U.S. patent application number 14/482894 was filed with the patent office on 2015-02-26 for synergistic antimicrobial preparations containing chlorite and hydrogen peroxide.
The applicant listed for this patent is S.K. Pharmaceuticals, Inc.. Invention is credited to Hampar Karageozian.
Application Number | 20150056272 14/482894 |
Document ID | / |
Family ID | 22616449 |
Filed Date | 2015-02-26 |
United States Patent
Application |
20150056272 |
Kind Code |
A1 |
Karageozian; Hampar |
February 26, 2015 |
Synergistic Antimicrobial Preparations Containing Chlorite and
Hydrogen Peroxide
Abstract
Antimicrobial/pharmaceutical preparations (e.g., solutions,
gels, ointments, creams, sustained release preparations, etc.)
which comprise chlorite (e.g., a metal salt of a chlorite) in
combination with a peroxy compound (e.g., hydrogen peroxide), and
methods for using such preparations for disinfection of articles or
surfaces (e.g., contact lenses, counter tops, etc.), antisepsis of
skin or other body parts, prevention or deterrence of scar
formation and/or treatment and prophylaxis of dermal (i.e., skin or
mucous membrane) disorders (e.g., wounds, burns, infections, cold
sores, ulcerations, psoriasis, acne, or other scar-forming
lesions).
Inventors: |
Karageozian; Hampar; (San
Juan Capistrano, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
S.K. Pharmaceuticals, Inc. |
San Juan Capistrano |
CA |
US |
|
|
Family ID: |
22616449 |
Appl. No.: |
14/482894 |
Filed: |
September 10, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10938797 |
Sep 9, 2004 |
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14482894 |
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09722919 |
Nov 27, 2000 |
6488965 |
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10938797 |
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09169620 |
Oct 8, 1998 |
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09722919 |
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Current U.S.
Class: |
424/450 ;
424/616 |
Current CPC
Class: |
A61K 33/40 20130101;
A01N 59/00 20130101; A61K 9/0014 20130101; Y10S 514/969 20130101;
Y10S 514/97 20130101; A61P 17/10 20180101; A61K 33/14 20130101;
A61P 27/14 20180101; A61K 47/02 20130101; A61P 17/02 20180101; Y10S
424/13 20130101; Y10S 514/964 20130101; A61K 9/06 20130101; A61K
33/40 20130101; A61P 27/04 20180101; A61P 17/06 20180101; A61K
9/0048 20130101; A61K 33/40 20130101; Y10S 514/944 20130101; A61K
33/14 20130101; A01N 59/00 20130101; A01N 2300/00 20130101; A61K
2300/00 20130101; A61K 9/127 20130101; A01N 59/00 20130101; A61K
47/38 20130101; A01N 59/00 20130101; A61K 33/20 20130101 |
Class at
Publication: |
424/450 ;
424/616 |
International
Class: |
A61K 33/40 20060101
A61K033/40; A61K 9/06 20060101 A61K009/06; A61K 9/127 20060101
A61K009/127; A61K 47/38 20060101 A61K047/38; A61K 33/20 20060101
A61K033/20; A61K 33/14 20060101 A61K033/14 |
Claims
1. A chlorine dioxide-free preparation comprising: approximately
0.02-0.10 percent by weight of a chlorite compound; approximately
0.005-0.01 percent by weight of a peroxy compound; sodium chloride;
and water; wherein the preparation has a pH in the range of 6.8 to
7,8; and wherein no chlorine dioxide is generated within the
solution when stored at room temperature for up to 18 months .
2. A preparation according to claim 1 wherein the chlorite is
present as a metal chlorite.
3. A preparation according to claim 2 wherein the metal chlorite is
selected from the group of metal chlorites consisting of: sodium
chlorite; potassium chlorite; calcium chlorite; and, magnesium
chlorite.
4. A preparation according to claim 1 wherein the peroxy compound
is hydrogen peroxide.
5. A preparation according to claim 1 in liquid form, said
preparation comprising: TABLE-US-00005 Sodium Chlorite 0.02%-0.10%;
Hydrogen Peroxide 0.005%-0.01%; Methocel A 0.05%-0.2%; Boric Acid
0.15%; Sodium Chloride 0.75%; Pluronic F-68 0.1%; HCl or NaOH to
adjust pH to about 7.4; and, Purified water Q.S. to volume.
6. A preparation according to claim 1 in gel form, said preparation
comprising: TABLE-US-00006 Sodium Chlorite 0.02%-0.10% Hydrogen
Peroxide 0.005%-0.01% Methocel A 0.05%-2.0% Boric Acid 0.15% Sodium
Chloride 0.75% Pluronic F-68 0.1% HCl or NaOH Adjust pH 7.4
Purified water Q.S. to volume
7. A preparation according to claim 1 further comprising: a
sustained delivery component which limits the rate at which the
chlorite becomes available for generation of chlorine dioxide and
hydrogen peroxide becomes available for generation of oxygen.
