U.S. patent application number 15/562144 was filed with the patent office on 2018-03-22 for methods and compositions for treating inflammatory and immunological disorders.
The applicant listed for this patent is Realm Therapeutics, Inc.. Invention is credited to Svetlana Panicheva, Mark Sampson, Cary Schockemoehl, Ethan Solomon.
Application Number | 20180078578 15/562144 |
Document ID | / |
Family ID | 57006380 |
Filed Date | 2018-03-22 |
United States Patent
Application |
20180078578 |
Kind Code |
A1 |
Sampson; Mark ; et
al. |
March 22, 2018 |
METHODS AND COMPOSITIONS FOR TREATING INFLAMMATORY AND
IMMUNOLOGICAL DISORDERS
Abstract
The present invention provides a method for treating,
preventing, or managing local inflammatory symptoms, including
symptoms associated with acute or chronic inflammation, and
particularly for conditions that are characterized by an underlying
immunological disease or condition. The invention further provides
methods for controlling inflammatory processes relating to cancer
and the microbial flora.
Inventors: |
Sampson; Mark; (Malvern,
PA) ; Panicheva; Svetlana; (Malvern, PA) ;
Schockemoehl; Cary; (Malvern, PA) ; Solomon;
Ethan; (Wilmington, DE) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Realm Therapeutics, Inc. |
Malvern |
PA |
US |
|
|
Family ID: |
57006380 |
Appl. No.: |
15/562144 |
Filed: |
March 28, 2016 |
PCT Filed: |
March 28, 2016 |
PCT NO: |
PCT/US16/24453 |
371 Date: |
September 27, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14670641 |
Mar 27, 2015 |
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15562144 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/06 20130101; A61P
29/00 20180101; A61K 33/20 20130101; A61P 35/00 20180101; A61K
9/0014 20130101; A61K 9/08 20130101; A61K 2300/00 20130101; A61P
37/00 20180101; A61K 45/06 20130101; A61K 33/20 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 33/20 20060101
A61K033/20; A61K 45/06 20060101 A61K045/06 |
Claims
1. A method for treating or preventing inflammation local
inflammatory symptoms in a patient having an underlying
immunological or inflammatory disorder, the method comprising:
administering a hypochlorous acid composition to an area affected
by local inflammation, wherein the hypochlorous acid composition
has from 100 to 5000 ppm of available free chlorine.
2. The method of claim 1, wherein the immunological disorder is
characterized by one or more of type I hypersensitivity, type II
hypersensitivity, type III hypersensitivity, and type IV
hypersensitivity.
3. The method of claim 1, wherein the underlying immunological
disorder is an autoimmune condition.
4. The method of any one of claims 1 to 3, wherein the underlying
immunological condition is systemic lupus erythematosus, psoriasis,
atopic dermatitis, rheumatoid arthritis, celiac disease, Crohn's
disease, ulcerative colitis, vasculitis, thyroiditis, severe
asthma, diabetes mellitus, hyper immunoglobulin E syndrome,
dermatomyositis, or multiple sclerosis.
5. The method of any one of claims 1 to 3, wherein the underlying
immunological or inflammatory disorder is eosinophilia, drug
allergy, food allergy, hemolytic anemia, myasthenia gravis,
systemic vasculitis, diabetes mellitus, multiple sclerosis (MS),
fibromyalgia, myelitis, peripheral neuropathy, Parkinson's Disease,
hepatitis, renal failure, pancreatitis, thyroiditis, graft versus
host disease, chronic transplant rejection, Hidradenitis
suppurativa, adult onset Still's disease, systemic onset juvenile
idiopathic arthritis (SJIA) Schnitzler syndrome, Behcet's disease,
SAPHO syndrome, macrophage activation syndrome, Familial
Mediterranean Fever (FMF), cryopyrin-associated periodic syndrome
(CAPS), TNF receptor associated periodic syndrome (TRAPS),
Hyper-IgD syndrome, periodic fever, aphthous stomatitis,
pharyngitis and adenitis (PFAPA), deficiency of interleukin-1
(IL-1) receptor antagonist (DIRA), Giant cell arteritis,
amyloidosis, recurrent pericarditis, neuromyelitis optica,
amyotrophic lateral sclerosis, gout, glomerulonephritis, myeloma,
Netherton Syndrome, Ichthyosis, and Epidermolysis Bullosa.
6. The method of any one of claims 1 to 5, wherein the local
inflammatory symptoms include one or more of conjunctivitis, dry
eye, ocular itch, uveitis, wet or dry AMD, sinusitis, rhinorrhea or
nasal congestion, stomatitis, pharyngitis, gingivitis, xerostomia,
airway hyper responsiveness, skin or mucosal sores or ulcers,
urticaria, blisters and/or skin rash or lesions.
7. The method of any one of claims 1 to 6, wherein the local
inflammatory symptoms affect one or more of skin, eyes, nose, sinus
cavity, ears, mouth or throat.
8. The method of any one of claims 1 to 6, wherein the local
inflammatory symptoms affect one or more of skin, colon, lungs,
urinary tract, vagina, skeletal muscle, ligaments, tendons, joint
space, bone, peritoneum, kidney, liver, pancreas, and
vasculature.
9. The method of any one of claims 1 to 8, wherein the hypochlorous
acid composition is administered from 1 to 10 times per day.
10. The method of claim 9, wherein the hypochlorous acid
composition is administered from 1 to 4 times per day.
11. A method for treating an immunological or inflammatory
disorder, comprising, administering a hypochlorous acid composition
to the patient, the immunological or inflammatory disorder being
selected from: eosinophilia, drug allergy, food allergy, hemolytic
anemia, angioedema, myasthenia gravis, Grave's Disease,
Goodpasture's Syndrome, Farmer's Lung, asthma, chronic obstructive
pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF),
cystic fibrosis, systemic vasculitis, diabetes mellitus, multiple
sclerosis (MS), myelitis, peripheral neuropathy, Parkinson's
Disease, hepatitis, osteomyelitis, renal failure, pancreatitis,
thyroiditis, graft versus host disease, chronic transplant
rejection, Hidradenitis suppurativa, adult onset Still's disease,
systemic onset juvenile idiopathic arthritis (SJIA) Schnitzler
syndrome, Behcet's disease, SAPHO syndrome, macrophage activation
syndrome, Familial Mediterranean Fever (FMF), cryopyrin-associated
periodic syndrome (CAPS), TNF receptor associated periodic syndrome
(TRAPS), Hyper-IgD syndrome, Hyper-IgE syndrome, periodic fever,
aphthous stomatitis, pharyngitis and adenitis (PFAPA), deficiency
of interleukin-1 (IL-1) receptor antagonist (DIRA), Giant cell
arteritis, amyloidosis, recurrent pericarditis, neuromyelitis
optica, amyotrophic lateral sclerosis, gout, glomerulonephritis,
Netherton Syndrome, Ichthyosis, Epidermylosis Bullosa, or
myeloma.
12. The method of claim 11, wherein a hypochlorous acid composition
is administered to one or more of skin, colon, lungs, urinary
tract, vagina, skeletal muscle, ligaments, tendons, joints or joint
space, bone, peritoneum, kidney, liver, pancreas, and
vasculature.
13. The method of claim 11, wherein the hypochlorous acid
composition is administered to the skin, eyes, nasal passages, or
by injection.
14. A method for treating a condition selected from allergic
asthma, occupational asthma, bronchitis, chronic obstructive
pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF),
cystic fibrosis, Goodpasture Syndrome, or Farmer's Lung;
comprising, administering a hypochlorous acid composition to the
lungs, the hypochlorous acid composition having from 100 to 5000
ppm of available free chlorine.
15. A method for treating a condition selected from contact
dermatitis, radiation dermatitis, ageing skin, sunburn, angioedema,
urticaria, Systemic lupus erythematosus, sarcoidosis, rosasea,
dermatitis herpetiformis, Netherton Syndrome, Ichthyosis,
Epidermylosis Bullosa, or cutaneous vasculitis, and hemorrhoids;
wherein the hypochlorous acid composition is administered to
affected portions of the skin as a hydrogel having from 100 to 5000
ppm of available free chlorine.
16. A method for treating a patient having cancer, comprising,
administering a hypochlorous acid composition to the patient,
wherein the hypochlorous acid composition has from 100 to 5000 ppm
of available free chlorine.
17. The method of claim 16, wherein the hypochlorous acid
composition slows or inhibits the progression or metastasis of the
cancer.
18. The method of claim 16 or 17, wherein the hypochlorous acid
composition reduces damage to, or lesions in, one or more of
mucosa, skin, and gastrointestinal tract, which results from one or
more or of chemotherapy or radiation therapy.
19. The method of any one of claims 16 to 18, wherein the cancer is
stage I or stage II cancer.
20. The method of any one of claims 16 to 18, wherein the cancer is
stage III or stage IV.
21. The method of any one of claims 16 to 20, wherein the cancer is
basal cell carcinoma, biliary tract cancer, bladder cancer, bone
cancer, brain and central nervous system cancer, breast cancer,
cancer of the peritoneum, cervical cancer, choriocarcinoma, colon
and rectum cancer, connective tissue cancer, cancer of the
digestive system, endometrial cancer, esophageal cancer, eye
cancer, cancer of the head and neck, gastric or intestinal cancer,
glioblastoma, hepatic carcinoma, hepatoma, intra-epithelial
neoplasm, kidney or renal cancer, larynx cancer, leukemia, liver
cancer, lung cancer, melanoma, myeloma, neuroblastoma, oral cavity
cancer, ovarian cancer, pancreatic cancer, prostate cancer,
retinoblastoma, rhabdomyosarcoma, rectal cancer, salivary gland
carcinoma, sarcoma, skin cancer, squamous cell cancer, testicular
cancer, thyroid cancer, uterine or endometrial cancer, cancer of
the urinary system, vulval cancer, and lymphoma.
22. The method of any one of claims 16 to 20, wherein the cancer is
skin cancer, cutaneous melanoma, breast cancer, colon cancer, lung
cancer, testicular cancer, cervical cancer, lymphoma, parathyroid
cancer, penile cancer, rectal cancer, small intestine cancer,
thyroid cancer, uterine cancer, Hodgkin's lymphoma, lip and oral
cancer, leukemia or multiple myeloma.
23. The method of claim 22, wherein the cancer is a cutaneous
cancer.
24. The method of claim 22, wherein the cancer is breast
cancer.
25. The method of claim 22, wherein the cancer is a cancer of the
mouth, throat, or sinus.
26. The method of claim 22, wherein the cancer is lung cancer.
27. The method of any one of claims 16 to 26, wherein the
hypochlorous acid is administered for at least about 2 months.
28. The method of any one of claims 16 to 27, wherein the
hypochlorous acid composition is administered directly to a
tumor.
29. The method of any one of claims 16 to 27, wherein the
hypochlorous acid composition is administered topically.
30. A method for normalizing the microbial flora in a patient with
an inflammatory condition, comprising administering a hypochlorous
acid composition to the patient, wherein the hypochlorous acid
composition has from 100 to 5000 ppm of available free
chlorine.
31. The method of claim 30, wherein the hypochlorous acid
composition is applied at least once per day for at least one week,
or optionally at least one month.
32. The method of claim 30, wherein normalization of the microbial
flora of a tissue is determined by rRNA gene sequencing.
33. The method of any one of claims 30 to 32, wherein the
hypochlorous acid composition is applied to the skin, oral or nasal
mucosa, gastrointestinal tract, or urogenital system.
Description
PRIORITY
[0001] This application claims the benefit of priority of U.S.
patent application Ser. No. 14/670,641, filed Mar. 27, 2015, which
is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to compositions and methods
for treating, preventing, or managing inflammatory conditions.
BACKGROUND OF THE INVENTION
[0003] Inflammation is part of the complex biological response of
body tissues to harmful stimuli, such as pathogens, damaged cells,
or irritants. Inflammation is a protective response that involves
immune cells, blood vessels, and molecular mediators. The purpose
of inflammation is to eliminate the initial cause of cell injury,
clear out necrotic cells and tissues damaged from the original
insult and the inflammatory process, and to initiate tissue repair.
Chronic inflammation can lead to a host of diseases, such as
periodontitis, atherosclerosis, rheumatoid arthritis, dermatitis,
and cancer. Inflammation is normally closely regulated by the
body.
[0004] Inflammation can be classified as either acute or chronic.
Acute inflammation is the initial response of the body to harmful
stimuli and is achieved by the increased movement of plasma and
leukocytes from the blood into the injured tissues. A series of
biochemical events propagates and matures the inflammatory
response, involving the local vascular system, the immune system,
and various cells within the injured tissue. Prolonged or chronic
inflammation leads to a progressive shift in the type of cells
present at the site of inflammation, such as mononuclear cells, and
is characterized by simultaneous destruction and healing of the
tissue from the inflammatory process.
[0005] Inflammation can be initiated by either pathogen-associated
molecular patterns (or PAMPs) or damage (or danger)-associated
molecular patterns (DAMPs). PAMPs are molecules associated with
pathogens that are recognized by cells of the innate immune system.
These molecules are recognized by Toll-like receptors (TLRs) and
other pattern recognition receptors (PRRs), and activate innate
immune responses to protect the host from infection. DAMPs are
molecules that can initiate and perpetuate a noninfectious
inflammatory response, and are often cytosolic or nuclear
components that are released from the cell, for example upon cell
necrosis. Innate immune responses activated by PAMPs and DAMPs
include inflammatory processes/cascades such as the inflammasome,
and itch and pain mediators and their respective receptors,
prurireceptors and nociceptors in the skin nerve terminal.
