U.S. patent application number 12/053536 was filed with the patent office on 2008-11-13 for physiologically balanced, ionized, acidic solution and methodology for use in wound healing.
This patent application is currently assigned to NovaBay Pharmaceuticals, Inc.. Invention is credited to Mansour Bassiri, Ramin Najafi, Lu Wang, Jane Yang.
Application Number | 20080279963 12/053536 |
Document ID | / |
Family ID | 46299885 |
Filed Date | 2008-11-13 |
United States Patent
Application |
20080279963 |
Kind Code |
A1 |
Najafi; Ramin ; et
al. |
November 13, 2008 |
PHYSIOLOGICALLY BALANCED, IONIZED, ACIDIC SOLUTION AND METHODOLOGY
FOR USE IN WOUND HEALING
Abstract
Described herein is a physiologically-balanced, acidic solution.
Typically the solution is prepared by a chemical reactions or by
the electrolysis of a solution comprising a mixture of an inorganic
salt to form a physiologically balanced solution. This invention
also relates to methods for use of the solutions, including a
specialized bandage which may be used in combination with the
solutions, or optionally with other topically applied materials. A
mixture of inorganic salts and, optionally minerals, is used in
order to mimic the electrolyte concentration and mixture of body
fluid in an isotonic state. The solution typically comprises of one
halide salt of lithium, sodium, potassium, calcium, and other
cations. Typically the halide is fluoride, chloride, bromide, or
iodide, and most typically chloride. A typical electrolyzed
solution of the present invention has a pH within the range of
about 2 to about 5, an oxidation reduction potential within the
range of about +600 mV to about +1200 mV, and hypohalous acid
concentration in the range of about 10 ppm to about 200 ppm. The
solution has bactericidal, fungicidal, and sporicidal properties.
The composition of the invention is nontoxic and has antibacterial
properties, and is useful in any application in which antimicrobial
properties are desirable.
Inventors: |
Najafi; Ramin; (Novato,
CA) ; Wang; Lu; (Emeryville, CA) ; Bassiri;
Mansour; (Emeryville, CA) ; Yang; Jane;
(Emeryville, CA) |
Correspondence
Address: |
HELLER EHRMAN LLP
4350 La Jolla Village Drive, 7th Floor
San Diego
CA
92122
US
|
Assignee: |
NovaBay Pharmaceuticals,
Inc.
|
Family ID: |
46299885 |
Appl. No.: |
12/053536 |
Filed: |
March 21, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10655493 |
Sep 3, 2003 |
7393522 |
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12053536 |
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10209681 |
Jul 30, 2002 |
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10655493 |
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10000919 |
Nov 2, 2001 |
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10209681 |
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09482159 |
Jan 12, 2000 |
6426066 |
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10000919 |
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Current U.S.
Class: |
424/661 |
Current CPC
Class: |
A61K 33/30 20130101;
A01N 59/00 20130101; A61K 33/40 20130101; C02F 2209/06 20130101;
A61K 33/14 20130101; A01N 59/00 20130101; C02F 2201/4618 20130101;
A61K 9/0048 20130101; C02F 2001/46185 20130101; A61K 2300/00
20130101; A61K 31/74 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; C02F 2103/026 20130101; A61K 2300/00 20130101; C02F
2201/46115 20130101; A01N 2300/00 20130101; A61P 17/02 20180101;
A61L 2/0088 20130101; A61K 33/40 20130101; A61K 33/14 20130101;
C02F 1/4618 20130101; A61K 33/24 20130101; A61K 2300/00 20130101;
A61K 33/24 20130101; C01B 11/04 20130101; A61K 31/74 20130101; C02F
2209/04 20130101; C02F 2303/04 20130101; A61L 2/0035 20130101; A61K
33/30 20130101 |
Class at
Publication: |
424/661 |
International
Class: |
A61K 33/14 20060101
A61K033/14; A61P 17/02 20060101 A61P017/02 |
Claims
1-36. (canceled)
37. A method for the treatment of a medical condition selected from
the groups consisting of disinfection or decontamination of open
wounds and burns, promotion of wound healing, in a patient in need
of such treatment comprising: applying to a treatment site an
effective amount of a stable aqueous physiologically balanced,
ionized solution comprising an acidic solution of hypohalous acid
with a concentration from about 0.1 ppm to about 1,000 ppm; a
halide comprising salt, the halide comprising salt is sodium
chloride at a concentration of about four-tenth to slightly higher
than full strength of normal or isotonic saline solution, said
solution having a pH range from about 3.0 to about 4.0, an original
reduction potential (ORP) at room temperature ranging from about
+600 mV to about +1200 mV, and said ORP ranging from no less than
about 90 to 97.5% of the original ORP after three months at room
temperature; and said solution when stored in a chemically
non-reactive container at room temperature over at least three
months, the solution is characterized as having a reduced
hypohalous acid concentration of between 1-95% as determined by
UV-VIS or by iodometric titration.
38. A method for the treatment of a medical condition selected from
the groups consisting of disinfection, decontamination of open
wounds and promotion of wound healing in a patient in need of such
treatment comprising: applying to a treatment site an effective
amount of a stable aqueous physiologically balanced, ionized
solution comprising an acidic solution of hypohalous acid with a
concentration from about 1 ppm to about 750 ppm; a halide
comprising salt, the halide comprising salt is sodium chloride at a
concentration of about four-tenth to slightly higher than full
strength of normal or isotonic saline solution, said solution
having a pH range from about 3.0 to about 4.0, an original
reduction potential (ORP) at room temperature ranging from about
+600 mV to about +1200 mV, and said ORP ranging from no less than
about 90 to 97.5% of the original ORP after three months at room
temperature; and said solution when stored in a chemically
non-reactive container at room temperature over at least three
months, the solution is characterized as having a reduced
hypohalous acid concentration of between 1-95% as determined by
UV-VIS or by iodometric titration.
39. A method of disinfecting or decontaminating open wounds and
promoting wound healing by treating a patient in need thereof with
an effective amount of a stable aqueous physiologically balanced,
ionized solution comprising an acidic solution of hypohalous acid
with a concentration from about 5 ppm to about 500 ppm; a halide
comprising salt, the halide comprising salt is sodium chloride at a
concentration of about four-tenth to slightly higher than full
strength of normal or isotonic saline solution, said solution
having a pH range from about 3.0 to about 4.0, an original
reduction potential (ORP) at room temperature ranging from about
+600 mV to about +1200 mV, and said ORP ranging from no less than
about 90 to 97.5% of the original ORP after three months at room
temperature; and said solution when stored in a chemically
non-reactive container at room temperature over at least three
months, the solution is characterized as having a reduced
hypohalous acid concentration of between 1-95% as determined by
UV-VIS or by iodometric titration.
40. The method of claim 37 wherein the pH range is from about 3.5
to about 4.0.
41. The method of claim 38 wherein the pH range is from about 3.5
to about 4.0.
42. The method of claim 39 wherein the pH range is from about 3.5
to about 4.0.
43. The method of claim 40 wherein the pH is about 3.5.
44. The method of claim 41 wherein the pH is about 3.5.
45. The method of claim 42 wherein the pH is about 3.5.
46. The method of claim 37 wherein the sodium chloride
concentration is from about 4 g/l to about 10 .mu.l.
47. The method of claim 38 wherein the sodium chloride
concentration is from about 4 g/l to about 10 g/l.
48. The method of claim 39 wherein the sodium chloride
concentration is from about 4 g/l to about 10 g/l.
49. The method of claim 46 wherein the sodium chloride
concentration is about 9 g/l.
50. The method of claim 47 wherein the sodium chloride
concentration is about 9 g/l.
51. The method of claim 48 wherein the sodium chloride
concentration is about 9 g/l.
52. The method of claim 37, the hypohalous acid is selected from
the group consisting of HOBr and HOCl.
53. The method of claim 38, the hypohalous acid is selected from
the group consisting of HOBr and HOCl.
54. The method of claim 39, the hypohalous acid is selected from
the group consisting of HOBr and HOCl.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/655,493, filed Sep. 3, 2003, which is a continuation-in-part
of U.S. application Ser. No. 10/209,681, filed Jul. 30, 2002, which
is a continuation-in-part of U.S. application Ser. No. 10/000,919,
filed Nov. 2, 2001, which is a divisional of U.S. patent
application Ser. No. 09/482,159, filed Jan. 12, 2000, all of which
are incorporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to a physiologically balanced,
ionized, acidic solution that is useful in wound healing and other
applications in which antimicrobial properties are desirable. The
ionized solution may be prepared by electrolysis, i.e., it is an
electrolyzed solution or by other methods including chemical or
physical methods. The solution may also be prepared in situ. In
addition, the invention relates to a methodology of using the
solution of the invention, in a variety of applications, for
example, a specialized bandage which may be used in combination
with the solution or with other solutions or topically applied
materials.
[0004] 2. Brief Description of the Background Art
[0005] Various electrolyzed acidic salt solutions, their
properties, and their uses have been described in the art. Several
examples are provided below.
[0006] U.S. Pat. No. 5,622,848, issued Apr. 22, 1997, to Morrow,
discloses a microbicidal solution for in vivo and in vitro
treatment of microbial infections. The solution comprises an
electrolyzed saline containing regulated amounts of ozone and
active chlorine species, wherein the ozone content is between about
5 and 100 mg/L, the active chlorine species content is between
about 5 and 300 ppm and a pH range from 7.2-7.6. The active
chlorine species comprises free chlorine, hypochlorous acid, and
the hypochlorite ion, as measured by a chlorine selective
electrode. The solution is prepared by subjecting a 1% or less
saline solution to electrolysis under conditions sufficient to
produce the desired active ingredients. The solution is preferably
utilized at an isotonic saline concentration, and may be adjusted
with hypertonic saline. The solution may be used for in vitro
treatment of infected whole blood, blood cells, or plasma to reduce
contamination, and may be used in the treatment of fluids infected
with HIV, hepatitis, and other viral, bacterial, and fungal agents.
The solution may also be administered to warm-blooded animals,
including humans, by intravenous injection or other modes, for
similar purposes.
[0007] PCT publication No. WO9934652, published Jul. 8, 1999, of
Marais, discloses the use of an electrochemically activated sodium
hypochlorite-free irrigating medium to reduce the proliferation of
bacteria and other microorganisms during tooth root canal. Anion-
and cation-containing solutions are obtained by electrolysis of a
10% aqueous NaCl solution. The anion-containing solution is used at
a pH of about 2-7 and an oxidation reduction potential (ORP) of
about +1170 mV; the cation-containing solution is used at a pH of
about 7-13 and an ORP of about -980 mV.
[0008] X. W. Li et al. (Chinese J. Epidem., 17(2), pp. 95-98, 1996)
reported a preliminary study of the microbicidal effect of
electrolyzed oxidizing water. Electrolyzed oxidizing water was
shown to completely kill Staphylococcus aureus and Escherichia coli
within 15 seconds, while 10 minutes were required to completely
kill all spores of Bacillus subtilus var. niger. Thirty seconds
were needed to destroy the antigenicity of HBsAg. The oxidation
reduction potential and pH values of electrolyzed oxidizing water
were not significantly changed when stored for three weeks at room
temperature under air-tight, light-free conditions.
[0009] A. Iwasawa et al. (J. Jap. Assoc. Infec. Diseases, 70(9),
pp. 915-922, 1996) evaluated the bactericidal effect of acidic
electrolyzed water on S. aureus, S. epidermidis, and Pseudomonas
aeruginosa. At pH 5.0 to approximately 6.0, three bacterial strains
were killed soon after being exposed to the acidic water containing
50 mg/L chloride, and the chloride concentration reportedly did not
change after standing open for 6 hours. At pH 2.67 to approximately
2.80, the bactericidal effects were observed at a chloride
concentration of 5 mg/L, and 80% of the chloride reportedly
remained after standing open for 6 hours.
[0010] H. Tanaka et al. (J. Hosp. Infect., 34(1), pp. 43-49, 1996)
reported on the antimicrobial activity of superoxidized water.
Superoxidized water is described as "a strong acidic and colorless
solution with a high oxidation-reduction potential. The solution
having an active chlorine concentration of 30 ppm, is prepared by
mixing a small amount of salt with tap water in an electrolyser".
The antimicrobial activity of superoxidized water was tested
against methicillin-sensitive S. aureus, Serratia marcescens, E.
coli, P. aeruginosa, and Burkholderia cepacia. The number of
bacteria was reduced below the detection limit following incubation
in superoxidized water for 10 seconds. The bactericidal activity of
superoxidized water was similar to that of 80% ethanol, but
superior to that of 0.1% chlorhexidine and 0.02% povidone
iodine.
[0011] Y. Inoue et al. (Artificial Organs, 21(1), pp. 28-31, 1997)
reported on the use of electrolyzed strong acid aqueous solution
lavage in the treatment of peritonitis and intraperitoneal abscess.
Peritoneal and abscess lavages were performed using an electrolyzed
strong acid aqueous solution to treat seven patients with
peritonitis and intraperitoneal abscesses. The period of irrigation
in the seven patients ranged from 9 to 12 days, with conversion to
microorganism negative state observed within 3 to 7 days. The
authors describe the solution as being "acidic water that contains
active oxygen and active chlorine and possesses a redox potential"
and having an active chlorine concentration less than 50 ppm.
[0012] S. Sekiya et al. (Artificial Organs. 21(1), pp. 32-38, 1997)
reported on the use of electrolyzed strong acid solutions in the
treatment of infectious skin defects and ulcers using. The
clinically applied therapy of electrolyzed strong acid aqueous
solutions were found to be effective in the treatment of infectious
ulcers. Sekiya et al. describe the strong aqueous solution (ESAAS)
as being "generated by electrolyzing water and a small quantity of
salt with a cation transfer filter."
