U.S. patent number RE37,263 [Application Number 08/787,144] was granted by the patent office on 2001-07-03 for anti-inflammatory formulations for inflammatory diseases.
This patent grant is currently assigned to Alcide Corporation. Invention is credited to Robert D. Kross, Elliott J. Siff.
United States Patent |
RE37,263 |
Kross , et al. |
July 3, 2001 |
Anti-inflammatory formulations for inflammatory diseases
Abstract
There is disclosed a method for treating dermatologic diseases
caused by microbial overgrowth or inflammation, such as psoriasis,
fungal infections, eczema, dandruff, acne, genital herpes lesions,
and leg ulcers. There is further disclosed an antiviral lubricating
composition that is effective in preventing the transmission of the
HIV virus and other sexually transmitted diseases. There is also
disclosed systemic and anti-inflammatory compositions and
formulations and a method for reducing tissue inflammation in
tissues such as the bowel, muscle, bone, tendon and joints (e.g.,
arthritis).
Inventors: |
Kross; Robert D. (Bellmore,
NY), Siff; Elliott J. (Westport, CT) |
Assignee: |
Alcide Corporation (Redmond,
WA)
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Family
ID: |
26886461 |
Appl.
No.: |
08/787,144 |
Filed: |
January 22, 1997 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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930088 |
Aug 14, 1992 |
|
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543655 |
Jun 26, 1990 |
|
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|
202758 |
Jun 3, 1988 |
4956184 |
|
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|
190798 |
May 6, 1988 |
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Reissue of: |
115461 |
Sep 1, 1993 |
05384134 |
Jan 24, 1995 |
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Current U.S.
Class: |
424/661;
424/78.06 |
Current CPC
Class: |
A61P
31/12 (20180101); A61P 29/00 (20180101); A61K
33/40 (20130101); A61P 17/00 (20180101); A61P
31/22 (20180101); A61K 33/40 (20130101); A61K
31/60 (20130101); A61K 31/19 (20130101); A61K
33/40 (20130101); A61K 2300/00 (20130101); Y10S
514/934 (20130101); Y10S 514/825 (20130101); Y10S
514/931 (20130101) |
Current International
Class: |
A61K
33/40 (20060101); A61K 033/14 (); A61K
031/74 () |
Field of
Search: |
;424/661,78.06 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
MS. Abdel Rahman et al., "Toxicity of alcide," J. Appl. Toxicol.
2(3): 160-164, 1982 (Dialog abstract). .
Scatina et al., "Pharmacodynamics of Alcide, a New Antimicrobial
Compound, in Rat and Rabbit," Fundamental and Applied Toxicology
4:479-484, 1984.
|
Primary Examiner: Criares; Theodore J.
Attorney, Agent or Firm: Seed and Berry LLP
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation of U.S. Ser. No. 07/930,088,
filed Aug. 14, 1992, now abandoned; which is a divisional of U.S.
Ser. No. 07/543,655, filed Jun. 26, 1990, abandoned; which is a
divisional of U.S. Ser. No. 07/202,758, filed Jun. 3, 1988; which
issued as U.S. Pat. No. 4,956,184; which is a continuation-in-part
of U.S. Ser. No. 07/190,798, filed May 6, 1988, abandoned.
Claims
What is claimed is:
1. A method for reducing tissue inflammation comprising topically
applying a pharmaceutically effective amount of an
anti-inflammatory composition comprising a mixture of a first
solution, cream, or gel consisting essentially of a chlorine
dioxide liberating compound and a second solution, cream, or gel
consisting essentially of a protic acid, wherein the chlorine
dioxide liberating compound comprises a metal chlorite, and wherein
the chlorite ion concentration in the form of chlorous acid is no
more than about 15% by weight of the total amount of chlorite ion
concentration in the composition and wherein the gel or cream
optionally contains a thickener.
2. The method of claim 1 wherein the pK of the protic acid is from
about 2.8 to about 4.2.
3. The method of claim 1 wherein the first solution, cream, or gel
is a gel and contains a polysulfonic acid salt as a thickener.
4. A method for treating inflammatory disorders comprising locally
administering a pharmaceutically effective amount of a composition
comprising a first solution or gel consisting essentially of a
chlorine dioxide liberating compound, and a second solution or gel
consisting essentially of a protic acid, wherein the chlorine
dioxide liberating compound comprises a metal chlorite, and wherein
the chlorite ion concentration in the form of chlorous acid is no
more than about 15% by weight of the total amount of chlorite ion
concentration in the composition and wherein the gel or cream
optionally contains a thickener.
