,
said gel being free of materials having antimicrobial properties
other than those provided by said composition.
10. The gel of claim 9 wherein said composition has a total solute
concentration of from 1.8 to 2.8 Osm/L.
11. The gel of claim 9 wherein said at least one cationic
surfactant comprises benzalkonium chloride.
12. The gel of claim 9 wherein said at least one cationic
surfactant is benzalkonium chloride.
13. The gel of claim 9 wherein said one or more organic acids
comprise at least one polyacid.
14. The gel of claim 13 wherein said at least one polyacid
comprises citric acid.
15. The gel of claim 14 wherein said at least one salt of one or
more organic acids comprises a salt of a polyacid.
16. The gel of claim 9 wherein each of said one or more organic
acids is a polyacid.
17. The gel of claim 9 wherein said one or more organic acids is
citric acid.
18. The gel of claim 17 wherein said at least one salt comprises a
salt of citric acid.
19. The gel of claim 9 wherein said at least one salt is a salt of
citric acid.
20. The gel of claim 9 wherein said one or more organic acids is
acetic acid.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/075,147, filed 19 Mar. 2016 and presently
pending, which is a continuation of U.S. patent application Ser.
No. 13/684,456, filed 23 Nov. 2012 and now issued as U.S. Pat. No.
9,314,017, which is a continuation of international appl. no.
PCT/US2012/059263, filed 8 Oct. 2012, which claims the benefit of
U.S. patent appl. No. 61/545,108, filed 8 Oct. 2011, and
61/660,649, filed 15 Jun. 2012, the disclosures of all of which are
incorporated herein by reference.
BACKGROUND INFORMATION
[0002] Microbes are found virtually everywhere, often in high
concentrations, and are responsible for a significant amount of
disease and infection. Killing and/or eliminating these
microorganisms is desirable for a variety of reasons.
[0003] Bacteria present special challenges because they can exist
in a number of forms (e.g., planktonic, spore and biofilm) and
their self preservation mechanisms make them extremely difficult to
treat and/or eradicate. For example, the bacteria in biofilms or
spores are down-regulated (sessile) and not actively dividing,
which makes them resistant to attack by a large group of
antibiotics and antimicrobials that attack the bacteria during the
active parts of their lifecycle, e.g., cell division.
[0004] In a biofilm, bacteria interact with and adhere to surfaces
and form colonies which facilitate continued growth. The bacteria
produce exopolysaccharide (EPS) and/or extracellular-polysaccharide
(ECPS) macromolecules that keep them attached to the surface and
form a protective barrier effective against many forms of attack.
Protection most likely can be attributed to the small diameter of
the flow channels in the matrix, which restricts the size of
molecules that can reach the underlying bacteria, and consumption
of biocides through interactions with portions of the EPS/ECPS
macromolecular matrix and bacterial secretions and waste products
contained therein. (Certain fungi also can form biofilms, many of
which present the same types of challenges presented here.)
[0005] Bacteria also can form spores, which are hard, non-permeable
protein/polysaccharide shells or coatings. Spores provide
additional resistance to eradication efforts by preventing attack
from materials that are harmful to the bacteria.
[0006] Due to the protection afforded by a macromolecular matrix
(biofilm) or shell (spore) and their down-regulated state, bacteria
in these states are very difficult to treat. The types of biocides
and antimicrobials effective in treating bacteria in this form are
strongly acidic and/or oxidizing, often involving halogen atoms,
oxygen atoms, or both. Common examples include hypochlorite
solutions (e.g., bleach), phenolics, mineral acids (e.g., HCl),
H.sub.2O.sub.2, and the like. Large dosages of such chemicals must
be allowed to contact the biofilm or spore for extended amounts of
time to be effective, which makes them impractical for many
applications.
[0007] Recently developed formulations intended for use in
connection with compromised animal/human tissue solvate a biofilm
matrix so that still-living bacteria can be rinsed or otherwise
removed from infected tissue; see, e.g., U.S. Pat. Nos. 7,976,873,
7,976,875, 7,993,675, etc. The concentrations of active ingredients
in these formulations are too low to effectively kill the bacteria,
however, thus making such formulations ill suited for use as
surface disinfectants.
[0008] Neutral-to-very acidic disinfecting solutions that can
disrupt macromolecular matrices, or bypass and/or disable their
inherent defenses, allowing ingredients in the solutions to access
the bacteria, attack cell membranes, and kill them have been
described in U.S. Pat. Publ. No. 2010/0086576 A1.
[0009] Animal tissue wounds present both a good environment for
bacterial, and even biofilm, growth and a surface or substrate
requiring gentle treatment, thus making a difficult problem even
worse.
[0010] Dental plaque, a biofilm that adheres to a tooth surface,
consists of bacterial cells (mainly Streptococcus mutans and
Streptococcus sanguis), salivary polymers and bacterial
extracellular products. The accumulation of microorganisms subject
the teeth and gingival tissues to high concentrations of bacterial
metabolites, which results in widespread problems such as
gingivitis and periodontal disease, including oral caries.
[0011] Nosocomial or hospital acquired infections (HAIs) can be
caused by viral, bacterial, and/or fungal pathogens and can involve
any system of the body. HAIs are a leading cause of patient deaths,
and they increase the length of hospitalizations for patients,
mortality and healthcare costs; in the developed world, they are
estimated to occur in 5-10% of all hospitalizations, even higher
for pediatric and neonatal patients. They often are associated with
medical devices or blood product transfusions. Three major sites of
HAIs are bloodstream, respiratory tract, and urinary tract. Most
patients who have HAIs have invasive supportive measures such as
central intravenous lines, mechanical ventilation, and catheters,
which provide an ingress point for pathogenic organisms.
Ventilator-associated pneumonia can be caused by Staphylococcus
aureus, methicillin-resistant Staphylococcus aureus (MRSA), Candida
albicans, Pseudomonas aeruginosa, Acinetobacter baumannii,
Stenotrophomonas maltophilia, Clostridium difficile, and
Tuberculosis, while other HAIs include urinary tract infections,
pneumonia, gastroenteritis, vancomycin-resistant Enterococcus
(VRE), and Legionellosis.
[0012] Medical equipment such as endoscopes, gastroscopes, the
flow-channels of hematology and dialyzer equipment, the airflow
path of respiratory equipment, ISE, HPLC, and certain catheters are
designed to be used multiple times. Significant risks have been
associated with inadequate or improper cleaning due to the presence
of residual soil and/or improper disinfection or sterilization, up
to and including HAIs from contaminated devices such as
bronchoscopes contaminated with Mycobacterium tuberculosis and the
transmission of Hepatitis C virus to patients during colonoscopy
procedures.
[0013] Any surface that is or becomes moist is subject to biofilm
formation. Thus, articles intended for permanent or temporary
implantation--such as artificial hearts, stents, contact lenses,
intrauterine devices, artificial joints, dental implants--are
particularly susceptible. Extreme measures are taken to prevent
biofilm formation because, once established, they are essentially
impossible to eradicate in vivo and can cause life-altering, even
lethal, infections.
[0014] Compositions and articles that can be used in the treatment
of microbes such as bacteria remain desirable. Liquids that break
down the EPS/EPCS macromolecular matrix or that bypass and/or
disable the defenses inherent in therein, thereby permitting the
liquid or a component thereof to access and kill the bacteria in a
down-regulated state, are particularly desirable. Such a liquid
that is lethally effective while having no or very limited toxicity
is of significant interest and commercial value.
[0015] Methods and articles capable of treating bacteria that
colonize acute wounds at the time of injury and during all stages
of healing, as well as in the treatment of chronic wounds, also are
highly desirable.
[0016] Also of significant interest are methods, compositions
capable of treating and/or remedying any of a variety of oral and
mucosal conditions associated with biofilms; preventing or
remedying HAIs and/or biofilms in which the microorganisms can be
entrained; preventing the growth of or removing biofilms from
implantable (or implanted) devices and articles; and sterilizing or
otherwise processing multiuse medical equipment.
SUMMARY
[0017] The present invention is directed to compositions and
articles that can be used in treatment or elimination of microbes
including but not limited to bacteria, regardless of whether they
are in planktonic, spore, or biofilm form.
[0018] An aqueous composition according to the present invention is
lethal toward a wide spectrum of gram positive and gram negative
bacteria and exhibits lethality toward other microbes such as
viruses, fungi, molds, yeasts, and bacterial spores.
[0019] In addition to having a pH greater than 7, the composition
includes a significant amount of one or more surfactants and large
amounts of osmotically active solutes. The composition is effective
at interrupting or breaking ionic crosslinks in the macromolecular
matrix of a biofilm, which facilitates passage of the solutes and
surfactant through the matrix to the bacteria entrained therein
and/or protected thereby. These ingredients, while typically
ineffective against bacteria when used in isolation or at low
concentrations, become very effective at breaking down the
bacterial biofilm or bypassing and disabling the bacterial biofilm
defenses, allowing the bacteria in its several states to be
accessed and killed (by inducing membrane leakage in bacteria,
leading to cell lysis) when provided in the correct combination and
in sufficient concentrations.
[0020] Articles, compositions and methods for treating wound areas
also are provided. Non-solid compositions can be applied to the
area; the composition can be non-flowing if it is intended to be
left in place or can be a liquid if it is intended to irrigate or
otherwise flow over or around a treatment area. A solid article can
be applied to a wound treatment area; such an article can be
adapted to be left in place on or near the treatment area or can be
intended for temporary application and removal. An antihemorrhagic
can be included in a composition or article to permit the
composition or article to stanch bleeding, in addition to providing
antimicrobial treatment. These aspects also provide methods of
cleaning, dressing and otherwise treating wounds.
[0021] Also provided are articles, compositions, and methods for
protecting against or treating microbial attack of the mouth,
teeth, gums, lips, oral mucosal lining, particularly attack by
biofilm-related conditions including, but not limited to, oral
caries, gingivitis, periodontitis, halitosis, and
peri-implantitis.
[0022] Further, HAIs can be prevented or remedied by applying a
liquid or solid antimicrobial composition to a surface located in a
medical treatment facility so as to prevent or remove a biofilm
and/or kill bacterial entrained therein. A patient possessing a HAI
also can be treated with an antimicrobial composition or an article
including or based thereon.
[0023] Additionally, the surfaces of permanently or removably
implantable objects can be treated so as to prevent biofilm
formation or, after implantation, can be treated to remove biofilm
on such surfaces.
[0024] Reusable medical equipment also can be processed so as to
remove EPS/ECPS, materials conducive to the growth of EPS/ECPS, and
organisms that are or can be entrained in EPS/ECPS. The processing
can involve sterilization or can supplement existing sterilization
techniques and results in medical equipment that is less likely to
introduce microbes, particularly bacteria, into a patient treated
therewith.