Mediators of the inflammatory cascade include various cytokines
such as, .alpha.-2 macroglobulins, TNF-.alpha., IL-2, IL-6,
IL-1.beta., IL-8, TSLP, IL-4, IL-13, IL-17, IL-18, IL-31, among
others. When regulated and localized, these cytokines can mediate
beneficial inflammatory responses as part of normal host defense
response. However, when cytokine activations become disordered,
these inflammatory responses can cause significant tissue injury or
even death. Inflammatory symptoms, regardless of origin, share
similar symptoms such as pain, heat, redness, fever, rash or
swelling, and lesions, including wounds and ulcers to the skin or
other tissues. Pain is often a key indicator of inflammation,
because the swelling of the affected area/organ is pushing against
sensitive nerve endings which then send pain and/or itch signals to
the brain.
[0006] Inflammatory symptoms are often treated with topical or
systemic anti-inflammatory agents, such as corticosteroids; however
use of conventional agents has significant limitations including
age restrictions, drug toxicity, irritation, hypersensitivity
and/or other side effects that may occur or develop especially with
chronic use. In addition, many treatments to control local symptoms
(e.g., by reducing discomfort and/or tissue damage at the affected
region) provide no appreciable systemic benefits. Therefore, if
there is an underlying immunological disorder that is causing the
inflammatory symptoms, topical agents often do very little to
improve the patient's overall condition.
[0007] It is an object of this invention to treat or manage
inflammatory and/or immunological conditions, by providing relief
of inflammatory symptoms, while positively affecting the underlying
condition. It is also an object of the invention to provide a
broadly effective and safe treatment for the prevention of diseases
and conditions associated with or caused by prolonged or untreated
inflammation, including cancer. It is further an object of this
invention to provide compositions and methods that are safe and
effective for prolonged and/or prophylactic use, by patients of all
ages including pediatric and geriatric patients, and/or
immunocompromised patients, for the prevention, reduction, and
management of inflammation.
SUMMARY OF THE INVENTION
[0008] The present invention relates to hypochlorous acid
compositions and their use for treating inflammatory or
immunological conditions.
[0009] In one aspect, the present invention provides a method for
treating, preventing, or managing local inflammatory symptoms,
including symptoms associated with acute or chronic inflammation,
and particularly for conditions that are characterized by an
underlying immunological disease or condition. The invention allows
for reduction, management, or prevention of local inflammatory
symptoms and/or tissue damage, while providing systemic benefits
that ameliorate the underlying immunological condition.
[0010] In another aspect, the invention provides for a method of
treating cancer, or slowing or inhibiting the progression of
cancer. Specifically, cancer relies on the inflammatory machinery
to progress and to metastasize. By modulating these inflammatory
processes, the invention helps to control the progression and
spread of cancer, and aids the bodies repair mechanisms,
particularly where the patient undergoes a primary cancer therapy
that is harmful to non-cancer cells and tissues, such as
chemotherapy or radiation therapy.
[0011] In another aspect, the invention provides methods for
controlling or normalizing the microbiome of a patient, and
particularly the microbiome of a tissue exhibiting acute or chronic
inflammation. Even in the absence of overt infection, there is a
complex interplay between the microbiome and tissue inflammation.
Simultaneous reduction of microbial burden and normalization of the
tissue microbiome, together with a reduction of host inflammation,
promotes tissue healing and normalization. Further, in some
embodiments, microbial flora at remote sites from administration of
the hypochlorous acid are positively impacted by the treatment.
[0012] In various embodiments the method comprises administering a
hypochlorous acid composition, wherein the hypochlorous acid
composition has from about 100 ppm to about 5000 ppm of available
free chlorine (AFC). In some embodiments, the available free
chlorine is at least about 70% hypochlorous acid relative to the
total concentration of hypochlorous acid, hypochlorite, and
Cl.sub.2 (molecular chlorine). As disclosed herein, hypochlorous
acid can exhibit anti-inflammatory properties that are
dose-dependent, and can affect both local and systemic inflammatory
mediators in some embodiments. The invention in various embodiments
inhibits and reduces inflammatory symptoms, and prevents
"flare-ups" of an underlying chronic inflammatory or immunological
condition. The invention in various embodiments can be used to
prevent diseases or conditions caused by prolonged and/or untreated
inflammation, including cancer.
[0013] In various embodiments, the invention provides for
administering the hypochlorous acid composition via enteral (oral,
gastric and rectal), parenteral (intravenous, intra-arterial,
intraosseous, intra-muscular, intrathecal, sub-cutaneous) or other
route (sublingually, buccally, rectally, vaginally,
intra-articular, by the ocular or otic route, nasally, cutaneously
for topical or systemic effect, by inhalation or nebulization, or
transdermally) or as an irrigant to one or more tissues or organs
(e.g., during surgery or after trauma). The application site of the
hypochlorous acid composition can be exhibiting signs of local
inflammation (an "affected region"), and in some embodiments, the
benefits are (also) intended for remote sites, such as internal
organs, vasculature, CNS, or the musculoskeletal system. For
example, in various embodiments, the affected region or the region
of administration is one or more of the eyes, ears, nose, sinus,
throat, mouth (e.g., gingiva), or skin. In other embodiments, the
affected region or remote tissue or organ is one or more of the
intestinal tract and/or colon, lungs, urogenital system (urinary
tract or vagina), skeletal muscle, ligaments, tendons, joints,
bones, peritoneum, kidney, liver, pancreas, or vasculature. In some
embodiments, the hypochlorous acid is administered topically (e.g.,
to the skin), with benefits exhibited systemically.
[0014] In some embodiments, the composition is used to treat local
inflammatory symptoms, including but not limited to conjunctivitis,
dry eye, ocular itch, sinusitis, airway hyper responsiveness,
sores, ulcers, blisters and/or skin rash or lesions. In some
embodiments, the method provides for systemic benefits to
ameliorate an underlying immune condition, such as an autoimmune
condition, genetic immune malady, or hyper allergic condition. Such
conditions include, without limitation, systemic lupus
erythematosus, psoriasis, atopic dermatitis, rheumatoid arthritis,
celiac disease, Crohn's disease, ulcerative colitis, vasculitis,
thyroiditis, severe asthma, severe allergy, diabetes mellitus,
hyper immunoglobulin E syndrome, dermatomyositis, multiple
sclerosis, Parkinson Disease, fibromyalgia, among others.
[0015] The invention provides a broadly effective method for
treating the inflamed and/or affected regions of a patient, and in
a manner relatively independent of the etiology of the
inflammation, and in a manner that avoids toxicity,
hypersensitivity, and other side effects of conventional agents.
The methods of the invention are useful as alternatives or adjunct
therapies to conventional antibiotics, antivirals, decongestants,
antihistamines, immunosuppressants/immunomodulators,
analgesics/anesthetics and steroid treatments, or as an alternative
to therapy using a combination of conventional medicaments.
[0016] The methods of the invention are particularly suitable for
prolonged and/or prophylactic use, because of the associated age
restrictions, side effects, and/or drug resistance issues with
alternative therapies. The methods are further suitable for
individuals prone to infections or bacterial over-colonization
and/or inflammatory conditions, or individuals that typically
experience hypersensitivity or severe side effects with other
treatments.
BRIEF DESCRIPTION OF THE FIGURES
[0017] FIG. 1 shows the ability of HOCl to reduce hyperemia in an
animal model in a dose dependent fashion. Treatment with steroid
(prednisolone) and antihistamine (olopatadine) are shown as
comparators. (A) 1 hour post-dose hyperemia; (B) 18 minutes
post-CAC (conjunctival allergen challenge) hyperemia.
[0018] FIG. 2 shows reduction of psoriasis clinical score as
compared to untreated controls and Clobetasol (corticosteroid) in
imiquimod-induced psoriasis-like skin inflammation in mice.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The present invention provides compositions and methods for
treating, preventing, or managing an immunological and/or
inflammatory condition, by administering a hypochlorous acid
composition to a subject in need thereof.
[0020] Hypochlorous acid (HOCl) is an oxidant and antimicrobial
that is produced by the human body's natural immune system. HOCl is
generated as the final step of the Oxidative Burst Pathway, with
large quantities of HOCl being released into phagocytic vesicles to
destroy invading microorganisms. Hypochlorous acid may exert an
antimicrobial effect by attacking the surface and plasma membrane
proteins, impairing transport of solutes and the salt balance of
bacterial cells (Pieterson et al., Water SA, 22(1): 43-48
(1996)).
[0021] In accordance with the present invention, exogenous
hypochlorous acid is administered for treating or preventing
immunological and/or inflammatory conditions. Without wishing to be
bound by theory, it is believed that administration of hypochlorous
acid treats, manages and/or prevents local inflammatory symptoms,
and helps to control or modulate an underlying immune condition at
a systemic level. Further, without wishing to be bound by theory,
it is believed that even topically or locally applied hypochlorous
acid modulates systemic inflammatory mediators in a beneficial
manner, allowing for a variety of conditions characterized by
chronic, systemic inflammation, to be conveniently managed and/or
treated with a topical hypochlorous acid composition.
[0022] The invention in various embodiments comprises applying a
hypochlorous acid formulation to ameliorate disease symptoms and/or
dampen or alter inflammatory responses. For example, cells
directing the immune response (which can include monocytes,
macrophages, dendritic cells, Langerhans cells, fibroblasts, and
keratinocytes) secrete cytokines and other soluble factors that may
include, for example, one or more of TNF, IFN.gamma., IL-1.beta.,
IL-2, IL-4, IL-6, IL-8, IL-10, IL-18. Cytokine release patterns
vary, both between cytokines as well as cell types. For example,
many immune mediators are secreted through classical secretory
pathways including regulated or constitutive exocytosis or by
degranulation. In classical secretory pathways, cytokines are
translated with signal peptides in the endoplasmic reticulum (ER),
trafficked in vesicles to the golgi complex, and subsequently to
the cell surface for release. In the case of degranulation,
cytokines and/or other cargo are stored in granules for later
release. On the other hand, certain cytokines, such as IL-1.beta.
and IL-18, which are activated by the inflammasome and play a basic
role in the initiation of inflammatory responses, are secreted via
nonclassical secretory pathways. Specifically, these molecules are
synthesized as inactive precursors, and once activated by caspase-1
cleavage, are potentially secreted either by membrane transporters,
in exosomes or microvesicles, or perhaps even by cell lysis. See,
for example, Lacy and Stow, Cytokine release from innate immune
cells: association with diverse membrane trafficking pathways,
Blood 118(1) (July, 2011).
[0023] While the role of endogenous reactive oxygen species (ROS)
in the inflammatory process has been somewhat clouded by
conflicting data, ROS are often considered as activators of the
inflammasome. See, Harijith A, et al., Reactive oxygen species at
the crossroads of inflammasome and inflammation, Front. Physiol.
5:352 (2014). For example, endogenously generated hypochlorous acid
is generally regarded as a pro-inflammatory molecule. See, Schieven
G L et al., Hypochlorous acid activates tyrosine phosphorylation
signal pathways leading to calcium signaling and TNFalpha
production, Antioxid. Redox Signal 4(3):501-7 (2002); Pullar J L,
et al., Living with a killer: the effects of hypochlorous acid on
mammalian cells, IUBMB Life, 50(4-5):259-66 (2000). HOCl generation
in vivo has been postulated to mediate inflammation in chronic
inflammatory disease. Halliwell et al., Oxidants, inflammation, and
anti-inflammatory drugs, FASEB 2:2867-2873 (1988). In contrast, the
present disclosure shows that HOCl can inhibit inflammatory
processes in a dose dependent fashion. Further, HOCl can reduce or
alter an underlying immune condition, including reducing or
altering the systemic immune response.
[0024] In accordance with the invention, hypochlorous acid (a
strong oxidant) is formulated for application to tissues for
treatment of acute and chronic inflammatory conditions and
diseases. While topical and systemic steroids are the most commonly
prescribed medications for the treatment of inflammatory diseases,
there is increasing awareness to the side effects and damage that
can result from long term steroid use, which include increased
appetite, weight gain, sudden mood swings, muscle weakness, blurred
vision, increased growth of body hair, easy bruising, lower
resistance to infection, swollen, puffy face, acne, osteoporosis,
worsening of diabetes, high blood pressure, stomach irritation,
nervousness, restlessness, difficulty sleeping, cataracts or
glaucoma and water retention or swelling, among others. Topical
retinoid, topical vitamin D (and analogues thereof), antihistamine,
and immunosuppressants are used for some dermatological conditions,
but these agents can be associated with substantial toxicity.
Further, some patients and conditions are refractory to available
treatments. Thus, more effective and/or safe alternatives are
desirable. The hypochlorous acid may be used as an alternative or
adjunct therapy to these conventional agents.
[0025] Conventional agents often result in a large range of
potential undesirable side effects that are not observed with HOCl
treatment. For example, antibiotics can induce rash, diarrhea,
abdominal pain, nausea/vomiting, drug fever, hypersensitivity
(allergic) reactions, serum sickness, vaginal candidiasis, and
photosensitivity. Common anti-virals are reported to induce nausea,
vomiting, diarrhea and headache, as well as agitation, confusion,
rash, anemia, muscle pain, hypersensitivity reactions, seizures,
and hepatitis. Antihistamines and decongestants are known to induce
drowsiness, dizziness, dry mouth/nose/throat, headache, upset
stomach, constipation, and trouble sleeping.