[0013] H. Hayashi et al. (Artificial Organs, 21(1), pp. 39-42,
1997) reported on the use of electrolyzed strong acid aqueous
solutions (ESAAS) in the treatment of mediastinitis following
cardiovascular surgery. Hayashi et al. described ESAAS as being
"produced by electrolyzing sodium chloride solution. ( . . . )
ESAAS is produced by electrolyzing the sodium chloride solution
using an ion-exchange membrane that separates the positive and
negative electrodes. A small amount of sodium chloride is added to
the water to facilitate electrolysis and increase the concentration
of dissolved chloride." The solution is disclosed as having a pH
less than 2.7, Cl.sub.2 more than 30 ppm, ORP more than 1100, and
dissolved O.sub.2 of more than 20 ppm. The mediastinal wound was
left open and irrigated with ESAAS one to three times daily until
the infection was eradicated. Satisfactory growth of granulation
tissue was observed in all patients treated, with no evidence of
adverse effects attributable to ESAAS.
[0014] N. Tanaka et al. (Artificial Organs, 23(4), pp. 303-309,
April 1999) reported on the use of electrolyzed strong acid aqueous
solutions to clean and disinfect hemodialysis equipment. The
solutions were found to directly inactivate bacterial endotoxins,
and proved to be more economical than the conventional disinfecting
method. The "electrolyzed strong acid aqueous solutions are
disclosed to be "strongly acidic water which is made by
electrolyzing tap water containing 500-1000 ppm salt (NaCl>99%
pure) in a cell partitioned by a polyester diaphragm. It has an
acidity of 2.3-2.7 pH, more than 1,000 mV in oxidation-reduction
potential and 10-50 ppm in available chlorine."
[0015] J. B. Selkon et al. (J. Hosp. Infec., 41 (1), pp. 59-70,
January 1999) evaluated the antimicrobial activity of a new
superoxidized water, STERILOX.RTM. (Sterilox Medical Limited, 85 E
Milton Park, Abingdon, Oxon OX14 4RY, UK) for the disinfection of
endoscopes. This superoxidized water is prepared from a 35.7% NaCl
in a 1 to 20 dilution, and is described as being "generated at the
point of use by passing a saline solution over coated titanium
electrodes at 9 amps. The product generated has a pH of 5.0-6.5 and
an oxidation reduction potential of >950 mV." The antimicrobial
activity of STERILOX.RTM. was tested against Mycobacterium
tuberculosis, M. avium-intracellulare, M. chelonae, E. coli
(including type 0157), Enterococcus faecalis, P. aeruginosa, B.
subtilus var. niger spores, methicillin-resistant S. aureus,
Candida albicans, poliovirus type 2, and human immunodeficiency
virus HIV-1. Under clean conditions, freshly generated
STERILOX.RTM. was found to be highly active against all these
microorganisms, giving a 5 log.sub.10 (99.999%) or greater
reduction in 2 minutes or less.
[0016] U.S. Pat. No. 6,296,744 assigned to Sterilox Technologies
International Limited, discloses an apparatus for the
electrochemical treatment of a liquid medium, which allows for the
production of a sterilizing solution as well as the decontamination
and purification of liquid mediums from toxic organic substances
and other impurities. The process utilizes solution having an
average salinity of 0.1 to 1.0 g/l and a chloride concentration of
up to 50 mg/l, and the process is carried out using a current of
500 to 1000 mA with potential difference of 10-12 volts. The patent
also discloses that the optimum pH parameters for
anodically-treated water are 6-7, and for cathodically-treated
water 8-9. However, the patent further discloses that the apparatus
proposed aims to achieve solutions of active chlorine with a pH of
between 4.5 and 7.5 used as a sterilizing solution, disinfectant,
decontaminant, bleaching agent, detergent or medicine with
antibacterial and antiviral action.
[0017] K. S. Venkitanarayanan et al. (Appl. & Env. Microbiol.,
65(9), pp. 4276-4279, September 1999) evaluated the efficacy of
electrolyzed oxidizing water for inactivating E. coli O157:H7,
Salmonella enteritidis, and Listeria monocytogenes. A five-strain
mixture of E. coli O157:H7, S. enteritidis, or L. monocytogenes was
inoculated in electrolyzed oxidizing water at various temperatures,
for various time periods. The electrolyzed oxidizing water is
produced from a saline base solution containing approximately 12%
by weight NaCl. The electrolyzed oxidizing water is also described
as having a 0.1% salt, Cl.sub.2 of 10-80 ppm, pH less than 2.7 as
well as an electrolyzed oxidizing water having Cl.sub.2 of 73-86
ppm, and pH of 2.38-2.48. At 4.degree. C. and 23.degree. C., an
exposure time of 5 minutes, the population of all three pathogens
in the treatment samples was reported to be reduced by
approximately 7 log CFU/mL, with compete inactivation by 10 minutes
of exposure. A reduction of greater than 7 log CFU/mL in the levels
of the three pathogens was reported to occur in the treatment
samples incubated for 1 minute at 45.degree. C. or for 2 minutes at
35.degree. C.
SUMMARY OF THE INVENTION
[0018] This invention relates to stable physiologically balanced,
non-cytotoxic ionized, acidic solutions and to a methodology for
their use. The invention also relates to applications of the
solutions of the invention, including a specialized bandage which
may be used in combination with the solutions, or with other
topically applied materials. The ionized solutions may be prepared
by electrolysis. In another aspect of the invention, the solutions
are prepared by chemical methods, including synthesis, or by
mechanical methods such as by mixing, or are prepared in situ.
[0019] A novel physiologically balanced solution was recently
disclosed in co-pending applications, U.S. application Ser. No.
10/209,681, filed Jul. 30, 2002, U.S. application Ser. No.
10/000,919, filed Nov. 2, 2001, and U.S. Ser. No. 09/482,159, filed
on Jan. 12, 2000 (corresponding to WO 01/54704 A1 published on Aug.
2, 2001), all of which are incorporated herein by reference in
their entirety.
[0020] The composition of the invention may be prepared using an
inorganic salt in physiologically balanced form. The inorganic salt
is used in order to mimic the electrolyte concentration and mixture
of extra cellular body fluid in an isotonic state. The solution
typically comprises the halide salt of sodium, or potassium, or
calcium, and other cations. Typically the halide is fluoride,
chloride, bromide, or iodide, and most typically chloride. In part,
the concentrations of the salinity, the pH and the active chlorine
concentration are such that they give the composition its unique
properties.
[0021] The solutions of the present invention may be prepared using
a single inorganic salt, forming an initial concentration of the
salt in the aqueous solution of about 0.4 to about 1.0%. The
halide-comprising salt may be selected from the group consisting of
lithium halide, sodium halide, potassium halide, magnesium halide,
calcium halide, zinc halide, cesium halide, rubidium halide and
barium halide. Non-limiting examples of the inorganic salt may also
include NaBr, NaI, NaF, LiBr, LiCl, LiI, MgI.sub.2, MgBr.sub.2, KI,
KCl, KBr and the like. The inorganic salt may be a metal halide
such as a chloride comprising salt selected from the group
consisting of LiCl, NaCl, KCl, MgCl.sub.2, CaCl.sub.2, and
ZnCl.sub.2. In one aspect of the invention, the initial salt
concentration used in the aqueous solution is about 0.4 to about
0.9%.
[0022] In another aspect of the invention, the inorganic salt is
sodium chloride at a concentration of about 0.4 to about 1.0% NaCl
which is about four-tenth to slightly higher than full strength of
normal or isotonic saline solution. According to Parker's
McGraw-Hill Dictionary of Scientific and Technical Terms, S. P.
Parker, editor, Fifth Edition, "normal saline", "physiological
saline", "physiological salt solution" are defined as a "solution
of sodium chloride in purified water, containing 0.9 grams of
sodium chloride in 100 milliliters; isotonic with body fluids." For
different salts such as lithium halides, potassium halides, and the
like, the concentration of the salt in solution making up an
isotonic solution may differ from the concentration of sodium
chloride in an aqueous solution in order to maintain the desired
osmolarity of the solution of the invention. In yet another aspect
of the invention, the sodium chloride in the aqueous solution is at
a concentration of about 0.4 to about 0.9%.
[0023] In one aspect of the present invention, we have created a
composition comprising a stable, physiologically balanced,
noncytotoxic acidic solution, herein also referred to as the
NVC-101 solution, where the starting solution prior to its
preparation, for example, by electrolysis, comprises a total
concentration of the halide-comprising salt ranging from about 0.4
g/L to about 16 g/L; more preferably ranging from about 4 g/L to
about 10 g/L; and, most preferably, ranging from about 4 g/L to
about 9 g/L. The solution may optionally contain minerals. The
solution is adjusted to a pH within the range of about 2 to about
5, and has an oxidation reduction potential within the range of
about +600 mV to about +1200 mV, and the solution having a total
active halogen concentration of 0.1 to about 1,000 ppm, preferably
from about 10 to about 200 ppm, and most preferably from about 40
to about 190 ppm. In one aspect of the invention, the active
halogen is selected from the group consisting of fluorine,
chlorine, bromine, and iodine. In another aspect of the present
invention, the halogen is chlorine.
[0024] The starting solution used to prepare the physiologically
balanced, acidic composition of the invention may comprise a
halide-comprising salt selected from the group consisting of
lithium halide, sodium halide, potassium halide, magnesium halide,
calcium halide, zinc halide, cesium halide, rubidium halide and
barium halide. The composition of the salts of the solution of the
present invention are physiologically balanced, as salt contents
that are too low or too high in concentration relative to a
physiological balanced solution may damage cells. The term
"starting solution" is defined as the solution containing the added
salt composition prior to any reaction or electrolysis of the
solution.
[0025] In another aspect of the invention, the starting solution of
the halide-comprising salt, and optionally containing minerals, is
converted to an acidic water solution through electrolysis. The
electrolyzed, halide-comprising solution has a typical oxidation
reduction potential (ORP) of about +600 to +1200 mV. The pH of the
electrolyzed, halide comprising solution, such as a
chlorine-comprising solution, is typically lowered to about 5 or
less, but not less than a pH of 2, preferably with a pH range of
about 3.0 to 4.0, more preferably a pH of about 3.5 to 4.0, most
preferably a pH of about 3.5, giving the solution virucidal,
bactericidal, fungicidal, and sporicidal properties. The
halide-comprising acidic solution is physiologically balanced.
Typically the salts are supplied in the form of a halide-comprising
salt which is ionized during electrolysis. These
physiologically-balancing halide-comprising salts are selected from
the group consisting of lithium halide, sodium halide, potassium
halide, magnesium halide, zinc halide, lithium halide, barium
halide, cesium halide, and rubidium halide. Preferably, these
physiologically-balancing halide-comprising salts are selected from
the group consisting of lithium halide, sodium halide, potassium
halide, magnesium halide, zinc halide, lithium halide, and barium
halide. Most preferably the salts are selected from sodium
chloride, potassium chloride, magnesium chloride, or zinc
chloride.
[0026] In another aspect of the invention, the starting solution
for the preparation of the electrolyzed solution comprises of at
least one metal halide salt. Where more than one metal halide salts
are present, the salts may be present in the same or different
concentrations from each other.
[0027] In one exemplary solution of the present invention, the
starting solution for the preparation of the electrolyzed solution
includes sodium halide present at a concentration ranging from
about 4.0 g/L to about 9.9 g/L. In one aspect of the invention, the
halide is chloride.
[0028] A particularly preferred starting solution for preparation
of the solution includes sodium chloride present at a concentration
ranging from about 0.4 g/L to about 14 g/L.
[0029] In one aspect of the invention, the solution of the
invention may be prepared by electrolysis by subjecting the
starting salt solution to electrolysis under conditions sufficient
to produce the desired composition.
[0030] In another aspect of the invention, the salt comprising
acidic solutions may be prepared by chemical methods, including
chemical synthesis, or by physical methods such as mixing the
components of the solution. In another aspect, the solution is
prepared in situ at the location where it is to be applied or used
directly. Methods for the preparation of the solution in situ are
provided below.
[0031] The acidic solution of the invention contains hypohalous
acid and may contain, among other components, hydroxyl free
radicals, oxygen, and ozone. These components comprise some of the
same oxidizing agents involved in physiological systems associated
with wound healing and tissue repair and regeneration. For example,
hypochlorous acid is the chief bactericidal agent produced by
neutrophils at sites of inflammation, injury, and wounds.
[0032] Because the solutions of the invention are physiologically
balanced, when applied to infected wounds, they enhance the process
of healing substantially. Antimicrobial properties of the solutions
of the inventions have been tested against many organisms,
including Escherichia coli, Listeria monocytogenes, Staphylococcus
aureus, methicillin-resistant S. aureus (MRSA), Pseudomonas
aeruginosa, Lactobacillus, yeast, vancomycin-resistant
enterococcus, molds, and spores, including spores of anthrax. In
particular, the solutions of the present invention have been used
to successfully treat three different strains of Bacillus
anthracis. Vancomycin-resistant bacteria, MRSA, and others are
easily destroyed by the solutions of the present invention. The
solutions of the invention are osmotically balanced,
environmentally friendly, and have minimal cytotoxicity. For
example, no cytotoxicity was observed in rabbits' eyes nor in in
vitro cytotoxicity studies carried out to date.