[0025] To assist in understanding the following description of
various embodiments, certain definitions are provided immediately
below. These are intended to apply throughout unless the
surrounding text explicitly indicates a contrary intention: [0026]
"microbe" means any type of microorganism including, but not
limited to, bacteria, viruses, fungi, viroids, prions, and the
like; [0027] "antimicrobial agent" means a substance having the
ability to cause greater than a 90% (1 log) reduction in the number
of one or more of microbes; [0028] "active antimicrobial agent"
means an antimicrobial agent that is effective only or primarily
during the active parts of the lifecycle, e.g., cell division, of a
microbe; [0029] "biofilm" means a community of microbes,
particularly bacteria and fungi, attached to a surface with the
community members being contained in and/or protected by a
self-generated macromolecular matrix; [0030] "residence time" means
the amount of time that an antimicrobial agent is allowed to
contact a bacterial biofilm; [0031] "biocompatible" means
presenting no significant, long-term deleterious effects on or in a
mammalian species; [0032] "biodegradation" means transformation,
via enzymatic, chemical or physical in vivo processes, of a
chemical into smaller chemical species; [0033] "antihemorrhagic"
means a compound or material that inhibits bleeding by any one or
more of inhibiting fibrinolysis, promoting coagulation, promoting
platelet aggregation, or causing vasoconstriction; [0034] "hospital
acquired infection" means a localized or systemic infection not
present, and without evidence of incubation, at the time that a
patient is admitted to a health care setting, most of which become
clinically evident within 48 hours of admission; [0035]
"polyelectrolyte" means a polymer with multiple mer that include an
electrolyte group capable of dissociation in water; [0036] "strong
polyelectrolyte" is a polyelectrolyte whose electrolyte groups
completely dissociate in water at 3.ltoreq.pH.ltoreq.9; [0037]
"weak polyelectrolyte" is a polyelectrolyte having a dissociation
constant of from .about.2 to .about.10, i.e., partially dissociated
at a pH in the range where a strong polyelectrolyte's groups are
completely dissociated; and [0038] "polyampholyte" is a
polyelectrolyte with some mer including cationic electrolyte groups
and other mer including anionic electrolyte groups.
[0039] Hereinthroughout, pH values are those which can be obtained
from any of a variety of potentiometric techniques employing a
properly calibrated electrode.
[0040] The relevant portions of any specifically referenced patent
and/or published patent application are incorporated herein by
reference.
DETAILED DESCRIPTION
[0041] Useful basic (caustic) liquid compositions display at least
moderately high tonicity, i.e., large amounts of osmotically active
solutes and a pH that is relatively high (7.5.ltoreq.pH.ltoreq.9)
or even very high (9.ltoreq.pH.ltoreq.11). The large amount of
solutes work with surfactants that are present to induce membrane
leakage in bacteria, leading to cell lysis.
[0042] The composition can contain as few as three ingredients:
water, the dissociation product(s) of at least one base, and at
least one surfactant, each of which generally is considered to be
biocompatible. The dissociation product(s) of one or more salts
also can be included.
[0043] Reductions in the concentration of hydronium ions, i.e.,
increases in pH, generally correspond with enhanced efficacy. This
effect may not be linear, i.e., the enhancement in efficacy may be
asymptotic below a certain hydronium ion concentration. As long as
the pH of the composition is greater than 7 and less than -10, the
basic composition generally will be considered to be biocompatible;
specifically, external exposure will result in no long-term
negative dermal effects.
[0044] Basicity is achieved by adding to water (or vice versa) one
or more bases such as, but not limited to, alkali metal salts of
weak acids including acetates, fulmates, lactates, phosphates, and
glutamates; alkali metal nitrates; alkali metal hydroxides, in
particular NaOH and KOH; alkali earth metal hydroxides, in
particular Mg(OH).sub.2; alkali metal borates; NH.sub.3; and alkali
metal hypochlorites (e.g., NaClO) and bicarbonates (e.g.,
NaHCO.sub.3).
[0045] In certain embodiments, preference can be given to those
organic compounds which are, or can be made to be, highly soluble
in water. In these and/or other embodiments, preference can be
given to those bases which are biocompatible. Alternatively or
additionally, preference can be given to those organic acids and
bases which can act to chelate the metallic cations ionic involved
in crosslinking the macromolecular matrix of a biofilm.
[0046] Surfactant can be added to water before, after or at the
same time as the base(s). Essentially any material having surface
active properties in water can be employed, although those that
bear some type of ionic charge are expected to have enhanced
antimicrobial efficacy because such charges, when brought into
contact with a bacteria, are believed to lead to more effective
cell membrane disruption and, ultimately, to cell leakage and
lysis. This type of antimicrobial process can kill even sessile
bacteria because it does not involve or entail disruption of a
cellular process. Potentially useful anionic surfactants include,
but are not limited to, sodium chenodeoxycholate,
N-lauroylsarcosine sodium salt, lithium dodecyl sulfate,
1-octanesulfonic acid sodium salt, sodium cholate hydrate, sodium
deoxycholate, sodium dodecyl sulfate, sodium glycodeoxycholate,
sodium lauryl sulfate, and the alkyl phosphates set forth in U.S.
Pat. No. 6,610,314. Potentially useful cationic surfactants
include, but are not limited to, cetylpyridinium chloride,
tetradecyltrimethylammonium borime, benzalkonium chloride,
hexadecylpyridinium chloride monohydrate and
hexadecyltrimethylammonium bromide, with the latter being a
preferred material. Potentially useful nonionic surfactants
include, but are not limited to, polyoxyethyleneglycol dodecyl
ether, N-decanoyl-N-methylglucamine, digitonin, n-dodecyl
B-D-maltoside, octyl B-D-glucopyranoside, octylphenol ethoxylate,
polyoxyethylene (8) isooctyl phenyl ether, polyoxyethylene sorbitan
monolaurate, and polyoxyethylene (20) sorbitan monooleate. Useful
zwitterionic surfactants include but are not limited to
3-[(3-cholamidopropyl) dimethylammonio]-2-hydroxy-1-propane
sulfonate, 3-[(3-cholamidopropyl) dimethylammonio]-1-propane
sulfonate, 3-(decyldimethylammonio) propanesulfonate inner salt,
and N-dodecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate. For other
potentially useful materials, the interested reader is directed to
any of a variety of other sources including, for example, U.S. Pat.
Nos. 4,107,328, 6,953,772, and 7,959,943. Particular classes and
types of surfactants can be preferred for certain end use
applications, with some of these being specifically referenced
later in this document.
[0047] The composition contains a sufficient amount of surfactant
to interrupt or rupture bacterial cell walls. The amount of
surfactant constitutes greater than .about.0.075%, .about.0.10%,
.about.0.125%, .about.0.15% or 0.175%, generally at least
.about.0.2%, typically at least .about.0.5%, more typically at
least .about.0.7%, often at least .about.0.9%, and preferably at
least 1% of the composition (all being weight percentages based on
total weight of the composition), with the upper limit being
defined by the solubility limits of the particular surfactant(s)
chosen. Some surfactants can permit extremely high loading levels,
e.g., at least 5%, at least 10%, at least 12%, at least 15%, at
least 17%, at least 20%, or even on the order of .about.25% or more
(again, all being weight percentages based on total weight of the
composition). Any of the foregoing minimum amounts can be combined
with any of the foregoing maximum amounts to provide an exemplary
range of potential amounts of surfactant.
[0048] Ionically charged compounds that do not qualify as a
surfactants might be able to replace some or all of the surfactant
component in some instances. Ionically charged compounds include
natural polymers such as chitosan and glucosides, as well as
charged molecules and atoms such as such as Cl.sup.-, Na.sup.+,
NH.sub.4.sup.+, HCO.sub.3.sup.-, SO.sub.4.sup.-2, HSO.sub.4.sup.-,
S.sub.2O.sub.3.sup.-2, SO.sub.3.sup.-2, OH.sup.-, NO.sub.3.sup.-,
ClO.sub.4.sup.-, CrO.sub.4.sup.-2, Cr.sub.2O.sub.7.sup.-2,
MnO.sub.4.sup.-2, PO.sub.4.sup.-3, HPO.sub.4.sup.-2,
H.sub.2PO.sub.4.sup.-, and the like. These types of ions also can
increase the osmolarity of a composition without increasing its pH
past a desired target; see also, e.g., U.S. Pat. No. 7,090,882.
Such compounds, upon dissociation, increase the effective amount of
solutes in the composition without greatly impacting the molar
concentration of hydroxyl ions while, in some cases, simultaneously
providing a buffer system in the composition.
[0049] The lethality of the surfactant component(s) is increased
and/or enhanced when the composition has at least moderate
effective solute concentrations (tonicity). The osmolarity of the
composition generally increases in proportion with the amount of
base(s) employed, with the osmolarity maximum for a given
composition primarily being a function of the solubility limits of
the specific base(s). An obvious corollary to increased levels of
base(s) in the composition is lower concentrations of hydronium
ions, i.e., high pH values.
[0050] As noted previously, some end-use applications can call for
a composition with only a moderately high pH. To increase the
osmolarity of a composition without increasing its pH past a
desired target, one or more types of other water soluble compounds
can be included. Such compounds, upon dissociation, increase the
effective amount of solutes in the composition without greatly
impacting the molar concentration of hydroxyl ions while,
simultaneously, providing a buffer system in the composition. The
ionically charged molecules and atoms discussed above are among
those materials which can serve this function; see also, e.g., U.S.
Pat. No. 7,090,882.
[0051] Regardless of how achieved, the tonicity of the composition
is at least moderately high, with an osmolarity of at least
.about.0.3, .about.0.5, .about.0.7, .about.0.8, .about.0.9 or
.about.1 Osm/L being preferred for most applications. Depending on
particular end-use application, the composition can have any of the
following concentrations: at least .about.1.5 Osm/L, at least
.about.1.75 Osm/L, at least .about.2.0 Osm/L, at least .about.2.25
Osm/L, at least .about.2.5 Osm/L, at least .about.2.75 Osm/L, at
least .about.3.0 Osm/L, at least .about.3.25 Osm/L, at least
.about.3.5 Osm/L, at least .about.3.75 Osm/L, at least .about.4.0
Osm/L, and even at least .about.4.25 Osm/L. Certain embodiments of
the composition can exhibit solute concentrations of 0.3 to 5
Osm/L, 0.5 to 4.5 Osm/L, 0.75 to 4.4 Osm/L, 1 to 4.3 Osm/L, 1.25 to
4.25 Osm/L, 1.4 to 4.1 Osm/L, and 1.5 to 4 Osm/L; other potentially
useful ranges include 3 to 5 Osm/L, 2.5 to 4.5 Osm/L, 3 to 4.5
Osm/L, 3.5 to 5 Osm/L, 3.25 to 4.5 Osm/L, and the like.
[0052] The composition can be employed in a variety of ways. For
example, when used to treat a biofilm on a surface (e.g., cutting
board, counter, desk, etc.), the composition can be applied
directly to the biofilm, optionally followed by physical rubbing or
buffing, or the composition can be applied to the rubbing/buffing
medium, e.g., cloth. Where a biofilm in an inaccessible area is to
be treated, soaking or immersion of the biofilm in an excess of the
composition can be performed for a time sufficient to essentially
solvate the biofilm, which then can be flushed or wiped from the
affected area. Regardless of contact method, the surfactant
component(s) are believed to kill significant numbers of bacteria
without a need for the bacteria to be removed from the biofilm or
vice versa.
[0053] Due to the abundance of microbial contamination, the
composition may find utility in a large number of potential uses
including, but not limited to, household applications including
non-compromised skin (hand, foot, hair, and body washing and/or
deodorization), kitchen cleaning (countertop and surface cleaning,
cleaning of food preparation utensils, dish washing, produce
washing, etc.), bathroom cleaning (countertop and surface cleaning,
fixture cleaning, toilet bowl cleaning, sink and floor drain
cleaning, and shower mildew eradication), laundry area cleaning
(including laundry detergent, linen disinfection, and diaper
sterilization), baby sensitive applications such as cleaning and or
disinfecting baby contact products (including toys, bottles,
pacifiers, nipples, teething rings, diapers, blankets, and
clothing); commercial applications include livestock care (facility
and equipment sterilization and dairy teat dip), produce
sterilization (an alternative to irradiation, which can be
particularly useful against E. coli, listeria, salmonella,
botulism, etc.), meat and poultry processing facilities (including
all surfaces, floors and drains, processing equipment and carcass
washing), commercial kitchen and food preparation facilities
(countertop and surface cleaning, food preparation utensil
cleaning, storage equipment and facilities cleaning, dish washing
and produce washing), mass food and beverage processing (processing
and storage equipment cleaning, tank sterilization, cleaning of
liquid transport lines, etc.), cleaning of water lines (e.g., for
drinking water, beverage dispensers, dental offices, plumbing, heat
exchanging systems, and the like), and food and beverage transport
(cleaning of tanker units for semi transport, cleaning of tanker
cars for railroad transport, and cleaning of pipelines); and
non-traditional uses such as denture cleaning, acne treatment,
spermicides, laboratory equipment cleaning, laboratory surface
cleaning, oil pipeline cleaning, and test article processing for
biofilm attachment.