8. A sustained release preparation according to claim 7, wherein
the sustained delivery component comprises a polymer matrix.
9. A sustained release preparation according to claim 7, wherein
the sustained delivery component comprises a liposome.
10. A sustained release preparation according to claim 7, wherein
the sustained delivery component is selected from the group
consisting of: a cellulose ester; hydroxymethylpropyl cellulose;
methylhydroxyethyl cellulose; hydroxypropyl cellulose; hydroxyethyl
cellulose; carboxymethyl cellulose; a salt of a cellulose ester;
cellulose acetate; hydroxypropylmethyl cellulose phthalte;
methacrylic acid-methyl methacrylate copoymer; methacrylic
acid-ethyl acetate copolymer; polyvinylpyrrolidone; polyvinyl
alcohol; a phospholipid; cholesterol; a phospholipid having a
neutral charge; a phospholipid having a negative charge;
dipalmytoyl phoshatidyl choline: dipalmytoyl phoshatidyl serine;
and, sodium salts thereof.
11. A sustained release preparation according to claim 7, wherein
the sustained delivery component comprises 1-20 percent by weight
of the preparation.
12. A preparation according to claim 1 which is a liquid,
13. A preparation according to claim 1 which is a gel.
14. A preparation according to claim 1 which is a cream.
15. A preparation according to claim 1 which is an ointment.
16. A preparation according to claim 1 which is a contact lens
solution, wherein said preparation further comprises at least one
additional component selected from: polymeric lubricants, non-ionic
polymeric lubricants, anionic polymeric lubricants; HPMC, Methocel
and carboxymethylcellulose.
17. A preparation according to claim 16 wherein the surfactant
comprises a block polymer based surfactant.
Description
RELATED APPLICATIONS
[0001] This is a continuation of copending U.S. patent application
Ser. No. 10/938,797 filed Sep. 9, 2004, which is a continuation of
U.S. patent application Ser. No. 10/308,229 filed Dec. 2, 2002,
which is a continuation of U.S. patent application Ser. No.
09/722,919 filed Nov. 27, 2000 and issued as U.S. Pat. No.
6,488,965, which is a continuation of U.S. patent application Ser.
No. 09/169,620 filed Oct. 8, 1998, the entire disclosure of each
such patent and application being expressly incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to medical
compositions and methods, and more particularly to certain
disinfectant/antimicrobial preparations and methods for using such
preparations i) to disinfect articles or surfaces, ii) as a topical
antiseptic for application to body parts, and iii) to prevent or
deter scar formation and iv) to treat dermatological disorders such
as wounds, burns, ulcers, psoriasis, acne and other scar forming
lesions.
BACKGROUND OF THE INVENTION
A. Antimicrobial and Disinfectant/Antiseptic Agents Used for
Disinfection/Antisepsis and Topical Treatment of Wounds, Burns,
Abrasions and Infections
[0003] The prior art has included numerous antimicrobial agents
which have purportedly been useable for disinfection of various
articles and/or for topical application to a living being for
antisepsis and/or treatment of dermal disorders (e.g., wounds,
burns, abrasions, infections) wherein it is desirable to prevent or
deter microbial growth to aid in healing. Such topical
antimicrobial agents have contained a variety of active
microbicidal ingredients such as iodine, mercurochrome, hydrogen
peroxide, and chlorine dioxide.
[0004] i. Prior Chlorine Dioxide Preparations
[0005] Chlorite, a precursor of chlorine dioxide, is known to be
useable as a disinfectant for drinking water and as a preservative
for contact lens care solutions. However, chlorite exhibits only
weak microbicidal activity within a concentration range that is
acceptable and safe for topical application to the skin (e.g.,
200-1000 parts per million). Thus, chlorite has not been routinely
used as an active microbicidal ingredient in preparations for
topical application to the skin.
[0006] In view of the limited usefulness of chlorite as an
antiseptic or topical microbicide, various compositions and methods
have been proposed for activation or enhancement of the
microbicidal activity of chlorite. Examples of such compositions
and methods for activation or enhancement of the microbicidal
activity of chlorite are described in U.S. Pat. No. 4,997.616
(describing general activation); U.S. Pat. No. 5,279,673
(describing acid activation) and U.S. Pat. No. 5,246,662
(describing transitional metal activation).
[0007] Chlorine dioxide (CO.sub.2) and "stabilized chlorine
dioxide" are known to be useable as antiseptics. Chemically,
chlorine dioxide is an oxidizing agent which has strong
microbicidal activity. Chlorine dioxide is generally regarded as
superior even to gaseous chlorine, in certain water treatment
applications where it is used as to eliminate algae and other
organic material and/or to remove odors or tastes. Chlorine dioxide
is also effective as a microbicide, for elimination of bacteria,
viruses, and microbial spores.