[0033] When the solution of invention is applied in in vitro
studies to human skin cells: keratinocytes, fibroblasts and
melanocytes, it is well tolerated and the minimal-cytotoxicity
parallels that of sterile saline solution. The solution of
invention was also applied in in vivo studies to rabbit eyes using
the Draize test, which provides direct observations of the eyes'
anatomical and physiological changes after exposure of the eyes to
test solutions. In comparative studies, rabbits received randomly
and in a double-blind fashion either saline (15 eyes) or the
solutions of the present invention (15 eyes). Each eye received 0.1
ml of solution every 8 hours and observations were collected at
various time points. The treated eyes were observed for ocular
irritation. The cytotoxicity index was zero for both arms of the
studies: saline and the solutions of the invention treated rabbits
tolerated both treatments similarly, and did not show any
irritation response. The isotonic solutions of the present
invention were determined to be non-toxic to biological tissues and
comparable to saline solutions.
[0034] In one aspect, the solution of the invention has the
following stability characteristics. After the solution is stored
in a container or storage medium for a period of about 25 months at
about 4.degree. C., the solution was determined to have a measured
oxidation reduction potential (ORP) of no less than about 90% but
not more than about 99.9%, preferably no less than about 95% but no
more than about 99.9%, and most preferably no less than about 97.5%
but not more than about 99.9% of the ORP of the solution freshly
prepared prior to storage, while maintaining up to 5 logs of
reduction in the activity of the microorganisms after 10 to 60
seconds of exposure to the solution.
[0035] The stable solutions prepared and stored in a medium
according to the methods of the present invention have extended
stability or shelf life characteristics, depending on the nature of
the medium of storage, the temperature of storage, and whether the
container or medium has been opened. For example, the solution may
have a ORP of no less than 95% of the ORP of the freshly prepared
solution for at least 24 months when stored at room temperature if
the container has not been previously opened or used after storage.
In one aspect, the stable solution of the present invention may be
stored in a gas tight, sealed container which further extends the
stability characteristics of the solution. In addition, the
solutions of the present invention will have a longer storage shelf
life if the solutions are stored below room temperature rather than
when stored at or above room temperature. "Room temperature" is
being defined herein as between 20 to 25.degree. C.
[0036] As defined herein, "stability" of the solution or a "stable
solution" means that the solution of the present invention
maintains up to 5 logs of reduction in the activity of the
microorganisms after 10 to 60 seconds of exposure to the
solution.
[0037] The relative stability of the solution of the invention may
also be determined from chemical analysis or by spectroscopy. The
stability of the solution may be determined by iodometric titration
or by UV-VIS for the presence of active halide as described
herein.
[0038] A stable solution as defined in this invention is a solution
prepared and stored according to the procedures described herein
and having a reduced concentration of active chlorine over a period
of time, preferably a reduction of between 1-95% of active chlorine
species, more preferably a reduction of between 5-15% of active
chlorine species, and most preferably a reduction of between 0-5%
of active chlorine species in solution as determined by UV-VIS or
iodometric titration over a period of at least one month,
preferably at least 2 months and more preferably, at least 3
months.
[0039] The measurement of the pH of a solution of the present
invention is another complementary method for determining the
stability of the solution in addition to the UV-VIS or iodometric
titration method.
[0040] The concentration of "active chlorine" or "free chlorine"
species as defined herein, refers to chlorine comprising species
such as HOCl, NaOCl and Cl.sub.2 present in a solution of this
invention, and the total concentration of all of the active
chlorine or free chlorine species in solution can be determined by
UV-VIS or by iodometric titration. The active chlorine species in
solution may also be expressed as [HOCl].sub.total where
[HOCl].sub.total is defined as the sum of the concentration of
HOCl, OCl.sup.-, and Cl.sub.2 in solution; that is,
[HOCl].sub.total=[HOCl]+[OCl.sup.-]+[Cl.sub.2]. The concentration
of active chlorine species may also be expressed in ppm, where the
ppm concentration is equal to the number of mM of the species times
the molecular weight of the particular species being measured. For
example, if a concentration of Cl.sub.2 is referred to in ppm unit,
conversion to the concentration in mM requires that the
concentration in ppm be divided by the molecular weight of Cl.sub.2
(MW of 71).
[0041] Similarly, the concentration of the "active halogen" or
"hypohalous acid" species refers to the concentration of the
corresponding halogen containing species HOX, NaOX, or X.sub.2 as
discussed above, where X is a halogen atom.
[0042] The species HOCl, NaOCl and Cl.sub.2 are equivalent in their
reactions in the iodometric titration methods or as determined by
the UV-VIS method as follows:
HOCl+HClCl.sub.2+H.sub.2O
HOCl+NaOHNaOCl+H.sub.2O
Cl.sub.2+2NaOHNaOCl+NaCl+H.sub.2O
[0043] The active chlorine species in a solution may be measured by
an iodometric titration method, by reacting the solution with KI
and then titrating the solution with a Na.sub.2S.sub.2O.sub.3
solution in the presence of starch. The reaction of the active
chlorine species occurs as follows:
HOCl+HCl+2KII.sub.2+2KCl+H.sub.2O
Cl.sub.2+2KII.sub.2+2KCl
2HCl+NaOCl+2KII.sub.2+2KCl+NaCl+H.sub.2O
I.sub.2+2Na.sub.2S.sub.2O.sub.3NaI+Na.sub.2S.sub.4O.sub.6
[0044] The active chlorine can also be reacted with NaOH and is
converted to NaOCl.
##STR00001##
[0045] NaOCl has an absorption at 292 nm with a known molar
absorptivity of 362 M.sup.-1 cm.sup.-1. Therefore, the
concentration of the active chlorine species can be measured and is
directly correlated with the concentration with any one of the
species HOCl, NaOCl, or Cl.sub.2 or with the combination of these
species in a 1:1 basis.
[0046] Similarly, the concentration of a hypohalous acid species in
solution as defined herein correspond to the concentration of the
active bromine or free bromine, active iodine or free iodine, and
active fluorine, or free fluorine species in the solution as
defined above.
[0047] In one aspect, the solution of the invention has the
following reduced cytotoxicity. When the solution of invention is
applied in in vitro studies to human skin cells such as
keratinocytes, fibroblasts and melanocytes, it is well tolerated
and no substantial cytotoxicity was measured using Tripan Blue
intergen detection and pro check cell viability assay. In another
aspect, the solution of the present invention exhibits the
minimal-cytotoxicity parallels to that of sterile saline
solution.
[0048] Without being bound by any theory offered herein, it is
believed that the minimal cytotoxicity of the solution of the
present invention depends on the concentration of OCl.sup.- in the
solution as disclosed herein.
[0049] Because the composition of the present invention is nontoxic
and has antibacterial properties it is useful in any application in
which antimicrobial properties are desirable. Such applications
include, without limitation, treatment of wounds, burns, and canker
sores; irrigation; cleaning of tissue sites (e.g., pre- and
post-operative); ophthalmic applications (e.g., in contact lens
cleaning solutions or for irrigation of the eye before, during, or
post ophthalmic surgery); for dermatological applications,
psoriasis; and numerous applications which are readily apparent to
one skilled in the art. Unlike many other inorganic halide
solutions used in similar applications, the composition of the
invention has minimal to no side effects. For example, in Draize
testing in Rabbit eyes, when compared to other antiseptic
solutions, the physiologically balanced, stable, acidic solution of
the present invention behaves in a manner similar to saline
solution.
[0050] In another Draize test, rabbit's eyes were treated with the
solution of invention and compared with the ophthalmic grade
Betadine (manufactured by: Alcon Co., TX, at a 5% concentration).
Each eye received 0.1 ml of solution every 8 hours and observations
were recorded at various time points. The Draize method relies on
direct observations of the eyes' anatomical and physiological
changes after exposure of the eyes to test solutions. Rabbits
treated with the solution of invention tolerated the treatment
without any signs of irritations, whereas, rabbits treated with
ophthalmic grade Betadine did not tolerate the treatment and showed
significant level of redness, ocular irritation and discomfort.
[0051] The composition of the invention can be incorporated into a
variety of applications, including a bandage or wound dressing, as
described subsequently herein. The physiologically balanced, acidic
solution may be used in combination with a specially designed
bandage in a wound treatment protocol as described subsequently
herein. The specialized bandage includes an opening or "window"
through which topical treatment materials such as the solution of
the present invention may be applied.
[0052] Also disclosed herein is an article of manufacture
comprising the composition of the invention packaged in a
container. Surfaces of the container which are in contact with the
composition of the invention are made of material which is not
reactive with an oxidizing agent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0053] FIG. 1 is a cross-sectional schematic of an electrolyzing
unit 1 having two compartments, identified in FIG. 1 as elements 2
and 3. Compartments 2 and 3 are separated by a semipermeable
membrane 4. A positive electrode 5 is located in compartment 2,
where a strong acidic solution 6 is generated. A negative electrode
7 is located in compartment 3, where an alkaline solution 8 is
generated. Electrodes 5 and 7 are connected to a power source 9
which generates a current across semipermeable membrane 4. A lid 10
keeps electrolyzing unit 1 free from ambient air 11.
[0054] FIG. 2A is a schematic top view of an air-permeable bandage
200, including outer portion 201 having a primary adhesive border
202; an inner portion 210 including a lifting flap 205 having a
secondary adhesive border 207, a lifting tab 204, which assists in
the lifting of flap 205, a hinge 206, and a dew/humidity indicator
208 (or other sensor/indicator as will be described subsequently
herein).
[0055] FIG. 2B is a schematic side view of air-permeable bandage
200, showing lifting flap 205 and lifting tab 204 in a partially
lifted position, to provide a window opening 203 through bandage
200. A portion of secondary adhesive border 207 has been lifted
above the upper surface 209 of bandage 200.
[0056] FIG. 2C is a schematic cross-sectional view of air-permeable
bandage 200, with lifting flap 205 and lifting tab 204 in a lowered
position, secured to upper surface 209 of bandage 200 by secondary
adhesive border 207.
[0057] FIG. 3 is a schematic cross-sectional view 300 of an
air-permeable bandage 200 of the kind shown in FIGS. 2A-2C, applied
over a subcutaneous wound 303. The subcutaneous tissue 304 is
packed with gauze 306 which has been soaked in the physiologically
balanced, electrolyzed, acidic solution 308 of the present
invention. The bandage 200 is adhered to the skin surface 302 by a
primary adhesive border 202. Bandage lifting flap 205 can be lifted
via tab 204 to expose gauze 306 for the application of additional
solution 308 when a dew/humidity indicator (not shown) or other
sensing/indication device (not shown) indicates a low level of
humidity of the gauze 306.
[0058] FIG. 4 represents PFA in NVC-101 in torch-sealed glass
ampules at 40.degree. C. (Oven).
[0059] FIG. 5 represents a distribution of chlorine species vs pH
in 0.9% NaCl.
[0060] FIG. 6a represents a HOCl stability of NVC-101 JY-1-175 in
torch-sealed clear glass ampules.
[0061] FIG. 6a represents a pH stability of NVC-101 JY-1-175 in
torch-sealed clear glass ampules.
DETAILED DESCRIPTION OF THE INVENTION
[0062] Described herein are stable, physiologically balanced,
acidic solutions; methods and apparatus used in the production of
the solution; methods for use of the solution, including the
description of a specialized bandage for administering the solution
or other topically applied treatment materials. Also disclosed are
recommended packaging for the solution.
[0063] I. The Composition of the Invention
[0064] The present invention is a physiologically balanced, acidic
solution, which may be generated from a starting solution
comprising a total concentration of one halide-comprising salt
ranging in osmolarity from about 0.014 to 0.547 osmol; more
preferably ranging from about 0.123 to 0.376 osmol; and most
preferably ranging from about 0.137 to 0.342 osmol. Optionally,
minerals may be added, depending on the end use application.
[0065] A typical starting solution, prior to electrolysis, by way
of example and not by way of limitation, may comprise of one
chloride comprising salt selected from the group consisting of
lithium chloride, sodium chloride, potassium chloride, magnesium
chloride, calcium chloride, zinc chloride, cesium chloride,
rubidium chloride, and barium chloride.
[0066] Representative concentration ranges for the various
chlorine-comprising salts that may be used in the starting
solutions used to prepare solution are presented in Table 1,
below.
TABLE-US-00001 TABLE 1 Compositions of Chloride Containing Salts In
Preferred Embodiment Starting Solutions For Preparation Of An
Acidic Solution Preferred More Preferred Most Preferred Solution
Salt MW (g/mole) Ranges (g/L) Ranges (g/L) Ranges (g/L) 1 NaCl
58.50 0.400 to 16.000 3.600 to 11.000 4.000 to 10.000 moles.fwdarw.
0.007 to 0.274 0.062 to 0.188 0.068 to 0.171 osmoles .fwdarw. 0.014
to 0.547 0.123 to 0.376 0.137 to 0.342 2 KCl 74.59 0.510 to 20.401
4.590 o 14.025 5.100 to 12.750 moles.fwdarw. 0.007 to 0.274 0.062
to 0.188 0.068 to 0.171 osmoles .fwdarw. 0.014 to 0.547 0.123 to
0.376 0.137 to 0.342 3 MgCl.sub.2 95.30 0.434 to 17.377 3.910 to
11.946 4.344 to 10.860 moles.fwdarw. 0.005 to 0.182 0.041 to 0.125
0.046 to 0.114 osmoles.fwdarw. 0.014 to 0.547 0.123 to 0.376 0.137
to 0.342
[0067] Definition of Osmolarity: A 1 M solution of a
non-dissociable solute is 1 Osmolar. (The solution contains
6.023.times.10E23 particles per liter). The solution of dissociable
salt is n Osmolar, where n is the number of ions produced per
molecules. Thus a 0.03 M solution of KCl is 0.06 Osmolar. (Irwin H.