[0054] The composition can be prepared in a number of ways.
Description of an exemplary method follows.
[0055] Base (e.g., NaOH) and optional solute (e.g., a phosphate or
sulfate) are combined with sufficient water to constitute 60-90% of
the calculated desired volume. This solution can be stirred and/or
heated. The desired amount of surfactant(s) then can be added. Once
stirring, if used, is complete, sufficient water is added so as to
bring the composition to the calculated tonicity and pH value.
Advantageously, no special conditions or containers are needed to
store the composition for an extended time, although refrigeration
can be used if desired.
[0056] A variety of additives and adjuvants can be included to make
a composition more amenable for use in a particular end-use
application without negatively affecting its efficacy in a
substantial manner. Examples include, but are not limited to,
emollients, fungicides, fragrances, pigments, dyes, defoamers,
foaming agents, flavors, abrasives, bleaching agents, preservatives
(e.g., antioxidants) and the like.
[0057] The composition does not require inclusion of an active
antimicrobial agent for efficacy, but such materials can be
included in certain embodiments. For example, one or more of
bleach, any of a variety of phenols, aldehydes, quaternary ammonium
compounds, etc., can be added.
[0058] The composition conveniently can be provided as a solution,
although other forms might be desirable for certain end-use
applications. Accordingly, the composition can provided as a
soluble powder (for subsequent dilution, an option which can reduce
transportation costs), a slurry, or a thicker form such as a gel or
paste (which might be particularly useful for providing increased
residence times). For the latter, the composition can include
additional ingredients such as a coalescent (e.g.,
polyvinylpyrrolidone).
[0059] Embodiments of the composition can provide very large
reductions in the number of bacteria, even with extremely short
residence times. For example, a composition having high
concentrations of surfactant (e.g., 1.5-2.5% by wt.) and total
solutes (e.g., 2-4 Osm) can provide a 2, 3 or 4 log (99.99%)
reduction in the number of bacteria in an entrenched biofilm with a
3, 4, 5, 7, 8, 9, or 10 minute residence time and a 3, 4, 5, or 6
log (99.9999%) reduction in the number of planktonic bacteria with
a mere 30-second residence time.
[0060] Quantitative Carrier Testing (ASTM E2197) is designed to
determine the contact time necessary to eradicate from a surface
(e.g., countertops, sinks, bathroom fixtures, and the like)
bacteria in a soil-loaded inoculum. In this test, bacteria combined
with a soil loading and a 10 .mu.L inoculum is placed on a
stainless steel carrier disk. After the inoculate is allowed to dry
completely, 50 .mu.L of antimicrobial treatment composition is
applied and allowed to stay in place for the desired treatment
time, after which dilution with a saline dilution is performed.
[0061] In addition to the foregoing general uses for the caustic
composition of the present invention, certain specific end uses can
employ the caustic antimicrobial composition, its acidic
counterpart or, in some instances, a solid antimicrobial material.
The following paragraphs set forth information about an acidic
antimicrobial composition and a solid antimicrobial material, as
well as specific novel end uses for such compositions and
materials.
[0062] Potentially useful acidic liquid compositions include those
described in the aforementioned U.S. Pat. Nos. 7,976,873,
7,976,875, and 7,993,675 as well as U.S. Pat. Publ. No.
2010/0086576 A1, all of which include large amounts of osmotically
active solutes. A primary difference among the liquid compositions
is pH, with those intended for use in the ear or sinus cavity being
very moderate (e.g., commonly about 6.ltoreq.pH.ltoreq.7), while
those intended for surface disinfection being more extreme, e.g.,
relatively low (about 3.ltoreq.pH.ltoreq.6).
[0063] An acidic antimicrobial composition can contain as few as
three ingredients: water, the dissociation product(s) of at least
one acid, and at least one surfactant, each of which generally is
considered to be biocompatible. The dissociation product(s) of one
or more alkali metal salts of organic acids also can be
included.
[0064] Increases in the concentration of hydronium ions, i.e.,
decreases in pH, generally correspond with enhanced efficacy and,
again, the effect may not be linear, i.e., the enhancement in
efficacy may be asymptotic past a certain hydronium ion
concentration. As long as the pH of the composition is greater than
.about.3, the composition generally will be biocompatible;
specifically, external exposure will result in no long-term
negative dermal effects.
[0065] Acidity is achieved by adding to water (or vice versa) one
or more acids, specifically strong (mineral) acids such as HCl,
H.sub.2SO.sub.4, H.sub.3PO.sub.4, HNO.sub.3, H.sub.3BO.sub.3, and
the like or, preferably, organic acids, particularly organic
polyacids. Examples of organic acids include monoprotic acids such
as formic acid, acetic acid and substituted variants, propanoic
acid and substituted variants (e.g., lactic acid, pyruvic acid, and
the like), any of a variety of benzoic acids (e.g., mandelic acid,
chloromandelic acid, salicylic acid, and the like), glucuronic
acid, and the like; diprotic acids such as oxalic acid and
substituted variants (including oxamic acid), butanedioic acid and
substituted variants (e.g., malic acid, aspartic acid, tartaric
acid, citramalic acid, and the like), pentanedioic acid and
substituted variants (e.g., glutamic acid, 2-ketoglutaric acid, and
the like), hexanedioic acid and substituted variants (e.g., mucic
acid), butenedioic acid (both cis and trans isomers), iminodiacetic
acid, phthalic acid, ketopimelic acid, and the like; triprotic
acids such as citric acid, 2-methylpropane-1,2,3-tricarboxylic
acid, benzenetricarboxylic acid, nitrilotriacetic acid, and the
like; tetraprotic acids such as prehnitic acid, pyromellitic acid,
and the like; and even higher degree acids (e.g., penta-, hexa-,
heptaprotic, etc.). Where a tri-, tetra-, or higher acid is used,
one or more of the carboxyl protons can be replaced by cationic
atoms or groups (e.g., alkali metal ions), which can be the same or
different.
[0066] In certain embodiments, preference can be given to those
organic acids which are, or can be made to be, highly soluble in
water; acids that include groups that enhance solubility in water
(e.g., hydroxyl groups), examples of which include tartaric acid,
citric acid, and citramalic acid, can be preferred in some
circumstances. In these and/or other embodiments, preference can be
given to those organic acids which are biocompatible; many of the
organic acids listed above are used in preparing or treating food
products, personal care products, and the like. Alternatively or
additionally, preference can be given to those organic acids which
can act to chelate the metallic cations ionic involved in
crosslinking the macromolecular matrix of a biofilm. This is
discussed in more detail below.
[0067] Surfactant can be added to water before, after or at the
same time as the acid(s). As with the basic antimicrobial
composition, those surfactants that bear some type of ionic charge
are expected to yield enhanced antimicrobial efficacy; such
charges, when brought into contact with a bacterium, are believed
to lead to more effective cell membrane disruption and, ultimately,
to cell leakage and lysis. Potentially useful surfactants are the
same as those described previously, with non-ionic and cationic
surfactants being at least somewhat preferred where the composition
is intended for contact with dermal tissue.
[0068] The amounts of such surfactants that can be employed in the
acidic antimicrobial composition are the same as those described
above in connection with the basic antimicrobial composition.
[0069] The lethality of the surfactant component(s) is increased
and/or enhanced when the composition has at least moderate
effective solute concentrations (tonicity). The osmolarity of the
composition generally increases in proportion with the amount of
acid(s) employed, with the osmolarity maximum for a given
composition primarily being a function of the solubility limits of
the specific acid(s). An obvious corollary to increased levels of
acid(s) in the composition is higher concentrations of hydronium
ions, i.e., low pH values. As noted previously, some end-use
applications can call for a composition with only a moderately low
pH. To increase the osmolarity of a composition without decreasing
its pH past a desired target, one or more types of other water
soluble compounds can be included. Such compounds, upon
dissociation, increase the effective amount of solutes in the
composition without greatly impacting the molar concentration of
hydronium ions while, simultaneously, providing a buffer system in
the composition. The materials and methods for enhancing tonicity,
as well as the osmolarities of the resulting compositions, are the
same as those described above in connection with the basic
antimicrobial composition.
[0070] Where one or more organic acids are used in the composition,
tonicity can be increased by including salt(s) of those acid(s) or
other acid(s). For example, where the composition includes x moles
of an acid, a many fold excess (e.g., 3x-10x, preferably at least
5x or even at least 8x) of one or more salts of that base also can
be included.
[0071] Both the basic and acidic antimicrobial liquid compositions
have been described primarily as solutions, although this is not
limiting. Additional forms include emulsions, gels (including
hydrogels, organogels and xerogels), pastes (i.e., suspension in an
organic, typically fatty, base), salves or ointments, aerosols,
foams, and even suspensions.
[0072] Solid articles intended for use in disinfecting applications
are described in U.S. Pat. Publ. No. 2012/0288469. Solid materials
include a crosslinked version of a water soluble polyelectrolyte
and entrained surfactant. This combination of components permits
the local chemistry within and immediately surrounding the solid
material, when in use in an aqueous environment, to mimic that of
the acidic versions of the aforedescribed liquid composition: high
tonicity and high surfactant concentration. The solid material can,
but need not, include biocidal additives, particularly active
antimicrobial agents. When a liquid is passed through or in
proximity to the solid material, any bacteria or other
microorganisms are exposed to the local chemistry conditions
discussed above: high tonicity, relatively low pH, and available
surfactant, a combination that can induce membrane leakage in
bacteria, leading to cell lysis. These characteristics permit the
solid material to be effective at bypassing and disabling bacterial
biofilm and spore defenses. In addition to being lethal toward a
wide spectrum of gram positive and gram negative bacteria, the
solid materials also can exhibit lethality toward other microbes
such as viruses, fungi, molds, and yeasts.
[0073] The solid material requires some level of water or humidity
to function effectively. This can determined or defined in a
variety of ways. The polyelectrolytes must be capable of localized
liquid charge interaction (meaning at least two water molecules are
contacting or very near an electrolyte group); alternatively,
sufficient water must be present to activate the charge of the
electrolyte and/or to permit bacterial growth.
[0074] A solid antimicrobial material does not itself have a true
pH. In use, however, the local pH of any aqueous composition in
which it is deployed preferably is lower than .about.7 to ensure
proper antimicrobial activity. Reduced pH values (e.g., less than
.about.6.5, .about.6.0, .about.5.5, .about.5.0, .about.4.5 and even
.about.4.0) generally are believed to correlate with increases in
efficacy of the solid material, although this effect might be
asymptotic for reasons described above.
[0075] In addition to more strongly acidic local environments, high
local osmolarity conditions also are believed to increase efficacy.
Accordingly, larger concentrations of polyelectrolytes, larger
concentrations of surfactant, surfactants with shorter chain
lengths (e.g., no more than C.sub.10, typically no more than
C.sub.8, commonly no more than C.sub.6), and surfactants with
smaller side groups around the polar group each are more desirable.
(These factors also are applicable to the previously described
liquid compositions.)
[0076] The lethality of the surfactant component(s) is increased
and/or enhanced when the solid material can provide to the local
environment in which it is deployed at least moderate effective
solute concentrations, similar to that described above. Local
osmolarity (tonicity) generally increases in proportion to the
number and type of electrolytes present in the polymeric network.