[0008] In addition to its use as a microbicide, chlorine dioxide is
a highly reactive, unstable radical which is useable as an
oxidizing agent in a number of other chemical and biochemical
applications. For example, as described in U.S. Pat. No. 4,855,135,
chlorine dioxide can be used for (a) oxidation of double bonds
between two carbon atoms; (b) oxidation of unsaturated fatty acids
(lipids) via double bonds between two carbon atoms; (c)
acceleration of hydrolysis of carboxylic anhydrides; (d) oxidation
of aldehydes to the corresponding carboxylic acids; (e) oxidation
of alcohols; (f) oxidation of amines; (g) oxidation of phenols,
phenolic derivatives and thiophenolic compounds; (h) moderate
oxidation of hydroquinones; (i) oxidation of amino acids, proteins
and polyamides; j) oxidation of nitrates and sulphides; and (k)
alteration of the CHO and CH.sub.2OH radicals of carbohydrates to
produce carboxylic functionality.
[0009] Concentrated chlorine dioxide in its liquid or gaseous state
is highly explosive and poisonous. As a result, concentrated
chlorine dioxide must be handled and transported with great
caution. For this reason, it is generally not feasible to dispense
pure chlorine dioxide for use as a topical antimicrobial agent or
disinfectant. Instead, same antimicrobial or disinfectant
preparations have been formulated to provide for "acid generation"
of chlorine dioxide. Such acid generation solutions contain a metal
chlorite (i.e., a precursor of chlorine dioxide available in
powdered or liquid form) in combination with an acid which will
react with the chlorite to liberate or release chlorine dioxide.
Generally, any acid may be used for acid generation of chlorine
dioxide, including strong acids such as hydrochloric acid and
sulfuric acid and relatively weak acids such as citric and tartaric
acid. Drawbacks or problems associated with these prior chlorine
dioxide generating systems include a) the inconvenience of handing
two separate containers or chemical components, b) the difficulty
of delivering such two-component systems to the intended site of
application, and c) the fact that these prior systems are of acid,
rather than neutral, pH. Moreover, the prior chlorine dioxide
generating systems which utilize acid-induced generation of
chlorine dioxide can, if uncontrolled, cause the generation of
chlorine dioxide to occur quite rapidly and, as a result, the
disinfectant or antimicrobial potency of the solution may be short
lived. Increasing the concentration of chlorite and acid within the
solution may prolong its disinfectant or antimicrobial shelf life,
but such Increased concentrations of these chemicals can result in
toxicities or (in topical applications) skin irritation. Such
increased concentrations may also result in the generation of more
chlorine dioxide than is required.
[0010] Various methods have been described to limit or control the
rate at which chlorine dioxide is produced in "acid generation"
solutions. For instance, U.S. Pat. No. Re. 31,779 (Alliger)
describes a germicidal composition which comprises a water soluble
chlorite, such as sodium chlorite, in combination with lactic acid.
The particular composition possesses improved disinfectant
properties, properties not attained by using the same composition
but replacing the lactic acid with other acids such as phosphoric
acid, acetic acid, sorbic acid, fumaric acid, sulfamic acid,
succinic acid, boric acid, tannic acid, and citric acid. The
germkilling composition is produced by contacting an acid material
containing at least 15% by weight of lactic acid with sodium
chlorite in aqueous media, the amount of lactic acid being
sufficient to lower the pH of the aqueous media to less than about
7. The methods disclosed of disinfecting and sanitizing a
germ-carrying substrate, such as skin, include either application
of the germ-killing composition, or application of the reactants to
provide in situ production thereof. Also, U.S. Pat. No. 5,384,134
(Kross) describes acid induced generation of chlorine dioxide from
a metal chlorite wherein the chlorite concentration is limited by
the amount of available chlorous acid. In particular, the Kross
patent describes a method for treating dermal disorders wherein a
first gel, which comprises a metal chlorite, is mixed with a second
gel, which comprises a protic acid. The chlorite ions present in
such solution as chlorous acid purportedly comprise no more than
about 15% by weight of the total chlorite ion concentration in the
composition, and the mixture of the two gels purportedly generates
chlorine dioxide over an extended time of up to 24 hours.
[0011] Other prior patents have purported to describe the use of
"stabilized" chlorine dioxide as a means of chlorine dioxide
generation. The term stabilized chlorine dioxide refers to various
compositions in which the chlorine dioxide is believed to be held
in solution in the form of a labile complex. The stabilization of
chlorine dioxide by the use of perborates was disclosed in U.S.