Segel, Biochemical Calculations, 2nd edition. Published by John
Wiley & Sons, New York). Osmolarity is often considered in
physiological studies where tissue or cells must be bathed in a
solution of the same osmolarity as the cytoplasm in order to
prevent the uptake or release of water. Blood plasma is 0.308
Osmolar. Thus the red blood cells suspended in a 0.308 Osmolar NaCl
solution (0.154 M) would neither shrink nor swell. The 0.154 M NaCl
solution is said to be isotonic with respect to the red blood cells
(Irwin H. Segel et al).
[0068] The properties of the physiologically balanced, acidic
solutions produced from the Starting Solutions described in Table 1
are presented in Table 2, below.
TABLE-US-00002 TABLE 2 Properties of Preferred
Physiologically-Balanced Acidic Solutions Generated From NaCl
Starting Solution Listed in Table 1 Preferred More Preferred Most
Preferred ORP (mV) +600 to +1200 +800 to +1190 +1000 to +1180 pH
2.0-6.0 2.2-5.5 2.4-5.0 Hypochlorous 0.1-1000 1-200 60-190 Acid
Conc.(ppm) Molar Ratio.sup.1 about 0-2.55 about 0-0.82 about 0-0.26
range of OCl.sup.- over sum of OCl-- and HOCl at 20.degree. C. (%)
.sup.1Geo. Clifford White: Handbook of Chlorination and Alternative
Disinfectants, page 218, 4.sup.th ed., John Wiley & Sons, Inc.
New York, 1999.
[0069] II. Apparatus and Method for Making the Physiologically
Balanced, Electrolyzed, Acidic Wound Healing Solutions
[0070] The physiologically-balanced, acidic solution of the
invention may be prepared using electrolysis. Electrolysis of water
is the process by which the hydrogen ions are reduced, providing
hydrogen gas, and the hydroxide ions are oxidized, providing oxygen
gas.
[0071] The wound healing solution described herein was prepared
using a SUNTRON.RTM. MWB-2 model electrolyzing unit of the kind
manufactured by Koshin Co. Ltd., Kyoto, Japan. Equivalent wound
healing solutions can be prepared using a SUPER OXSEED LABO.RTM.
electrolyzing unit of the kind manufactured by ARV Co., Japan.
[0072] With reference to FIG. 1, which shows a general schematic of
an electrolyzing unit in which a physiologically balanced,
electrolyzed, acidic wound healing solution is prepared, and with
reference to the SUNTRON.RTM. MWB-2 model electrolyzer, the
electrolyzing unit 1 has a first compartment 2 and a second
compartment 3, each of which have a capacity of about 3 liters.
Compartments 2 and 3 are separated by a semi-permeable membrane 4.
In the first compartment 2, a positive electrode 5 is located. In
the first compartment 2 a strong acidic solution 6 is generated. In
the second compartment 3, a negative electrode 7 is located. In the
compartment 3, an alkaline solution 8 is generated. Electrodes 5
and 7 are connected to a power source 9 which generates a 0.9 A,
100V current. A lid 10 keeps the electrolysis unit free from
contamination by ambient air 11.
[0073] 13.5 g of Sodium chloride (Non-iodated, Morton) was added to
2.5 liters of distilled water to form a 5.38 g/liter or a 0.538%
solution. 2.5 L of the solution was placed in first compartment 2
and 2.5 L of solution was placed in second Compartment 3. The power
source 9, shown in FIG. 1, was turned on and power was applied for
15 minutes. The electrolysis was carried out at room temperature
(about 25.degree. C. to 30.degree. C.), with no external heat added
and no heat removed.
[0074] Salt solutions allow currents to pass between the
electrodes, accelerating the process of electrolysis. The amount of
salt necessary to affect the electrolysis process is minimal.
During the electrolysis process, a halide salt, such as sodium
chloride is in ionized form, as shown below.
##STR00002##
[0075] During electrolysis of saline, the sodium ions are attracted
to the negatively charged electrodes, and will counterbalance the
hydroxide ions on the alkaline side; the chloride ions travel to
the positive electrode. The chloride ions then undergo an oxidative
process which results in the generation of small quantities of
chlorine gas that are immediately consumed to form hypochlorous
acid, as illustrated below.
##STR00003##
[0076] Chlorine species are in the form of HClO, ClO.sup.-, or
Cl.sup.-; the balance among these ions is greatly affected by the
pH of the solution. Without being bound by any theory, it is
believed that HClO and ClO.sup.- ions are effective sterilizing
agents, with HClO being ten times more effective than ClO.sup.-. In
acidic pH, most of the ClO.sup.- ions are in the form of HClO.
[0077] Other halide salts undergoing electrolysis participate in
similar ionization processes are well known and documented in the
art.
[0078] An example of a typical physiological-balanced acidic
solution of the invention has a concentration of sodium chloride
ranging from about 0.5 to 9.9 g/L.
[0079] In one aspect of the invention, the concentration of
hypohalous acid (HOX) in the solution is from about 0.1 to about
1,000 ppm, more preferably from about 1 to about 750 ppm, and most
preferably from about 5 to about 500 ppm.
[0080] In one aspect of the invention the physiologically-balanced,
electrolyzed acidic solution of the invention has a concentration
of sodium cations ranging from about 0.01 g/L to about 7 g/L.
[0081] A typical physiologically-balanced, electrolyzed acidic
solution produced using the starting materials described the
invention has a low pH (about 2 to about 5), and an HClO
concentration of about 0.1 ppm to about 1000 ppm. In one aspect of
the invention, the pH range of the solution is 2.4 to 5.0. This
combination of chemicals gives the electrolyzed acidic saline
solution of the invention its superior antiseptic ability and its
extended stability properties. In addition, the solution is
characterized by remaining stable and active when stored for at
least three months at room temperature.
[0082] A typical physiologically balanced solution of the invention
is characterized by an oxidation reduction potential (ORP) from
about +600 mV to about +1200 mV.
[0083] Standard electrolysis equipment, including the particular
apparatus named herein, can be used in the manufacture of the
electrolyzed salt solutions of the invention, as previously
mentioned.
[0084] III. Chemical Processes for Preparing the Physiologically
Balanced, Acidic Solutions
[0085] Various chemical processes for the preparation of aqueous
solution of hypochlorous acid are known in the art. For example,
see The Merck Index, Tenth Edition M. Windholz, Ed., Merck &
Co., Rahway, USA, 1983 and references cited therein. More
generally, non-limiting examples of processes for the preparation
of the solution of the present invention are provided in the
following Reaction Scheme:
##STR00004##
[0086] Non-limiting examples of processes for the preparation of
the aqueous solutions of the present invention are provided as
follows:
NaOCl+HCl.fwdarw.HOCl+NaCl
NaOCl+NaHSO.sub.4.fwdarw.HOCl+Na.sub.2SO.sub.4
Ca(OCl).sub.2+2HCl.fwdarw.2HOCl+CaCl.sub.2
Ca(OCl).sub.2+2NaHSO.sub.4.fwdarw.2HOCl+CaSO.sub.4
Na.sub.2SO.sub.4
[0087] In each of the above representative processes for the
preparation of the solution, upon the formation of the desired
solution of the invention, the pH of the solution may be adjusted
to the desired pH using standard methods known in the art for
adjusting the pH of aqueous solutions.
[0088] In one aspect of the invention, the relative concentrations
of reactants that will yield the composition of the stable aqueous
physiologically balanced solutions of the present invention will
vary according to the nature and type of reactants used to form the
desired solutions. For example, the concentration of the salts
comprising the solution of the invention may include the
concentration ranges as disclosed in Table 1.
[0089] In one aspect of the invention, the stable aqueous
physiologically balanced solution of the present invention may also
be prepared by the mixing of the appropriate starting chemicals
immediately before using the solution.
[0090] In another aspect of the invention, the stable aqueous
physiologically balanced solution of the present invention may also
be prepared in situ by mixing the chemicals immediately before use.
In situ mixing of the starting materials may be performed using
various known methods in the art. For example, starting materials
or reagents for the preparation of the composition of the invention
may be separately stored, encased or contained in glass beads,
ampules and the like, and the reagents can be admixed when the
individual containers or beads encasing the reagents are released
and allowed to react at the desired site for applying the solution.
Where the reagents are contained in glass beads, ampules or the
like, means for binding or holding the individual containers
together, while allowing the release of the reactive components of
the solution, may be accomplished to prevent the release of the
containers at the desired treatment site.
[0091] Following manufacture, the solutions of the invention must
be stored for use. Methods and materials of packaging are very
important in maintaining and extending the useful shelf life of the
solutions. For example, the surfaces of the containers which make
contact with the solution should be made of a material which tends
not to react with oxidizing agents.
[0092] We evaluated a number of different container materials, and
surprisingly discovered that while a glass contacting surface
preserves the long term strength (potency) of the solution, certain
plastic surfaces or materials are not compatible with the solution
for long term storage. By way of example and not by way of
limitation, chemically resistant, coated soda lime amber glass 1 L
or 500 mL bottles (manufactured by Lawson Mardon Wheaton,
Millville, N.J. 08332), meeting the requirements for Type III as
established by the United States Pharmacopoeia, Volume XXIII
(1995), and supplements thereto, under "Chapter <661>,
Chemical Resistance-Glass Containers" make excellent storage
containers for the physiologically-balanced solutions of the
present invention. These bottles also meet the requirements for
light protection established by the USP under Chapter <661>,
"Light Transmission", which may be helpful in some instances. The
bottle cap is fabricated from phenolic, and has a liner facing made
out of TEFLON.RTM. (PTFE) which is less reactive than phenolic, and
which helps seal the cap, preventing the passage of ambient air
into the bottle. This bottle is available from AllPak Corp.,
Bridgeville, Pa.
[0093] A white (clear) glass bottle produced by the same
manufacturer (AllPak Corp.), but absent the amber coloring also
functions well in maintaining the stability of the solution. In one
aspect of the invention, a gas tight sealing of the solution
storage container preserves or extends the stability
characteristics of the solution. Gas tight sealing methods employed
for the storage, sealing and resealing of the containers after used
may include methods known in the art such as using air tight screw
caps, air tight lids, caps or lids having chemical resistant
O-rings or gaskets, the use of sealing tapes, such as electrical
tapes, or related methods known in the art for the airtight sealing
or resealing of containers.
[0094] Cl.sub.2 and HOCl are known as strong oxidants, and these
species are known to react with many different synthetic plastic
materials. An appropriate non-glass packaging material for the
NVC-101 solution should be non-reactive to both Cl.sub.2 and HOCl,
and also not permeable to the species of the NVC-101 solution. We
have studied the stability of HOCl at pH 3.5 in PET bottle, Barex
bottle (British Petroleum), LDPE bottle, high density polyethylene
bottle, polypropylene bottle, PFA bottle (Saville Corporation),
Eastman Plastics bottle, PVC bottle and Pouch (white poly, foil,
special high chemical resistant adhesive). In order to test if
there are reactions of the materials with HOCl or Cl.sub.2, the
materials were cut into small pieces (about 1 gram strips) and
sealed in the 30 mL ampules with the HOCl solutions (about 25 ml)
at pH 3.5. The results show that among all of the above materials
tested, PFA, a type of Teflon material, is the only material tested
that does not react with HOCl or Cl.sub.2 in the NVC-101 solution
under these conditions (FIG. 4). Therefore, PFA can be used as the
packaging material for the NVC-101 solution.
[0095] As defined herein, container materials or compositions that
may be used for the storage of the NVC-101 solutions are considered
to be "non-reactive", "does not react", "not permeable", are
"chemically non-reactive", or are "resistant to oxidative
degradation" are materials that are resistant to react with the
NVC-101 solution and allow long term storage of the solution
without adversely affecting the stability of the solution.
TABLE-US-00003 TABLE 3 Preparation of Solution 1 in Table 1 using a
Synthetic Method (0.9% salt solution).sup.a MW Weight Volume
Molarity Reagent (g/mole) (g) mmoles (mL) (moles/liter) H.sub.2O 18
~494.7 NaCl 4.34 NaOCl 74.5 1.8 1.3 1.60 0.805 HCl 36.5 3.7 3.7 3.7
1 .sup.aSee the Procedure #1 for the preparation of the 0.9% salt
solution.
Stability of Hypochlorous Acid in 0.9% Saline Solution:
[0096] The decomposition of a mixture of hypochlorous acid and
sodium hypochlorite was studied by Chapin from pH 1 to pH 13 in
1934. Chapin, R. M. J. Am. Chem. Soc. 1934, 56, 2211-2215. Chapin
found a maximum decomposition rate in the neutral pH range. The
following stoichiometry and rate expression was found to
approximate the experimental observations:
2HOCl+OCl.sup.-.fwdarw.ClO.sub.3.sup.-+2H.sup.++2Cl.sup.- Eq. 1
-d[HOCl]/3dt=k[HOCl].sup.2[OCl.sup.-] Eq. 2
[0097] The decomposition was also studied by Yokoyama and Takayasu
in the neutral pH range. See Yokoyama, T.; Takayasu, O. Kogyo
Kagaku Zasshi 1967, 70, 1619-1624. Their work was carried out in
0.8-4.6 M chloride ion to control the ionic strength, and no buffer
was used. The authors proposed Eq. 3 as the rate expression based
on their results, where a and b are constants.
--d[HOCl]/3dt=a[HOCl].sup.2[OCl.sup.-]/(1+b[OCl.sup.-]) Eq. 3
[0098] A more detailed study of the decomposition of hypochlorous
acid from pH 5.0 to pH 8.0 was reported by Adam and co-workers. See
Adam, L. C.; Fabian, I.; Suzuki, I., Gordon, G. Inorg. Chem. 1992,
31, 3534-3541. Under these conditions, they found that hypochlorous
acid has a maximum decomposition rate at pH 6.89. The overall
stoichiometry of decomposition of hypochlorous acid and
hypochlorite ion (HOCl+OCl.sup.-) in the neutral pH region was
determined as shown in Eq. 4.
xHOCl+(3-x)OCl.sup.-.revreaction.ClO.sub.3.sup.-+2Cl.sup.-+xH.sup.+
Eq. 4
[0099] A mechanism (Eq. 5-10) for the decomposition was proposed by
these authors, in which Cl.sub.2O.H.sub.2O is formed as an
intermediate.