5. The method of claim 4 wherein the pK of the protic acid is from
about 2.8 to about 4.2.
6. The method of claim 5 wherein the chlorine dioxide liberating
compound is sodium chlorite.
7. The method of claim 4 wherein the inflammatory disorder is
selected from the group consisting of arthritis, lupus, bowel
inflammation, tendon inflammation and muscle
inflammation..Iadd.
8. The method of claim 1 wherein the tissue inflammation is a viral
lesion..Iaddend..Iadd.
9. The method of claim 8 wherein the viral lesion is a herpes
lesion..Iaddend..Iadd.
10. The method of claim 1 wherein the tissue inflammation is a
wound site..Iaddend.
Description
TECHNICAL FIELD
This invention relates generally to topical formulations that are
useful for treating various dermatologic disorders, including
genital herpes lesions, facial and body acne, topical fungal
infections, psoriasis, eczema, dandruff, skin ulcers (e.g.,
decabutus), and other dermatologic diseases associated with
microbial proliferation. This invention also relates to the
anti-inflammatory properties and uses of pharmaceutical
compositions.
BACKGROUND OF THE INVENTION
There are a Large number of dermatological diseases that are
thought to be caused by microbial overgrowth somehow result in a
dermatologic infection and/or inflammatory reaction. These diseases
include acne vulgaris and other pilosebaceous inflammatory
disorders, which are thought to be caused in part by an overgrowth
of the anaerobic bacterium Propionibacterium acnes (P. acnes),
which is normally present in the sebaceous follicles but
proliferates in large numbers during acute acne. P. acnes generates
a lipase, a protease, and other potentially damaging substances.
Follicular contents are known to be chemo-attractive for
leukocytes, and complement activation is probably also important in
the inflammatory process. Although the precise mechanisms are not
entirely clear, inflammation and edema in the follicular wall
result in follicular rupture, leaking follicular contents into the
surrounding dermis and creating further inflammation. The visible
consequence of this series of dermal events is a deep inflammatory
nodule, called a "cyst." An accumulation of neutrophils in the
mouth of a follicle produces a pustule. Deep inflammatory or cystic
lesions may arise from preexisting closed comedones in an area of
normal-appearing skin.
Genital herpes is also called "Herpes Progenitalis" and is caused
by the herpes simplex virus, usually type 2. Primary genital herpes
follows an incubation period of 3 to 7 days. The disease can be
found by localized burning or paresthesia and followed by eruption
of grouped vesicles, often at multiple sites on the genitalia. The
lesions generally heal in 2 to 4 weeks, but the virus remains in
the nerve heads and can remain dormant or trigger secondary lesions
by migrating down the nerve fiber to the nerve ending to reproduce
into more lesions. Recurrent genital herpes is common after the
primary infection. Secondary lesions heal within two weeks, and
secondary attacks become less frequent with time. Treatments
include drying agents to symptomatically lessen the discomfort of
the lesion. Acyclovir, applied topically, tends to decrease pain of
the primary lesions, but it has not proven very effective for
decreasing vital shedding or lesion duration. Topical acyclovir has
not been shown to be particularly effective for reducing or
treating recurrent disease.
Acyclovir is a purine nucleoside analog that is selectively cidal
to the herpes simplex virus because only the thymidine kinase
enzyme of herpes simplex virus can convert acyclovir to its
monophosphate form while host cell thymidine kinase cannot. The
monophosphate form is converted to an acyclovir triphosphate, which
can interfere with vital DNA replication. Topical acyclovir is
applied as a 5% ointment every three hours, or up to eight times
daily, for at least seven days. The up to eight-times-a-day dosing
is a difficult procedure for patients and creates patient
compliance problems for dosing in the genital areas throughout the
day and throughout the night. A further problem of acyclovir has
been the development resistant strains of herpes simplex, caused by
a mutation of the thymidine kinase gene. Accordingly, no backup
treatments are available for acyclovir-resistant herpes simplex
infections. This problem exists with most antibiotic microbial
treatments, but is generally not a problem non-antibiotic
treatments.