Pat. No. 2,701,781 (de Guevara). According to the de Guevara
patent, an antiseptic solution of stabilized chlorine dioxide can
be formed from an aqueous solution of chlorine dioxide and an
inorganic boron compound with the boron compound and the chlorine
dioxide being present in the solution as a labile complex. The
chlorine dioxide, fixed in this stable condition, is an essential
ingredient of the antiseptic solution. The de Guevara patent
discloses that the chlorine dioxide may be introduced into the
compositions either by in situ generation or it may be generated
externally and introduced into the solution, as by bubbling the
chlorine dioxide gas into the aqueous solution. Various methods may
be employed for the external production of the chlorine dioxide,
such as reaction of sulfuric acid with potassium chlorate or the
reaction of the chlorate with moist oxalic acid. Alternatively,
chlorine dioxide can be generated in situ by reaction of potassium
chlorate and sulfuric acid. Note that whether the chlorine dioxide
is produced in situ or externally, it is essentially an acid
induced liberation of the chlorine dioxide from potassium
chlorate.
[0012] U.S. Pat. No. 4,317,814 (Lasa) describes stabilized chlorine
dioxide preparations for treatment of burns in humans. Aqueous
mixtures of perborate stabilized solutions of chlorine oxides, such
as chlorine dioxide, in combination with glycerin are described for
topical application to burned areas and may also be administered by
oral application for treatment of bums. The aqueous solutions of
perborate stabilized chlorine oxides are disclosed as being
prepared by mixing with water the following: sodium chlorite,
sodium hypochlorite, hydrochloric acid, sulfuric acid, an inorganic
perborate, and a peroxy compound, such as sodium perborate. Thus,
the solutions prepared in accordance with the Laso patent contain
chlorine dioxide, hypochlorite and peroxy compounds as strong
oxidizing agents and appear to utilize acid activation of the
chlorine dioxide. The Laso patent states that the methods disclosed
therein resulted in an immediate subsidence of burn related pain in
many cases, that healing was rapid and characterized by an absence
of infection or contraction, and that the burn scars were smooth
and resembled normal tissue, thus eliminating the need for plastic
surgery in certain cases. However, long term storage and stability
are issues with the aqueous solutions described in the
above-identified Laso patent, because such mixtures tend to
generate chlorine dioxide very quickly, thus diminishing the long
term stability of such mixtures.
[0013] U.S. Pat. No. 3,271,242 (McNicholas et al.) describes
stabilized chlorine dioxide solutions which are formed by combining
chlorine dioxide gas with an aqueous solution containing a peroxy
compound, and subsequently heating the solution to a temperature
which is high enough to drive off all free peroxide, but low enough
not to destroy the chlorine dioxide. McNicholas et al. States that
temperatures "much below" 70 degrees C. are ineffective to drive of
the free peroxide in the solution and that temperatures should not
exceed 92 degrees C. because at higher temperatures the chlorine
dioxide will be driven off. McNicholas further states that,
although not "entirely understood," it was believed that heating of
the solution to drive off free peroxide was necessary because any
free hydrogen peroxide allowed to remain in the solution would act
as a leaching agent to release the chlorine dioxide from the
solution.
[0014] ii. Antibiotic Preparations
[0015] Antibiotic compounds have also been commonly used for the
therapeutic treatment of bums, wounds and skin infections. While
antibiotics may provide an effective form of treatment, several
dangers are often associated with the use of antibiotics in the
clinical environment. These dangers may include but are not limited
to: (1) changes in the normal flora of the body, with resulting
"superinfection" due to overgrowth of antibiotic resistant
organisms; (2) direct antibiotic toxicity, particularly with
prolonged use which can result in damage to kidneys, liver and
neural tissue depending upon the type of antibiotic; (3)
development of antibiotic resistant microbial populations which
defy further treatment by antibiotics.
B. Difficult-To-Treat Dermal Disorders Other Than Wounds, Burns,
Abrasions and Infections
[0016] While even minor wounds and abscesses can be difficult to
treat in certain patients and/or under certain conditions, there
are well known dermal disorders such as psoriasis and dermal
ulcerations, which present particular challenges for successful
treatment.
[0017] i. Psoriasis
[0018] Psoriasis is a noncontagious skin disorder that most
commonly appears as inflamed swollen skin lesions covered with
silvery white scale. This most common type of psoriasis is called
"plaque psoriasis". Psoriasis comes in many different variations
and degrees of severity. Different types of psoriasis display
characteristics such as pus-like blisters (pustular psoriasis),
severe sloughing of the skin (erythrodermic psoriasis), drop-like
dots (guttate psoriasis) and smooth inflamed lesions (inverse
psoriasis).
[0019] The cause of psoriasis is not presently known, though it is
generally accepted that it has a genetic component, and it has
recently been established that it is an autoimmune skin disorder.
Approximately one in three people report a family history of
psoriasis, but there is no pattern of inheritance. There are many
cases in which children with no apparent family history of the
disease will develop psoriasis.