2HOCl.revreaction.Cl.sub.2O.H.sub.2O Eq. 5
OCl.sup.-+Cl.sub.2O.H.sub.2O.fwdarw.HOCl+HCl.sub.2O.sub.2.sup.-
k.sub.2=3.0 M.sup.-1s.sup.-1 (50.degree. C.) Eq. 6
HCl.sub.2O.sub.2.revreaction.HClO.sub.2+Cl.sup.- Eq. 7
HOCl+Cl.sub.2O.H.sub.2O.fwdarw.HOCl+H.sub.2Cl.sub.2O.sub.2
k.sub.2=3.6.times.10.sup.-3 M.sup.-b 1s.sup.-1 (50.degree. C.) Eq.
8
H.sub.2Cl.sub.2O.sub.2.revreaction.HClO.sub.2+Cl.sup.-+H.sup.+ Eq.
9
HOCl+HCl.revreaction.Cl.sub.2+H.sub.2O Eq. 10
[0100] Above pH 6, the step in Eq. 6 is the rate determining step.
Below pH 6, Eq. 8 becomes the rate determining step. This step is
very slow. The k.sub.2 and k.sub.2 values determined by Adam et al
show that the reaction of Cl.sub.2O.H.sub.2O with OCl.sup.- is
nearly 1000 times faster than with HOCl, suggesting that HOCl is
much more stable in the acidic condition than in the neutral pH
region. However, as the pH becomes acidic (pH<3), HOCl is
converted rapidly to Cl.sub.2 in the present of Cl.sup.- (Eq. 10),
which is generated from HOCl self-decomposition (Eq. 5-10).
Synthesis of HOCl: In general, HOCl solutions were prepared by
acidifying a NaOCl solution with HCl. The concentration of HOCl was
determined by either Iodometric titration with Hatch solution or
UV-VIS method. For analysis by UV-VIS method, aliquot of HOCl
solution was converted to OCl.sup.- (=362 M.sup.-1 cm.sup.-1 @ 292
nm; see Furman, C. F.; Margerum, D. W. Inorg. Chem. 1998, 37, 4321)
with 0.1 M NaOH solution. A Beckman pH meter was used to measure
the pH of the solution. Distribution of Chlorine Species vs. pH in
0.9% Saline: The studies of Chapin, R. M., Yokoyama, T.; Takayasu,
O., and Adam, L. C. et al show that the decomposition of HOCl to
give inorganic ions ClO.sub.3.sup.- and Cl.sup.- is slow in acidic
condition. However, decomposition of HOCl may also occur via the
formation of Cl.sub.2 gas in the presence of excess NaCl (Adam, L.
C. et al, 1992). The NVC-101 solutions as prepared according to a
procedure described herein contains HOCl, 0.9% NaCl (0.155 M), and
has a pH of about 3.5. Equations 11-14 show the equilibria existing
in NVC-101 solution.
HOCl.revreaction.H.sup.++OCl.sup.- pKa=7.5 Eq. 11
HOCl+C.sup.-+H.sup.+.revreaction.Cl.sub.2(aq)+H.sub.2O
K.sub.1=9.6.times.10.sup.2 M.sup.-2 Eq. 12
Cl.sub.2(aq)+Cl.sup.-.revreaction.Cl.sub.3.sup.-.revreaction.K.sub.2=0.1-
8 M.sup.-1 Eq. 13
Cl.sub.2(aq).revreaction.Cl.sub.2(g) K.sub.3=10.87 atm M.sup.-1 Eq.
14
[0101] The pKa of HOCl is 7.5. See Gerrisen, C. M.; Margerum, D, W.
Inorg. Chem. 1990, 29, 2758-2762. At pH 3.5, hypochlorite exists
predominantly as its conjugate acid form. At pH 7.5,
[HOCl]/[OCl.sup.-]=1:1. As shown in Eq. 12, high acidity (or higher
concentrations of H.sup.+) favors the formation of Cl.sub.2. See
Wang, T. X.; Margerum, D. W. Inorg. Chem. 1994, 33, 1050-1055. As
the concentration of Cl.sub.2 is increased in the solution, the
formed Cl.sub.2 may equilibrate to gaseous chlorine and is
liberated to the headspace of a container (Eq. 14). Therefore,
degassing of Cl.sub.2 to the head space may become a major path for
decreasing the concentration of HOCl at low pH in 0.9% NaCl
solution in storage containers with large a headspace.
[0102] The distribution of chlorine species over a pH range in a
0.9% NaCl is shown in FIG. 5. The Figure shows the specific pH
ranges wherein Cl.sub.2 concentrations may be minimized. The
chlorine species distribution curves (% vs pH) in FIG. 5 were
calculated based on the pKa, K.sub.1, K.sub.2 and K.sub.3 values
available from literature. See Gerrisen, C. M.; Margerum, D, W.
Inorg. Chem. 1990, 29, 2758-2762; Wang, T. X.; Margerum, D. W.
Inorg. Chem. 1994, 33, 1050-1055; Wang, T. X.; Kelly, M. D.;
Cooper, J. N.; Beckwith, R. C. Margerum, D. W. Inorg. Chem. 1994,
33, 5872-5878; and Bartlett, W. B.; Margerum, D. W. Environ. Sci.
Technol. 1999, 33, 3410-3414. The calculation results were verified
by experiments. The experiments were carried out by using multiple
wavelengths method, in which the molar absorptivities of HOCl,
Cl.sub.2(aq), and Cl.sub.3.sup.- are at wavelengths 220, 232, and
325 nm. The absorbances at these wavelengths were used to set three
equations according to Eq. 15:
A=.epsilon..sup.HOCl[HOCl]+.epsilon..sup.Cl3-[Cl.sub.3.sup.-]+.epsilon..-
sup.Cl2[Cl.sub.2] Eq. 15
[0103] The molar absorptivities used in this study are listed in
Table 4.
TABLE-US-00004 TABLE 4 Wavelength .epsilon..sup.HOCl
.epsilon..sup.Cl2 .epsilon..sup.Cl3- nm M.sup.-1 cm.sup.-1 M.sup.-1
cm.sup.-1 M.sup.-1 cm.sup.-1 220 69.89 57 1.04 .times. 10.sup.4 232
100 0 8800 325 10.8 70 180
[0104] Solving these equations give the concentrations of the
chlorine species. The experimental results are also shown in FIG.
5. As shown in FIG. 5, appreciable amount of Cl.sub.2 begins to
form at pH<3.5. In order to minimize the formation of Cl.sub.2
gas, the pH of the solution should be controlled at 3.5 or
higher.
NVC-101 Solution Stability Experiments: The stability experiments
were focused on measuring the total concentration of the active
chlorine species. The experiments were carried out in ampules at
40.degree. C., room temperature and 4.degree. C. with an initial
total active chlorine species concentration of 100 ppm (i.e.
[HOCl].sub.total=100 ppm). The plots of [HOCl].sub.total vs Time
and pH vs time in FIG. 6 show that the HOCl at three temperatures
is stable as determined by both [HOCl].sub.total and by the pH of
the solution. An initial drop in [HOCl].sub.total is observed with
samples taken within the first 24-48 hours. This initial drop may
be attributed to the loss of Cl.sub.2 from the solution into the
headspace. When the first data point was measured, the equilibrium
as expressed in Eq. 14 had not been established. By the time the
ampule was opened for analyzing the second data point after about
48 hours, the equilibrium in Eq. 14 was reached. Compared to the
first data point, more Cl.sub.2 in the solution had gone into the
headspace of the ampule. After the initial drop in
[HOCl].sub.total, no appreciable loss of HOCl was observed over 180
days. This experiment shows that HOCl is stable at pH 3.5 in a 0.9%
NaCl solution after the equilibrium distribution of Cl.sub.2 in
solution and the gas phase was reached after about 48 hours.
Effect of Storage on the pH and Orp of the Solution in Screw Cap
Bottles:
[0105] We conducted a study of the shelf life of the solution
described according to the composition of Table 3 to determine the
effect of extended storage in bottles made from various materials,
and on the pH and oxidation-reduction potential (ORP) of the
solution. Freshly prepared solution was stored over a period of 3
months in 4 types of screw cap bottle: The amber glass; the white
(clear) glass; High Density PolyEthylene (HDPE); and TEFLON.RTM.. A
variety of chemically non-reactive screw caps and liners were also
tested. The stability and activity of the solution of the present
invention may also be measured by determining the active halogen
concentration using UV-VIS spectroscopy. For solutions containing
active chlorine, the stability and activity of the solution of the
present invention may also be measured by determining the active
chlorine concentration using iodometric titration or using UV-VIS
spectroscopy.
[0106] At given times over intervals of 5 to 10 days, known
aliquots were withdrawn to measure the pH and ORP. Thirteen
aliquots were taken over the testing period and each aliquots were
measured for the pH and the ORP. At a starting pH of 2.8, the
solutions stored in amber glass, white glass, HDPE, and in Teflon
maintained a pH of 2.8 over a period of more than 75 days without
change. It was also determined that containers using a Teflon liner
that is backed by soft silicone was most effective in preventing
the degassing of Cl.sub.2 from the containers.
[0107] At a starting ORP value of 1175-1180, the solutions stored
in amber glass, white glass, HDPE, and in Teflon maintained an ORP
between 1150 and 1175 over a period of more than 75 days without a
significant reduction in the ORP.
Stability of NVC-101 Solution in Sealed Ampules:
[0108] 20 mL of the NVC-101 solutions prepared according to
Procedure #1 was added via a dispenser to 25 mL glass ampules. The
glass ampules were sealed immediately using a torch. The initial
total concentration of active chlorine species of the solution was
2.69 mM (i.e. [HOCl].sub.total=2.69 mM) as measured by iodometric
titration.
[0109] The ampules were stored at 40.degree. C., at room
temperature, and at 4.degree. C. Individual ampules stored at the
different temperatures were opened after 11 day, 15 days, 20 days,
29 days, 46 days, 62 days, 75 days, 103 days, 127 days, 180 days
and analyzed for the total concentration of active chlorine species
by iodometric titration. In addition, the pH of the solution was
measured using a freshly calibrated Beckman pH meter.
[0110] A graphical plot (FIG. 6(a)) of the [Chlorine].sub.ppm vs.
time (in days) shows that the NVC-101 solutions at a pH of about
3.5 in a 0.9% NaCl solution prepared according to the methods
described herein and stored in unreactive, sealed containers were
stable at 40.degree. C., at room temperature, and at 4.degree. C.
over a period of 180 days.
[0111] A graphical plot (FIG. 6(b)) of the pH of the solution vs.
time (in days) shows that the NVC-101 solutions at an initial pH of
about 3.5 in a 0.9% NaCl solution prepared according to the methods
described herein and stored in unreactive, sealed containers were
stable at 40.degree. C., at room temperature, and at 4.degree. C.
over a period of 180 days.
[0112] The stability of a solution of this invention was
investigated using different forms of packaging that would be
practical for use by patients (Table 5). Sample A below represents
the solution packaged in nine single-use 30 ml amber glass bottles
with Teflon-lined screw caps and sealed with tape to ensure gas
tightness. Sample B represents the same solution packaged in a 250
ml amber glass bottle and Sample C represents the same solution
packaged in a 250 ml plastic bottle.
[0113] At the beginning of the experiment the concentration of free
chlorine was measured. Each day (except for two weekend days) the
following procedure was employed. [0114] 1. At the beginning of the
day, the 250 ml bottles were opened for a period of two minutes and
then closed. [0115] 2. At the end of the day, the 250 ml bottles
were opened, a 20 ml sample was withdrawn and the bottle was closed
after two minutes. The 20 ml samples were tested for free chlorine
concentration. [0116] 3. At the end of the day one of the 30 ml
bottles was opened and tested for free chlorine concentration. The
bottle was then discarded.
TABLE-US-00005 [0116] TABLE 5 Stability of Solution over time in
opened and closed containers [HOCl].sub.total in ppm.sup.a Closed
container Opened container Opened container Day Sample A Sample B
Sample C 0 184 184 184 1 184 171 150 2 172 145 121 3 181 128 103 4
-- -- -- 5 -- -- -- 6 180 110 66 7 182 98 54 8 180 59 38 9 177 49
31 10 179 42 27 .sup.a[HOCl].sub.total in ppm with a 5-10%
experimental error.
[0117] The opening of the 250 ml bottles twice a day for two
minutes was designed to reflect the pattern of usage of a normal
patient, where the patient or a health care giver would be changing
the dressing on the patient's wounds and applying the solution
twice a day.
[0118] It was surprisingly observed that the concentration of free
chlorine and thus of hypochlorous acid was reduced very
significantly over the period of the experiment when the larger
bottles were repeatedly opened as described, whereas the single use
bottles (30 ml) (Sample A in Table 5) maintained their
concentration within acceptable levels. This indicates that each
application of the solution of this invention should be from a
container that has not been opened multiple times and preferably
from a single-use container, such as a bottle.
[0119] In one aspect, the solutions of the present invention may be
stored in single-use containers. In another aspect, the solutions
of the invention may be stored in single-use containers of various
different sizes, configurations, and having different volumes as
suitable for the desired applications as disclosed herein. In some
applications, for example, the solution of the invention may be
stored in single-use 30 mL, optionally disposable containers.