Immunosuppressants/immunomodulators are reported to induce
headache, nausea, vomiting, diarrhea, and malaise, as well as
decreased kidney function, hepatitis, increased risk of infections,
diabetes, increased cholesterol levels, sleep problems, mild
tremor, high blood pressure, swollen gums, tingling of the fingers
and feet, increased facial hair, and increased risk of lymphoma.
Analgesics and anesthetics, such as opioids, have shown common side
effects that include sedation, dizziness, nausea, vomiting,
constipation, physical dependence, tolerance, and respiratory
depression. Common side effects of local anesthetics include
flushing or redness of the skin, itching skin, small red or purple
spots on the skin, and unusually warm skin. Steroids are reported
to induce increased appetite, weight gain, sudden mood swings,
muscle weakness, blurred vision, increased growth of body hair,
easy bruising, lower resistance to infection, swollen, puffy face,
acne, osteoporosis, worsening of diabetes, high blood pressure,
stomach irritation, nervousness, restlessness, difficulty sleeping,
cataracts or glaucoma and water retention or swelling. By providing
HOCl as an alternative therapy, side effects of conventional agents
can be avoided.
[0026] The hypochlorous acid composition may contain a mixture of
oxidizing species, but the oxidizing species are predominantly
hypochlorous acid (HOCl). Hypochlorous acid and hypochlorite are in
equilibrium and the position of the equilibrium is determined
solely by the pH. For example, the hypochlorous acid composition
may have a pH of from about 3 to about 7.5, or from about 3.5 to
about 7.5, or a pH of from about 4 to about 7.5, or from about 5 to
about 7.5, or a pH of from about 4 to about 7, or a pH of from
about 4.5 to about 7, or a pH of from about 5 to about 7, or a pH
of from about 3 to 6.5, or a pH or from about 4 to about 6.5, or
from about 5 to about 6.5. For example, the hypochlorous acid
composition may have a pH of from about 5 to about 6.
[0027] In certain embodiments, the hypochlorous acid composition
contains at least about 70% or at least about 80% hypochlorous acid
relative to the total concentration of hypochlorous acid,
hypochlorite, and molecular chlorine (Cl.sub.2) (as 100%). The
hypochlorous acid composition may have at least 90%, at least 95%,
or at least 98% hypochlorous acid relative to the total
concentration of hypochlorous acid, hypochlorite, and molecular
chlorine (Cl.sub.2) (as 100%). Such embodiments may allow for
higher levels of active chlorine to be administered, while avoiding
any irritation as a result of the composition. Hypochlorite has
been known for quite some time to have toxic properties on
mammalian cells due to high pH in addition to required
concentration of available chlorine, and thus may not be desirable
for long term use or may not have a sufficient therapeutic window
for some anti-inflammatory applications. Thus, in some embodiments,
the level of hypochlorite in the solution or composition is limited
(e.g., about 10% or less, about 5% or less, or about 3% or less
relative to the total concentration of hypochlorous acid,
hypochlorite, and molecular chlorine (Cl.sub.2) (as 100%).
[0028] The hypochlorous acid composition in various embodiments
contains available free chlorine (AFC) at from about 100 to about
5000 parts per million (ppm), or from about 250 to about 2000 ppm
in some embodiments. In some embodiments, the composition has AFC
of greater than about 500 ppm, or greater than about 600 ppm, or
greater than about 700 ppm, or greater than about 800 ppm, or
greater than about 1000 ppm, or greater than about 1200 ppm, or
greater than about 1500 ppm. For example, the composition may have
AFC of from about 400 to about 3000 ppm, such as from about 500 to
about 2000 ppm, or from about 500 to about 1500 ppm, or from about
500 to about 1000 ppm. In some embodiments, the HOCl composition is
formulated with AFC of from about 1000 to about 2000, or from about
1000 to about 1500 ppm. Hypochlorous acid displays
anti-inflammatory actions that are dose dependent.
[0029] The hypochlorous acid composition can be formulated for any
delivery route, selected to benefit the desired organ or tissue,
with the anti-inflammatory effects being local and/or systemic. In
some embodiments, anti-inflammatory properties or immunomodulating
properties of the composition are observed at sites that are remote
from the application site.
[0030] As used herein, the term "affected area" is any tissue,
organ, or part of the body in which symptoms of the inflammatory
condition manifest, and which may include the skin, mucus
membranes, eyes, ears, nose, sinus cavity, throat, mouth (e.g.,
gingiva), lymph nodes, lungs, connective tissue (including skeletal
muscles, ligaments, tendons, joints), nervous system (including
activation or inhibition of nerve-based signaling responses such as
scratching/itching or pain), intestinal tract (e.g., colon),
urogenital system (including urinary tract or vagina), as well as
systemic inflammation affecting the vasculature, or in some
embodiments the peritoneum or one or more organs such as the
kidney, liver, or pancreas. The affected region in some embodiments
will determine the route of administration, which will range from
via enteral (oral, gastric and rectal), parenteral (intravenous,
intra-arterial, intraosseous, intra-muscular, intrathecal,
sub-cutaneous) or other (sublingually, buccally, rectally,
vaginally, intra-articular, by the ocular or otic route, nasally,
cutaneously for topical or systemic effect, by inhalation or
nebulization, or transdermally) or as an irrigant to one or more
tissues or organs (e.g., during surgery or trauma). In some
embodiments, the affected area is one or more of skin, eyes, lungs,
or mucus membranes. In some embodiments, the affected area is
remote from the application site of the composition.
[0031] As used herein, the term "treating" refers to providing
therapy to a patient to prevent (by means of prophylactic
treatment), reduce, inhibit, ameliorate, or manage symptoms (e.g.,
inflammatory symptoms) of a disease, or to slow or stop progression
of the disease, as well as in some embodiments, to prevent onset or
re-occurrence of a condition or symptom. For example, in various
embodiments the invention provides methods of treating tissues to
inhibit, reduce, or prevent inflammatory processes in the tissue,
or at remote sites, including acute, chronic, and delayed
reactions, thereby allowing regeneration and/or healing of tissues,
and/or preventing tissue damage or loss of tissue integrity.
[0032] As used herein, the term "prolonged use" refers to treatment
of a chronic condition. Generally, a chronic condition is a
condition that will not be eliminated even with therapy, and thus
the therapy is intended to reduce, inhibit, or prevent (e.g., by
means of prophylactic treatment) inflammatory symptoms, thereby
managing the condition. Prolonged use generally includes treatment
for at least about two months, at least about six months, at least
about one year, at least about two years, or more. Prolonged use in
some embodiments, is employed where systemic effects are desired,
such as for treatment of an underlying autoimmune condition or
cancer.
[0033] In accordance with certain embodiments of the invention, the
hypochlorous acid composition may be administered, for example,
once daily or more than once daily. For example, the hypochlorous
acid composition may be administered from about 1 to 10 times daily
(e.g., about 2 times, 3 times, 4 times, 5 times, 6 times, 7 times,
8 times, 9 times, or 10 times daily). Alternatively the
hypochlorous acid composition may be administered once a week or
more than once a week (e.g., about 2 to 5 times per week). In some
embodiments, the hypochlorous acid composition is administered
topically from one to four times daily (e.g., twice daily).
[0034] Administration of the hypochlorous acid may be for any
period of time as determined to be appropriate by, for example, a
physician. In various embodiments, the hypochlorous acid
composition is administered for at least one week, at least two
weeks, at least three weeks, at least four weeks, at least five
weeks, at least six weeks, at least seven weeks, at least eight
weeks, at least nine weeks, at least ten weeks, at least eleven
weeks, or at least twelve weeks. In cases of prolonged use, the
hypochlorous acid composition may be administered for at least
about two months, at least about three months, at least about four
months, at least about five months, at least about six months, at
least about seven months, at least about eight months, at least
about nine months, at least about ten months, at least about eleven
months, or at least about twelve months. In some embodiments, the
hypochlorous acid is administered for at least about one year, or
at least about two years, or more.
[0035] The inflammatory condition may be present in a human or
animal patient of any age (including pediatric and geriatric
patients) as well as immunocompromised patients. Exemplary animal
patients include mammals such as dogs, cats, horses, lamb, cattle,
goats, pigs, and guinea pigs. The present invention further
contemplates preventive care (including prophylactic use) for such
inflammatory conditions or prevention of such conditions where the
patient is genetically or environmentally pre-disposed to such
conditions, as well as conditions that don't completely resolve
with antimicrobial or steroidal treatment, or treatment with
retinoid, vitamin D ointment, immunosuppressant, or biologic
anti-inflammatory agent. Pediatric patients include infants,
children, and adolescents, and the age limit usually ranges from
birth up to 18 years of age (age 21 in the United States). In some
embodiments, the patient is under 12 years of age, or is an infant.
Geriatric patients in accordance with this disclosure include
individuals over the age of 60. Immunocompromised patients include
those having an immune response attenuated by administration of
immunosuppressive drugs, chemotherapy, by irradiation, by
malnutrition, genetic malady, or by certain disease processes such
as acquired immunodeficiency syndrome (AIDS).
[0036] The hypochlorous acid composition may be formulated as a
liquid, such as an eye drop, eye wash, gargle, oral rinse, nasal
rinse or throat spray, or ear drop. In still other embodiments, the
composition may take the form of a paste, cream, emulsion, gel
(e.g., hydrogel), and/or foam for application to the skin, dentia,
or gingiva. Such formulations may be prepared using conventional
additives known in the art and/or as described herein. In
embodiments employing pastes, creams, emulsions, gels, and/or
foams, the solution is better contained around the site of
inflammation by limiting run-off. Convenient applicators for
creams, foams, and the like are known, and may be used in
accordance with the present invention. Alternatively still, the
composition may be formulated so as to be delivered by aerosol,
mist, or steam, impregnated into wound dressings, adhesive, or
dissolving strips, patches, suppositories, or encapsulated in
silicon or other carriers, as nanoparticles or free-standing in
liquids, suspensions, powders, pills or capsules, or particles for
the purposes of release, targeted release or extended-release via
enteral or parenteral administration.
[0037] The hypochlorous acid composition may also contain from
about 0.1 to 2.0% w/v salt, such as NaCl. In some embodiments, the
hypochlorous acid composition contains 0.4 to 1.5% w/v salt, or may
be a normal saline solution (0.9% w/v NaCl). In some embodiments,
the solution is isotonic with physiological fluids, such as blood,
saliva or tears. In some embodiments, the solution is hypotonic
with physiological fluids.
[0038] The composition in various embodiments can be administered
by aerosol to the lungs or by intravenous or subcutaneous delivery
of particles that encapsulate and release HOCl in the circulation,
either in a sustained manner or targeted to particular tissues or
organs. In some embodiments, the solution or composition is
formulated for colonic, vaginal, urinary tract, or peritoneal
irrigation, or is formulated for injection into joint spaces. In
some embodiments, the solution or composition is formulated for
irrigation of tissues or organs during or following surgery to
prevent or reduce inflammatory complications, such as those that
may occur post-surgery. In some embodiments, the composition is
formulated for treating donor tissue or organs (e.g., kidney,
liver, lung, heart, skin, and cornea) prior to or during
transplantation.
[0039] In certain embodiments of the present invention, the
hypochlorous acid is formulated or administered in combination
(e.g., administered separately) with another therapeutic or
cleansing agent. Non-limiting examples of therapeutic agents
include anti-microbial agents such as antibiotics, antivirals,
anti-fungal and anti-parasitics, immune-modulators/suppressants
anti-inflammatory agents, anti-histamines, analgesics, local
anesthetics, anti-oxidants such as vitamins, and moisturizing
agents. For example, the hypochlorous acid may be formulated or
administered with antibiotics such as bacitracin, neomycin,
neosporin, framycetin, fusidic acid, chloramphenicol, gentamicin,
tobramycin, ceftriaxone, sulfacetamide, erythromycin, gentamicin,
ciprofloxacin, ofloxacin, cefoxitin, cefotaxime, spectinomycin,
tetracycline, doxycycline, and azithromycin; anti-virals such as
acyclovir, valacyclovir, famciclovir, and oseltamivir; anti-fungals
such a as ketoconazole, fluconazole, itraconazole, voriconazole,
terbinafine, and nystatin; anti-parasitics such as metronidazole,
ivermectin, pyrantel pamoate, albendazole, and
atovaquone-proguanil; immune-modulators/suppressants such as
thalidomide, lenalidomide, apremilast, cyclosporine, rapamycin,
prednisone and tacrolimus; corticosteroids and NSAIDs such as
aspirin, ibuprofen, naproxen sodium, celecoxib; anti-histamines
such as diphenhydramine, loratadine, fexofenadine, cimetidine,
ranitidine, ciproxifan, and cromoglycate; analgesics such as
acetaminophen/paracetamol, buprenorphine, codeine, meperidine, and
tramadol; local anesthetics such as epinephrine, lidocaine,
bupivacaine, and benzocaine; anti-oxidants such as vitamin A &
E; moisturizing agents such as silicones, emollients, lanolin,
mineral oil, urea, alpha-hydroxy acids, glycerine, fatty acids,
ceramides, collagen or keratin. Non-limiting examples of cleansing
agents include alcohol, betaine, mild soap solutions, bicarbonate
or saline solutions, or electrolyzed solutions including
catholytes.
[0040] The composition may comprise a pharmaceutically acceptable
carrier. Non-limiting examples of suitable carriers include
hectorite, bentonite, laponite, oil emulsions, polyvinyl alcohol,
povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl
cellulose, hydroxyethyl cellulose, and purified water. The
composition may also include various other ingredients, such as
tonicity agents, buffers, surfactants, co-solvents, viscosity
building agents, preservatives, and other therapeutic agents.