[0020] The occurrence of psoriasis in any individual may depend on
some precipitating event or "trigger factor." Examples of "trigger
factors" believed to affect the occurrence of psoriasis include
systemic infections such as strep throat, injury to the skin (the
Koebner phenomenon), vaccinations, certain medications, and
intramuscular injections or oral steroid medications. Once
something triggers a person's genetic tendency to develop
psoriasis, it is thought that in turn, the immune system triggers
the excessive skin cell reproduction.
[0021] Skin cells are programmed to follow two possible programs:
normal growth or wound healing. In a normal growth pattern, skin
cells are created in the basal cell layer, and then move up through
the epidermis to the stratum corneum, the outermost layer of the
skin. Dead cells are shed from the skin at about the same rate as
new cells are produced, maintaining a balance. This normal process
takes about 28 days from cell birth to death. When skin is wounded,
a wound healing program is triggered, also known as regenerative
maturation. Cells are produced at a much faster rate, theoretically
to replace and repair the wound. There is also an increased blood
supply and localized inflammation. In many ways, psoriatic skin is
similar to skin healing from a wound or reacting to a stimulus such
as infection.
[0022] Lesional psoriasis is characterized by cell growth in the
alternate growth program. Although there is no wound at a psoriatic
lesion, skin cells (called "keratinocytes") behave as if there is.
These keratinocytes switch from the normal growth program to
regenerative maturation. Cells are created and pushed to the
surface in as little as 2-4 days, and the skin cannot shed the
cells fast enough. The excessive skin cells build up and form
elevated, scaly lesions. The white scale (called "plaque") that
usually covers the lesion is composed of dead skin cells, and the
redness of the lesion is caused by increased blood supply to the
area of rapidly dividing skin cells.
[0023] Although there is no known cure for psoriasis, various
treatments have been demonstrated to provide temporary relief in
some patients. However, the effectiveness of the currently accepted
treatments for psoriasis is subject to considerable individual
variation. As a result, patients and their physicians may have to
experiment and/or combine therapies in order to discover the
regimen that is most effective. The currently available treatments
for psoriasis are often administered in step-wise fashion. Step 1
treatments include a) topical medications (e.g., topical steroids,
topical retinoids), b) systemic steroids, c) coal tar, d)
anthralin, e) vitamin D3; and sunshine. Step 2 treatments include
a) phototherapy (e.g, ultraviolet radiation), b) phochemotherapy
(e.g., a combination of a topically applied radiation-activated
agent followed by radiation to activate the agent) and c)
combination therapy. Step 3 treatments include a) systemic drug
therapies such as methotrexate, oral retinoids and cyclosporine and
b) rotational therapy.
[0024] ii. Dermal Ulcerations
[0025] Dermal ulcerations are known to occur as a result of
pressure, wear, or primary/secondary vascular disorders. Dermal
ulcerations are generally classified according to their etiology,
as follows:
[0026] a. Decubitus/Pressure Ulcers--A decubitus ulcer or pressure
sore is a lesion caused by unrelieved pressure resulting in damage
of the underlying tissue. Decubitus ulcers usually develop over a
bony prominence such as the elbow or hip. The unrelieved pressure,
along with numerous contributing factors, leads to the skin
breakdown and persistent ulcerations.
[0027] b. Venous Ulcers--Venous ulcers may result from trauma or
develop after chronic venous insufficiency (CVI). In CVI, venous
valves don't close completely, allowing blood to flow back from the
deep venous system through the perforator veins into the
superficialvenous system. Over time, the weight of this column of
blood causes fluid and protein to exude into surrounding tissues,
resulting in swollen, hyperpigmented ankles, tissue breakdown, and
ulceration. Venous ulcers may be shallow or extend deep into
muscle.
[0028] c. Arterial Ulcers--Leg ulcers also can develop in patients
with arterial insufficiency caused by arterial vessel compression
or obstruction, vessel wall changes, or chronic vasoconstriction.
Smokers face an especially high risk of arterial disease because
nicotine constricts arteries, encourages deposits of
atherosclerotic plaque, and exacerbates inflammatory arterial
disease (Buerger's disease) and vasoconstrictive disease (Raynaud's
disease or phenomenon). Arterial ulcers, caused by trauma to an
ischemic limb, can be very painful,
[0029] d. Diabetic Ulcers--Arterial insufficiency can be the cause
of a nonhealing ulcer in a patient with diabetes. However, most
diabetic ulcers result from diabetic neuropathy--because the
patient can't feel pain in his foot, he's unaware of injuries,
pressure from too-tight shoes, or repetitive stress that can lead
to skin breakdown.
[0030] There remains a need in the art for the formulation and
development of new disinfectants and topically applicable
preparations for the treatment of dermal disorders, such as wounds,
burns, abrasions, infections, ulcerations, psoriasis and acne.