Preparation of HOCl Solutions: in General, HOCl Solutions were
Prepared by acidifying the NaOCl solution with HCl. The
concentration of HOCl was determined by either Iodometric titration
with Hatch solution or UV-VIS method. For analysis by UV-VIS
method, aliquot of HOCl solution was converted to OCl.sup.-
(.epsilon.=362 M.sup.-1 cm.sup.-1 @ 292 nm; see Furman, C. F.;
Margerum, D. W. Inorg. Chem. 1998, 37, 4321) with 0.1 M NaOH
solution. A Beckman pH meter was used to measure the pH of the
solution. Reagents. All solutions were made with Millipore water,
which was validated with HPLC grade water. NaOCl (6%) solution was
purchased from VWR. NaCl and HCl used are reagent-grade.
Procedure #1: Preparation of NVC-101 Solutions
[0120] In a 500 mL Erlenmyer flask was placed NaCl (4.344 g). To
this was added 450 mL of distilled water, followed by 1.6 ml of
0.6% NaOCl (VWR International), and 3.7 mL of 1 Molar hydrochloric
acid. This solution was transferred to a 500 mL volumetric flask
and then enough distilled water was added to reach the 500 mL mark.
ORP, pH, and total available chlorine were measured and
recorded.
[0121] If sufficient acid is initially present in the solution to
obtain the desired pH range, then no pH adjustment is needed.
Otherwise, the pH may be adjusted to the desired range using
standard methods known in the art for increasing or decreasing the
pH of the aqueous solution.
[0122] In one example, when the physiologically-balanced, acidic
solution of the invention is stored in a glass bottle, the
composition has been shown to be stable for at least 90 days at
room temperature.
Procedure #2: Preparation of 50 Liters of 1.70 mM HOCl Solution in
0.9% Saline at pH 3.5
[0123] The HOCl solution (1.70 mM) in 0.9% NaCl at pH 3.5 have been
prepared in large scale using a 50-liter polyolefin plastic
container as a reaction vessel. Table 6 lists the reagents and
their quantity that may be used to obtain the desired concentration
and pH value.
TABLE-US-00006 TABLE 6 MW Molarity (g/ Weight Volume (moles/
Reagent mole) (g) mmoles (L) liter) Remarks H.sub.2O 18 49.8 NaCl
58.5 440 440 g makes a 0.9% solution in total volume of 50 liters
NaOCl 74.5 92 1.70 0.98 HCl 36.5 2.5 0.124 1.0
[0124] In order to avoid losing active chlorine during the
manufacturing of the solution, NaOCl was added in the last. An
example of the manufacturing procedure for an HOCl solution in 0.9%
saline at pH=3.5 is described as follows: [0125] 1. 440 g of NaCl
was weighed in a 1000 mL-beaker, and then 500 mL Millipore water
was added into the beaker to dissolve NaCl. [0126] 2. The solution
was stirred for 5 minutes using a glass stir. About half of the
NaCl remained undissolved. The NaCl solution was transferred into a
1000 mL volumetric flask. The undissolved NaCl solid was retained
in the beaker. [0127] 3. The 1000 mL volumetric flask was filled
with Millipore water up to the 1000 mL mark and the NaCl solution
in the 1000 mL volumetric flask was transferred into the vessel.
[0128] 4. Another 500 mL Millipore water was added into the 1000 mL
beaker to dissolve the remaining NaCl solid. The solution was
stirred until all NaCl dissolved. Repeat step 3. [0129] 5. 124 mL
of 1.0 M HCl was pipetted into the 1000 mL volumetric flask. The
flask was filled with Millipore water up to the 1000 mL mark. The
HCl solution in the 1000 mL volumetric flask was transferred into
the vessel. [0130] 6. The vessel was filled with Millipore water up
to 47 liters, and the solution was stirred while the Millipore
water was added. [0131] 7. 92 grams of NaOCl (6%) was weighed into
a 500 mL beaker and the transferred into a 1000 mL volumetric flask
and the flask was filled with Millipore water up to 1000 mL mark.
The solution was transferred into the vessel. The volumetric flask
was rinsed and filled up to the 1000 mL mark with Millipore water.
The solution was transferred into the vessel. [0132] 8. The vessel
was filled up to 50 liter. [0133] 9. The solution was stirred
slowly and gently with a long glass stir bar for about 2 minutes.
[0134] 10. After about 2 minutes, a test for the active chlorine
concentration and pH of solution using UV-VIS method and pH meter,
respectively, was made to determine if the solution has the desired
concentration and pH. [0135] 11. The vessel was tightly capped. The
solution was allowed to sit in the vessel for about 2 hours to
reach equilibrium. [0136] 12. The concentration of HOCl and pH of
solution are analyzed on UV-VIS spectrophotometer and pH meter
before the solutions are added to containers such as ampules or
bottles.
[0137] Using the manufacturing methods described above, the desired
free chlorine concentration (1.70.+-.0.05 mM) and pH (3.55.+-.0.05)
are consistently obtained.
[0138] An iodometric titration or UV-VIS method was used to
determine the concentration of active chlorine species in
solution.
Iodometric Titration:
[0139] In an iodometric titration, the following reactions take
place:
KI+HOCl.fwdarw.I.sub.2+KCl
KI+Cl.sub.2.fwdarw.I.sub.2+KCl
KI+OCl.sup.-.fwdarw.I.sub.2+KCl
I.sub.2+starch (used as an indicator).fwdarw.Blue complex
I.sub.2+2S.sub.2O.sub.3.sup.2-.fwdarw.S.sub.4O.sub.6.sup.2-+2I.sup.-
(end point is colorless)
The total concentration may be determined as
[HOCl].sub.total=[HOCl]+[OCl.sup.-]+[Cl.sub.2]
Procedure for Iodometric Titration for Active Chlorine:
[0140] 1. Set up titration apparatus using a HACH TetraStir.TM.
apparatus as described by HACH Digital Titrator Manual. 2. Start
with a clean 125-ml Erlenmeyer flask with a small stir bar in the
flask. 3. Add the contents of 1 foil packet of Potassium Iodide
Reagent (purchased from HACH) and one Dissolved Oxygen Powder
Pillow (purchased from HACH) to flask. 4. Add Millipore water to
the flask up to the 50-ml mark. Place flask on stir plate to
completely dissolve the reagents. 5. Add 5 ml of sample test
solution to the flask using an acclimated 5-ml pipet. Solution will
turn yellow. 6. Ensure that there is sodium thiosulfate solution
throughout the delivery tube, the counter is at zero, and the tip
of the delivery tube is dry. Then begin titration. 7. Add sodium
thiosulfate until the solution turns a very pale yellow. Then add
4-5 drops of starch indicator. The solution will turn blue. 8.
Continue titration with sodium thiosulfate until the solution turns
clear and remains clear for 30 seconds.
[0141] Using the above procedure for the analysis of NVC-101
solution in ampules, each data point reported is the average
concentration of solutions analyzed from three ampules.
UV-VIS Method:
[0142] The solution to be tested is basified before it is measured
by UV-VIS. Basification converts both HOCl and Cl.sub.2 into a same
species, OCl.sup.-. OCl.sup.- has a strong absorbance at 292 nm,
and therefore can provide a better signal and enhance the detecting
limit.
[0143] Analysis using the UV-VIS method, the total concentration of
the active chlorine species may be determined as
[HOCl].sub.total=[HOCl]+[Cl.sub.2]+[OCl.sup.-].
HOCl+NaOH.fwdarw.NaOCl+H.sub.2O
Cl.sub.2+2NaOH.fwdarw.NaOCl+NaCl+H.sub.2O
Procedure for Measurement of Active Chlorine by UV-VIS:
[0144] 1. Pipet 10 ml of 0.1 M NaOH solution into a clean and dry
50-ml beaker. 2. Add 5 ml of NVC-101 test solution to this beaker.
Mix with the NaOH solution well. 3. Use the basified NVC-101
solution to rinse the cell three times. 4. Fill the cell with
basified NVC-101 solution and cap the cell. 5. Measure the
OCl.sup.- absorbance at 292 nm. 6. The total chlorine concentration
may be calculated using the following equation:
[HOCl].sub.Total=3*(A.sub.292nm/362)
where "3" is the dilution factor when the solution is basified, and
"362 M.sup.-1 cm.sup.-1" is the molar absorption of OCl.sup.- at
292 nm.
[0145] Using the above procedure for the analysis of NVC-101
solution in ampules, each data point is the average concentration
of the solutions from three ampules.
Antimicrobial Activity
[0146] Antimicrobial efficacy of a solution of the invention
containing 9 g/L NaCl, 170 ppm hypohalous acid, having a pH of 3.0
and an ORP of 1175 was tested against microorganisms including
Candida albicans, spergillus niger, Streptococcos pnemonea, MRSA,
VRE, Baccilus subtillis, Bacillis ceruis, Baccilus thorangensis,
Baccilus anthracis, Pseudomonas aeruginosa, Escherichia coli,
Staphylococcus aureus, Listeria monocytogenes 10403s wild type,
catalase-deficient mutant L. monocytogenes LM1370, Aspergillus
niger (spores), Penecillium oblatum (spores), Lactobacillus, and E.
coli 0157:H7. Up to 5 logs of reduction in the activity of the
microorganisms was achieved after 10 to 60 seconds of exposure to
the solution of the present invention.
[0147] Antimicrobial properties: The solution of invention was
effective in the treatment of all microorganisms, including gram
positive, gram negative, yeast, fungi and spore forming Bacillus,
including different strains of Bacillus anthracis. The solution was
found to exert pronounced antibacterial action against all the
microorganisms tested.
Eve and Skin Irritation
Eve Irritation Experiment
[0148] The solution of the invention was evaluated for primary
ocular irritation based on the requirements of the International
Organization for Standardization 10993: Biological Evaluation of
Medical Devices, Part 10: Tests for Irritation and
Sensitization.
[0149] A 0.1 ml dose of the solution of the invention was instilled
into the lower conjunctiva sac of the right eye of the screen
rabbit and the lid was gently closed for 1 second. The opposite eye
was dosed with 0.1 ml of 0.9% sodium chloride (USP) as per sponsor
to serve as the comparative control. The animal was returned to its
cage following treatment. At 1, 24, 48, and 72 hours after dosing,
the test eye of each rabbit was examined with an auxiliary light
source for ocular irritation. Under the conditions of this study,
the solution of the invention was not considered an irritant to the
ocular tissue of the rabbit.
Skin Irritation Experiment
[0150] The solution of the invention was also evaluated for primary
skin irritation based on the requirements of the International
Organization for Standardization 10993: Biological Evaluation of
Medical Devices, Part 10: Tests for Irritation and Sensitization.
In cumulative skin irritation studies, two intact and two abraded
skin sites were prepared on the skin on the back of each of six
animals. Then, 0.5 mL of the solution of the present invention was
applied to one intact skin site and one abraded skin site on each
animal for 4 hours a day for a period of 5 days; 0.5 mL of
distilled water was applied to the second intact skin site and the
second abraded skin site on each animal for the same time period,
as a control. No cumulative skin irritation effects were noted at
the application sites of the solution of the invention compared to
the distilled water.
[0151] We have studied the antimicrobial properties of the
solutions of the present invention as well as the behavior of these
solutions with respect to eye and skin irritation and find the
following results:
[0152] Skin irritation index of the solution of invention was zero
as it was compared to sterile saline.
[0153] Eye irritation index of the solution of invention was also
zero as it was compared to sterile saline.
[0154] IV. Methods for Using the Composition of the Invention
[0155] Application of the stable aqueous physiologically-balanced,
non-cytotoxic ionized acidic solution of the present invention, has
been demonstrated to help wound healing progress remarkably.
Antimicrobial properties of acidic salt solutions of the invention
are such that they enhance the healing process of any wound
contaminated with microorganisms. The compositions of the invention
function specifically to maintain the necessary antimicrobial
environment for wounds to heal faster, without the usual
complications associated with superficial infections. In addition,
the solutions provide topical microbial control and humidification
of chronic wounds.
[0156] The use of acidic salt solutions of the present invention
has been instrumental in healing a number of patients with deep
wounds which were not responding to usual medications and locally
applied treatments. In one aspect, the present invention provides a
method for the treatment of various medical conditions such as
promoting wound healing, reduction of pathogens in open wounds,
wound decontamination, ocular disinfection or decontamination, oral
disinfection, antifungal therapy, ophthalmic applications,
reduction of pathogens in pulmonary infections, reduction of
pathogens in burns, lavage, reduction of infectious load in organs
for transplantation, reduction of bacterial load in autologous or
artificial tissue transplantation, oral disinfection antifungal
therapy, treatment of biofilm for cystic fibrosis and related
diseases, treatment of viral infections, treatment of skin
diseases, and tissue repair and regeneration, which method
comprises using the solution of the present invention by applying
the solution to the site where treatment is required. Non-limiting
examples of biofilm that may be treated using the solutions of the
present invention include those cited in the review article
entitled "Is there a role for quorum signals in bacterial
biofilms?" by S. Kjelleberg, and S. Molin, PMID: 12057677
(PubMed-indexed for MEDLINE).
[0157] The physiologically balanced, solutions of the invention may
be effective in reducing bacterial load thus improving wound
healing. Preliminary product development studies in human patients
with chronic wounds suggest that solutions are well tolerated,
improve the granulation of wound tissue, reduce the need for
debridement compared to prior art solutions with patients reporting
less pain during their treatment. In addition, preliminary product
development studies suggest that, when solutions are applied to
patients with artificial skin grafts that are infected and normally
need surgical replacement of the graft, the infections are
eliminated and the grafts are saved.
[0158] Three recent case studies involving the treatment of human
subjects with a preferred composition of the invention are
presented below. In these case studies, the acidic salt solution
was essentially the same as that described for the solution in
Table 2. This composition provides osmolarity compatible with blood
plasma.