[0041] Regarding tonicity agents, such agents may be employed to
adjust the tonicity of a composition, for example, in the case of
an ophthalmic composition, to the tonicity of natural tears. For
example, sodium chloride, potassium chloride, magnesium chloride,
calcium chloride, dextrose and/or mannitol may be added to the
composition to approximate physiological tonicity. Such an amount
of tonicity agent will vary, depending on the particular agent to
be added and the type of composition. In general, however, the
compositions will have a tonicity agent in an amount sufficient to
cause the final composition to have an acceptable osmolality. For
example, for an ophthalmic composition, the composition is
generally in the range of about 150 to 450 mOsm, preferably 250 to
350 mOsm.
[0042] Regarding buffers, an appropriate buffer system (such as,
for example, sodium phosphates, potassium phosphates, potassium
carbonate, sodium bicarbonate, sodium borate or boric acid,
phosphoric acid, or HCl) may be added to the compositions to
prevent pH drift under storage conditions. The particular amount of
buffering agent will vary, depending on the agent employed.
Preferably, however, the buffer will be chosen to maintain a target
pH.
[0043] Hypochlorous acid is highly unstable, a problem made more
difficult when using higher strength solutions (e.g., above a few
hundred ppm AFC) as well as other formulation ingredients that can
be destabilizing. Thus, in some embodiments, the formulation
includes a stabilizing amount of dissolved inorganic carbon (DIC)
as disclosed in U.S. Pat. No. 8,871,278, which is hereby
incorporated by reference in its entirety. For example, the
formulation may employ a stabilizing amount of DIC, which may be
incorporated as a bicarbonate or carbonate salt of an alkali or
alkaline earth metal, such as, for example, sodium, potassium,
calcium, or magnesium. In some embodiments, the bicarbonates or
carbonates are added prior to the formation of hypochlorous acid
(e.g., by electrochemical treatment), and in other embodiments, the
bicarbonates or carbonates are added after electrochemical
treatment. For example, the bicarbonate(s) or carbonate(s) may be
contained in the precursor aqueous solution (e.g., water) or dry
electrolyte, and/or incorporated in the electrolyzed solution or
during formulation.
[0044] The DIC is incorporated at a "stabilizing amount," which can
be determined with reference to the change in the pH or AFC content
of the formulation over time. Generally, the formulation is
considered stabilized if the amount of AFC does not drop below
about 75% of the initial value over a period of about 6 months. In
certain embodiments, the AFC content is stabilized for at least one
year from the production date of the formulation. Further, the
stability of the formulation may be determined with reference to
the pH. Generally, the formulation is considered stabilized if the
pH does not vary by 1 unit over a period of about 6 months. In
certain embodiments, the pH is stabilized for at least one year
from the production date of the formulation. The formulation should
be stored at 25.degree. C. or at 20.degree. C., or less for greater
stability. 20.degree. C. is the reference temperature for
determination of stability. For stability testing, solutions or
formulations are packaged in glass or PET bottles, stored in the
dark, and kept unopened. For the best stability, the formulations
are stored at 4.degree. C. until use in some embodiments.
[0045] The stabilizing amount of DIC (e.g., carbonate or
bicarbonate) can be determined with reference to the AFC content.
For example, in certain embodiments, the stabilizing amount of the
carbonate or bicarbonate is at a molar ratio of from about 5:1 to
1:5 with respect to the AFC level, or from about 3:1 to about 1:2
with respect to the AFC level. In some embodiments, the
bicarbonates or carbonates are present in at least equal molar
amounts with respect to the AFC content (e.g., hypochlorous acid
content). In still other embodiments, the DIC (e.g., bicarbonate or
carbonate) is present at about 5:1, about 4:1, about 3:1, about
2:1, about 1:1, about 1:2, about 1:3, about 1:4, or about 1:5 with
respect to AFC content. In various embodiments, other buffering
components such as phosphate buffers are also employed. For
example, for formulation having AFC of from about 500 ppm to about
2000 ppm, carbonate or bicarbonate may be present at an amount of
from about 500 mg/L to about 3000 mg/L to stabilize the
formulation. In certain embodiments, the formulation is for topical
treatment of skin, and has AFC in the range of 500 to 2000 ppm, and
comprises sodium bicarbonate in the range of about 500 to about
2000 mg/L, has a pH in the range of 5 to 7, and comprises a
fluorosilicate (e.g., sodium magnesium fluorosilicate) at from 2 to
5% (e.g., about 3% or about 4%). In some embodiments, the
formulation is a hydrogel employing a silicate-based carrier such
as sodium magnesium fluorosilicate or lithium magnesium
fluorosilicate, comprises sodium bicarbonate (e.g., from 500 to
2000 mg/L) to stabilize the HOCl, and comprises phosphoric acid
(and optionally sodium phosphate buffer) to target a slightly
acidic pH (e.g., from 5 to 6.5). The formulation may have a
viscosity of from about 500 to about 150,000 cP, such as from about
1000 to about 840,000 cP, or from 1000 to about 30,000 cP. The
formulation in some embodiments has a conductivity of less than 10
mS/cm, such as from about 0.5 to about 5 mS/cm, such as from 0.5 to
about 3 mS/cm, or about 1 or about 2 mS/cm in some embodiments.
[0046] Without being bound by theory, dissolved inorganic carbon
(DIC), which generally includes carbonates, bicarbonates, carbonic
acid and dissolved CO.sub.2, provides low or minimal buffering
capacity in the pH range targeted by the solutions and formulations
described herein. Nevertheless, these solutions are effectively
stabilized, such that the solutions and compositions are not
dependent on "on-demand" production. The stabilizing effect can be
due to, in-part, free radical scavenging ability of DIC to thereby
slow the decomposition of HOCl.
[0047] The stabilized formulation may be packaged for sale, using
any suitable container, such as any suitable plastic or glass
bottles, or bags, tubes, or cans (e.g., spray or aerosol). Certain
container materials may provide advantages in shelf-life. In
certain embodiments, the packaging material has minimal gas
permeability (e.g., are non-permeable), including by species such
as CO.sub.2 and O.sub.2. Thus, these containers maintain the
stabilizing amount of dissolved inorganic carbon, without losing
the stabilizer in the form of CO.sub.2. The containers may be
transparent, or may be opaque so that they are impenetrable by
light. However, it is preferred that transparent containers filter
out UV light, since UV light can cause dissociation of HOCl. While
the volume of the container has been considered to impact stability
and shelf-life, the formulations described herein may be in the
range of about 5 ml to about 20 liters, or from about 100 ml to
about 1 liter. Exemplary containers have a unit volume of about 5
ml, about 16 ml, about 50 ml, about 100 ml, about 125 ml, about 250
ml, about 0.5 liter, about 1 liter, about 2 liters, about 3 liters,
about 4 liters, about 5 liters, or about 10 liters.
[0048] Regarding a surfactant, various surfactants useful in
conventional formulations may be employed, and particularly
surfactants that are resistant to oxidants such as HOCl.
Surfactants include CREMOPHOR EL, lauramine oxide, myristyl
dimethylamine oxide, polyoxyl 20 ceto stearyl ether, polyoxyl 40
hydrogenated castor oil, polyoxyl 23 lauryl ether and poloxamer
407.
[0049] Regarding viscosity building agents, such agents may be
added to HOCl compositions of the present invention to increase the
viscosity of the carrier. Examples of viscosity enhancing agents
include, but are not limited to: synthetic silicates,
polysaccharides, such as hyaluronic acid and its salts, chondroitin
sulfate and its salts, dextrans, various polymers of the cellulose
family; vinyl polymers; and acrylic acid polymers. For example, the
composition may exhibit a viscosity of 1 to 400,000 centipoises
("cps").
[0050] Regarding preservatives, no additional antimicrobial agent
is required, since the HOCl will function as a preservative;
however, in some embodiments HOCl is combined with a second
preservative or antimicrobial agent such as silver. In various
embodiments, the HOCl is manufactured as sterile. The composition
can also include other therapeutic agents such as anti-inflammatory
agents, antihistamines, decongestants, antibiotics, analgesics,
immune-modulators and suppressants and/or moisturizing agents known
in the art.
[0051] In various embodiments, the inflammatory condition treated
in accordance with the various embodiments is characterized, at
least in part, by type I hypersensitivity, type II
hypersensitivity, type III hypersensitivity, and/or type IV
hypersensitivity. The inflammatory condition may be acute or
chronic, and may be of autoimmune or allergic origin.
[0052] Type I hypersensitivity or (immediate-type hypersensitivity)
is an allergic reaction provoked by re-exposure to an antigen
(e.g., allergen). In type I hypersensitivity, an antigen is
presented to CD4+ Th2 cells specific to the antigen that stimulate
B-cell production of IgE antibodies also specific to the antigen.
During sensitization, the IgE antibodies bind to receptors on the
surface of tissue mast cells and blood basophils. Later exposure to
the same allergen cross-links the bound IgE on sensitized cells,
resulting in degranulation and the secretion of pharmacologically
active mediators such as histamine, leukotriene (LTC4 and LTD4),
and prostaglandin that act on the surrounding tissues. The
principal effects of these products are vasodilation and
smooth-muscle contraction. Exemplary Type I conditions for which
the invention can be effective include allergic asthma (including
severe asthma), allergic conjunctivitis, allergic rhinitis,
anaphylaxis, angioedema, urticaria, eosinophilia, drug allergy
(e.g., penicillin, cephalosporin), or food allergy. Type I
hypersensitivity can be further classified into an immediate and
late-phase reaction. The immediate hypersensitivity reaction occurs
minutes after exposure and includes release of vasoactive amines
and lipid mediators, whereas the late-phase reaction occurs 2 to 4
hours after exposure and includes the release of cytokines.
[0053] In some embodiments, the patient suffers from a
hyperimmunoglobulin E syndrome, which may be characterized by
recurrent staphylococcal infections, eczema-like skin rashes,
severe lung infections that result in pneumatoceles (balloon-like
lesions that may be filled with air or pus or scar tissue) and very
high concentrations of the serum antibody IgE.
[0054] In type II hypersensitivity (or cytotoxic hypersensitivity)
the antibodies produced by an immune response bind to antigens on
the patient's own cell surfaces. The antigens recognized may be
self-antigens or extrinsic antigens that are adsorbed onto the
cells during exposure to some foreign antigen. These cells are
recognized by macrophages or dendritic cells, which act as
antigen-presenting cells. This causes a B cell response, wherein
antibodies are produced against the foreign antigen. Examples of
type II hypersensitivity where the invention finds use include
Haemolytic Anaemia, Myasthenia Gravis, Grave's Disease, and
Goodpasture's syndrome. Another form of type II hypersensitivity is
called antibody-dependent cell-mediated cytotoxicity (ADCC). Here,
cells exhibiting the foreign antigen are tagged with antibodies
(IgG or IgM). These tagged cells are then recognized by natural
killer cells (NK) and macrophages which in turn kill these tagged
cells.
[0055] Type III hypersensitivity occurs when antigen-antibody
complexes that are not adequately cleared by innate immune cells
accumulate, giving rise to an inflammatory response and attraction
of leukocytes. Type III hypersensitivity occurs when there is an
excess of antigen, leading to small immune complexes being formed
that do not fix complement and are not cleared from the
circulation. Large complexes can be cleared by macrophages but
macrophages have difficulty in the disposal of small immune
complexes. These immune complexes insert themselves into small
blood vessels, joints, and glomeruli, causing symptoms. Unlike the
free variant, a small immune complex bound to sites of deposition
(like blood vessel walls) are far more capable of interacting with
complement. Such depositions in tissues often induce an
inflammatory response, and can cause damage wherever they
precipitate. The damage can result from the action of cleaved
complement anaphylotoxins C3a and C5a, which, respectively, mediate
the induction of granule release from mast cells, and recruitment
of inflammatory cells into the tissue. Skin response to type III
hypersensitivity is referred to as an arthus reaction, and is
characterized by local erythema and some induration. Other examples
of type III hypersensitivity include Systemic lupus erythematosus
(SLE) (which can involve, for example, nephritis, skin lesions, and
arthritis); glomerulonephritis, systemic vasculitis, arthritis,
cutaneous vasculitis, Farmer's lung (which manifests as alveolar
inflammation).
[0056] Type IV hypersensitivity is often called delayed-type
hypersensitivity as the reaction takes two to three days to
develop. Unlike the other types, it is not antibody mediated but
rather is a type of cell-mediated response. CD4+ helper T cells
recognize antigen in a complex with Class II major
histocompatibility complex. The antigen-presenting cells in this
case are macrophages that secrete IL-12, which stimulates the
proliferation of further CD4+ Th1 cells. CD4+ T cells secrete IL-2
and interferon gamma, further inducing the release of other Th1
cytokines, thus mediating the immune response. Activated CD8+ T
cells destroy target cells on contact, whereas activated
macrophages produce hydrolytic enzymes and, on presentation with
certain intracellular pathogens, transform into multinucleated
giant cells.
[0057] Examples of type IV hypersensitivity include the following.