SUMMARY OF THE INVENTION
[0031] The present invention provides antimicrobial preparations
(e.g., solutions, gels, ointments, creams, etc.) for disinfection
of articles or surfaces (e.g., contact lenses, counter tops, etc.),
antisepsis of skin or other body parts, prevention or minimization
of scarring, and/or treatment or prophylaxis of dermal (Le., skin
or mucous membrane) disorders (e.g., wounds, burns, infections,
cold sores, ulcerations, psoriasis, scar forming lesions, acne).
The antimicrobial preparations of this invention generally comprise
from about 0.001% to about 0.10 by weight of a metal chlorite in
combination with from 0.001% to 0.05% of a peroxy compound such as
hydrogen peroxide. Additionally, the chlorite/peroxide preparations
of the present invention may contain additional components such as
polymeric lubricants and surfactants, and/or may be formulated in a
polymeric drug delivery system or liposomal preparation. The
chlorite/peroxide preparations of the present invention have broad
antimicrobial activity, including for example activity against gram
negative and gram positive bacteria, yeasts and fungi. Moreover,
when applied or administered to treat dermal disorders
(e.g.,wounds, bums, infections, ulcerations, acne and psoriasis),
the chlorite/peroxide preparations of the present invention will
not only prevent or lessen microbial infection, but will
additionally provide oxygen to the affected tissue, aid in healing
and deter scar formation.
[0032] Further in accordance with the invention, there are provided
methods for disinfection of items (e.g., contact lenses) and
methods for treatment of dermal disorders (e.g.,wounds, bums,
infections, ulcerations and psoriasis) by application or
administration of a chlorite/peroxide preparation of the present
invention. Further in accordance with the invention, there are
provided methods for deterring scar formation by application or
administration of a chlorite/peroxide preparation of the present
invention.
[0033] Further aspects and objects of the present invention will
become apparent to those of skill in the art upon reading and
understanding of the following detailed description and the
examples set forth therein.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0034] The following detailed description and examples are provided
for the purpose of describing certain exemplary embodiments of the
invention only, and are not intended to limit the scope of the
invention in any way.
[0035] The present invention provides preparations which contain
chlorite (e.g., a metal chlorite) in combination with a small
amount of hydrogen peroxide in neutral aqueous (pH 6.8-7.8,
preferably pH 7.0-7.4) solution. These preparations exhibit
synergistic antimicrobial activity without generating chlorine
dioxide during storage, thereby rendering the stability of these
solutions acceptable for pharmaceutical use. For example, an
aqueous solution containing 400 ppm chlorite plus 100 ppm hydrogen
peroxide remains stable beyond 18 months at room temperature, and
is effective to reduce candida albicans activity by 1.0 log within
a 6 hrs of challenge, even though the individual components of such
solution are ineffective when applied separately at the same
concentrations, to reduce candida albicans activity. Additionally,
the hydrogen peroxide present within the chlorite/peroxide
solutions of the present invention readily decomposes into
molecular oxygen and water, upon contact with the peroxidase and
catalase enzymes present in tissue and/or some body fluids. Such in
situ generation of molecular oxygen contributes to cell vitality
and enhances wound healing.
[0036] The chlorite/H.sub.2O.sub.2 solutions of the present
invention are sufficiently stable to be formulated in combination
with polymeric lubricants (non-ionic and/or anionic; e.g., HPMC,
Methocel, CMC, etc.) and/or in combination with block polymer based
surfactants (e.g., pluronics). For example, an aqueous
chlorite/hydrogen peroxide system can be formulated together with
methocel as a lubricant and pluronics as a surfactant for contact
lens disinfectant solution (viscosity up to 50 cps at 25 degrees
C.) in an ophthalmically acceptable tonicity (e.g., osmolality of
at least about 200 mOsmol/kg) and a buffer to maintain the pH of
the formulation within an acceptable physiological range. The
formulation of the contact lens disinfection solution contains
chlorite preferably from about 0.03 to about 0.06 weight/volume
percent and hydrogen peroxide preferably from about 0.0002 to about
0.05 weight/volume percent. Again, the presence of hydrogen
peroxide provides the beneficial oxygen molecule to the cornea upon
contact with catalase in the tear.
A. Formulations
[0037] The chlorite/peroxide preparations of the present invention
may be formulated in various ways, including liquid solutions,
gels, ointments, creams, sprays, etc. Set forth herebelow are but a
few examples of the types of specific formulations which may be
prepared in accordance with this invention.