[0159] The wounds were kept continuously moist with the composition
of the invention, and were covered with Vaseline gauze to prevent
evaporation of the solution.
Case Study #1
[0160] The patient was a 70 year-old female, with a long history of
severe venous edema, lymphaedema, and obesity. Her vascular supply
was normal. She developed a cutaneous ulcer 2 years ago in the
lower right leg. A second ulcer subsequently developed in the
lateral right leg. The ulcers had previously been treated using
multiple methods, including debridement, antibiotics, topical
solutions including BETADINE.RTM. (Purdue Frederick, Norwalk,
Conn.); SILVADINE.RTM. (BASF Corporation, Mt. Olive, N.J.);
ELASE.RTM. (Fujisawa Co., Deerfield, Ill.); and FURACIN.RTM.
(Roberts Pharmaceutical Corp., Meridian Center, Illinois). By way
of explanation, BETADINE.RTM. is an antiseptic cleanser, used
externally on wounds; an iodine-containing preparation used as a
broad spectrum antimicrobial. SILVADINE.RTM. is a soft white cream
containing 1% silver sulfadiazine antimicrobial agent which is
applied to wounds after cleaning and debriding. ELASE.RTM. is an
enzymatic powder or cream used as a debridement agent in wounds
where circulation is poor, to destroy dead tissue and leave healthy
tissue intact. FURACIN.RTM. is a nitrofurazone broad-spectrum
antibacterial cream used against pathogens commonly causing surface
infections. Use of these agents in the wound healing had not
produced the desired results.
[0161] A biopsy revealed benign ulceration and granulation tissue.
The possibility of Pyodermo Gangrenosum was considered. The initial
measurements of these severely necrotic ulcers were 130.times.180
mm and 98.times.125 mm. Treatment included bedrest, debridement,
antibiotics, and topical application of the composition of the
invention made according to experimental detailed previously in
Example #1, for hydration and topical bacterial control. Within 10
days, the ulcers were almost completely covered with crisp red
granulation tissue and the pain was gone. Within 14 days, a split
thickness skin graft closed the wound; the patient was able to
leave the hospital 8 days later. Within two months following the
start of treatment, the ulcers had completely healed, and the
patient remained pain-free.
Case Study #2
[0162] The patient was a 50 year-old male, with a history of
thrombophlebitis, pulmonary emboli, and obesity. The patient had
experienced infected hematomatous ulceration in both groins and
bilateral venous ulcers in both legs for several months. He had an
antithrombin III deficiency and had been coumadinized. By way of
explanation, Antithrombin III is a protein consisting of normal
plasma and extracellular sites that inactivates thrombin in a
time-dependent irreversible reaction and serves as a cofactor of
heparin into its anticoagulant activities. Antithrombin III also
inhibits certain coagulation factors-occurs in certain disease
process i.e., liver disease or may be genetic. Coumadinized refers
to the use of crystalline warfarin tabs or Heparin I.V.
Anticoagulant to treat patients who have thrombosis to prevent
further thrombus. COUMADINE.RTM. is manufactured by DuPont.RTM.
Pharmaceutical, Wilmington, Del. Because of the recent hemorrhages
in his groin, he developed large deep ulcerations on the right
(measuring 140.times.90 mm) and more superficial ulcerations on the
left (50.times.50 mm and 60.times.60 mm). After the first
debridement of infected necrotic fat, the culture revealed the
presence of vancomycin-resistant Enterococcus. Treatment consisting
of topical application of the composition of the invention was
started. Infectious disease consultation recommended no further
antibiotic treatment. Topical dressings consisting of sponges
soaked with the composition of the invention were packed into the
wound and the patient was subjected to bedrest. The distal venous
ulcers healed fairly rapidly and required only two more
debridements. The left groin ulcer undermined and required opening
further while the packing was soaked with the composition of the
invention. The patient then began healing, with good granulation
tissue forming and epidermal coverage to 90% in the right groin
ulcer. The left groin ulcer required debridement for undermining,
but began healing without antibiotic treatment.
Case Study #3
[0163] The patient was a 57 year-old male, who had experienced
recurrent ulcers of both feet and ankles over the past four years.
Local wound care had initially been started by coagulating veins
and using topical wound therapy. His UNNA.RTM. boots caused an
increase in his ulcerations, which then became more severe. By way
of explanation, an UNNA.RTM. boot is an elastic adhesive bandage
applied over zinc oxide cream as a protective treatment. An
UNNA.RTM. boot is a boot-like dressing of the lower extremity made
of layers of gauze and UNNA.RTM.'s paste; 100% soft cotton gauze
impregnated with non-hardening zinc oxide paste. The manufacturer
of UNNA.RTM.'s paste is Glenwood, Inc. of Tenalty, N.J. He had been
using a JOBST.RTM. pump for edema control. This pump is designed
for intermittent home use and is connected to an inflatable
pneumatic appliance which is typically preset to alternate 90
seconds of inflation with 30 seconds of deflation. The manufacturer
of JOBST.RTM. pumps is Nutech, of San Antonio, Tex.
[0164] At the time we examined the patient, his wound measurements
were 33.times.65.times.2 mm, 17.times.25.times.2 mm, and
5.times.9.times.2 mm. Physical evaluation verified excellent
pulsatile inflow to the leg; the wounds were therefore diagnosed as
venous ulcers because of the significant edema present. The patient
began compression therapy and debridement, culturing the leg at the
same time; the bacteria present were found to be
coagulase-negative, methicillin-resistant Staphylococcus and
Enterococcus sensitive to vancomycin. He also had Haemophilus and
diphtheroids cultured with polymicrobial infection. The patient had
persistent nonhealing infections for several months, and the
infections had become resistant to the classic antibiotic
treatments. The infections were only sensitive to
CIPROFLOXACIN.RTM. and BACTRIM DS.RTM.. CIPROFLOXACIN.RTM. is a
broad spectrum antibiotic, manufactured by Miles Pharmaceutical,
West Haven, Conn., which is active on Gram+ and Gram- bacteria, and
is typically used to treat skin, bone and joint infections. BACTRIM
DS.RTM. is manufactured by Roche of Nutley, N.J. BACTRIM DS.RTM. is
a sulfonamide antibiotic, which is typically used to treat urinary
tract infections, and is also used to treat E. coli, Proteus
species, Shegellosis and Pneumocystic pneumonia infections. The
patient was started on CIPROFLOXACIN.RTM., which was then
discontinued, and then BACTRIM DS.RTM. was started. He had topical
debridements.
[0165] Since no significant improvement was shown after the
treatment described above, topical application of the composition
of the invention was begun for control of the bacteria and
hydration. The infections were rapidly controlled after the start
of treatment with the composition of the invention, and the wounds
began healing fairly rapidly. He has now shown healing of the two
ulcers, with the final measurements down to 7.times.41 mm and
7.times.11 mm on the right medial and lateral ankle,
respectively.
Oral Care
[0166] The physiologically-balanced, acidic solution of the
invention may be used to treat canker sores (mouth ulcers) or cold
sores by rinsing the affected area. The solution can be used by
soaking the cold sore 3-4 times a day, each time with 2-3
applications, and putting the solution in contact with the sore for
20-30 seconds. The solution may also be used as a mouth rinse for
dental and mouth hygiene and to control infection. In this
instance, the solution may be used as a gargling solution to fight
throat infection. The solution may be applied with the help of a
cotton swab for more specific areas. The solution can be used once
or several times a day according to patient's needs and
condition.
Ophthalmic Care
[0167] The physiologically-balanced, acidic solution of the
invention may be used in place of a saline solution to remove a
foreign body from, to rinse, or to irrigate the eyes. It can also
be applied topically before or after surgery to disinfect an eye
and surrounding tissues. Our studies on rabbits eyes showed that
this solution is as safe as saline solution when applied to
rabbits' eyes and has no toxicity to the eyes when compared to
ophthalmic grade BETADINE.RTM. (5%) typically used pre-surgery. The
solution can be used once or several times a day according to a
patient's needs and condition. The solution can be applied by
dropping it directly into the eyes as necessary. It can also be
applied by soaking a gauze and applying the saturated gauze to the
eyes for 1 or several minutes. It can also be used to clean the
eyes by gently wiping the eyes with a saturated gauze. The solution
can also be poured into a small eye washer, then the washer is
inverted over the eye washer and the eyelid opened and closed
several times.
[0168] The stable, physiologically-balanced, acidic solution of the
invention may be used for the treatment of ocular disinfection or
decontamination. In addition, it may be used as a replacement for
silver nitrate in the disinfection of the eyes of neonates. The
reader will see that the solution of the invention has applications
in the treatment of many different types of wounds, including,
without limitation, diabetic ulcers, gangrene, venous ulcers,
decubitus ulcers, pressure ulcers, wounds due to bites, acute
trauma wounds, surgical wounds and burns. The composition of the
invention is also useful as an irrigation solution, for example,
during dental, periodontal, and ophthalmic procedures. The
composition of the invention can also be used for pre- and
post-operative cleaning of tissue sites, and as a gargling solution
for treatment of canker sores. In addition, the HOCl contained in
the solution may stimulate or enhance growth factors essential for
the wound healing process. As such, the solution may find uses in
many other applications in which disinfection and growth factor
stimulation are desirable.
Methods of Using Solution for Skin Disinfection:
[0169] The solution of the present invention may also be used to
treat skin that are infected. In a skin of a patient showing
medical signs of infection, the solution of the present invention
may be applied directly to the area of the skin that are infected.
After at least one application of the solution onto the infected
skin using standard methods of application known in the art, the
disinfection properties of the solution maybe noted.
Reduction of Pathogens in Pulmonary Infections:
[0170] The solution of the present invention may be used for the
reduction of pathogens in pulmonary infections. For example,
various viral or bacterial infections may be effectively treated
with the solution of the present invention. Non-limited examples of
infections that may be effectively treated using the solution of
the present invention include anthrax spores present in the lungs,
and the reduction of pneumonia causing bacteria in the lungs,
including strep bacteria and the like.
Method of Using the Solution of Invention for Cleaning Eves in
Pediatrics:
[0171] The solution of the present invention may be used for the
cleaning eyes in adults and in pediatrics. For example, various
viral infection, bacterial infections, or pathogenic agents may be
effectively treated with the solution of the present invention.
Non-limiting examples of pathogenic agents that have been
successfully treated with the solution of the present invention
include chlamydia trachomatis, gonorrhea as well as other viral
infections.
Method of Using the Solution of Invention in Gynecology:
[0172] The solution of the present invention may be used for the
treatment of gynecological infections, such as urinary tract
infections and the like. For example, various microorganisms,
yeasts (e.g., Monilia, Candida albicans, etc . . . . ), bacterial
infections, HSV-2 or other pathogenic agents may be effectively
treated with the solution of the present invention. Optionally, the
application of the solutions of the present invention can be used
with other medications for the treatment of gynecological
infections.
Method of Wound Care:
[0173] Patients suffering from long-lasting non-healing wounds
should be treated with the physiologically-balanced, acidic
solution of the present invention on a daily basis, typically about
twice a day. The solution of the invention, for example, having a
concentration of about 180 ppm of total active chlorine and a pH of
2.5 may be used in place of a saline solution, to control infection
and to help the wound healing mechanisms. The solution of the
invention may be used as follows: a gauze material or gauze pad is
presoaked with enough solution to saturate it and is then squeezed
to remove excess solution. This removes species present in the
gauze which would react with and reduce the effectiveness of the
solution of the invention. The gauze is wetted after this
procedure, but not soaked. Additional solution is then applied to
completely wet the gauze, which is then immediately applied to the
wound. In the alternative, the gauze may be applied to the wound
and then additional solution applied. Typically the wound site is
packed with the solution-soaked gauze, and optionally, a Vaseline
gauze can be applied on top of the packed wound to keep it moist
and free of contaminating germs. The wound site is then wrapped
with wound dressings as is standard in the art. The solution may
also be used to clean a wound by pouring it directly on the wound
site to remove any necrotic tissue by a mechanical procedure, and
also as a cleanser or irrigant.
[0174] The patient may also make use of a "wound care kit" which
permits the patient to periodically pour the solution of the
present invention onto the wound site without having to remove the
dressing. This kit provides ease-of-use, portability and
dramatically reduce exposure of the wound. The wound care kit
includes a package containing the solution of the invention and
bandaging material.
[0175] Preferably the kit contains a package containing the
solution of the invention and a specialized bandage for use in
combination with the solution. The specialized bandage keeps the
skin surrounding the wound dry while the wound is treated. Further,
the bandage may be applied in a physician's office or at a
hospital, with the patient continuing care at home; may be applied
and used at home under the instructions of a physician; or for
minor injuries, the wound care kit may be used as an "over the
counter" treatment by the patient alone.
[0176] In another aspect of the invention, the solutions of the
present invention may be packaged to contain the solution in
individual, single use containers. The single-use containers may be
used for example, for application in single change of dressing or
equivalents thereof. The single-use containers of the present
invention may be used in conjunction with the specialized bandages
disclosed in the present invention. In another aspect of the
invention, a wound care kit may comprise single-use containers of
the solutions of the present invention with the specialized
bandages for various applications disclosed herein.
IV. Description of the Wound Care Kit
[0177] The wound care kit includes bandaging material and a package
of the solution of the invention. Preferably the packaging material
provides the kind of non-reactive (with the solution) surface
previously described herein. In addition, the bandaging material
preferably includes a specially designed wound "bandage" made out
of an oxygen-permeable bandage material to prevent the wounded
tissue from drying. FIGS. 2A-2C and FIG. 3 describe the bandage and
illustrate the use of the bandage on a wound surface, respectively.