Topical fungal or yeast diseases represent a large class of
diseases. These can include tinea versi color, which is a
superficial fungal infection caused by the lipophilic yeast
Pityrosporum orbiculare. The infected areas do not pigment normally
and produce a whitish, spotted appearance in dark-skinned or tanned
persons. Treatments include the use of dandruff shampoos on the
affected areas and typical antifungal agents, including the
imidazole derivatives miconazole and clotrimazole. Fungal lesions
on the skin surface are named "tinea" and the Latin name of the
particular type of location. For example, "tinea capitis" is for
scalp lesions, while "tinea cruris" is for groin lesions. Tinea
cruris is often manifest as symmetrical scaly patches on the inner
surfaces of the thighs. The infection spreads with a central
clearing area and a sharply demarcated border. Itching is common
and severe. The major causitive organisms are T. rubrum, T.
mentagrophytes, and Epidermophyton floccsum.
Tinea pedis is commonly called "athlete's foot." It is often caused
by Trichophyton rubrum or Trichophyton mentagrophytes. It often
begins as a scaly lesion between the toes and spreads to produce an
acute inflammatory vesicular disease, accompanied by itching,
burning and pain. Tineas corpotis is also called "ringworm" and is
a dermatophyte infection involving nonspecific areas of skin. The
infection is an erythematous, scaly patch on the skin with sharp,
acute borders and central clearing. Current treatments for topical
fungal diseases include the imidazole derivatives, miconazole and
clotrimazole. Griseofulvin is a systemic agent, and ketoconazole is
also used systemically but is expensive and is associated with
severe side effects. Side effects of griseofulvin include headaches
and abdominal discomfort.
Eczema is a superficial inflammation of the skin characterized by
an initial erythematous, papulovesicular process often accompanied
by oozing and crusting and followed by a chronic phase of scaling,
thickening and post-inflammatory pigment changes. Causes of eczema
are largely uncertain but can include fungal infection. Treatments
are largely symptomatic and can include topical corticosteroids for
the inflammatory reaction.
Psoriasis is a papulosquamous disease characterized by chronic
periodic remissions and exacerbations. Lesions usually consist of
erythematous plaques with silvery scale, and possibly a pustular
form. The causes of psoriasis include several theories. One theory
advances that psoriasis is an inflammatory overreaction to a yeast
infection, such as that caused by P. ovale. The disease is
characterized histologically by accelerated cellular turnover.
Psoriasis is a chronic condition and an affected individual can
develop lesions at any time. Treatments vary, depending on what one
believes is the cause of the disease. However, no single treatment
has yet proven to be successful for a wide variety of cases.
Dandruff is a scaling condition of the scalp. It is thought to be
caused by an overgrowth of P. ovale, a yeast. Treatment is usually
an antimicrobial agent such a pyrithione zinc, a keratolytic agent
such as salicylic acid, or by a cytostatic agent such as a coal
tar.
Statis dermatitis is a leg ulcer and is a form of eczema and often
the result of venous insufficiency. It often develops in a patch
just distal to where a vein was removed for a bypass procedure.
Treatment is usually with a topical steroid or with an
antibacterial and keratolytic agent, such as 20% benzoyl
peroxide.
Acquired Immune Deficiency Syndrome (AIDS) is believed to be spread
by sexual contact, and more specifically, through transmission of
the HIV virus. The current preventive means for transmission by
sexual contact with an individual suspected of harboring the HIV
virus is a barrier, such as a condom. At present, there are no
known virucidal chemical barrier preparations available that can be
used alone or with a condom for prevention of the spread of HIV
during sexual contact.
Anti-inflammatory agents are usually classified as steroid or
non-steroidal agents. The non-steroidal anti-inflammatory agents
most often function by inhibition of prostaglandin or leukotriene
biosynthetic pathways. For example, non-steroidal anti-inflammatory
drugs such as aspirin (acetylsalicylic acid), indomethacin, and
ibuprofen are known to inhibit the fatty acid cyclooxygenase enzyme
in the prostaglandin pathway from arachidonic acid. Steroid drugs
have anti-inflammatory activity but also have numerous side
effects, including sodium retention, hepatic deposition of
glycogen, and dramatic redistribution of body fat. The steroid
anti-inflammatory properties are mediated by inhibiting edema,
fibrin deposition, capillary dilation, migration of leukocytes, and
deposition of collagen. Steroid anti-inflammatory agents have
immunosuppressant side effects.
While it is difficult to give an adequate description of the
inflammatory phenomenon in terms of the underlying cellular events
in the injured tissue, there are certain features of the process
that are generally agreed to be characteristic. These include
fenestration of the microvasculature, leakage of the elements of
blood into the interstitial spaces, and migration of leukocytes
into the inflamed tissue. On a macroscopic level, this is usually
accompanied by the clinical signs erythema, edema, tenderness
(hyperalgesia), and pain. During this complex response, chemical
mediators such as histamine, 5-hydroxytryptamine (5-HT),
slow-reacting substance of anaphylaxis (SRS-A), various chemotactic
factors, bradykinin, and prostaglandins are liberated locally.