Diabetes mellitus type 1 affects pancreatic beta cells, leading to
beta cell destruction and/or insulitis. Multiple sclerosis results
from an attack on oligodendrocyte proteins, and resulting in
demyelinating disease, perivascular inflammation, paralysis, and/or
ocular lesions. Rheumatoid arthritis (RA) results from an attack on
antigen in synovial membrane, and leading to chronic arthritis. RA
often leads to the destruction of articular cartilage and bone
(which can also involve type III hypersensitivity). Peripheral
neuropathy which can result from attack on Schwann cell antigen,
leading to neuritis or paralysis. Hashimoto's Thyroiditis results
from attack on thyroglobulin antigen, leads to hypothyroidism,
goiter, and/or follicular thymitis. Crohn's disease involves
inflammation of the ileum and colon. Allergic contact dermatitis
results from contact with environmental chemicals including poison
ivy and nickel, and manifests as itching and can include exposure
to radiation, whether by exposure to artificial or natural UV in
the course of living (leading to UV-damaged/aged skin), and/or
exposure to radiation for the purposes of cancer treatment or for
interventional procedures. Other examples include celiac disease,
graft-versus-host disease, and chronic transplant rejection.
[0058] In various embodiments, administration of the hypochlorous
acid composition results in a systemic reduction of
pro-inflammatory cytokines, such as one or more of IL-1.beta.,
IL-2, IL-4, IL-6, IL-8, IL-18, and TNF-.alpha., as well as other
soluble or cellular factors such as .alpha.-2 macroglobulin and
NF-k.beta..
[0059] In various embodiments, the HOCl composition is applied to
prevent diseases or conditions caused by or associated with
prolonged and/or untreated inflammation, including those conditions
mentioned above. Examples of these diseases or conditions include:
cancer (e.g. bowel cancer, lung cancer, skin cancer, ovarian
cancer, breast cancer among others); cardiovascular disease;
diabetes; and metabolic disease.
[0060] In some embodiments, the hypochlorous acid is administered
to a cancer patient, to slow or inhibit the progression of cancer.
Specifically, cancer relies in the inflammatory machinery to
progress and to metastasize. By modulating these inflammatory
processes, the invention helps to control the progression and
spread of cancer, and aids the bodies repair mechanisms,
particularly where the patient undergoes a primary cancer therapy
that is harmful to non-cancer cells and tissues (including but not
limited to mucosa, skin, and GI), such as chemotherapy or radiation
therapy.
[0061] As used herein, cancer refers to any uncontrolled growth of
cells that may interfere with the normal functioning of the bodily
organs and systems, and includes both primary and metastatic
tumors. Primary tumors or cancers that migrate from their original
location and seed vital organs can eventually lead to the death of
the subject through the functional deterioration of the affected
organs. A metastasis is a cancer cell or group of cancer cells,
distinct from the primary tumor location, resulting from the
dissemination of cancer cells from the primary tumor to other parts
of the body. Metastases may eventually result in death of a
subject. For example, cancers can include benign and malignant
cancers, polyps, hyperplasia, as well as dormant tumors or
micrometastases. In some embodiments, the cancer is stage I or
stage II cancer. In other embodiments, the cancer is stage III or
stage IV.
[0062] Illustrative cancers that may be treated include, but are
not limited to, basal cell carcinoma, biliary tract cancer; bladder
cancer; bone cancer; brain and central nervous system cancer;
breast cancer; cancer of the peritoneum; cervical cancer;
choriocarcinoma; colon and rectum cancer; connective tissue cancer;
cancer of the digestive system; endometrial cancer; esophageal
cancer; eye cancer; cancer of the head and neck; gastric cancer
(including gastrointestinal cancer); glioblastoma; hepatic
carcinoma; hepatoma; intra-epithelial neoplasm; kidney or renal
cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g.,
small-cell lung cancer, non-small cell lung cancer, adenocarcinoma
of the lung, and squamous carcinoma of the lung); melanoma;
myeloma; neuroblastoma; oral cavity cancer (lip, tongue, mouth, and
pharynx); ovarian cancer; pancreatic cancer; prostate cancer;
retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the
respiratory system; salivary gland carcinoma; sarcoma; skin cancer;
squamous cell cancer; stomach cancer; testicular cancer; thyroid
cancer; uterine or endometrial cancer; cancer of the urinary
system; vulval cancer; lymphoma including Hodgkin's and
non-Hodgkin's lymphoma, as well as B-cell lymphoma (including low
grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic
(SL) NHL; intermediate grade/follicular NHL; intermediate grade
diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic
NHL; high grade small non-cleaved cell NHL; bulky disease NHL;
mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's
Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute
lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic
myeloblastic leukemia; as well as other carcinomas and sarcomas;
and post-transplant lymphoproliferative disorder (PTLD), as well as
abnormal vascular proliferation associated with phakomatoses, edema
(e.g. that associated with brain tumors), and Meigs' syndrome.
[0063] In various embodiments, cancers that may be treated include,
but are not limited to, skin cancer, cutaneous melanoma, breast
cancer, colon cancer, lung cancer, testicular cancer, cervical
cancer, lymphoma, parathyroid cancer, penile cancer, rectal cancer,
small intestine cancer, thyroid cancer, uterine cancer, Hodgkin's
lymphoma, lip and oral cancer, leukemia or multiple myeloma. In an
embodiment, the cancer is a cutaneous cancer such as basal cell
carcinoma or squamous cell carcinoma. In an embodiment, the cancer
is breast cancer. In another embodiment, the cancer is a cancer of
the mouth, throat, or sinus. In a further embodiment, the cancer is
lung cancer.
[0064] In some embodiments, the hypochlorous acid composition is
administered directly to the tumor or to tissue or organ harboring
the tumor. For example, in some embodiments, the hypochlorous acid
composition is administered during surgical removal of the cancer.
In other embodiments, the location of the tumor will instruct the
most appropriate route of delivery, including by topical
administration, pulmonary administration, colonic irrigation,
catheter, intra-tumoral injection, or delivery to the oral cavity
or sinus cavity. In some embodiments, the hypochlorous acid
composition is administered topically, whether or not the cancer is
cutaneous in origin, or proximal to the skin. In some embodiments,
the hypochlorous acid provides systemic effects upon topical
delivery, allowing for even remote cancers (such as liver,
pancreatic, bladder, colorectal, and others) to be effectively
treated using this route. In some embodiments, prolonged treatment
with the hypochlorous acid composition is employed for the
treatment of cancer.
[0065] In various embodiments, the HOCl composition is applied to
treat or prevent lesions caused by inflammatory conditions by
inhibiting the inflammatory processes and/or by maintaining skin
homeostasis or by stimulating cell (e.g., skin cell) proliferation
to heal lesion wounds. Thus, in some embodiments, the patient has
an inflammatory condition that manifests as skin or mucosa lesions,
and the HOCl formulation protects intact skin (e.g., from
developing lesions) and/or promotes closing of wounds once
developed. In some embodiments, the patient may have a condition
that predisposes the patient to skin lesions, and is characterized
by microbial infection or burden, inflammation, itch, high pH, and
compromised barrier. HOCl as described herein acts in a multi-modal
fashion to inhibit various stages of the condition, including
reduction of the microbial burden, normalizing the pH, reducing
itch, while reducing inflammatory mediators.
[0066] In some embodiments the invention provides methods for
controlling or normalizing the microbiome of a tissue, including
but not limited to skin, eyes, mouth, gingiva, nasal passages,
sinus cavity, urogenital system, vagina, intestine, etc. In some
embodiments, the tissue is affected by acute or chronic
inflammation, and in some embodiments, is characterized by
microbial over-colonization, or is characterized by the presence of
one or more microbes associated with an inflammatory or
immunological condition.
[0067] Even in the absence of overt infection, there is a complex
interplay between the microbiome and tissue inflammation. See,
McDermott and Huffnagle, The microbiome and regulation of mucosal
immunity, Immunology Vol. 142(1): 24-31 (2014). Simultaneous
reduction of microbial burden and normalization of the tissue
microbiome, together with a reduction of local inflammation, can
promote tissue healing and normalization. In some embodiments, the
microflora from the inflamed tissue, or other region, is determined
(e.g., by rRNA gene sequencing). In embodiments where microbes (or
populations or profiles of microbes) associated with immunological
or inflammatory conditions are present, the hypochlorous acid
composition can be administered to normalize the microbial
flora.
[0068] In some embodiments, topically applied HOCl, especially with
prolonged use, helps to maintain a healthy microflora (including
skin, mucosal membranes, gut, etc.), which is beneficial for
controlling chronic inflammation.
[0069] In various embodiments, the inflammatory condition involves
as an affected region, one or more of the eyes, ears, nose, sinus,
throat, mouth, gingiva, or skin. In other embodiments, the
inflammatory condition may have as an affected region, one or more
of the intestinal tract/colon, lungs, urogenital system (e.g.,
urinary tract, vagina), skeletal muscle, ligaments, tendons,
joints, bones, kidney, liver, pancreas, or vasculature.
[0070] Various localized inflammatory conditions or symptoms that
may be treated in accordance with the invention include: conditions
of the eye such as allergic conjunctivitis, blocked glands,
chalazion, stye, red eye, dry eye disease, uveitis, inflammation
after eye surgery, dry or wet age-related macular degeneration
(AMD); conditions of the nose or sinus cavity such as rhinitis,
rhinorrhea, sinusitis, nasal congestion; conditions of the mouth or
throat such as stomatitis, xerostomia, gingivitis, or pharyngitis;
and conditions of the skin such as keratitis, dermatitis, acne,
psoriasis, Netherton Syndrome, Ichthyosis, bullous disease of the
skin (e.g., epidermolysis bullosa), Bullous Pemphigoid, Actinic
Keratosis, pruritis, rash, lesions, blisters, and bumps.
[0071] Additional inflammatory conditions to be treated in various
embodiments, which can affect a particular target tissue, or affect
multiple tissues, organs, or systems, are as follows. Exemplary
conditions that affect the lungs include allergic asthma,
occupational asthma, bronchitis, chronic obstructive pulmonary
disease (COPD), idiopathic pulmonary fibrosis (IPF), cystic
fibrosis, Goodpasture Syndrome, or Farmer's Lung. Exemplary
conditions that affect the skin include contact dermatitis, acne,
angioedema, urticaria, Systemic lupus erythematosus (SLE),
psoriasis, sarcoidosis, rosasea, dermatitis herpetiformis,
sun-burn, and cutaneous vasculitis. Exemplary conditions that
affect the colon or intestinal tract include Crohn's disease,
celiac disease, ulcerative colitis, and hemorrhoids. Exemplary
conditions that affect the joints or bones include arthritis (e.g.,
rheumatoid arthritis or osteoarthritis), multifocal osteomyelitis,
traumatic knee injury, SLE, and gout. Exemplary conditions that
affect the kidneys include Goodpasture Syndrome, SLE,
glomerulonephritis, and kidney stones. Other exemplary conditions
involving inflammation of an organ, system, or systemic
inflammation include eosinophilia, drug allergy, food allergy,
hemolytic anemia, myasthenia gravis, systemic vasculitis, diabetes
mellitus type 1 and 2, Hidradenitis suppurativa, multiple sclerosis
(MS), myelitis, peripheral neuropathy, Parkinson's Disease,
hepatitis, renal failure, pancreatitis, Hashimoto's Thyroiditis,
adult onset Still's disease, systemic onset juvenile idiopathic
arthritis (SJIA) Schnitzler syndrome, Behcet's disease, SAPHO
syndrome, macrophage activation syndrome, Familial Mediterranean
Fever (FMF), cryopyrin-associated periodic syndrome (CAPS), TNF
receptor associated periodic syndrome (TRAPS), Hyper-IgD syndrome,
periodic fever, aphthous stomatitis, pharyngitis and adenitis
(PFAPA), deficiency of interleukin-1 (IL-1) receptor antagonist
(DIRA), Giant cell arteritis, graft versus host disease,
amyloidosis, recurrent pericarditis, and neuromyelitis optica,
amyotrophic lateral sclerosis, myeloma, and chronic transplant
rejection.
[0072] In some embodiments, the HOCl is applied to the skin, either
to reduce or inhibit inflammation, or to prevent inflammation in a
patient with an acute or chronic inflammatory condition. For
example, the affected areas of the skin may be characterized by an
alkaline pH as compared to normal healthy skin. In such
embodiments, the weak--acidic pH of the hypochlorous acid helps
bring the skin to a pH that is more conducive to healing and
healthy regeneration. Further, in some embodiments, application to
intact but inflamed skin promotes healthy skin regeneration and
barrier integrity, by inhibiting or reducing the tissue-damaging
inflammatory response, thereby allowing the cells (e.g., dermal
fibroblasts and/or keratinocytes) to proliferate in a manner
consistent with the healing process. Further still, HOCl is not
cytotoxic to these cells at the levels applied. The healing
environment is further aided by reducing the microbial burden of
the inflamed tissue, where otherwise infection might spawn due to
loss of barrier integrity. Thus, in various embodiments, the
hypochlorous acid formulation results in one or more of a reduction
of microbial burden, a reduction of inflammation, reduced pruritis,
enhanced skin cell regeneration, and normalized skin pH. In some
embodiments, the patient has a condition characterized by microbial
bioburden (e.g., over-colonization) or infection, inflammation,
itch, lesions, and high skin pH at the affected region. In some
embodiments, the patient has a condition characterized by skin
lesions, with or without active lesions. While the HOCl formulation
promotes healing of active lesions and normalization of the skin,
new lesions are prevented from forming.
[0073] In some embodiments, the subject has an underlying
immunological condition that affects a plurality of organs or
tissues, including the skin. In these embodiments, the hypochlorous
acid composition relieves inflammatory symptoms at affected regions
of the skin, while dampening or altering the underlying systemic
immunological condition, which may have an autoimmune or
hypersensitivity component.