(By local osmolarity is meant that of a liquid contained in the
solid material. While this might vary from place to place
throughout the article, preference is given to those solid
materials capable of providing high local osmolarities
throughout.)
[0077] The polyelectrolyte(s) that form the bulk of the solid
material preferably are at least somewhat water soluble but also
essentially water insoluble after being crosslinked. A partial list
of polyelectrolytes having this combination of characteristics
includes, but are not limited to, strong polyelectrolytes such as
polysodium styrene sulfonate and weak polyelectrolytes such as
polyacrylic acid, pectin, carrageenan, any of a variety of
alginates, polyvinylpyrrolidone, carboxymethylchitosan, and
carboxymethylcellulose. Included in potentially useful
polyamphyolytes are amino acids and betaine-type crosslinked
networks; examples would be hydrogels based on sodium acrylate and
trimethylmethacryloyloxyethylammonium iodide,
2-hydroxyethylmethacrylate, or 1-vinyl-3(3-sulfopropyl)imidazolium
betaine. Those polymeric materials having electrolyte groups that
completely (or nearly completely) dissociate in water and/or
provide relatively low local pH values are desired for efficacy are
preferred. Also preferred are those polyelectrolytes having a high
density of mer with electrolyte-containing side groups.
[0078] Several crosslinking mechanisms including but not limited to
chemical, high temperature self-crosslinking, and irradiation can
be employed in forming the solid material. Another option is to
create crosslinks during the polymerization process itself, such as
by condensing adjacent sulfonic acid groups to yield sulfonyl
crosslinks. Solid materials with higher crosslink densities tend to
maintain higher surfactant concentrations for a longer period of
time due to, presumably, longer mean free paths in the polymeric
network.
[0079] Independent of crosslinking method, the solid material can
be formed by crosslinking polymers (or polymerizable monomers) in
an aqueous solution contained in a heat conductive mold, followed
by rapid freezing and subsequent lyophilizing. The resulting
sponge-like material generally takes the shape of the mold in which
it was formed. Solids resulting from this type of process often
have a spongy appearance, with relatively large pores connected by
tortuous paths. Often, pores less than .about.0.22 m, less than
.about.0.45 m, less than .about.0.80 m, and less than .about.0.85
.mu.m are desirable (based on the diameters of endotoxins,
bacteria, and spores); for these and other applications, a solid
material with at least some larger pores (e.g., less than .about.1,
2, 5, 10, 50, or 100 .mu.m) can be used.
[0080] The solid material contains a sufficient amount of
surfactant to interrupt or rupture cell walls of bacteria
contacting or coming into the vicinity of the solid material. The
surfactant component(s) generally constitute as low as .about.0.03%
and as high as .about.10%, .about.15% or even .about.17.5% (all by
wt.) of the solid material. The same types of surface active
materials discussed previously also can be used in this form.
[0081] The surfactant preferably is present in the polymer network
at the time that crosslinking occurs (or the time of polymerization
in the case of the type of simultaneous polymerization and
condensation discussed above). If it is not, a crosslinked polymer
article or film must be post-treated to ensure proper entrainment
of the surfactant. A possible method for accomplishing this is
immersion of the article or film in a solution, typically but not
always aqueous, that contains one or more surfactants, followed by
removal of excess water via a drying (e.g., thermal or freeze) or
evacuation process. In addition to the surfactant(s), one or more
ionic compounds (salts) can be incorporated into the solid material
so as to enhance its ability to create localized regions of high
tonicity.
[0082] Regardless of how achieved, the local tonicity around the
solid material is at least moderately high, with an osmolarity of
at least .about.0.1 Osm/L being preferred for most applications.
Solid materials that create local tonicities greater than
.about.0.1 Osm/L will have enhanced bactericidal activity with
further increases in the osmotic pressure providing further
enhanced antimicrobial efficacy.
[0083] The solid material can take any of a variety of intermediate
and final shapes or forms including, but are not limited to, a
spongy solid that is permeable to vapor and or liquids; a molded,
extruded or deposited sheet; a coating on a surface or layer in a
multilayer structure; and an extruded fiber or thread. Once in a
particular shape, the material then can be further processed or
manipulated so as to provide a desired shape, e.g., a sheet good
can be rolled or folded so as to provide a membrane of a particular
geometry or a larger solid can be ground into a powder.
[0084] Both the liquid and solid forms can act at least in part to
interrupt or break ionic crosslinks in the macromolecular matrix of
a biofilm, facilitating the passage of solutes and surfactant
through the matrix to bacteria entrained therein and/or protected
thereby. Both forms also typically do not involve C.sub.1-C.sub.4
alcohols, yet can result, after no more than 10 minutes residence
time, in at least 6 log (99.9999%) reductions in the number of
bacteria in an entrenched biofilm. Embodiments of the composition
which are non-toxic if ingested can result, after no more than 10
minutes residence time, in at least 2 log (99%), 3 log (99.9%) or 4
log (99.99%) reductions in the number of bacteria in an entrenched
biofilm.
[0085] In the discussion of particular applications of the
previously described compositions and solid materials, terms such
as "low," "moderate," and "high" are used in connection with
properties such as toxicity and efficacy. Toxicity refers to
negative effects on biological tissues or systems, with low
toxicity referring to little or no irritation even upon repeated
applications, high LD50 values, little or no cytotoxicity, and/or
no systemic toxicity, and high toxicity referring to irritation
upon repeated exposure, low LD50 values, and/or moderate-to-high
cytotoxicity; toxicity generally increases with increasing
surfactant concentration, increasing tonicity, and/or departure of
pH from neutral. Efficacy refers to lethality against microbes
and/or ability to disrupt or even remove the EPS/ECPS in which
certain bacterial colonies reside, with low efficacy referring to
<2 log, or even <1 log reduction in bacteria (particularly
those in an entrenched biofilm) and high efficacy referring to
>2 log, >3 log, >4 log, >5 log and even >6 log
reductions in bacteria; efficacy generally increases with
departures of pH from neutral, surfactant loading increases,
tonicity increases, and optimization of surfactant architecture
(e.g., higher charge potentials, smaller groups near a charged
site, smaller hydrophilic sites, etc.) or type (i.e.,
cationic>zwitterionic>anionic>non-ionic).
Wounds
[0086] A number of pathogenic bacteria often are present in and
around wounds. Gram positive bacteria include Enterococcus
faecalis, Staphylococcus epidermidis, and Staphylococcus aureus.
Gram negative bacteria include Klebsiella pneumonia, Acinetobacter
baumanii, Haemophilus influenza, Burkholderia cenocepacia, and
Pseudomonas aeruginosa. Various fungi also can be present in burn
wounds.
[0087] Wound colonization often occurs in stages, with bacterial
flora in the wound changing over time. Initially, wounds are
colonized by aerobic gram positive cocci, such as S. aureus, S.
epidermidis, Streptococcus spp., and Enterococcus spp., followed by
gram negative rods such as P. aeruginosa, E. coli, K. pneumoniae,
and A. baumannii. The wound later is colonized by anaerobic species
such as Prevotella spp., and Porphorymonas spp.
[0088] Bacteria can colonize a wound and form a biofilm having
mixed species communities of aerobic bacteria near the surface and
anaerobic bacteria deeper in the biofilm. Biofilms are a major,
perhaps primary, factor in making a wound chronic and preventing
healing because neither the body's natural defenses or antibiotics
are able to eradicate bacteria in a biofilm. Additional reasons
that wound infections can be difficult to treat include the
avascular nature of wound eschars and the presence of antibiotic
resistant microorganisms.
[0089] Human and animal wounds can classified as (1) acute, which
includes skin abrasions, surgical incisions, trauma, and burns, or
(2) chronic, which includes diabetic ulcers, pressure ulcers, and
venous arterial ulcers.
[0090] Acute wounds generally heal through an orderly and timely
regenerative process with sequential, yet somewhat overlapping,
stages of healing: haemostasis, inflammation, and regeneration and
repair.
[0091] In haemostasis, damaged endothelial lining exposes platelets
to sub-endothelial collagen, which then releases von Willebrand
factor and tissue thromboplastin. The von Willebrand factor
facilitates platelet adhesion to sub-endothelial collagen and the
adhered platelets release ADP and thromboxane A2, which leads to
further platelet aggregation. Tissue thromboplastin then activates
the coagulation pathways, leading to the formation of fibrin, which
forms a plug into which platelets and red blood cells are trapped,
thereby leading to clot formation.
[0092] In inflammation, platelets release platelet-derived growth
factor and transformation growth factor .beta., which are
chemotactic to neutrophils and monocytes. Neutrophils and
macrophages phagocytose foreign material and bacteria.
[0093] Platelet-derived growth factor and transformation growth
factors are mitogenic to epithelium and fibroblasts. In the
regeneration and repair phase, this leads to proliferation of
epithelial cells and fibroblasts, which produce collagen. Vascular
endothelial growth factor is mitogenic to endothelial cells, and it
is released by monocytes in response to hypoxia and promotes
angiogenesis.
[0094] During the first 24 hours of the healing process in acute
wounds, neutrophils are the predominant cell type; this is the
acute inflammation phase where epithelial cells start proliferating
and migrating into the wound cavity. Over the next 24-48 hours,
where macrophage and fibroblasts are the dominant cell types,
epithelial cell proliferation and migration continues and
angiogenesis begins. Granulation tissue appears and collagen fibers
are present but are vertical and do not bridge the wound gap.
Granulation tissue includes newly formed capillary loops.
[0095] By the end of fifth day, the predominant cell type is
fibroblasts, which synthesize collagen to bridge the wound edges.
Epidermal cells continue to divide, the epidermis becomes
multilayered, and abundant granulation tissue is present.
[0096] During the second week, acute inflammation subsides, and
collagen continues to accumulate.
[0097] The foregoing is inapplicable to burns and chronic wounds.
In burn wounds, the lack of a protective barrier due to the injury
often results in septic infections. In chronic wounds, the wound
fails to proceed through an orderly progression, causing the wound
to remain in the inflammation phase of the healing process.
[0098] The forms that the treatment can take, the stages of a wound
that can benefit from a treatment, the types and forms of bacteria
present in the wound, and the portions of the wound and surrounding
skin that can be treated all are indicative of the breadth of the
present invention. Each possible combination of variables cannot be
described individually; instead, many of the variables will be
discussed separately, and the ordinarily skilled artisan is capable
of combining these individual descriptions to provide for a given
form that can be used in or near a particular type of wound at a
particular stage of the healing process.
Wound Types
[0099] Both chronic and acute wounds can affect only the epidermis
and dermis or can affect tissue down to the fascia.
[0100] Chronic wounds, which primarily affect humans although also
occur with horses, most often are caused by poor circulation,
neuropathy, and lack of mobility, although other factors such as
systemic illness (including infection and diabetes), age, repeated
trauma and co-morbid ailments such as vasculitis, pyoderma
gangrenosum, neoplasia, metabolic disorders, and diseases that
cause ischemia (e.g., chronic fibrosis, atherosclerosis, edema,
sickle cell disease, arterial insufficiency-related illnesses,
etc.) or that suppress the immune system. All of these can act to
overwhelm the body's ability to deal with wound damage via the
common healing process be disrupting the precise balance between
production and degradation of molecules such as collagen seen in
acute wounds, with degradation playing a disproportionately large a
role.
[0101] Many of the aforementioned causes result in inadequate
tissue oxygenation, leading to a higher risk for infection. The
immune response to the presence of bacteria prolongs inflammation
and delays healing, leading to a chronic wound and damaged tissue.