[0038] A Stable Chlorite/Peroxide Liquid Solution
[0039] The following Formula 1 is a presently preferred formulation
of a liquid chlorite/peroxide solution of the present
invention:
TABLE-US-00001 FORMULA 1 Sodium Chlorite 0.02%-0.10% Hydrogen
Peroxide 0.005%-0.01% Methocel A 0.05%-0.2% Boric Acid 0.15% Sodium
Chloride 0.75% Pluronic F-68 0.1% HCl or NaOH Adjust pH 7.4
Purified water Q.S. to volume
[0040] The chlorite/peroxide solutions of the present invention,
such as the solution of the above-shown preferred formulation, may
be used for a variety of medical and non-medical applications
including but not necessarily limited to a) disinfection of
articles and surfaces such as contact lenses, medical/dental
instruments, counter tops, treatment tables, combs and brushes,
etc; antisepsis of skin or body parts (e.g., a disinfectant hand
wash, antiseptic facial scub, etc.) and b) treatment or prophylaxix
of dermal (I.e., skin or mucous membrane) disorders such as wounds,
bums, infections, ulcerations, cold sores, psoriasis, acne, and c)
deterrence or prevention of scar formation.
[0041] As pointed out earlier, the chlorite/hydrogen peroxide
system of the present invention is sufficiently stable to be
formulated in a polymeric gel form or in a paste form, Furthermore,
such polymeric gel or paste formulation can contain polymers which
delay or control the release of the chlorite/hydrogen peroxide
(e.g,, a sustained release delivery system). Such sustained release
formulations provide outstanding benefits of increasing therapeutic
index by maintaining the effective concentration of chlorite/H202
for a prolonged time on the injured sites, by preventing the
injured sites from external microbial contamination by forming a
seal over the injured sites, and by providing oxygen molecule to
the injured tissues. Unlike the conventional ointment, the
polymeric gel provides a dry, clean, and comfortable coating on the
injured sites upon application. Such gel formulations may contain
polymeric drug delivery vehicles like hydroxypropyl methylcellulose
(HPMC), methylcellulose (Methocel), hydroxyethylcellulose (HEC),
and carboxymethylcellulose (CMC), etc.
[0042] ii. A Stable Chlorite/Peroxide Gel
[0043] The following Formula 2 is a presently preferred formulation
of a chlorite/peroxide gel of the present invention:
TABLE-US-00002 FORMULA 2 Sodium Chlorite 0.02%-0.10% Hydrogen
Peroxide 0.005%-0.01% Methocel A 2.0% Boric Acid 0.15% Sodium
Chloride 0.75% Pluronic F-68 0.1% HCl or NaOH Adjust pH 7.4
Purified water Q.S. to volume
[0044] Any of the preparations of the present invention may be
formulated for sustained release of the active components by
forming liposomes of the preparing in accordance with well known
liposomal forming techniques and/or by adding to the formulation a
pharmaceutically acceptable and effective amount (e.g., typically
1-20 percent by weight) of a sustained release component such as a
polymer matrix or one or more of the following: [0045] a cellulose
ester; [0046] hydroxymethylpropyl cellulose; [0047]
methylhydroxyethyl cellulose; [0048] hydroxypropyl cellulose;
[0049] hydroxyethyl cellulose; [0050] carboxymethyl cellulose;
[0051] a salt of a cellulose ester; [0052] cellulose acetate;
[0053] hydroxypropylmethyl cellulose phthalte; [0054] methacrylic
acid-methyl methacrylate copoymer; [0055] methacrylic acid-ethyl
acetate copolymer; [0056] polyvinylpyrrolidone; [0057] polyvinyl
alcohol; [0058] a phospholipid; [0059] cholesterol; [0060] a
phospholipid having a neutral charge; [0061] a phospholipid having
a negative charge; [0062] dipalmytoyl phoshatidyl choline; [0063]
dipalmytoyl phoshatidyl serine; and, [0064] sodium salts
thereof.
B. Examples of Therapeutic Applications
[0065] The following are specific examples of therapeutic
applications of the chlorite/peroxide preparations of the present
invention.
i. EXAMPLE 1
Treatment of Psoriasis-No Crossover
[0066] A human patient having psoriasis plaques present on both
arms is treated as follows: [0067] Twice daily application to
plaques on the left arm only, of a chlorite/peroxide solution
having the following formulation:
TABLE-US-00003 [0067] Sodium Chlorite 0.06% Hydrogen Peroxide 0.01%
HPMC 2.0% Boric Acid 0.15% HCl or NaOH to adjust pH 7.4 Purified
water Q.S. to volume
[0068] Twice daily application to plaques on the right arm only of
a commercially available 0.1% triamcinolone acetonide cream.