[0074] For example, in some embodiments, the subject has Systemic
Lupus Erythematosus (SLE). SLE or lupus, is a systemic autoimmune
disease in which the body's immune system attacks healthy tissues.
SLE often affects the heart, joints, skin, lungs, blood vessels,
liver, kidneys, and nervous system. Lupus patients can present with
skin lesions/rash. The three main categories of lesions are chronic
cutaneous (discoid) lupus, subacute cutaneous lupus, and acute
cutaneous lupus. Discoid lupus exhibits as thick, red scaly patches
on the skin. Similarly, subacute cutaneous lupus manifests as red,
scaly patches of skin but with distinct edges. Acute cutaneous
lupus manifests as a rash. The hypochlorous acid composition in
some embodiments ameliorates and/or relieves skin lesions or
rashes, while providing systemic anti-inflammatory benefits. Thus,
other tissues and organs commonly affected in Lupus can benefit
from cutaneous treatment with HOCl as described herein.
[0075] In other embodiments, the subject has psoriasis, such as
plaque psoriasis, erythrodermic psoriasis, pustular psoriasis,
scalp psoriasis, guttate psoriasis, or inverse psoriasis. While
psoriasis manifests heavily as skin lesions, psoriasis can also
affect joints and surrounding connective tissue, eyes, and mucous
membranes (including ears and nasal passages). The hypochlorous
acid composition in some embodiments ameliorates and/or relieves
psoriatic skin lesions, while providing systemic anti-inflammatory
benefits. Thus, other tissues affected in psoriasis can benefit
from cutaneous treatment with HOCl as described herein.
[0076] In some embodiments, the subject has rheumatoid arthritis
(RA). RA is a chronic inflammatory disorder that affects joint
linings causing painful swelling that may eventually result in bone
erosion and joint deformity. In addition to causing joint problems,
RA can affect other organs of the body including the skin. For
example, some RA patients experience rheumatoid nodules on the
skin, vasculitis, rash, ulcers, blisters, and bumps. In addition,
RA can also induce skin conditions including Pyoderma gangrenosum,
Sweet's syndrome, erythema nodosum, lobe panniculitis, atrophy of
finger skin, palmar erythema, and diffuse thinning and skin
fragility (often worsened by corticosteroid use). In various
embodiments, the hypochlorous acid composition prevents,
ameliorates and/or relieves skin symptoms associated with RA, while
providing systemic anti-inflammatory benefits for RA patients.
[0077] In some embodiments, the subject has celiac disease. Celiac
disease is an autoimmune disorder that occurs in genetically
predisposed subjects who develop an immune reaction to eating
gluten. Patients with celiac disease exhibit gastrointestinal
symptoms including diarrhea, abdominal pain, and cramping. In
addition, celiac disease can also affect other organ systems such
as the skin resulting in symptoms such as mouth ulcers or sores.
About 15-25% of celiac disease patients also develop dermatitis
herpetiformis which is manifested as an extremely itchy skin rash
with bumps and blisters. In various embodiments, the hypochlorous
acid composition prevents, ameliorates and/or relieves mouth
ulcers, sores, and skin rash (when topically applied) associated
with celiac disease as well as providing systemic benefits to the
condition as a whole.
[0078] In some embodiments, the subject has Crohn's disease.
Crohn's disease is a type of inflammatory bowel disease causing
inflammation of the linings of the digestive tract. The
inflammation caused by Crohn's disease often leads to severe
abdominal pain, diarrhea, fatigue, weight loss, and malnutrition.
Crohn's disease can also cause other complications outside of the
gastrointestinal tract including the skin. For example, Crohn's
disease can cause skin symptoms including mouth ulcers or sores,
erythema nodosum manifested as raised red nodules on the skin, and
pyoderma gangrenosum which causes painful ulcerating skin nodules.
In various embodiments, administration of the hypochlorous acid
composition prevents or ameliorates the dermatological symptoms
associated with Crohn's disease and provides additional systemic
benefits to other organs or tissues affected by the disease.
[0079] In some embodiments, the subject has ulcerative colitis.
Similar to Crohn's disease, ulcerative colitis is also a type of
inflammatory bowel disease. The disease causes inflammation and
ulcers in the colon causing symptoms such as diarrhea.
Additionally, ulcerative colitis can cause dermatological symptoms
such as mouth ulcers or sores, erythema nodosum, and pyoderma
gangrenosum. The hypochlorous acid composition (applied locally) in
some embodiments prevents, ameliorates and/or relieves the mouth
ulcers, sores, and painful or necrotic ulcers associated with
ulcerative colitis, while providing systemic anti-inflammatory
benefits. Thus, other tissues and organs affected in ulcerative
colitis can benefit from cutaneous treatment with HOCl as described
herein.
[0080] In some embodiments, the subject has vasculitis. Vasculitis
is a condition that involves inflammation of the blood vessels, and
can cause skin complications. For example, patients with vasculitis
often develop skin rash as well as skin hemorrhage or discoloration
due to palpable purpura and livedo reticularis. In some
embodiments, the hypochlorous acid composition prevents,
ameliorates and/or relieves these skin symptoms while providing
systemic anti-inflammatory benefits.
[0081] In some embodiments, the subject has thyroiditis, which is
an inflammation of the thyroid gland. Thyroiditis can cause a
variety of symptoms due to either hypothyroidism or
hyperthyroidism. For example, thyroiditis often causes dry skin,
which may be prevented or relieved by applying the hypochlorous
acid composition. Application of the hypochlorous acid composition
may also provide systemic effects by providing relief to other
tissues and organs affected by thyroiditis such as the eyes and
muscles.
[0082] In some embodiments, the subject has type I diabetes.
Diabetes can affect every part of the body, including the skin, and
many people with diabetes develop a skin disorder caused or
affected by diabetes. In some cases, skin problems can be the first
sign that a person has diabetes. Some common skin conditions in
people with diabetes include, acanthosis nigricans, skin rashes,
bumps, or blisters, dry and/or itchy skin, diabetic dermopathy
which can cause scaly patches on the skin, digital sclerosis,
disseminated granuloma annulare, eruptive xanthomatosis,
necrobiosis lipoidica diabeticorum, scleroderma diabeticorum, and
vitiligo. In various embodiments, application of the hypochlorous
acid composition prevents, ameliorates and/or relieves the various
skin symptoms associated with diabetes as well as providing benefit
to the other tissues or organs affected or caused by diabetes.
[0083] In some embodiments, the subject has dermatomyositis.
Dermatomyositis is an inflammatory disease marked by muscle
weakness and a distinctive skin rash. Patients with this disease
often exhibit a red-purple scaly rash on the face and eyelids, and
in areas around the nails, knuckles, elbows, knees, chest, and
back. In various embodiments, applying the hypochlorous acid
composition to the skin may prevent, ameliorate and/or relieve the
rash associated with this disorder while providing systemic
anti-inflammatory benefits. Thus, other tissues such as the muscles
affected in dermatomyositis can also benefit from treatment with
HOCl as described herein.
[0084] The doses used for the above described purposes can be
determined by a physician or other qualified medical personnel and
can depend, for example, on the type of skin condition and
underlying immune condition, the frequency of administration (i.e.
for chronic or acute use), the severity of the condition, the age
and overall health of the patient, the dosage form of the
hypochlorous acid, and other factors. For example, in one
non-limiting embodiment, the HOCl composition may be administered 1
to 10 times per day. In another embodiment, the composition is
administered 1 to 4 times per day (e.g., about twice daily) to
affected areas of the skin. The hydrogel composition described
herein can be administered in these embodiments, and may be
administered for a prolonged period as described.
[0085] In certain embodiments, the present invention relates to
treating an ocular condition. The ocular condition may affect any
portion of the eye or surrounding areas, such as the conjunctiva,
uvea, eyelid, oil glands, and lacrimal ducts. Exemplary ocular
conditions include: red eye; dry eye (including dry eye syndrome);
conjunctivitis of bacterial, viral, or allergic origin; uveitis,
blepharitis; external or internal hordeolum; canaliculitis;
dacrocystitis; and chalazions.
[0086] The invention includes the treatment and prevention of
ocular infections caused by a variety of pathogens, such as, for
example, a bacterial agent, a viral agent, a parasitic agent,
and/or a fungal agent. Non-limiting examples of bacterial agents
include Streptococcus spp. (e.g. pneumoniae), Staphylococcus spp.
(e.g., aureus), Haemophilus spp. (e.g., influenzae), Pseudomonas
spp. (e.g., aeuruginosa), Chlamydia spp. (e.g., trachomatis,
psittaci, pecorum), Neisseria spp. (e.g. gonorrhoeae), and
Actinomyces species. Non-limiting examples of viral agents include
adenovirus, respiratory syncytial virus (RSV), influenza (including
parainfluenza), coxackie virus, rhinovirus, coronavirus, and herpes
simplex virus. Non-limiting examples of fungal agents include
Candida species, Fusariu species, and Aspergillus species. A
non-limiting example of a parasitic agent is an eyeworm. Certain
bacterial agents may be more common in certain patient
subpopulations. For example, different strains of Chlamydia
psittaci and Chlamydia pecorum cause significant eye infection in
cats, lambs, goats, and guinea pigs. These infections are
occasionally transmitted to humans. Further, eyeworms are common
parasites of horses and cattle, goats, pigs, dogs and cats. Thus,
in invention provides further provides additional benefits in the
farming industry where antibiotics and other active agents should
be used sparingly.
[0087] These microbial agents may be involved in various ocular
infections including blepharitis; hordeola, such as external
hordeolum and internal hordeolum; conjunctivitis, such as viral
conjunctivitis or bacterial conjunctivitis, conjunctivitis in
newborns (opthalmia neonatorum) due to Chlamydia trachomatis or
Neisseria gonorrhoeae, chlamydial disease in adults such as
inclusion conjunctivitis and trachoma, or gonococcal conjunctivitis
in adults; iridocyclitis and panopthalmitis caused by Bacillus
subtilis; lacrimal system infections such as canaliculitis and
dacrocystitis; keratitis, such as viral keratitis (herpes simplex
virus), bacterial keratitis and fungal keratitis (e.g., Fusarium),
including among soft contact lens wearers; toxoplasmosis, including
in dogs and cats; feline herpes virus, which is a common cause of
eye and upper respiratory infections in cats; uveitis, including in
large animals, such as cattle, caused by Listeria; and eye
infections caused by avian flu or other eye conditions and
infections secondary to other medical conditions.
[0088] In certain embodiments, the ocular condition involves an
inflammatory disorder or hypersensitivity reaction (including types
I, II, III, and/or IV). For example, the ocular condition may
involve an immediate-type hypersensitivity reaction such as
allergic conjunctivitis. In other embodiments, the condition may
result from a blocked gland or chronic inflammatory condition,
including styes and chalazions, which may also develop an acute
bacterial infection. Such conditions may be recurring or may be
difficult to completely clear. Other inflammatory ocular conditions
that may or may not involve microbial infection include
uveitis.
[0089] In some embodiments, the ocular condition (including but not
limited to dry eye) is associated with an underlying immunological
condition. In these embodiments, the hypochlorous acid composition
not only relieves the local ocular symptoms, but also dampens or
positively alters the underlying systemic immunological condition,
which is an autoimmune condition in some embodiments.
[0090] For example, in some embodiments, the subject may be
afflicted with SLE and exhibit ocular symptoms. These symptoms
include, but are not limited to, dry eyes, scleritis (which is
inflammation in the white scleral layer of the eye), retinal
vascular lesions, and skin lesions around the eye lids. SLE may
also cause nerve damage to the eyes thus affecting eye movement and
vision. In various embodiments, the hypochlorous acid solution
prevents or ameliorates some or all of the local ocular symptoms
associated with SLE, while providing systemic anti-inflammatory
effects to benefit the other organs and systems affected with
SLE.
[0091] In some embodiments, the present hypochlorous acid
composition effectively treats the ocular symptoms associated with
psoriasis. For example, uveitis and iritis are often complications
of psoriasis. In addition, psoriatic patients may also present with
flare-up around the eye resulting in scales and dryness around the
eyelids. Hypochlorous acid solutions may be applied to the eye and
surrounding regions to prevent or relieve these local inflammatory
symptoms, while potentially providing systemic benefits.
[0092] In some embodiments, the hypochlorous acid composition is
used to treat the ocular symptoms associated with rheumatoid
arthritis (RA). In RA patients, inflammation may also cause damages
to the eyes. For example, these patients may experience
episcleritis and scleritis, which involve inflammation of the
sclera. RA patients may also experience uveitis, which involves
inflammation of the uvea. In addition, RA patients may present with
keratoconjunctivitis sicca (also known as dry eyes syndrome),
glaucoma, and/or cataracts. Further, some RA patients develop
Sjogren's syndrome, which is a chronic, autoinflammatory condition
causing extreme dryness to the eyes, nose, and mouth. In various
embodiments, hypochlorous acid composition may be applied to the
local region to prevent or relieve these symptoms as well as to
ameliorate systemic symptoms.
[0093] In some embodiments, the subject has Crohn's disease. In
various embodiments, the hypochlorous acid composition may be
administered to treat or prevent the local ocular symptoms
associated with Crohn's disease including for the treatment of
uveitis, episcleritis, and scleritis, while potentially providing
systemic improvement of the overall condition.
[0094] In some embodiments, the subject has ulcerative colitis.
Patients with ulcerative colitis may also develop ocular symptoms
including uveitis, iritis, and episcleritis. The hypochlorous acid
composition may be applied locally to these patients to prevent or
ameliorate and/or relieve these ocular inflammatory symptoms, while
providing systemic anti-inflammatory benefits.