Bacterial colonization and infection damage tissue by causing a
greater number of neutrophils to enter the wound site. Although
neutrophils fight pathogens, they also release inflammatory
cytokines and enzymes that damage cells as well as produce Reactive
Oxygen Species (ROS) to kill bacteria; enzymes and ROS produced by
neutrophils and other leukocytes damage cells and prevent cell
proliferation and wound closure by damaging DNA, lipids, proteins,
the extracellular matrix, and cytokines that facilitate healing.
Neutrophils remain in chronic wounds longer than in acute wounds
and contribute to the fact that chronic wounds have higher levels
of inflammatory cytokines and ROS, and chronic wound fluid has an
excess of proteases and ROS, so the fluid itself interferes with
healing by inhibiting cell growth and breaking down growth factors
and proteins in the extracellular matrix.
[0102] Chronic wounds typically are classified as diabetic ulcers,
venous ulcers and pressure ulcers, although a small number of
wounds not falling into one these categories can be caused by, for
example, radiation poisoning or ischemia.
[0103] Generally accepted wisdom is that disinfectants are
contraindicated for the treatment of chronic wounds. This belief is
based on a variety of factors, including the potential to damage
tissue, potential delay in wound contraction, and general
ineffectiveness in the presence of organic matter, e.g., blood and
exudates.
[0104] An acute wound results from a force that exceeds the
resistive strength of the skin and/or underlying supporting
tissues, resulting in an abrasion, puncture, laceration, or
incision. Most acute wounds result from a trauma, with most of the
remainder resulting from a medical procedure, e.g., surgery.
Surgical wounds commonly are classified on a sliding scale that
ranges from clean to contaminated to dirty, with surgical wounds
that are contaminated or dirty (or known to be infected)
occasionally being left open for treatment prior to being sutured.
Surgical wounds almost always are dressed, with dressing selection
based on the amount of exudate to be absorbed (leakage of exudate
onto surrounding skin can cause blistering, particularly in the
area under the dressing), supporting haemostasis and protecting
against infection.
Wound Treatment
[0105] Fundamental wound care protocol involves cleansing (i.e.,
removal of debris and softening of necrotic tissue), possible
debridement, absorbing excess exudate, promoting granulation and
epithelialization, and treating infection. The cleansing agents
used at this stage tend to be based on surfactants targeted at
physical removal of dirt and bacteria with very little (if any)
killing of bacteria being effected.
[0106] Common treatments for wounds involve dressing changes,
medicated dressings, and cleansing or debridement. These often are
combined with systemic and/or topical antibiotics which,
unfortunately, are ineffective when treating bacteria in a biofilm
due to their sessile state. (Orders of magnitude more antibiotic(s)
are needed to kill bacteria in a biofilm, an amount which makes
most/all antibiotics toxic to the host.)
[0107] Changing dressings to dry ones, if performed, can be a means
of mechanical debridement which causes injury to new tissue growth,
causes pain, predisposes a wound to infection, becomes a foreign
body and delays healing time.
[0108] Debridement is performed for necrotic tissue and infection
in the wound. This can be accomplished by multiple methods,
including mechanical, autolytic, surgical, enzymatic or
biochemical, or biological. Hydrogels are often applied to wounds
to keep them hydrated. Negative pressure wound therapy can be used
to pull bacteria from a wound. Hyperbaric chambers can also be used
to attempt to improve wound healing.
[0109] Topical application of an antibacterial product such as
alcohols, H.sub.2O.sub.2, povidone-iodine and dilute HClO,
sometimes is performed to control bacterial load. A number of gels
and dressing are marketed for the treatment of infections in
wounds, including antibacterial silver-loaded gels, calcium fiber
gels and alginates (which entrap bacteria). None of these are
effective against biofilms, however, and therefore are not
effective in treating many wounds.
[0110] As mentioned previously acute wounds generally heal through
an orderly, multi-stage regenerative process that includes
haemostasis, inflammation, and regeneration/repair. The
aforementioned compositions and solid materials can be useful in
treatments at each of these stages. Further, the treatments can be
targeted at preventing bacterial colonization, including the
formation of biofilms, or at treating an infection, including in
biofilm form, in or near a wound.
[0111] Concurrent with or soon after wound formation, the wound and
surrounding skin can be treated so as to minimize the risk of
infection. This treatment can be effected by cleansing the area
with a liquid composition or by contacting the area with a solid
form carrier such as, for example, a topical wipe. At this stage,
long term exposure to the treating medium is not expected, so
increasing efficacy at the cost of reducing biocompatibility is
acceptable.
[0112] Efficacy can be bolstered by increasing osmolarity, pushing
the pH farther from neutral and/or using more aggressive
surfactants. For example, liquid compositions (which includes
semi-solid materials such as gels, salves and balms) intended for
immediate removal or topical wipes intended for use in field
situations where other treatment will not be immediate can have a
relatively extreme pH (e.g., 2 to 4 or 10 to 12), whereas liquid
compositions not intended for immediate removal and topical wipes
intended for use in situations other than extreme situations can
have an intermediate pH (e.g., 4 to 5 or 9 to 10), and liquid
compositions not intended to be removed, or compositions/wipes
intended for use with children or small animals, can have a gentle
pH (e.g., 5 to 6.5 or 7.5 to 9).
[0113] In addition to or instead of pushing pH farther from
neutral, a topical composition also can have a very high osmolarity
and/or surfactant loading. Particularly because biofilms are
unlikely to have formed at such an early stage, the need for
H.sub.3O.sup.+ or OH.sup.- ions to assist in breaking up the
EPS/ECPS macromolecular matrix might not be as great and,
accordingly, higher loadings of other solutes, buffers and/or
surfactants might be sufficient to provide significant lethality
against many types of bacteria in planktonic form. For example, at
this stage of wound care, a liquid composition with an osmolarity
greater than .about.300 mOsm/L and a surfactant loading greater
than .about.0.075% (by wt.) often can be adequate for preventing
biofilm growth. Adjusting the osmolarity and/or surfactant loading
upward (using the amounts provided previously) can provide more
effective (i.e., biocidal) compositions, but at the cost of
potential for skin irritation.
[0114] For biocompatibility reasons, non-ionic and cationic
surfactants (particularly benzalkonium chloride and cetylpyridinium
chloride) are preferred.
[0115] A variety of grades of liquid antimicrobial compositions for
wound care also are envisioned. For example, various grades of
compositions can be provided based on formulations such as those
shown in the following table:
TABLE-US-00001 TABLE 1 Exemplary wound care compositions A B Acid
or base weak acid strong base Amount of acid/base, g/L 75-150 25-50
Tonicity, Osm/L 1.8-2.8 3.0-4.0 Solute trisodium citrate dihydrate
NaH.sub.2PO.sub.4 Amount of solute, g/L 75-150 25-50 Amount of
surfactant, g/L 0.9-1.7 10-20
Grades having intermediate properties also are envisioned.
[0116] Liquid antimicrobial compositions can be applied directly or
can be delivered and continuously removed, e.g., fed via an
instrument like a debrider (e.g., any of the Pulsavac Plus.TM.
family of products, commercially available from Zimmer Inc.,
Warsaw, Ind.) or even a syringe with a special flow restriction
(increased pressure) tip. Also, a liquid composition or one of the
foregoing additional (solid or semi-solid, particularly gels
including those based on any of a variety of PEGs) forms can be
used to provide articles with disinfectant properties such as
sponges, topical wipes, bandages, pads, gauze, surgical packing,
and the like.
[0117] In addition to being applied to a wounded area to halt or
prevent microbial infection, embodiments of a liquid composition
(including gels and foams) or a topical wipe can be used to
disinfect the skin of those treating the wound as well as the
instruments used in that treatment including, but not limited to,
syringes, debriders, tourniquets, and the like.
[0118] Certain types of wounds, patients and/or treatments argue
for the inclusion of other types of materials in or with the
disinfecting composition or material. Non-limiting examples of such
materials include, but are not limited to, emollients, lotions,
humectants, glycosaminoglycans such as hyaluronic acid, analgesics
(e.g., pramoxine, lidocaine, capsaicin, isobutylpropanoicphenolic
acid, etc.), colloidal silver (for treatment of burns) and
antimicrobials including sporicides, antifungals, antibiotics
(e.g., bacitracin, neomycin, polymyxin B, etc.), fragrances,
preservatives (e.g., antioxidants), and the like.
[0119] Adding an antihemorrhagic to the disinfecting
(antimicrobial) composition or material, or adding the disinfectant
to an antihemorrhagic, is potentially quite useful. Examples of
common antihemorrhagic materials used in military and emergency
medical settings include fibrin, collagen oxidized starch,
carboxymethyl cellulose, thrombin and chitosan. Various embodiments
of the disinfecting composition or material can be added to an
antihemorrhagic material or article such as a haemostatic bandage
(HemCon Medical Technologies, Inc.; Portland, Oreg.), Tisseel.TM.
fibrin sealant (Baxter International Inc.; Deerfield, Ill.),
Thrombi-Gel.TM. gelatin foam hemostat (Pfizer Inc.; New York,
N.Y.), GelFoam.TM. gelatin sponge (Pfizer), GelFoam.TM. Plus
haemostasis kit (Baxter), and the like; alternatively, addition of
an antihemorrhagic material to a liquid disinfecting composition or
to a solid disinfecting material or article also can be useful. For
purpose of exemplification, addition of at least .about.5%, often
at least .about.10%, commonly at least .about.20% of disinfecting
composition or material in solid or semisolid antihemorrhagic
materials (e.g., gel-foam and chitosan bandages). Conversely, from
.about.1 to .about.80% (by wt.), commonly from .about.3 to
.about.70% (by wt.), and typically from .about.5 to .about.60%
antihemorrhagic material (with the amount varying primarily based
on the identity and efficacy of the antihemorrhagic, e.g.,
thrombin, chitosan, oxidized cellulose, or carboxymethyl cellulose)
can be added to or incorporated in a disinfecting composition or
material.
[0120] Embodiments of the foregoing are expected to find utility in
military battlefield (e.g., pourable powders carried by field
medics) and emergency medical applications (e.g., EMT and ambulance
kits as well as surgical theater usages), where disinfecting
capability (efficacy) preferably is high, e.g., high osmolarity and
surfactant levels. Blood and wound fluid can hydrate a solid
material or a concentrated liquid composition, so levels of water
or other carrier can be kept low.
[0121] Other embodiments are expected to find utility in connection
with less traumatic wounds, such as shaving cuts or improperly
trimmed animal nails, where an embodiment of the liquid or solid
disinfecting material might be added to a styptic such as alum or
TiO.sub.2.
[0122] From the foregoing, the ordinarily skilled artisan can
envision numerous articles, techniques and ways in which wounds can
be cleansed.
[0123] Embodiments of the previously described liquid compositions
and solid materials also can be used at during various stages of
the wound healing process.
[0124] As described in more detail above, wounds are believed to
heal via a process that involves haemostasis, inflammation, and
repair and/or regeneration. During these phases, a variety of
topical medicaments and articles are applied to wounds and
surrounding areas, some for brief periods of time and others for an
extended duration.
[0125] For example, many wounds are bandaged soon after occurrence
and, in certain circumstances, re-bandaged over time. A bandage
that includes an embodiment of the liquid composition can help to
prevent infection, treat infection, prevent biofilms, or break up a
biofilm and kill the bacteria entrained therein. In this particular
form, a strong disinfecting composition (high osmolarity and
relatively extreme pH, e.g., .about.3.5 to 5 or .about.9 to 10.5)
can be preferable because high efficacy and microbial toxicity are
desired and because the bandage typically only overlays the wound.
Methods of making such a bandage include soaking bandage material
in a liquid composition or by coating or entraining in the bandage
material a gel, optionally one that undergoes a temperature-based
phase change, i.e., becomes less viscous between .about.25.degree.
to .about.40.degree. C. (Alternatively, some PEG-based gels
themselves can act as bandages.) Tailoring the elution rate of the
disinfecting composition over the expected use period of the
bandage can be desirable.