Phagocytic cells migrate into the area and cellular lysosomal
membranes may be ruptured, releasing lytic enzymes. All these
events may contribute to the inflammatory response. However,
aspirin-like drugs have little or no effect upon the release or
activity of histamine, 5-HT, SRS-A, or lysosomal enzymes; and
similarly, potent antagonists of 5-HT of histamine have little or
no therapeutic effect on inflammation.
The inhibitors of prostaglandin biosynthesis by aspirin and other
non-steroidal anti-inflammatory agents, such as ibuprofen, has been
demonstrated in three different systems, cell-free homogenates of
guinea pig lung, per fused dog spleen, and human platelets. There
are now numerous systems in vitro and in vivo in which inhibition
of prostaglandin biosynthesis by aspirin, ibuprofen, or similar
compounds has been demonstrated, and it is evident that this effect
is not restricted to any one species or tissue. The effect is
dependent only on the drug reaching the enzyme, cyclooxygenase
(prostaglandin synthetase); the distribution and pharmokinetics of
each agent thus have an important bearing on the drug's
activity.
The migration of leukocytes into inflamed areas is an important
component of inflammation. Although the classical aspirin-like
drugs (salicylates, pyrazolone derivatives, ibuprofen,
indomethacin, etc.) block prostaglandin biosysthesis, they do not
inhibit the formation of the major chemotactic metabolite of
arachidonic acid, HETE, and may even increase concentrations of
this compound in tissue.
Hypoxia and ischemia are inevitable fates of any kind of tissue
injury. Oxygen tension in tissue wounds, when measured by implanted
polarographic oxygen electrode, was found to be only 5 to 15 mm Hg,
as compared to control tissue values of 40 to 50 mm Hg. (Sheffield,
"Tissue Oxygen Measurements with Respect to Soft Tissue Wound
Healing with Normobaric and Hyperbaric Oxygen," Hyperbaric Oxygen
Rev. 6:18-46, 1985.) Tissue ischemia is associated with an
inflammatory response mediated by stimulated Hagemann factor arid
complement cascades. (Weiss et al., "Phagocyte-Generated Oxygen
Metabolites and Cellular Injury", Lab Invest. 47:5-18, 1982.) These
factors activate polymorphonuclear leukocytes (PMNs) and result in
a massive influx of phagocytic leukocytes into the wound.
Paradoxically, the antimicromial properties of PMNs are greatly
impaired in the ischemic wound region in vivo because of the lack
of molecular oxygen. (Mandell, "Bactericidal Activity of Aerobic
and Anaerobic Polymorphonuclear Neutrophils," Infect. Immunol.
9:337-41, 1974.) Oxygen therapy, including hyperbaric oxygen
treatment, has been suggested to facilitate wound healing and is
often used as adjunctive therapy in problem wounds and wound
infections. However, the optimal times and mode of oxygen therapy
still remain clouded. Oxygen radicals are involved in the
phagocytic actions of PMNs, which, upon activation, generate
superoxide and hydroxyl radicals as well as hydrogen peroxide and
hypochlorous acids at the site phagocytosis.
Any wounding, whether surgical or traumatic causes disruption of
blood vessels, tissue hemorrhage, activation of Hageman factor, and
stimulation of complement pathways. These morphologic and
biochemical events result in the massive influx of PMNs into the
wound site and the production of superoxide radicals by PMNs as
part of the phagocytic response [Reaction (i)]. The generated
superoxide radicals undergo the Haber-Weiss reaction [Reaction
(ii)] or iron-catalyzed Fenton type reactions [Reaction (iii)],
producing cytotoxic OH radicals and H.sub.2 O.sub.2, which
ultimately form hypohalite radicals via the myeloperoxidase, system
[Reaction (iv)]. ##STR1##
Although the presence of these oxygen-free radicals is necessary
for the oxidative killing of microorganisms, excessive generation
of these cytotoxic radicals may be extremely harmful to native
tissues. Tissues are generally equipped with adequate antioxidative
defense systems, consisting of such enzymes as superoxide
dismutase, catalase, and glutathione peroxidase. However, these
antioxidative enzymes are known to be reduced during ischemia and
hypoxia.