[0069] The chlorite/peroxide treated psoriatic plaques on the right
arm began to become less severe within 24 hours of beginning
treatment and had substantially disappeared within 3 days of
beginning treatment. However, the triamcinolone acetonide treated
psoriatic plaques present on the left arm remained unchanged and
inflamed during the two (2) week treatment period.
ii. EXAMPLE 2
Treatment of Psoriasis-Crossover
[0070] A human patient having psoriasis plaques present on both
arms is treated for two (2) weeks, as follows: [0071] Twice daily
application to plaques on the left arm only, of a chlorite/peroxide
solution having the following formulation:
TABLE-US-00004 [0071] Sodium Chlorite 0.06% Hydrogen Peroxide 0.01%
HPMC 2.0% Boric Acid 0.15% HCl or NaOH to adjust pH 7.4 Purified
water Q.S. to volume/100%
[0072] Twice daily application to plaques on the right arm only of
a commercially available 0.1% triamcinolone acetonide cream.
[0073] The chlorite/peroxide treated psoriatic plaques on the right
arm began to become less severe within 24 hours of beginning
treatment and had substantially disappeared within 1 week of
beginning treatment. However, the triamcinolone acetonide treated
psoriatic plaques present on the left arm remained unchanged and
inflamed during the two (2) week treatment period.
[0074] Beginning the day after the end of the initial two (2) week
treatment period, and continuing for a second two (2) week
treatment period, the patient was treated as follows: [0075] Twice
daily application to plaques on the left arm only of the same
commercially available 0.1% triamcinolone acetonide cream described
herebove in this example. [0076] Twice daily application to plaques
on the right arm only, of the same chlorite/peroxide sustained
release gel described hereabove in this example.
[0077] Within 24 hours of commencing the second treatment period,
the psoriatic lesions on the right arm began to subside. By day 3
and continuing through the end of the second two (2) week treatment
period, the psoriatic lesions on the right arm had substantially
disappeared.
iii. EXAMPLE 3
Treatment of Cold Sores
[0078] A patient with painful, fluid-containing cold sores (i.e.,
chancre sores) on his lips was treated twice daily by application
to the lips of a chlorite/peroxide preparation prepared in
accordance with Formula 1 above.
[0079] Within 6 to 12 hours of the first application of the
chlorite/peroxide preparation, the patient reported that the pain
had subsided. Within 24 hours of the first application of the
chlorite/peroxide preparation, the fluid contained within the cold
sores had substantially dissipated and the cold sores appeared dry.
Within 6 days of the first application of the chlorite/peroxide
preparation the cold sores had substantially disappeared and the
lips appeared normal, whereas cold sores of such severity typically
require substantially longer than 6 days to completely disappear
and heal.
iv. EXAMPLE 4
Treatment of Venous Ulcer
[0080] A patient with a venous ulcer on the right leg of 3-4 cm
diameter which had been present for 9-12 months was treated by
twice daily application to the ulcer of gauze soaked with a
chlorite/peroxide liquid solution prepared in accordance with
Formula 1 above.
[0081] Within 3 days after commencement of treatment the ulcer
appeared clean and dry. Within 14 days of the commencement of
treatment the ulcer began to decrease in size and healthy new
tissue was observed about its periphery. At 35 days after
commencement of treatment, the ulcer had completely healed, without
scarring, and the area where the ulcer had been located was free of
pain.
v. EXAMPLE 5
Treatment of Diabetic Decubitus Ulcer
[0082] A non-ambulatory, diabetic patient with decubitus ulcers on
both legs and some toes, of 12-18 month duration, was treated by
daily application of clean, sterile gauze to the ulcers and
saturation of each gauze, 3 times each day, with a liquid
chlorite/peroxide solution prepared in accordance with Formula 1
above. Within 4 to 7 days of commencing the chlorite/hydrogen
peroxide treatments the ulcers began to appear less inflamed, clean
and dry. About 7 to 10 days after commencement of the
chlorite/hydrogen peroxide treatment, granulation tissue began to
form within the ulcers. Within 12 to 14 days, re-epithelialization
was observed to have begun within the ulcerated areas except for
one toe ulcer which had been particularly sever and had permeated
to the bone of the toe. Within 30 to 45 days of the commencement of
treatment, all of the ulcers except for the severe toe ulcer had
completely closed and re-epithelialized, without irregular scar
formation. Also, at 30 to 45 days after the commencement of
treatment, the toe ulcer had also become substantially smaller (but
was not completely closed) and the patient was able to walk. The
liquid and or gell formulations of the present invention, such as
Formulas 1 and 2 above, may also be applied topically to prevent
scar formation due to wounds, burns, acne, infections, trauma,
surgical incision, or any other scar-forming lesion or
disorder.
[0083] It will be appreciated by those skilled in the art, that the
invention has been described hereabove with reference to certain
examples and specific embodiments. However, these are not the only
examples and embodiments in which the invention may be practiced.
Indeed, various modifications may be made to the above-described
examples and embodiments without departing from the intended spirit
and scope of the present invention, and it is intended that ally
such modifications be included within the scope of the following
claims.
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