[0126] Alternatively, an embodiment of a solid form disinfectant
can be used to provide a bandage. The solid article can be in
as-made form (e.g., spongy solid) or in further processed form
(e.g., a fiber made from a solid). Here, the bandage material
itself is antimicrobial, although such a material certainly can be
further loaded with additional composition or with other
antimicrobials.
[0127] A variation on the foregoing theme involves surgical
packing, which is structurally similar to a bandage although
typically is intended for insertion into the body for a limited
time or to be bioresorbed within a predetermined amount of time.
The method of making a surgical packing is essentially the same as
those set out above with respect to bandages, although the efficacy
and toxicity levels and/or the elution rate can be downwardly
adjusted.
[0128] Ongoing wound treatment sometimes involve repeated
applications of a gel, paste or salve directly to the wound.
Because of the amount of time that such materials are allowed to
reside on or in the wound, these materials typically involve gentle
or only moderately strong disinfecting composition embodiments. In
other words, efficacy and toxicity can be reduced to avoid pain or
tissue damage, a sacrifice that is offset by the proximity of the
treatment to the wound and its length of contact.
[0129] Both bandages and topical treatments can be used in
connection with burn wounds. In such circumstances, addition of a
variety of adjuvants and additional treatments can be preferable.
Potentially useful adjuvants include colloidal silver, analgesics,
antifungals, emollients, hyaluronic acid, and the like. Because
wound edema is common, a somewhat concentrated, even solid, form of
topically applied disinfectant can be used.
[0130] Similarly, both bandages and topical treatments can be used
in connection with diabetic and pressure ulcers, i.e., chronic
wounds. Similar adjuvants, particularly analgesics, hyaluronic
acid, and emollients, can be included in embodiments intended for
this use.
[0131] Embodiments of the liquid composition also can find utility
in connection with debridement techniques and equipment.
Specifically, such liquid compositions can be used to irrigate or
flush an area prior to, simultaneously with, or immediately after
debridement.
[0132] While most of the foregoing embodiments have been described
as single use, articles intended for multiple applications are
envisioned. These are expected to have high loading levels that are
intended to elute over time.
Oral Care
[0133] The oral environment initially changes due to an increased
concentration of carbohydrates in the diet of the host. The
anaerobic bacteria in the plaque biofilm product acid by fermenting
these carbohydrates, thus reducing the pH of the biofilm; some of
the more common bacteria responsible for this shift in composition
include S. mutans, S. sorbrinus, and Lactobacillus casei, all of
which can survive at a pH level as low as 3.0. As the pH drops, the
microflora shift towards acid-tolerant bacteria, as intolerant
bacteria cannot survive in the acidic conditions formed.
[0134] At highly acidic pH, the acid-tolerant bacterial biofilm can
de-mineralize the tooth enamel, with greater degrees of acidity
causing faster rates of demineralization. (Demineralization of
tooth enamel can also occur solely from the presence of highly
acidic substances in the oral cavity.) Caries result if
demineralization persists at a rate greater than re-mineralization
occurs. S. mutans, Lactobacilli, Lactobacillus acidophilus,
Actinomyces viscosus, Nocardia spp., and Streptococcus sanguis are
most closely associated with oral caries but, because most
plaque-induced oral diseases occur with a diverse microflora
present, the specific causal species is not known.
[0135] Plaque and tartar (hardened plaque) become more harmful the
longer that they remain on the teeth. The bacteria within the
biofilm cause inflammation of the gums, commonly known as
gingivitis, a mild form of gum disease that does not include any
loss of bone and tissue holding the teeth in place. Spirochetes,
Actinomyces naeslundii, and P. gingivalis are often associated with
the gingivitis.
[0136] Untreated gingivitis progresses to inflammation around the
tooth, commonly known as periodontitis, a condition where the gums
retract from the teeth and form gaps or pockets that can become
infected because they are easily colonized by microbes due to
dentinal tubules and enamel fissures that lead directly into the
gums; the biofilm plaque spreads and grows below the gum line. The
majority of the bacteria within the microflora in these gum pockets
are gram-negative anaerobes, although the identity of the microbes
in the biofilm change as the biofilm itself changes. At a certain
point, the organisms must disperse to other locations in the oral
cavity to ensure survival.
[0137] Periodontitis involves progressive loss of the alveolar bone
around the teeth and the connective tissue that holds the teeth in
place due to the bacterial toxins in the biofilm and the body's
immune response to the biofilm. If left untreated, this can lead to
loosening and subsequent loss of teeth. The areas around and under
the gums are difficult to reach via typical oral health care
mechanisms that are mechanical in nature and, as such, the diseased
states of gingivitis or periodontitis occur. The same bacteria
listed above in connection with gingivitis can be involved in
periodontitis, but an enormous variety of other bacteria can be
found in these biofilms.
[0138] Peri-implantitis, which is similar to periodontitis but
occurs on the surface of dental implants, refers to the destruction
of the supporting peri-implant tissue due to a microbial infection.
These infections tend to occur around residual teeth or failing
implants, which can act as reservoirs for bacteria and form biofilm
colonies, as they have no inherent host response to fight the
infecting organisms. The bacterial species involved in
peri-implantitis are similar to those involved in
periodontitis.
[0139] The primary treatment for dental diseases is prevention. For
the consumer, this involves tasks such as tooth brushing
(mechanical debridement), usually with a fluoride-containing
toothpaste; oral rinsing with a mouthwash containing
cetylpyridinium chloride, stannous fluoride, or a combination of
eucalyptol, menthol, methyl salicylate and thymol in an alcohol
vehicle; and flossing. (Mouthwashes and rinses are not particularly
effective at removing plaque, which necessitates continued use of
floss in the inter-dental regions, as plaque tends to accumulate in
these areas which brushing does not clean.) Regardless, because
these preventive treatments are not effective at removing and
disinfecting a biofilm, regular prophylactic treatment (removal of
biofilm from the teeth, typically by mechanical scraping, although
lasers have been used additionally or alternatively) by a dental
professional usually is necessary.
[0140] When dental disease has progressed to periodontitis,
mechanical scraping (debridement) has been the only way to remove a
biofilm. Professional treatment by a dental professional is
performed by scaling (scraping of tartar from above and below the
gum line) and root planning (removal of rough spots on the tooth
root where the biofilm gathers), sometimes in combination with a
laser. In more serious cases, to remove more tartar, flap surgery
may be performed, where the gums are lifted so that tartar can be
removed, followed by suturing. Bone and tissue grafts may also be
performed in the area of bone loss.
[0141] Medications are sometimes used in conjunction with
mechanical treatments. These include prescription antimicrobial
mouth rinses containing chlorhexidine; gum pocket inserts such as
an antiseptic chip containing chlorhexidine, an antibiotic gel
containing doxycycline, antibiotic microspheres containing
minocycline, etc.; tablets containing doxycycline; or even systemic
antibiotics.
[0142] The aforedescribed antimicrobial compositions, both acidic
and caustic, can be incorporated into any of a variety of oral care
vehicles such as, but not limited to oral rinses and washes
intended for preventive use, oral rinses intended to treat existing
dental and gum disease, oral rinse treatment after dental implants,
dental implant sterilization solutions (pre-surgical), disinfecting
solutions for orthodontic devices (e.g., braces, retainers, etc.),
irrigation solutions (both for use in surgical procedures, such as
root canals and impacted teeth prior to closure, as well as in
general and localized dental procedures), and the like. The vehicle
can be a liquid, gel (e.g., a sealing or packing gel used during
and/or after oral surgery), paste (e.g., toothpaste), or salve
(e.g., topical treatment for mouth and lip conditions such as
canker sores) and can be used with components such as fluoride ions
and antibiotics, if desired.
[0143] Where a liquid antimicrobial composition is to be introduced
directly into an oral cavity (e.g., a mouthwash or rinse), some
preference can be given to caustic compositions. Because most
mouths naturally are a somewhat acidic environment, dental plaque,
tartar and other forms of EPS/ECPS seem to be more impervious or
resistant to chelation by acids than many other types of biofilm
EPS/ECPS. Exemplary pH ranges for caustic compositions used here
range from .about.7.5 to .about.10, commonly from .about.7.7 to
.about.9.8, more commonly from .about.7.8 to .about.9.7, and
typically .about.9.+-.0.5 pH units. This basicity preferably is
achieved with a strong inorganic base such as KOH or NaOH.
[0144] With respect to tonicity, preferred ranges center around
.about.1.75 Osm/L, commonly from .about.1.25 to .about.2.5 Osm/L,
more commonly from .about.1.33 to .about.2.25 Osm/L, and typically
from .about.1.5 to .about.2 Osm/L. To reach this type of tonicity
without the pH going outside the previously noted ranges, one or
more ionic compounds can be included in the composition. Exemplary
materials include, but are not limited to, NaHSO.sub.4,
NaH.sub.2PO.sub.4, NaCl, KCl, KI and the like.
[0145] Non-ionic and cationic surfactants are preferred for the
same reasons set forth above in connection with wound care. Both
benzalkonium chloride and cetylpyridinium chloride are known to be
safe for oral applications. Exemplary surfactant loading levels
range from .about.0.5 to .about.1.8 g/L, commonly from .about.0.6
to .about.1.7 g/L, and typically from .about.0.75 to .about.1.5
g/L.
[0146] The following table provides the composition and properties
of a non-limiting example of a liquid antimicrobial composition
intended for oral care applications.
TABLE-US-00002 TABLE 2 Exemplary oral care composition pH 9.0 .+-.
0.3 base NaOH additional solute NaH.sub.2PO.sub.4 tonicity, Osm/L
1750 .+-. 75 cationic surfactant(s), g/L 1.1 .+-. 0.3 additives
sweetener, essential oil
[0147] The antimicrobial compositions also can be incorporated into
solid forms, such as chewing gums, lozenges, denture cleaning
tablets, breath mints, removable or dissolving strips, powders and
the like. They also can be used as, or incorporated in, liquids
intended for aerosolizing or other spray techniques, such as breath
sprays and dog teeth cleaning solutions.
[0148] For additional information on the type and amounts that can
be employed exemplary liquid and solid formulations, as well as
methods of making, the interested reader is directed to any of a
variety of references including, for example, U.S. Pat. Publ. Nos.
2005/0169852, 2006/0210491, 2007/0166242, 2008/0286213,
2009/0252690, and 2010/0330000. Those treatments intended for
preventive applications typically will be formulated around lower
toxicity thresholds than those intended for use by dental
professionals.
[0149] Adjuvants that can be included in such treating compositions
include, but are not limited to, bleaching agents, binders,
flavorings (e.g., essential oils and artificial sweeteners),
humectants, foaming agents, abrasives, desensitizers, tooth
whiteners, and analgesics.
[0150] Treatment of adenoids and tonsils, although not strictly
oral care, also is possible.
[0151] Acute infections of the tonsils and adenoids generally are
treated with systemic antibiotics. If tonsillitis is caused by
group A streptococcus, penicillin or amoxicillin are commonly used
with some success, while cephalosporins and macrolides being used
less frequently. If these fail against .beta. lactamase-producing
bacteria (which reside in tonsil tissues and can shield group A
streptococcus from penicillin-type antibiotics), clindamycin or
amoxicillin-clavulanate may be used.
[0152] Group A .beta.-hemolytic streptococcus (GABHS) is the most
common reason for chronic tonsil infections. Systemic antibiotics
fail to treat GABHS due to a number of factors, including the
presence of .beta. lactamase-producing organisms that protect GABHS
from penicillins, coaggregation with M. catarrhalis, absence of
competing bacterial flora, poor penetration of antibiotics into
tonsil cells, etc. Additionally, GABHS is known to form biofilms.