Accordingly, there is a need in the pharmaceutical art for a
therapeutic agent that has both strong and broad spectrum
antimicrobial properties for a wide variety of bacterial, fungal,
vital, and yeast infections, as well as anti-inflammatory activity,
yet not be an antibiotic with the risk of developing resistant
microbial strains. It is further desirable to develop a chemical
agent that can be used as an antimicrobial sexual barrier and
lubricating gel that has strong antiviral properties to kill active
HIV virus and thereby help prevent the spread of AIDS. There is
also a need in the pharmaceutical art for an anti-inflammatory
therapeutic agent that does not possess the side effect problems of
the aspirin-like non-steroidal anti-inflammatory agents or the
immunosuppressant properties of the corticosteroids.
SUMMARY OF THE INVENTION
The aforementioned therapeutic problems are treated by a strongly
antimicrobial and anti-inflammatory formulation wherein the active
antimicrobial and/or anti-inflammatory effects are provided by a
composition which comprises a chlorine dioxide liberating compound
and a protic acid. Preferably, the chlorine dioxide liberating
compound is an alkaline metal chlorite. Most preferably, the
chlorine dioxide generating compound is sodium chlorite or
potassium chlorite. Topical formulations are useful for the topical
treatment of dermatologic disorders thought to be caused by
overgrowth of pathogenic microorganisms that possibly result in an
inflammatory response, or for inflammatory conditions. These
dermatologic disorders include topical fungal diseases, vital
lesions such as from genital herpes, and inflammatory/bacterial
disorders such as acne. Additionally, the formulations containing
the active agents of the present invention are useful for the
treatment of decubitus ulcers, psoriasis, eczema and as an
antimicrobial sexual lubricant to prevent the transmission of
sexually transmitted diseases, such as HIV (AIDS), chlamydia,
genital herpes, warts, gonorrhea, and syphilis. Systemic
formulations that are administered orally, or by injection into
muscles, joint capsules, peritoneum, intralymphatically or directly
into inflamed tissue. The inventive formulations have an added
benefit of broad spectrum antimicrobial activity.
All of the formulations involve infusion, tissue, dermatologic or
topical uses of a formulation containing chlorous acid in
metastable balance, which provides chlorine dioxide as the active
antimicrobial and anti-inflammatory agent. The formulations involve
two solutions, gels, or creams adapted to be mixed and either
infused or injected into the site of activity, taken orally, or
topically applied so as to adhere to the epithelial surface and
penetrates into the dermis. The first solution, gel, or cream
contains an amount of metal chlorite, such that, when combined in
equal parts with the first gel, the chlorite ion concentration in
the form chlorous acid is no more than about 15% by weight of the
total amount of chlorite ion concentration. The second solution,
gel, or cream contains an aqueous solution containing suitable
amounts of a protic acid. Preferably, the first gel contains a
polysulfonic acid wherein the anion of the salt has the formula:
##STR2##
wherein X has a value such that the molecular weight of the anionic
portion of the polymer is from about 1,000,000 to about 5,000,000
daltons.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the in vitro chemotaxis of the inventive composition
at the active concentration of Example 1 and the non-steroidal
anti-inflammatory agent ibuprofen (0.5 mg/ml). The inventive
composition is shown by .circle-solid.--.circle-solid. and
ibuprofen by .box-solid.--.box-solid.. When there is a dotted Line,
the inventive composition and ibuprofen were reacted with BSA
(bovine serum albumin).
FIG. 2 shows the effect of the inventive composition (called
"Alcide") and ibuprofen on the thiobarbituric acid-reactive
material production at the wound site during the healing
process.
FIG. 3 shows the effect of the inventive composition (called
"Alcide") and ibuprofen on the conjugated dienes formation at the
wound site during the healing process.
FIG. 4 is a scintigraphic comparison of Indium-111-radioactivity
accumulation at the wound site during the healing process. The
inventive composition is termed "Alcide." Gamma-scintigraphy was
performed 4 hours following the Indium-111-labeled PMN injection.
Images were digitized in a 128.times.128 matrix, and regions of
interest in wound and nonwound areas were studied.
DETAILED DESCRIPTION OF THE INVENTION
The compositions described herein are useful as topical
formulations to treat human skin disorders caused by microbial
overgrowth or by inflammation. The skin disorders include facial or
body acne, topical fungal infections, genital herpes, psoriasis,
leg and decubitus ulcers, eczema, and dandruff. The composition can
function as a lubricating barrier gel for the prevention of
transmission of sexually transmitted diseases. Dandruff, psoriasis,
and eczema are hyperproliferative or inflammatory disorders that
are believed to be initiated by, or associated with fungal or yeast
microbial overgrowth. Accordingly, the skin disorders are often
caused by microorganisms, including bacterial, viral, yeast and
fungal sources. The compositions or formulations are also useful as
anti-inflammatories.