[0095] In some embodiments, the subject has vasculitis. Vasculitis
can affect many organs and tissues including the eye. For example,
some patients with vasculitis may experience inflammation of the
eye which can cause reduced visual acuity and vision loss. In
various embodiments, hypochlorous acid composition applied to the
eye to prevent or relieve these symptoms while providing systemic
effects to treat the underlying inflammatory condition.
[0096] In some embodiments, the subject has thyroiditis. In these
patients, eye symptoms often develop. For example, these patients
may develop thyroid eye disease which is an eye condition in which
the eye muscles and fatty tissue behind the eye become inflamed.
This can cause the eyes to be pushed forward (staring' or `bulging`
eyes) and the eyes and eyelids to become swollen and red. In some
cases there is swelling and stiffness of the muscles that move the
eyes so that the eyes are no longer in line with each other; this
can cause double vision. The hypochlorous acid composition of the
invention may be used to prevent or relieve these local eye
symptoms as well as additional systemic symptoms affecting other
tissues or organs.
[0097] In some embodiments, the subject has allergic asthma, which
is an inflammatory disorder triggered by allergens. During an
asthmatic attack, the subject's airways become inflamed, narrow,
and swell, making it difficult to breathe. The subject may also
experience itchy, glassy, or water eyes. In various embodiments,
the hypochlorous acid composition may be applied to the eyes of
these subjects to prevent or relieve local eyes symptoms in
addition to mediating systemic anti-inflammatory effects, which can
be observed in terms of less frequent attacks, or attacks of
reduced severity.
[0098] In some embodiments, the subject has type I diabetes. In
some embodiments, the hypochlorous acid composition is used to
treat diabetic eye disease. Diabetic eye disease refers to a group
of eye conditions that affect people with diabetes. These
conditions include diabetic retinopathy, diabetic macular edema
(DME), cataract, and glaucoma. All forms of diabetic eye disease
have the potential to cause severe vision loss and blindness.
Diabetic retinopathy involves changes to retinal blood vessels that
can cause them to bleed or leak fluid, thereby distorting vision.
DME is a consequence of diabetic retinopathy that causes swelling
in the area of the retina called the macula. Diabetes may also
cause cataract, which is a clouding of the eye's lens, as well as
glaucoma, which is associated with elevated pressure inside the eye
causing damage to the optic nerve. Application of the hypochlorous
acid composition to the eye may prevent or relieve one or more
symptoms of the diabetic eye disease as well as other systemic
symptoms.
[0099] In some embodiments, the hypochlorous acid composition of
the invention may be used to treat one or more ocular symptoms
associated with dermatomyositis. Subjects with dermatomyositis may
be afflicted with local inflammation of the eyes, resulting in
swollen or puffy eyes due to edema. The hypochlorous acid
composition may be applied to the eyes to prevent or ameliorate
these local eye symptoms while providing systemic anti-inflammatory
benefits.
[0100] In some embodiments, the subject has conjunctivitis,
commonly known as pink eye. Conjunctivitis is an inflammation of
the conjunctiva, the outer-most layer of the eye that covers the
sclera. While many of the signs and symptoms of conjunctivitis are
relatively non-specific, there are several etiologies that may be
causative in a given case. The three most common causes of
conjunctivitis are bacterial infection, viral infection, or an
allergic reaction.
[0101] In some embodiments, the composition is applied to treat or
prevent blepharitis, chalazion, or hordeola. Blepharitis is an
inflammation of the eyelid margins, and is usually caused by an
infection of Staphylococcus aureus. Blepharitis can lead to a
chalazion, or lead to a stye (hordeolum). A chalazion is a cyst in
the eyelid caused by inflammation of a blocked meibomian gland,
usually on the upper eyelid. A chalazion may spawn bacterial
infection. When the condition does not resolve on its own, a
chalazion may be injected with corticosteroid or be surgically
removed. Hordeola include both external hordeolum, or "stye", and
internal hordeolum (acute meibomianitis). Styes are lesions at the
base of the eyelashes and are predominantly caused by infection of
Staphylococcus aureus.
[0102] In some embodiments, the composition is applied to treat or
prevent infection and/or inflammation of the lacrimal system, such
as canaliculitis and dacrocystitis. Canaliculitis can be caused by
Actinomyces infection. Dacrocystitis is often due to streptococci
or Staphylococcus aureus.
[0103] In certain embodiments, the ocular condition is prevention
of infection and/or inflammation resulting from an eye surgery or
trauma to the eye.
[0104] In certain other embodiments, the hypochlorous acid
composition is administered prophylactically, especially where eye
infections are likely to occur or be transmitted among persons.
Thus, in this embodiment, the invention involves administering the
hypochlorous acid before an infection and/or inflammation develops.
Such prophylactic care might include routine cleaning of the eyes
and surrounding areas, such as the eyelids, with the hypochlorous
acid, or routine rinsing of contact lenses by applying the
hypochlorous acid to the contact lenses to decontaminate and clear
debris and biofilm. Such embodiments can result in the prevention
of an ocular infection, can prevent the worsening of an existing
ocular infection caused by contaminated lenses, or can prevent
irritation of the eyes caused by bacterial biofilm. In other
embodiments, the invention involves administering hypochlorous acid
to the environment via fogging, misting, or humidifying, to prevent
the transfer of pathogens from air droplets into the eyes of
susceptible individuals.
[0105] In certain embodiments, the ocular condition may result from
an acute or chronic inflammatory condition, which may develop an
acute infection. In these embodiments, the hypochlorous acid is
administered to treat both the infection and the underlying
inflammation. Thus, the hypochlorous acid may be administered
instead of steroidal drops or systemic steroidal medications, or
antibiotics, thereby avoiding the potential adverse reactions of
such treatments. In certain other embodiments, the hypochlorous
acid composition is administered to clean the region during the
duration of steroidal and/or antibiotic treatment. In one
embodiment, hypochlorous acid is administered to the eye of a
patient inflicted with uveitis, during the duration of steroid
treatment. For example, the hypochlorous acid may be used in
conjunction with glucocorticoid steroids, either as topical eye
drops (such as betamethasone, dexamethasone or prednisolone) or
oral therapy with prednisolone tablets. Likewise, when the
condition has an allergic origin, such as allergic conjunctivitis,
the hypochlorous acid may be used alongside an antihistamine to
more effectively inhibit release of inflammatory mediators from
mast cells.
[0106] In certain embodiments, the hypochlorous acid solution may
be administered to two or more sites in the ocular system of a
patient. For example, the hypochlorous acid may be administered as
drops to the eye or eye wash, and as a cleanser for the eye lids
and/or eyelid margins.
[0107] The hypochlorous acid and compositions of the present
invention may be administered in any appropriate dosage form such
as a liquid, aerosol, gas, or semi-solid including a solution,
suspension, viscous or semi-viscous gel, ointment, cream, or other
types of compositions. Preferably, the solution is administered
topically either dropwise into the eye or to the tissue surrounding
the eye. The solution or composition comprising the solution can
also be formulated into a sterile solution for administration by
intracameral injection into the anterior chamber of the eye or
directly into the trabecular meshwork of the eye (e.g., for the
treatment of dry or wet AMD). The doses used for the above
described purposes can be determined by a physician or other
qualified medical personnel and can depend, for example, on the
type of ocular condition, the frequency and/or duration of
treatment (i.e. for chronic or acute use), the severity of the
condition, the age and overall health of the patient, the dosage
form of the hypochlorous acid, and other factors. For example, when
applying as drops to the eyes, in one non-limiting embodiment, 1 to
2 drops of an HOCl solution is administered 1 to 10 times per day.
In another embodiment, the solution (e.g., about 1 or 2 drops per
eye) is administered 1 to 4 times per day (e.g., about twice
daily). This regimen may be employed for a prolonged period of
time, as described.
[0108] The present invention provides treatments as well as
preventive care for conditions characterized by inflammation of the
ears (including the outer ear, middle ear, and inner ear), nose
(including sinus care), mouth, and throat. Exemplary conditions
include: rhinitis, rhinorrhea, nasal congestion, otitis media,
external otitis, pharyngitis, and stomatitis, and may be present in
a human or animal patient. The present invention further provides
preventive care for such conditions, especially where such
conditions are recurring, such as recurring ear infection, sinus
infection, sore throat, or mouth ulcer.
[0109] In various embodiments, the present invention provides
sinus/nasal treatments for subjects with an inflammatory condition.
In various embodiments, administration of the hypochlorous acid
compositions ameliorates and relieves the local sinus and nasal
symptoms while providing systemic anti-inflammatory benefits.
[0110] In some embodiments, the present invention provides relief
of local sinus and nasal symptoms in a subject with systemic lupus
erythematosus. In such embodiments, the hypochlorous acid
composition may be administered to the subject to prevent or
provide relief for nasal ulcers or nasal sores. In various
embodiments, application of the hypochlorous acid composition also
dampens or alters systemic inflammation in the subject.
[0111] In some embodiments, the composition is used to treat
subjects with psoriasis. Psoriatic patients may develop scales
inside their nose which can be prevented or ameliorated by applying
the hypochlorous acid composition.
[0112] In some embodiments, the composition is used to treat
subjects with rheumatoid arthritis. For example, the composition
may be applied to a RA subject to prevent or provide local relief
to the excessive dry nose in those RA subjects that secondarily
develops due to Sjogren's syndrome.
[0113] In some embodiments, the hypochlorous acid composition is
administered to a subject with vasculitis. For example, the
composition may be applied to the nose to prevent or provide relief
for nose bleeds.
[0114] In some embodiments, the composition is used to treat a
subject with allergic asthma. For example, the composition may be
applied to the nose or sinuses to prevent or provide relief for
congestion. In various embodiments, administration of the
hypochlorous acid composition not only treats these nasal symptoms,
but also provides systemic benefits to other tissues and
organs.
[0115] In some embodiments, the hypochlorous acid composition is
used to treat sinusitis and/or sinus infections in a subject
afflicted with diabetes such as type 1 diabetes. In various
embodiments, administration of the hypochlorous acid composition
prevents or ameliorates the local sinus inflammation as well as any
systemic inflammation in these subjects.
[0116] In some embodiments, the composition is applied to treat or
prevent rhinitis, rhinorrhea, or nasal congestion. Rhinitis, an
inflammation of the nasal mucous membrane, may produce nasal
decongestion and rhinorrhea. Rhinitis is typically of viral origin,
but may involve secondary bacterial infection. Rhinorrhea and nasal
congestion are typically of viral or allergic origin. In certain
instances, congestion is observed as an after-effect of topical
decongestants (rhinitis medicamentosa). While topical or oral
decongestants (e.g., pseudoephedrine) can prevent or provide some
symptomatic relief, prolonged use is not recommended.
[0117] In some embodiments, the present hypochlorous acid
composition is administered to treat the ear symptoms associated
with various inflammatory conditions. Administration of the
composition can prevent and ameliorate the local symptoms in the
ear and provide systemic anti-inflammatory benefits.
[0118] For example, in some embodiments, the hypochlorous acid
composition is administered to a subject with systemic lupus
erythematosus. SLE subjects may present local inflammation in the
ear passages leading to ringing the ears due to, for example,
peripheral nerve damage. Administration of the composition prevents
or provides relief to these local ear symptoms as well as other
systemic symptoms affecting other tissues and organs. In some
embodiments, the composition is administered to treat the ear
symptoms of subjects with psoriasis. Psoriatic patients may develop
scales that build up in the ear passages. The composition may be
applied to these patients to prevent or ameliorate scale build
up.
[0119] In some embodiments, the composition is administered to
treat or prevent otitis media or external otitis. Otitis media,
inflammation of the middle ear structures, can lead to loss of
equilibrium and deafness. Otitis media is generally of bacterial or
viral origin. Viral infections may spawn secondary bacterial
infections, including infections of Streptococcus pneumonia,
Moraxella catarrhalis, and non-typable Haemophilus influenzae.
External otitis is an acute or chronic inflammation of the external
ear canal, and may involve bacterial (e.g., Pseudomonas aeruginosa,
Proteus vulgaris, and Staphylococcus aureus) or fungal (e.g.,
Aspergillus and Candida) infection.
[0120] In still other embodiments, the composition is administered
to treat or prevent pharyngitis (sore throat) or stomatitis.
Pharyngitis is characterized by pain and swelling in the posterior
pharynx. Pharyngitis is commonly caused by bacterial (e.g.,
Streptococcal) or viral infection. Stomatitis is a painful ulcer or
inflammation of the oral mucosa. Stomatitis may be caused, for
example, by infection (bacterial, viral, or fungal), chemical
irritant, or allergic reaction, and may be common for patients
having Xerostomia. Some common infectious agents include herpes
simplex virus, varicella zoster, Epstein-Barr virus, influenza,
cytomegalovirus, Gonorrhea, and Candida.
[0121] In certain embodiments, the condition may involve a
bacterial infection that produces a discharge, for example,
external otitis or otorrhea. In these embodiments, the hypohalous
acid effectively cleans discharge, biofilm, or debris from the ear
in a manner that reduces the risk of spreading infection.
[0122] In addition to the skin, ear, nose, mouth, and/or throat,
many inflammatory conditions affect other organs and tissues as
well. For example, as expected in a multisystem disease, the entire
pulmonary system is vulnerable to injury. The pulmonary
manifestations are diverse, affecting all anatomic locations of the
respiratory tract (i.e., airways, alveoli, blood vessels, and
pleura). In various embodiments, administration of the hypochlorous
acid composition of the invention provides local as well as
systemic anti-inflammatory benefits to various tissues and organs
including the lungs.