This bacteria, as well as other pathogenic strains, can form
biofilms on and within the tonsils and/or adenoids. Infectious
bacteria in biofilm form are relatively impervious to systemic
antibiotics, meaning that such high levels of antibiotics are
necessary to treat them (i.e., orders of magnitude more than is
necessary to kill planktonic bacteria) that the patient is unlikely
to survive. Biofilm infections often become chronic.
[0153] When the condition becomes chronic, surgical methods are
employed to remove the tonsils and adenoids. The current treatment
for chronic infections of the tonsils and adenoids is surgical
removal through a tonsillectomy and adenoidectomy. This can be done
by powered ablation which essentially burns away the tonsils and/or
adenoids, a technique that minimizes or prevents bleeding of the
tonsil bed post-surgery, or by cold steel instruments or mechanical
debridement, in which case localized cauterization is performed on
bleeding vessels to prevent re-bleeding after surgery.
Tonsillectomy, with or without adenoidectomy, is one of the most
common surgical procedures in the developed world. These surgical
interventions are not without risk, however, with post-operative
bleeding, airway obstruction, and adverse reaction to anesthesia
being three of the most common problems. A substantial amount of
pain and hospital recovery times also can be associated with these
procedures. Bleeding can occur when scabs begin sloughing off from
the surgical sites, generally 7 to 11 days after surgery. This
occurs at a rate of about 1% to 2%, with both risk and severity
being higher in adults than in children.
[0154] A topical treatment for these infections is not available,
as no commercially available product can disinfect and remove the
biofilm and EPS from the tonsil/adenoid surface, nor can these
products penetrate into the tonsil and adenoid surface to treat
bacteria within the tissue. Of the oral mouth rinses on the market,
which have active ingredients that include chlorhexidine,
cetylpyridinium chloride, SnF.sub.2 and mixtures of therapeutic
oils, none can disinfect a biofilm in the short treatment times
available in the oral cavity.
[0155] Antimicrobial compositions of the type described above,
however, can be effective in treating infected adenoids and
tonsils. A treatment regimen might be to gargle or rinse with up to
100 mL from 1 to 4 times each day, with the treatment running for
as long as necessary, generally from 5-70 days, commonly from 7-65
days, more commonly from 8-60 days, and typically from 10-50 days,
with 30.+-.10 days being envisioned as most typical. In addition,
direct application of an antimicrobial solid material directly to
the affected area(s) also is envisioned.
[0156] Advantages of this type of treatment include, but are not
limited to, elimination of post-operative bleeding, avoidance of
anesthesia, elimination of post-operative pain, preservation of
anatomy, elimination of the risks of morbidity/mortality due to
surgery and post-surgical complications, and overall lower
healthcare costs.
Medical Equipment
[0157] Prior to disinfection or sterilization, all reusable medical
devices must be cleaned thoroughly, a step that requires that all
surfaces, internal and external, be made completely free of
so-called bioburden, i.e., residual body tissue and fluids,
bacteria, fungi, viruses, proteins, and carbohydrates. After the
manual and/or mechanical cleaning, the devices must be thoroughly
rinsed to remove all residual bioburden and detergent. With current
technology, if the device is not clean, sterilization cannot be
achieved.
[0158] Current chemical treatments are ineffective at treating
biofilms because of their inherent resistance to biocides. Biofilms
can be removed by physical methods such as ultrasound and
mechanical cleaning reasonably effectively, but ensuring that it
occurs correctly and completely each time is very difficult.
[0159] Endoscopes are particularly susceptible to biofilm formation
due to their use within the body. Removal of biofilm from the
internal surfaces of small diameter tubing within endoscopes is
difficult due to limited access and the degradation of these
surfaces. Biofilm formation within endoscope channels can result in
failure of disinfection procedures and can create a vicious cycle
of growth, disinfection, partial killing or inhibition and
regrowth, and patients who undergo endoscopy with a
biofilm-containing endoscope are at risk for an endoscopy related
infection. Bacteria in a biofilm have been shown to be capable of
surviving in a down-regulated state after being cleaned and
disinfected by present methods.
[0160] The cleaning and disinfecting processes used are dependent
upon the training and diligence of the operator and, while
guidelines for endoscope disinfection have been developed by many
organizations, no method to determine the efficacy of these regimes
on a routine basis is currently available. Failure to completely
clean and dry an endoscope using the current guidelines can lead to
biofilm formation, with studies suggesting that human error is a
major contributing factor, along with the need for rapid turnover
of equipment and inadequate training.
[0161] Similar problems are inherent in the cleaning and
disinfection processes used with other medical devices and
equipment, although endoscopes seem to be linked to more outbreaks
of HAIs, a problem discussed in more detail below.
[0162] Also problematic are devices and equipment that are not
necessarily designed for invasive insertion. This includes manual
instruments, powered surgical instruments, and even devices cages
and guides for performing spinal surgery. These too are cleaned and
disinfected post-usage, with the procedure generally involving
wiping followed by sterilization (normally by steam, but
occasionally by peroxide or other high performance procedures).
Some devices are returned to their manufacturer for reprocessing,
often with steam sterilization both before and after
reprocessing.
[0163] The formulation of reprocessing cleaning solutions are
unique; however, most contain some combination of at least six
components: water, detergent, surfactant, buffer, and chelating
agents. Enzymes are also used to increase cleaning efficacy, speed
the cleaning process and help to minimize the need for manual
brushing and scrubbing. A variety of enzymes, each targeting a
particular type of soil, are employed, with the most common being
protease (which helps to break down protein-based soils such as
blood and feces), amylase (which breaks down starches like those
found in muscle tissue), cellulase (which breaks down carbohydrates
like those found in connective fluid and joint tissue), and lipase
(which breaks down fats like those found in adipose tissue). Any
combination of these enzymes may be present in a solution.
Solutions containing enzymes can often be used at a more neutral pH
and at lower temperatures than those without enzymes.
[0164] Enzymatic cleaning agents are used as the first step in
medical device disinfection to remove biofilms. However, physical
cleaning with an enzymatic cleaning agent does not disinfect the
device. Even a few viable organisms that might remain after
cleaning can accumulate into a biofilm over time. It has been found
that commonly used enzymatic cleaners fail to reduce the viable
bacterial load or remove the bacterial EPS. Cleaners with high
enzyme activity remove some biofilm but fail to reduce bacterial
numbers more than 2 logs (i.e., 99%), and some enzymatic solutions
actually can contribute to the formation of biofilms. Accordingly,
proper disinfection is required to kill down-regulated microbes and
prevents the formation of biofilm.
[0165] All devices undergo a disinfection process and users perform
a chemical disinfection process following cleaning. Either an
oxidative or aldehyde-based chemistry is used. However, some
disinfection chemistries have demonstrated a tendency to promote
the formation of biofilms and none completely remove a biofilm that
has already formed. Gluteraldehyde solution buildup over several
uses actually has been found to promote formation of biofilms
within the lumens of endoscopes.
[0166] Disinfectants employing oxidative chemistries are more
effective at controlling the formation of biofilms. However, it has
been found that even the harsh environment created by some
disinfectants can be survived by these well-protected microbes,
which can survive by using several food sources not typically
thought to be possible. These disinfectants are also susceptible to
deactivation by proteins that may be present on the endoscopes and
medical devices, especially if the cleaning step is not adequately
performed.
[0167] Cleaning chemicals require unimpeded contact with all
surfaces of the device, internal and external, to assure microbial
inactivation; any residuals left on the device, including medical
soil, contaminants and detergent residue can interfere with that
direct contact. Further, even if they have access to a biofilm,
they cannot kill bacteria entrained therein.
[0168] The shape and design of some devices and instruments make it
impossible to remove all of the proteins and EPS/ECPS which may be
on them. Presently available cleaners or disinfection techniques
are unable to completely remove EPS/ECPS, especially if there is
protein which can prevent cleaning chemicals from reaching these
areas. Remaining EPS/ECPS can allow for rapid biofilm reformation
on the device, and the EPS/ECPS can be dislodged into the surgical
field, including into the patient, allowing for a nidus of
infection.
[0169] Advantageously, antimicrobial compositions of the type
described above can be effective in cleaning, disinfecting and
sterilizing reusable medical equipment. In these techniques, both
toxicity and efficacy can be pushed to extremely high levels.
[0170] Depending on the nature of the materials from which the
equipment is made, either acidic or basic compositions can be
preferred. For example, a caustic composition might be preferred
for a metallic piece of equipment, while an acidic composition
might be preferred for a plastic piece. Extremely acidic or caustic
compositions preferably are avoided, i.e., the composition employed
commonly has a pH within 4 units, preferably within 3 units, and
more preferably within 2 units of neutral.
[0171] Where an acidic composition is employed, a conjugate base of
the acid preferably also is present. Tonicities of solutions
employed here generally are at least .about.2.0 Osm/L, commonly at
least .about.2.5 Osm/L, more commonly at least .about.3.0 Osm/L,
and typically at least .about.3.5 Osm/L. In both acidic and caustic
compositions, additional solute(s) can be present. In compositions
with moderate pH (i.e., 5.ltoreq.pH.ltoreq.9, particularly
6.ltoreq.pH.ltoreq.8), large amounts of such solutes can be used;
for example, for a composition of 6.5.ltoreq.pH.ltoreq.7.5, the
amount of accompanying salt or solute can be as high as 200 g/L,
250 g/L, 300 g/L, 350 g/L, 400 g/L, 450 g/L or even 500 g/L.
[0172] Regardless of the nature of the material, cationic
surfactants are strongly preferred, with particular preference
being given to tetradecyltrimethylammonium halides. Surfactant
loading can be pushed to very high levels, e.g., 10 g/L, 15 g/L, 20
g/L, or even 30 g/L or more can be used.
[0173] Advantageously, the equipment need stay in the composition
for no more than a few hours. For example, in no case should static
dwell time be required to exceed 250 minutes, with less than 200
minutes being common, less than 150 minutes being more common, less
than 100 minutes being even more common, and less than 50 minutes
being typical. Depending on the particular antimicrobial
composition employed, the dwell time can range from 1 to .about.30
minutes, from .about.2 to .about.25 minutes, from .about.3 to
.about.20 minutes, or from .about.5 to .about.15 minutes. The
amount of dwell time can be decreased even more with flow for
treatment and/or mechanical scrubbing to remove the EPS.
Higher-than-ambient temperatures and pressures also can increase
efficacy, which can be particularly useful equipment having high
loadings of bioburden and/or difficult geometry (e.g., scopes).
[0174] As an example of the extreme efficacy of the liquid
antimicrobial compositions described herein in this application, a
citric acid/sodium citrate dihydrate composition having a pH of
.about.6.5 and a tonicity of .about.3.5 Osm/L and including
.about.15 g/L tetradecyltrimethylammonium chloride surfactant was
able to achieve a 9 log reduction (i.e., 99.9999999%) in
Pseudomonas in small diameter silicone and polyethylene tubing as
well as on metal and plastic coupons.
HAI
[0175] Basic routes of infection involve transmission via contact
(direct and indirect), droplets, airborne, common vehicle
(contaminated items such as food, water, medications, devices, and
equipment), and vector (from mosquitoes, flies, rodents, etc.),
with direct contact being the most frequent mode.
[0176] In direct contact, a colonized person (e.g., a caregiver or
another patient) transfers the microorganism from his body to that
of a susceptible patient. Indirect transmission involves contact
between the host, usually a caregiver, and a contaminated object
which then becomes the vector for infecting the susceptible
patient; examples of objects that can become contaminated include
instruments and equipment such as needles, dressings, disposable
gloves, saline flush syringes, vials, bags, blood pressure cuffs,
stethoscopes, and the like, as well as non-medical surfaces such as
door handles, packaging, mops, linens, pens, keyboards, telephones,
bed rails, call buttons, touch plates, seating surfaces, light
switches, grab rails, intravenous poles, dispensers, dressing
trolleys, countertops, tabletops, and the like.