The therapeutic compositions are useful for the treatment of skin
diseases that involve an inflammatory and/or a microbial
proliferation component or both components. Thus, the topical
application of the inventive compositions containing a chlorine
dioxide liberating compound in one solution, cream, or gel and a
protic acid in the other solution, cream, or gel, when mixed, yield
chlorine dioxide that is the active antimicrobial or
anti-inflammatory agent. A gel composition should have superior
skin-adherence properties.
Topical application of the therapeutic compositions described
herein relates to application to the surface of the skin and to
certain body cavities such as the mouth, vagina, colon, bladder,
nose, and ear.
Systemic application can be localized directly by injection into
inflamed tissue, such as the joint for arthritis or encapsulated in
an enteric-coated capsule that can release its contents in the
intestine after passing through the stomach.
The therapeutic compositions and formulations described herein are
useful for the treatment of inflammatory disorders. For example,
inflammatory disorders caused by influx of PMNs into a wound site
can be inhibited by the inventive compositions and formulations.
Similarly, ibuprofen, a non-steroidal anti-inflammatory agent also
has been found to inhibit PMN influx into inflammatory tissues. The
inhibition of PMN influx into a wound site can simultaneously
reduce the formation of malondialdehyde and conjugated dienes,
suggesting that most of the free radicals generated during the
early stage of wound healing are mediated by PMNs. The majority of
PMNs have been found to reach the site of inflammation at the early
stage of tissue injury. The compositions and formulations of the
present invention comprising a chlorine dioxide liberating compound
in a protic acid inhibited the rate of PMN influx into the wound
site during the healing process. The decrease in PMN influx was
accompanied by the reduced formation of malondialdehyde and
conjugated dienes, implying a simultaneous reduction in free
radical formation. Accordingly, the ability of the inventive
compositions and formulations to inhibit PMN influx into a wound
site is evidence of anti-inflammatory activity.
One aspect of the inventive process is for the treatment of skin
disorders caused by microbial overgrowth or inflammation, such as
acne, psoriasis, eczema, genital herpes simplex lesions, topical
fungal infections, decubitus and leg ulcers and dandruff, with a
formulation comprising two solutions, creams, or gels. The first
solution, cream, or gel contains a pharmaceutically effective
amount of a chlorine dioxide generating compound. The second
solution, cream, or gel contains an effective amount of a protic
acid to maximally and controllably release chlorine dioxide from
the chlorine dioxide generating compound, chlorous acid, formed
when the two solutions, creams, or gels are mixed. Preferably, the
first and second solutions are aqueous solutions.
The inventive process applies a composition formed by the
combination of the first gel, cream, or solution and the second
gel, cream, or solution. Preferably, the dermatalogic composition
is formed by the combining of the first and second gels. More
preferably, the first gel, containing the chlorine dioxide
releasing compound, has a metal chlorite and a polysulfonic acid
salt. The final concentrations of chlorite and acid are relatively
low. The final concentration range of chlorite concentration from
about 100 ppm to about 5000 ppm. Preferably, the final range of
chlorite concentration is from about 800 ppm to about 1600 ppm. The
final concentration range of acid is from about 0.1% w/w to about
5% w/w. Preferably, the final concentration range of acid is from
about 0.5% w/w to about 1.3% w/w.
A second aspect of the inventive process is for the treatment of
inflammatory disorders such as arthritis, interstitial cystitis,
and inflamed bowel by specifically localizing the inventive
composition to the inflamed tissue. This can be accomplished, for
example, by injecting the mixed solution directly into the joint
capsule or by simultaneously injecting both the first and second
solutions with a double syringe and needle of the type disclosed in
U.S. Pat. No. 4,330,531. Thus the first and second solutions will
mix at the site of injection and locally form chlorous acid for
modulated release of chlorine dioxide. Alternatively, the solutions
can be mixed prior to administration and delivered by G-I tube
infusion (orally or rectally) to the inflammed section of the G-I
tract. A further delivery mode is by encapsulation in a specially
coated pharmaceutical matrix that is designed to release its
contents in the small intestine upon oral administration.