The bandage is described in more detail subsequently. The kit may
also include gauze or a similar material for packing of the wound,
to be used in combination with the solution and a bandage.
V. Description of the Specialized Bandage
[0178] The specialized bandage of the present invention comprises
an opening, which may also be described as a "window" through which
the solution of the invention or other topical material may be
applied periodically as needed depending on the indication.
Preferably, the bandage includes a dew/moisture sensor, an
electrically-conductive sensor which measures ion content, or other
bandage property sensor which provides an indication of the status
of the bandage related to treatment of the wound. For example, and
not by way of limitation, a dew/moisture indicator which provides a
colored indication when the bandage solution content has become
low, or a signal-producing device such as a sound indicator or an
electrical signal output indicator when the ion content of the
treatment solution has become low so that the bandage is no longer
sufficiently effective.
[0179] One embodiment of the bandage invention is shown in FIGS.
2A-2C, The bandage 200 includes an outer portion 201 having a
primary adhesive border 202; an inner portion 210 including a
lifting flap 205 having a secondary adhesive border 207, a lifting
tab 204, which assists in the lifting of flap 205, and a hinge 206.
Optionally the bandage has a dew/humidity indicator 208, or an
electrically-conductive sensor, where the sensor may be attached to
a signal generator, which occupies a position within inner portion
210 of bandage 200. FIG. 2B is a schematic side view of
air-permeable bandage 200, showing lifting flap 205 and lifting tab
204 in a partially lifted position, to provide a window opening 203
through bandage 200. A portion of secondary adhesive border 207 has
been lifted above the upper surface 209 of bandage 200. FIG. 2C is
a schematic cross-sectional view of air-permeable bandage 200, with
lifting flap 205 and lifting tab 204 in a lowered position, secured
to upper surface 209 of bandage 200 by secondary adhesive border
207. One skilled in the art can envision a number of similar
designs which will accomplish the function and utility of the
bandage in a similar manner, and such designs are considered to be
included in the present invention.
[0180] FIG. 3 is a schematic cross-sectional view 300 of an
air-permeable bandage 200 of the kind shown in FIGS. 2A-2C, applied
over a subcutaneous wound 303. The subcutaneous tissue 304 is
packed with a packing material 306 such as gauze, which has been
treated to reduce or eliminate reactivity with oxidants and then
soaked in the physiologically balanced, electrolyzed, acidic
solution 308 of the present invention. The bandage 200 is adhered
to the skin surface 302 by a primary adhesive border 202. Bandage
lifting flap 205 can be lifted via tab 204 to expose packing
material 306 for the application of additional solution 308 when
desired. A dew/humidity indicator (not shown), or
electrically-conductive indicator (not shown) may be used to
indicate the appropriate time for addition of solution 308.
[0181] In another aspect of the bandage invention, the window may
have no permanent connecting hinge with the bandage and may be
removably attached or secured to the bandage by various connecting
or attaching means known in the art. Non-limiting examples of such
connecting or attaching means include Velcro attachments, removable
adhesives or tacking surfaces. The removable windows in the
bandages of the present invention permit the changing or
replacement of the windows without the need for replacing the
entire outer bandage.
[0182] In another aspect of the bandage invention, individual
bandages of variable sizes and configurations may be supplied and
sold separately with the corresponding detachable windows of
particular sizes and configurations that may accommodate the
bandage. Optionally, the windows may be designed such that the
windows properly overlaps with the bandage such that the windows
fully cover the wounds and have overlapping surfaces with the
bandage such that the windows may be securely attached to the
bandage.
[0183] The bandage provides ease-of-use to the patient by allowing
the patient to pour the solution onto his wound or onto wound
packing without having to remove the entire dressing. A more
complicated version of the bandage, such as one having an
electrically-conductive sensor which may be connected to monitoring
equipment is particularly helpful in a hospital setting.
[0184] In another aspect of the bandage invention, the bandages of
variable sizes, contours and shapes may be pre-fabricated with
perforated outlines of one or more windows of variable sizes,
dimensions and configurations such that the bandage may be adapted
or custom fitted to the size, shape and configuration of the
wounds. The bandages maybe designed for variable sizes, shapes, and
contours that can be made to accommodate the specific anatomical
dimensions of the body. Particular areas of the body that may
require specially designed bandages include various joints, the
elbows, knees, fingers and toes, and other locations of the human
anatomy having non-flat surfaces or curves.
[0185] The perforations in the bandages allows a health caregiver
or the patient to use a generically manufactured, perforated
bandage to manually remove the inner window of the bandage by
cutting or tearing along the perforations defining or outlining a
window that custom matches the size, shape or configuration of the
wound. In addition, the perforations permit the application of a
single bandage for application to wounds of various sizes and
dimensions, and permit medical facilities and suppliers to stock
only a small number of intermediate sizes of bandages that may
accommodate wounds of various sizes and configurations.
ASPECTS OF THE INVENTION
[0186] In one aspect of the invention, there is provided a stable
aqueous physiologically balanced, ionized solution comprising: (a)
an acidic solution of hypohalous acid with a concentration from
about 10 ppm to about 200 ppm; (b) a halide comprising salt, from
about 0.4 g/L to about 20.4 g/L, said solution having a pH range
from about 3.0 to about 4.0, and (c) said solution when stored in a
chemically non-reactive container at room temperature over at least
three months, the solution is characterized as having a reduced
hypohalous acid concentration of between 1-95% as determined by
UV-VIS or by iodometric titration.
[0187] In another aspect of the invention, the solution is further
characterized as having a pH range from about 3.5 to about 4.0. In
another aspect, the stable solution has a pH of about 3.5.
[0188] In another aspect, the solution is further characterized as
capable of being stored in a chemically non-reactive container at
room temperature over at least three months, the solution is
characterized as having a reduced hypohalous acid concentration of
between 0-5% as determined by UV-VIS or by iodometric
titration.
[0189] In yet another aspect, the stable solution may be stored in
a chemically non-reactive container at room temperature over at
least three months, the solution is characterized as having a
reduced hypohalous acid concentration of between 5-15% as
determined by UV-VIS or by iodometric titration.
[0190] In another aspect of the invention, the hypohalous acid
comprises the active chlorine species HOCl, NaOCl, and Cl.sub.2,
and the pH of the solution is about 3.5.
[0191] In one aspect of the invention, there is provided a stable
aqueous physiologically balanced, ionized solution, wherein the
chemically non-reactive container is a gas-tight, sealed container
is made from material that is non-permeable and resistant to
oxidative degradation.
[0192] In another aspect, the chemically non-reactive container is
a gas-tight, sealed container made from PFA or equivalent PFA
compositions or Teflon compositions. In another aspect, the
container is non-permeable to the species of the NVC-101
solution.
[0193] In yet another aspect, the stable solution is further
characterized as having an original oxidation reduction potential
(ORP) at room temperature ranging from about +600 mV to about +1200
mV, and said ORP ranging from no less than about 90 to 97.5% of the
original ORP after three months at room temperature.
[0194] In one aspect, the hypohalous acid is selected from the
group consisting of HOBr, HOI, HOCl, and HOF. In another aspect,
the hypohalous acid concentration is from about 40 to about 190
ppm.
[0195] In yet another aspect, the halide comprising salt is a
member selected from the group consisting of lithium, sodium,
potassium, magnesium, zinc, cesium, rubidium, and barium
halide.
[0196] In yet another aspect, the halide comprising salt is a
single salt. In yet another aspect, the hypohalous acid
concentration of the stable solution is measured by iodometric
titration or UV-VIS spectroscopy.
[0197] In another aspect, the chemically non-reactive container is
designed for single use or single application packaging.
[0198] In a further aspect, there is provided a stable aqueous
physiologically balanced, ionized solution comprising: (a) an
acidic solution of hypochlorous acid (HOCl) with a concentration,
from about 10 ppm to about 200 ppm; (b) a chloride comprising salt,
from about 0.4 g/L to about 16 g/L, said solution having a pH range
from about 3.5 to about 4.0, and (c) said solution when being
stored in a chemically non-reactive, single use container at room
temperature over at least three months and having a reduced
hypochlorous acid concentration of between 1-95% as determined by
UV-VIS or by iodometric titration.
[0199] In one aspect, the container is a single use PFA lined
container.
[0200] In one aspect, there is provided a method for the treatment
of various medical conditions selected from the groups consisting
of promoting wound healing, reduction of pathogens in open wounds,
wound decontamination, ocular disinfection or decontamination, oral
disinfection, antifungal therapy, ophthalmic applications,
reduction of pathogens in pulmonary infections, reduction of
pathogens in burns, lavage, reduction of infectious load in organs
for transplantation, reduction of bacterial load in autologous or
artificial tissue transplantation, oral disinfection antifungal
therapy, treatment of biofilm for cystic fibrosis or other diseases
that produces biofilms, treatment of viral infections, treatment of
skin diseases, and tissue repair and regeneration, which method
comprises using a solution of the invention by applying the
solution to the site where treatment is required.
[0201] In yet another aspect, there is provided a method for the
treatment of various medical conditions selected from the groups
consisting of promoting wound healing, reduction of pathogens in
open wounds, wound decontamination, ocular disinfection or
decontamination, oral disinfection, antifungal therapy, ophthalmic
applications, reduction of pathogens in pulmonary infections,
reduction of pathogens in burns, lavage, reduction of infectious
load in organs for transplantation, reduction of bacterial load in
autologous or artificial tissue transplantation, oral disinfection
antifungal therapy, treatment of biofilm for cystic fibrosis or
other diseases that produces biofilms, treatment of viral
infections, treatment of skin diseases, and tissue repair and
regeneration, which method comprises using a solution of the
invention by applying the solution to the site where treatment is
required.
[0202] In another aspect, the solution is characterized as having
an original oxidation reduction potential (ORP) at room temperature
ranging from about +600 mV to about +1200 mV, and said ORP ranging
from no less than about 90 to 97.5% of the original ORP after at
least three months at room temperature.
[0203] In a further aspect, there is provided a solution wherein
the hypochlorous acid concentration is from about 40 to about 190
ppm. In another aspect, the chloride comprising salt is a member
selected from the group consisting of lithium, sodium, potassium,
magnesium, zinc, cesium, rubidium, and barium chloride. In yet
another aspect, the chloride comprising salt is a single salt.
[0204] In another aspect, there is provided a solution wherein the
pH ranges from about 3.5 to about 4.0. In another variation of the
solution, the chloride comprising salt is sodium chloride. In one
aspect, the concentration of sodium chloride is from about 4 g/L to
about 9 g/L.
[0205] In one aspect of the invention, the molar ratio range of
OCl.sup.- over the sum of OCl.sup.- and HOCl at 20.degree. C. is
about 0 to about 0.26%.
[0206] In another aspect, there is provided a method for the
treatment of various medical conditions selected from the groups
consisting of promoting wound healing, reduction of pathogens in
open wounds, wound decontamination, ocular disinfection or
decontamination, oral disinfection, antifungal therapy, ophthalmic
applications, reduction of pathogens in pulmonary infections,
reduction of pathogens in burns, lavage, reduction of infectious
load in organs for transplantation, reduction of bacterial load in
autologous or artificial tissue transplantation, oral disinfection
antifungal therapy, treatment of biofilm for cystic fibrosis or
other diseases that produces biofilms, treatment of viral
infections, treatment of skin diseases, and tissue repair and
regeneration, which method comprises using a solution of the
invention by applying the solution to the site where treatment is
required.
[0207] In one aspect, there is provided a process for the
preparation of a solution of the invention, wherein the solution is
prepared by chemical methods, including chemical synthesis,
mechanical methods such as by mixing, electrolysis or prepared in
situ.
[0208] In another aspect, the halide comprising salt solution is
converted to an acidic solution by electrolysis.
[0209] In yet another aspect for the process for preparing a
solution of the invention, the pH of the solution is adjusted to
about 3.5 to about 4.0. In yet another aspect, the solution is
prepared by chemical synthesis comprising of the following
reactions:
NaOCl+HCl.fwdarw.HOCl+NaCl
wherein the concentration of NaOCl in solution is about 2.5 mmol/L
and the concentration of HCl is about 7.4 mmol/L, the resulting
solution is adjusted to a pH of about 3.5 to about 4.0, and the
solution is allowed to reach equilibrium without agitation for at
least 2 hours.
[0210] In another aspect, there is provided a process wherein the
solution is prepared in situ by mixing chemicals to form the stable
aqueous physiologically balanced, non-cytotoxic ionized solution at
the site of the tissue in need of treatment.
[0211] In yet another aspect, there is provided a method of
promoting wound healing, reduction of pathogens in open wounds,
wound decontamination, ocular disinfection or decontamination, oral
disinfection, antifungal therapy, ophthalmic applications,
reduction of pathogens in pulmonary infections, reduction of
pathogens in burns, lavage, reduction of infectious load in organs
for transplantation, reduction of bacterial load in autologous or
artificial tissue transplantation, oral disinfection antifungal
therapy, treatment of biofilm for cystic fibrosis or other diseases
that produces biofilms, treatment of viral infections, treatment of
skin diseases, and tissue repair and regeneration, or a combination
thereof, by treating a patient in need of such therapy with an
effective amount of a stable, physiologically-balanced, acidic
composition comprising an aqueous stable solution of the present
invention. In a further aspect, there is provided the above method
that comprises a) exposing area of damaged tissue; b) applying the
solution to dermal tissue; c) irrigation of damaged tissue using
the solution; and d) cleaning or treating tissue using the
solution.
[0212] Accordingly, the above described preferred embodiments are
not intended to limit the scope of the present invention, as one
skilled in the art can, in view of the present disclosure, expand
such embodiments to correspond with the subject matter of the
invention claimed below.
* * * * *