[0177] Droplet transmission occurs when droplets containing
microbes from an infected person are propelled a short distance
through the air and deposited on the patient's body. Droplets may
be produced from the source person by coughing, sneezing, talking,
and during the performance of certain procedures such as
bronchoscopy.
[0178] Airborne transmission can be by either airborne droplet
nuclei of evaporated droplets containing microorganisms that remain
suspended in the air for long periods of time or dust particles
containing the infectious agent. Microorganisms carried in this
manner can be dispersed widely by air currents and may become
inhaled by a susceptible host in the same room as or quite remote
from the original source. Microorganisms commonly transmitted in
this manner include Legionella, Mycobacterium tuberculosis and the
rubeola and varicella viruses.
[0179] Of particular and growing interest and concern are MRSA and
VRE. Contamination of the environment with MRSA or VRE occurs when
infected or colonized individuals are present in hospital rooms,
often medical personnel carrying the organism in or on their
clothing. MRSA contamination of gloves also has been observed in
many personnel who had no direct contact with the patient but who
had touched surfaces in infected patient's rooms. The hands, gloved
or otherwise, of healthcare workers can become contaminated by
touching surfaces in the vicinity of an infected patient.
[0180] In undried form, MRSA can survive for up to 48 hours on a
plastic surface; in dried form, it can survive for several weeks.
It is stable at a wide range of temperatures and humidities, and
can survive exposure to sunlight and desiccation.
[0181] Once a surface becomes contaminated, pathogens can be
transferred to other surfaces and patients in the vicinity. Hand
washing and gloves can help prevent the spread of HAIs via
hand-surface transmission but cannot eradicate surface or
indwelling contamination, nor do they eliminate the potential for
direct transfer by the patient. However, these methods do nothing
to treat the presence of these pathogenic bacteria on surfaces and
indwelling devices. Touch surfaces commonly found in hospital rooms
often are contaminated with MRSA and VRE, with objects in closest
proximity to patients having the highest levels of
contamination.
[0182] The efficacy of traditional cleaning products (e.g.,
alcohols, quaternary ammonia compounds, and bleach) to remove
surface contamination is limited. One recent study of contamination
in the hospital environment detected MRSA on 74% of swab samples
prior to cleaning and on 66% of swab samples after cleaning,
indicating that current methods for disinfecting hospital surfaces
are ineffective.
[0183] Some modern sanitizing methods are more effective against
select pathogens; for example, non-flammable alcohol vapor in
CO.sub.2 has been demonstrated to be effective against
gastroenteritis, MRSA, and influenza, while H.sub.2O.sub.2, as a
liquid or vapor, has been shown to reduce infection rates and risk
of acquisition, particularly in connection with endospore-forming
bacteria such as Clostridium difficile. However, these are
so-called "contained" methods (i.e., done in a closed, controlled
environment) and cannot be performed unless the object can be
removed and taken to a separate treatment facility, and, even then,
none have proven to be effective against biofilms and, even in
those instances when sanitization is achieved, the biofilm EPS is
not removed by any of these treatments (thereby permitting much
more rapid re-growth of the bacterial biofilm as compared to an
EPS-free surface when a pathogen is re-introduced).
[0184] From the foregoing, the ordinarily skilled artisan can
envision many potential applications for the antimicrobial
compositions described previously in the battle against HAIs, as
well as biofilms containing or capable of entraining HAI-causing
microorganisms. Common examples include cleaning and/or
disinfection of any of the types of hard surfaces mentioned above,
as well as floors and walls; water transport articles including
sinks, therapeutic tubs, showers and drains; beds; transport
devices such as gurneys and wheelchairs; surgical suites; and the
like. In these instances, high efficacy and low toxicity generally
are preferred. Particularly preferred are those compositions which
will not harm (e.g., warp or discolor) the surface being
treated.
[0185] Other common examples include cleaning and/or disinfection
of any of the types of medical equipment mentioned above,
particularly those which are intended for insertion into a patient
(e.g., respiratory tubes, IV lines, and catheters) or application
to the skin (e.g., stethoscopes, blood pressure cuffs, and the
like). Again, high efficacy and low toxicity generally are
preferred for this type of application.
[0186] Other examples include laundering compositions for linens
and clothing, hand disinfectants and washes, surgical site
preparation solutions, and the like. Laundering compositions are
envisioned as typically being caustic and including high loading
levels of surfactant, as well as being capable of being provided in
either liquid or solid form for addition to wash water. Hand washes
and surgical preparation compositions would be very similar to the
OTC and Rx wound washes described previously.
[0187] No particular limitation on the types of microbes that can
be treated are envisioned, with particularly problematic pathogenic
organisms like Clostridium difficile, Pseudomonas aeruginosa,
Candida albicans, MRSA, and VRE being specifically envisioned. Also
envisioned is any microbe that forms or can reside in a biofilm,
with treatment involving both destruction/removal of the biofilm as
well as killing of the microbes entrained therein.
Implants
[0188] Although terminally sterilized, medical device implants can
become colonized, prior to and during implantation, with bacteria
from the environment, from a healthcare worker, or more commonly
from bacteria present on the patient's own skin. After insertion,
implants can become colonized from systemic bacteria which make
their way to the implant which provides a surface for biofilm
growth because the implant surface is not protected by the host
immune defenses.
[0189] In addition, currently employed sterilization techniques are
not designed to remove EPS/ECPS. Therefore, even a sterilized
device/article that is properly implanted can have EPS/ECPS on its
surface from previous exposure. The presence of EPS/ECPS greatly
facilitates formation of a biofilm.
[0190] Soon after a device or article is implanted, a conditioning
layer composed of host-derived adhesins (including fibrinogen,
fibronectin, and collagen) forms on the surface of the implant and
invites adherence of free-floating (planktonic) organisms.
Bacterial cell division, recruitment of additional planktonic
organisms, and secretion of bacterial products (such as the
glycocalyx) follow, resulting in a three-dimensional structure of
biofilm that contains complex communities of tightly attached
(sessile) bacteria. These bacteria display cell-to-cell signaling
and exist within a polymer matrix containing fluid channels that
allow for the flow of nutrients and waste.
[0191] Once a biofilm forms on an implant, no currently available
treatment can eradicate it. Systemic antibiotics are ineffective
against such infections, certainly due to the inherent protection
by the EPS/ECPS but also perhaps due to limited blood supply at the
surface of the implanted article.
[0192] Most implants infected by S. aureus or candida require
surgical removal. Infections with less virulent coagulase-negative
staphylococci may not require surgery to remove the implant. If a
decision is made to remove the infected implant, complete
extraction of all components is performed, regardless of the type
of infecting organism.
[0193] An infected joint prosthesis can be retained after
debridement or, more commonly, removed. In removal situations, the
affected area is treated with large doses of antibiotics,
optionally followed by insertion of a new device either immediately
or, more commonly, after a 35-45 day course of a systemic
antibiotic. Infections (and treatments) associated with orthopedic
devices often result in serious disabilities.
[0194] Infections associated with surgical implants are
particularly difficult to manage because they require longer
periods of antibiotic therapy and repeated surgical procedures.
Mortality attributable to such infections is highest among patients
with cardiovascular implants, particularly prosthetic heart valves
and aortic grafts.
[0195] A biofilm-fouled pacemaker-defibrillator implant often is
treated by a combined medical and surgical treatment. Surgical
treatment is done in two-stages: the entire implanted system,
including the cardiac leads, is completely removed, even in
patients with clinical infection of only the pocket, because their
cardiac leads may already be colonized (with cardiac rhythm being
controlled by a temporary mechanism), a lengthy course of systemic
antibiotics is administered (up to two weeks for infections of the
pulse-generator pocket or 35-45 days for lead-associated
endocarditis), and a replacement device/article is implanted on the
contralateral side of the patient.
[0196] Infections of fracture-fixation devices that involve bone
are treated with a 6-week course of systemic antibiotics, whereas
10 to 14 days of antibiotic therapy are sufficient for superficial
infections. Infection of intramedullary nails is often associated
with nonunion of bone and requires removal of the infected nail,
insertion of external-fixation pins, and if necessary, subsequent
insertion of a replacement nail. Surgical treatment of infection of
external-fixation pins usually consists of a single procedure to
remove the infected pins and, if bone union has not occurred,
either insert new pins at a distant site or fuse the bones.
[0197] Treatment of infected mammary implants usually entails a
two-stage replacement procedure: removal of the infected implant
and debridement of the capsule surrounding it. After administration
of a course of systemic antibiotics and time for the area to heal
somewhat, the contralateral implant is removed, and a replacement
pair of mammary implants is inserted.
[0198] An infected penile implant typically is removed, and a
malleable penile prosthesis is inserted to preserve space. After
the necessary systemic antibiotic treatment, a new inflatable
implant is inserted in place of the malleable prosthesis.
[0199] Even cutaneous implants such as tracheotomy tubes, ostomy
bags, catheters, and piercings can become fouled with biofilms that
are difficult to remove, a problem exacerbated by the non-removal
nature of certain types of these articles.
[0200] The aforedescribed antimicrobial compositions can be
effective topical treatments, applied to a to-be-implanted device
or article or can be used to wash the infected implant and
surrounding tissue to rid the body of a biofilm and/or
biofilm-forming materials such as EPS/ECPS. The types of surfaces
involved can be or include PTFE, PVC, silicone gels and rubbers,
polyethylene, polypropylene, poly(meth)acrylates, stainless steel,
precious metals (e.g., gold, silver, and platinum), ceramics, and
titanium.
[0201] The pocket where the implant is or was located likewise can
be treated with a liquid composition of the types mentioned above
in connection with wound care. This can be done at the time of the
original implantation (i.e., immediately following insertion of the
article and prior to suturing), and can be followed with
rinsing/irrigation, suctioning or both.
[0202] For implants in contact with body tissue, low toxicity but
moderate-to-high efficacy is desired; this might be achievable with
a composition having a fairly neutral pH (e.g.,
5.ltoreq.pH.ltoreq.9) but moderate-to-high osmolarity, e.g., at
least .about.1.5 Osm/L, commonly at least .about.1.75 Osm/L, more
commonly at least .about.2.0 Osm/L, and typically at least
.about.2.25 Osm/L. Compositions with tonicities of .about.2.5,
.about.2.75, .about.3.0, .about.3.25, .about.3.5, .about.3.75 or
even -4 Osm/L can be used. Cationic surfactants again are
preferred, preferably at levels of .about.0.5 to .about.2 g/L, more
preferably of .about.0.7 to .about.1.8 g/L, and most preferably of
.about.0.8 to .about.1.5 g/L.
[0203] For devices not yet in contact with body tissue, the
conditions can be more extreme, i.e., higher toxicity and very high
osmolarity. In either case, the application of the antimicrobial
composition can be by rinsing, wiping, flushing, etc., optionally
in conjunction with scraping/debridement and optionally followed by
a rinsing step. In extreme cases, the implanted article can be
removed and treated ex vivo with the composition prior to
re-implantation.
[0204] Alternative or additional techniques involve preparing a
body area in which an implant is to be inserted by washing, wiping
and/or irrigating that area with an antimicrobial composition. This
can be done in conjunction with surgical preparation sterilization
with the same or similar composition.
[0205] While various embodiments of the present invention have been
provided, they are presented by way of example and not limitation.
To the extent feasible, as long as they are not interfering or
incompatible, features and embodiments described above in isolation
can be combined with other features and embodiments.
* * * * *