The composition provides a metastable chlorous acid composition
formed from small amounts of chlorite, preferably from a metal
chlorite, and acid, preferably an organic acid with a pK from about
2.8 to about 4.2. The composition is capable of generating chlorine
dioxide over an extended time up to about 24 hours, at continuing
levels of effectiveness. As chlorine dioxide forms, more of the
chloride converts to chlorous acid by interacting with hydrogen
ions further generated by ionization of the organic acid.
Weak organic acids which may be used in the second solution or gel
to form the composition of the inventive process include citric,
malic, tartaric, glycolic, mandelic and other structurally similar
acids as described in Formula I hereinbelow: ##STR3##
R.sup.1 and R.sup.2 may be the same or different and may be
selected from the group consisting of hydrogen, methyl, --CH.sub.2
COOH, --CH.sub.2 OH, --CHOHCOOH, and --CH.sub.2 C.sub.6 H.sub.5.
Compositions of a metal chlorite and the weak organic acids of
Formula I are disclosed in copending U.S. patent application Ser.
No. 850,009, filed on Apr. 10, 1986. The entire disclosure of that
application is hereby incorporated by reference.
The second gel, containing the protic acid, also contains a gelling
agent or thickener which is well known to those skilled in the art.
Any gelling agent or thickener which is nontoxic and nonreactive
with the other ingredients of the composition may be used, such as
cellulose gels, typically methyl cellulose, or preferably, hydroxy
ethyl cellulose. Furthermore, that gel may also contain a
preservative, such as benzyl alcohol or sodium benzoate. Other
additives, such as buffers to adjust the pH of the composition to
become more compatible with the skin, may be used.
The amount of thickener in the second, protic acid-containing gel
may be generally from about 0.5% to about 5%, typically from about
0.8% to about 4%, and preferably from about 1% to about 3% of the
gel, by weight, of the total composition. The amount of
preservative in the gel may be generally from about 0.1% to about
0.05%, typically from about 0.01% to about 0.04%, and preferably
from about 0.02% to about 0.03% by weight of the total composition.
The chlorine dioxide liberating compound or metal chlorite and the
protic acid are present in separate gels, and the amount of the
preservative is present in only that gel containing the protic
acid.
The first gel, containing a metal chlorite, is preferably thickened
with a polysulfonic acid salt. The amount of polysulfonic acid salt
added will depend on the desired use of the resulting composition.
The amount of polysulfonic acid salt is generally from about 5% to
about 15%, typically from about 5% to about 10%, and preferably
from about 6% to about 8% by weight of the total composition. The
polysulfonic acid is prepared from: ##STR4##
or a salt thereof. The polymerization reaction may be accomplished
by a solution, emulsion, or suspension polymerization process. The
medium for the polymerization is water, an alcohol, or a mixture
thereof. The polymerization reaction is described in copending U.S.
patent application Ser. No. 038,016, filed Apr. 14, 1987 and
incorporated by reference herein.
The treatment of certain skin diseases or certain body cavity and
joint inflammatory conditions can be additionally accomplished by
the synergistic combination of the chlorous acid/chlorine dioxide
formed upon admixture of the two gels, creams or solutions and from
the protic acid itself. For example, the composition for acne
contains salicylic acid as the protic acid in the second gel. It is
known that salicylic acid is a keratolytic agent useful for its
desquamatory properties in the treatment of acne. Further, another
protic acid useful for topical treatments is lactic acid, which
also functions to form chlorous acid from the metal chlorite, from
which chlorine dioxide is formed.
The gel, cream, or solution containing the protic acid (second gel,
cream, or solution) and the gel, cream, or solution containing the
metal chlorite (first gel, cream, or solution) are mixed either
before application to the affected skin area or in situ. After the
gels, creams, or solutions are mixed, the pH of the final mixture
composition is generally less than about 7, typically from about 2
to about 5, and preferably from about 2.5 to about 4. In the
treatment process, the mixture composition is ordinarily applied to
the affected skin area at a level of about 0.00.1 gram to about 0.1
gram per square centimeter of the affected substrate.
The present invention also encompasses a method of treatment of
certain skin diseases, wherein the mixture composition of two
creams, solutions or gels is applied topically to affected skin at
least once daily. Preferably, the mixture composition is applied
topically to affected skin twice daily (e.g., b.i.d.). The mixture
composition should not be applied to affected skin more than eight
times a day.
The present invention is illustrated by the following examples.
Unless otherwise noted, all parts and percentages in the examples
as well as the specification and claims are by weight.