[0123] In some embodiments, the composition may be used to treat or
prevent the pulmonary symptoms associated with systemic lupus
erythematosus. Pulmonary involvement is frequent in SLE, and can
affect the pleura, pulmonary vasculature, and parenchyma. In
various embodiments, the composition may be used to prevent or
treat one or more of, pleuritis, unilateral or bilateral pleural
effusion, pulmonary hemorrhage, pulmonary emboli, pulmonary
fibrosis, lupus pneumonitis, interstitial lung disease, pulmonary
hypertension, and shrinking lung syndrome associated with SLE.
[0124] In some embodiments, the composition may be used to treat or
prevent local pulmonary symptoms in patients with rheumatoid
arthritis. Lung disease is a leading cause of death in RA, second
only to infection. Pulmonary complications of RA include pleural
effusion, nodular lung disease, diffuse interstitial fibrosis,
pulmonary vasculitis, alveolar hemorrhage, obstructive pulmonary
disease, pulmonary hypertension, interstitial lung disease,
pulmonary arteritis, and infections. In various embodiments,
administration of the hypochlorous acid composition may prevent,
ameliorate, or relieve one or more of these pulmonary symptoms
associated with RA.
[0125] In some embodiments, the composition may be used to prevent
or treat the pulmonary symptoms of a subject with Crohn's disease
or ulcerative colitis. Pulmonary complications of these disorders
include inflammation of small and large airways, pulmonary
parenchymal disease, serositis, and pulmonary embolism. In various
embodiments, methods of the invention prevent or ameliorate one or
more of these symptoms.
[0126] In some embodiments, the hypochlorous acid composition is
used to treat a subject with allergic asthma, including severe
and/or uncontrolled asthma. Asthma is a chronic condition
characterized by inflammation of the air passage that results in a
temporary narrowing of the airways. This results in asthmatic
symptoms including coughing, wheezing, shortness of breath, fast
breathing, and tightening of the chest. The hypochlorous acid
composition can provide relief to one or more of these symptoms
while reducing inflammation systemically. In some embodiments, the
severity and/or frequency of attacks is reduced.
[0127] Pulmonary delivery of the HOCl composition can be conducted
by nebulizer, for example. For example, in one non-limiting
embodiment, the HOCl composition may be administered 1 to 4 times
per day. In another embodiment, the composition is administered 1
or 2 times per day.
[0128] Many immune conditions also affect muscles and joints
resulting in muscle and joint pain and swelling. In various
embodiments, administration of the hypochlorous acid composition,
for example, topically, relieves one or more of these
musculoskeletal symptoms and provides systemic anti-inflammatory
benefits.
[0129] In some embodiments, the composition treats musculoskeletal
symptoms in a subject with systemic lupus erythematosus.
Involvement of the musculoskeletal system is very common in
patients with SLE. Arthralgia, arthritis (pain with or without
swelling), osteonecrosis (avascular necrosis of bone), and myopathy
are the principal manifestations. In various embodiments, the
composition of the invention prevents or treats the local
musculoskeletal symptoms while providing systemic anti-inflammatory
effects.
[0130] In some embodiments, the subject is a psoriatic patient who
has developed psoriatic arthritis. There are several types of
psoriatic arthritis depending on the joints being affected.
Symmetric psoriatic arthritis affects several joints in pairs on
both sides of the body and can be disabling. Asymmetric psoriatic
arthritis typically affects only a few joints. Distal
interphalangeal predominant (DIP) psoriatic arthritis mainly
affects small joints at the ends of the fingers and toes, as well
as the nails. Spondylitis affects the backbone and can cause
inflammation and stiffness between the vertebrae, including the
bones of the neck, spine, lower back, and pelvis. Arthritis
mutilans is the most severe and destructive form of psoriatic
arthritis and often results in deformity of the fingers and toes.
Administration of the hypochlorous acid composition can prevents or
treats one or more forms of psoriatic arthritis by relieving local
as well as systemic inflammatory symptoms.
[0131] In some embodiments, the composition effectively prevents or
treats one or more symptoms of rheumatoid arthritis. Such symptoms
include local inflammation of the synovial membrane causing the
affected joints to become swollen, warm, painful, and stiff.
Inflammation is mostly associated with small joints of the hands,
feet, and cervical spine, but larger joints like the shoulder and
knees can also be involved. In various embodiments, the
hypochlorous acid composition effectively prevents or ameliorates
the local and systemic inflammatory symptoms of RA. In some
embodiments, the hypochlorous acid composition (gel or lotion) is
applied at least once per day (e.g., 1 to 4 times per day) to the
hands and/or feet of a patient with RA, thereby slowing progression
of RA, relieving RA symptoms, and/or reducing inflammation in the
joints of the hands and feet.
[0132] In some embodiments, the composition is administered to
prevent or relieve the musculoskeletal symptoms of subjects with
Crohn's disease or ulcerative colitis. In an embodiment, the
composition is administered to provide relief to arthritis in these
subjects. In another embodiment, the composition is administered to
prevent or treat spondyloarthropathy, which is a type of arthritis
that attacks the spine and sometimes the joints of the arms and
legs.
[0133] In some embodiments, the composition is administered to
prevent or treat one or more musculoskeletal symptoms in subjects
afflicted with vaculitis. For example, the composition may be
administered to prevent or treat one or more of myalgia or
myositis, arthralgia or arthritis.
[0134] In some embodiments, the composition is administered to
prevent or treat the musculoskeletal complications associated with
diabetes such as type I diabetes. Diabetic patients may experience
localized inflammation of the nerves and joints resulting in
conditions such as stiff hands syndrome, carpal tunnel syndrome,
adhesive capsulitis of the shoulder, trigger finger, neuropathic
joints, peripheral neuropathy, and reflex sympathetic dystrophy
syndrome. Administration of the hypochlorous acid composition may
provide prevent or relief to one or more of these symptoms while
providing systemic anti-inflammatory effects.
[0135] In certain embodiments, the condition may result from an
acute or chronic immune condition such as an autoimmune condition,
which may develop an acute infection. In these embodiments, the
hypochlorous acid is administered to prevent or treat both the
infection and the underlying immune condition. Thus, the
hypochlorous acid may be administered instead of steroidal drops or
systemic steroidal medications, or antibiotics, thereby avoiding
the potential adverse reactions of such treatments. In certain
other embodiments, the hypochlorous acid is used to clean the
region during the duration of steroidal and/or antibiotic
treatment. In one embodiment, hypochlorous acid is administered to
the nasal passages and/or sinuses of an allergic patient, during
the duration of steroid treatment. For example, the hypochlorous
acid may be used in conjunction with steroid treatment, or
alongside an antihistamine to more effectively inhibit release of
inflammatory mediators from mast cells.
Examples
Evaluation of Inflammation Reduction
[0136] In an investigator--blinded, randomized study, hypochlorous
acid composition in the form of gel was evaluated for reduction of
inflammation, by means of itching reduction. 30 subjects aged 12 to
75 years old with mild to moderate atopic dermatitis participated
over a period of 3 days. The patients, 20 subjects, treated with
hypochlorous acid composition, .ltoreq.450 ppm AFC, were compared
to 10 untreated control subjects. The evaluation included an
assessment of tolerability by investigator and participant.
[0137] Overall irritation, stinging, burning and itching on a
5-point ordinal scale were evaluated on day 1 (baseline visit), day
2 and day 3. Investigator assessment was calculated as the mean of
5-point scale for erythema, desquamation, lichenification, overall
irritation, and excoriation. Subject queries were based on
stinging, burning and itching at day 1, day 2, and day 3. Incidence
of all adverse events, including serious adverse events, local skin
reaction, and adverse events leading to discontinuation, were
documented.
[0138] Treatment with the HOCl composition effectively reduced itch
in subjects with mild to moderate atopic dermatitis as early as day
1.
[0139] The HOCl treatment group had significantly reduced itch
compared with the Untreated group at Day 3 (p=0.007).
[0140] Treatment with the HOCl composition at least BID was very
well tolerated, and there were no serious adverse events and no
treatment-related discontinuations.
Case Study Evaluation of Inflammation Reduction
[0141] An evaluation of inflammation reduction by means of itching
reduction and skin quality improvement was conducted on a 4 year
old male treated with HOCl gel. The patient had eczema of the
palmar aspect of the patient's hands and plantar aspect of the
feet. The patient experienced severe itching, severe erythema (beet
redness) to eschar formation, cracking, yellow plaques/hardening of
skin and peeling of the skin over the course of two months. As a
first line of therapy, the patient was prescribed Hydrocortisone
Valerate Ointment USP, 0.2%, a topical corticosteroid twice daily
to the affected areas. After 4 weeks of treatment twice daily with
corticosteroids, the patient had no resolution of symptoms.
[0142] The patient was taken off the topical corticosteroid and
instead treated with hypochlorous acid composition .ltoreq.450 ppm
AFC, twice daily to the affected areas.
[0143] Treatment with HOCl composition effectively reduced symptoms
in a subject with moderate eczema as early as Day 1.
[0144] At both Day 1 and Day 3, the patient exhibited marked
reduction of symptoms including: reduction of itch, reduction of
erythema (reduction of redness), skin wound healing (reduction of
cracks), softening of plaques and movement towards normal skin
color, and reduction of peeling.
[0145] Treatment with HOCl composition at least BID was very well
tolerated.
[0146] The patient went on to complete resolution of all symptoms
over the course of two weeks BID treatment.
[0147] There were no serious adverse events and no treatment
related discontinuations.
[0148] The patient and guardian reported increased "ease-of-use"
with the HOCl composition in form of gel vs treatment with
corticosteroids, as there were no warnings regarding getting the
product in/or near the eyes, nose or mouth, which is difficult when
the product must be applied to the hands and fingers.
Reduction in Hyperemia in an Animal Model
[0149] HOCl solution was studied for topical treatment of redness
and itching associated with allergic conjunctivitis in systemic
sensitization model. In this model, a systemic sensitization with
an allergen (Short Ragweed, SRW) was followed by topical challenge
with the same allergen. The objective of this study was to evaluate
the effectiveness of three hypochlorous acid formulations in
reducing the signs and symptoms associated with ocular allergic
conjunctivitis.
[0150] The results of this study indicate the hypochlorous acid was
able to reduce hyperemia in this model of allergic conjunctivitis
in a dose dependent manner. The 500 ppm and 1000 ppm hypochlorous
acid significantly reduced redness in the eyes of balb/c mice
similar to that of a steroid (prednisolone, 1%). The controls in
this study worked as they should, with the vehicle control
producing a high amount of hyperemia post challenge and the
prednisolone group maintaining low redness scores throughout all
challenges. As expected, the mast cell stabilizer group
(olopatadine) was able to significantly reduce hyperemia after the
first challenge, but loses efficacy over time. The high
concentration hypochlorous acid groups were able to significantly
reduce hyperemia throughout the entire challenge process, whereas
the lowest concentration of 100 ppm could not reduce redness.
Efficacy of Hypochlorous Acid (HOCl) Hydrogel on Imiquimod
(IMQ)-Induced Psoriasis-Like Skin Inflammation Mouse Model
[0151] A study was conducted to determine the efficacy of HOCl
hydrogel, containing 1000 parts per million (ppm) of free available
chlorine, on a mouse model of psoriasis. Psoriasis was induced by
the application of IMQ cream to the shaved backs of BALB/c mice.
Animals treated with IMQ developed clinical signs of psoriasis such
as erythema and plaques on affected areas. Application of HOCl
hydrogel reduced the clinical symptoms of psoriasis more
significantly than an untreated control and animals treated with
clobetasol (corticosteroid). Results indicated that treatment with
HOCl hydrogel reduced clinical symptoms of psoriasis in a mouse
model.
[0152] Psoriasis-like skin inflammation was induced by daily
application of 31.25 mg of imiquimod (IMQ) on the shaved back of
BALB/c mice (Harlan Laboratories). IMQ cream is used to treat
several skin conditions such as warts and basal cell carcinoma.
Application of IMQ to the healthy skin of mice has been
demonstrated to result in clinical symptoms of psoriasis and is
therefore used as a model to determine efficacy of topical
treatment.
[0153] The study was conducted over the course of 10 days and
consisted of four treatment groups: naive (untreated), animals
treated with IMQ only, clobetasol treated, and HOCl hydrogel
treated. IMQ cream was applied each day at 4 PM to the backs of
each mouse in the 3 treated groups. The clobetasol group was
treated at 2 PM daily with 50 mg of clobetasol. The HOCl hydrogel
group was dosed twice daily (10 AM and 3 PM) with 200 mg on the
back of each animal. Psoriasis clinical scores were determined
daily by visual inspection. Treatments were compared to naive
animals as a negative control.
[0154] Treatment with HOCl-hydrogel and clobetasol cream resulted
in significantly reduced clinical scores compared to animals
receiving IMQ only (FIG. 2). The reduction in clinical scores were
significant at the p=0.01 level. In addition, the clinical scores
of HOCl-treated animals were lower than those treated with
clobetasol from day 4 of the study onward through day 10.
Collectively, these results demonstrate that HOCl-hydrogel
containing 1000 ppm of free available chlorine was able to
significantly reduce the clinical symptoms of psoriasis in a mouse
model.
[0155] Modifications of the disclosed embodiments incorporating the
spirit and substance of the invention may occur to persons skilled
in the art and such modifications are within the scope of the
present invention. All references cited herein are incorporated by
reference in their entirety.
* * * * *