EXAMPLE 1
This example illustrates a formulation useful for the topical
treatment of genital herpes according to the methods of the present
invention. This formulation also can be used for hemorrhoids and
has anti-inflammatory activity, as shown in Examples 7-9. There is
prepared a two-part topical composition according to the invention,
having a first gel with sodium chlorite as the chlorine dioxide
liberating agent and a second gel with lactic acid as the activator
protic acid. The formulations on a percent weight basis are as
follows:
% First Gel Poly (sulfonic acid) 45.0 (16% solution .+-. 1%) Sodium
hydroxide 1 N 45.0 Sodium chlorite (80% .+-. 5%) 0.32 Tetrasodium
EDTA 0.19 Water q.s. Second Gel Lactic Acid (38% .+-. 5%) 2.64
Natrosol 150 MR 1.75 Isopropyl alcohol U.S.P. 5.0 Poloxamer 188 0.4
Sodium Benroate 0.04 Water q.s.
EXAMPLE 2
The composition of Example 1 was prepared for a clinical trial in a
pair of unit dose sachets. A 2-gram quantity of gel containing
0.16% of active chlorite was prepared by mixing the contents of
both sachets immediately prior to application. Thirty-five patients
(30 males and 5 females) were enrolled. Thirty-four were diagnosed
as having active genital herpes. Thirty-one patients complied with
the treatment of twice daily dosing for seven days. Three patients
received the compositions of Example 1 t.d.s., and one patient
defaulted. Patients were examined daily until the lesions were
healed (defined as re-epithelialization of the original lesions).
The results of the study were compared to a similar study conducted
with topical acyclovir and placebo (Fiddian et al, J. Antimicrob.
Chem. 12:Suppl. B:67-77, 1983) and are presented together in Table
1 below:
Median Median Duration of Viral Median Recurrence Symptoms Shedding
Healing Rate (d) Time (d) Time (d) % Example 1 3* 1** 8 (1-17) 19.4
(32) Acyclovir 5 3 7-8 35 Placebo 8 6-9 10-13 55 *Twenty-one of
twenty-four patients had a duration of symptoms of 5 or less days.
**Sixteen of twenty-two patients had viral shedding time of 1 day
or less.
Clinically, 34/35 patients were suffering from first episode
(primary) herpes. One patient had a typical lesion (ulcer) which
was infected with Haemophyllis ducryiae which crusted over and
failed to respond to treatment with the composition of Example 1.
The treatment was virologically effective and patient compliance
was good. Positive factors mentioned by the patients influencing
compliance were:
twice daily dosing (compared with 5 times daily with some
treatments such as Acyclovir)
the formation of a dry protective film over the lesions; reduction
of odor; and sanitizing effect.
EXAMPLE 3
The following formulation can be used as a dermatologic gel for
psoriasis treatment:
% Base Sodium chlorite (80% .+-. 5%) 0.32 Tetrasodium EDTA 0.19
Poly (sulfonic acid) 45.0 (16% solution .+-. 1%) Sodium hydroxide 1
N 40.0 Nacconol 90F 1.8 Water q.s. Activator Propylene glycol
U.S.P. 40.0 Salicylic acid U.S.P. 2.0 Poloxamer 188 0.4 Sodium
Benzoate 0.04 Natrosol 250 MR 2.1 Isopropyl alcohol U.S.P. 5.0
Water q.s.
EXAMPLE 4
The following formulation can be use as an acne treatment gel:
% Base Sodium chlorite (80% .+-. 5%) 0.32 Tetrasodium EDTA 0.19
Poly (sulfonic acid) 45.0 (16% solution .+-. 1%) Sodium hydroxide 1
N 40.0 Nacconol 90F 1.8 Water q.s. Activator Salicyclic acid U.S.P.
2.0 Isopropyl alcohol U.S.P. 30.0 Natrosol 250 MR 2.1 Poloxamer 188
0.4 Sodium benozate 0.04 Water q.s.
EXAMPLE 5
The following gel can be used for topical fungal infections,
including tinea cruris:
% Base Sodium chlorite (80% .+-. 5%) 0.32 Tetrasodium EDTA 0.19
Nacconol 90F 1.8 Poly (sulfonic acid) 45.0 (16% solution .+-. 1%)
Sodium hydroxide 1 N 45.0 Water q.s. Acitvator Maadeiic acid 2.0
Poloxamer 188 0.4 Sodium benzoate 0.04 Natrosol 250MR 1.75 Water
q.s.
EXAMPLE 6
The following cream cam be used for the topical treatment of leg or
decubitus ulcers, topical fungal infections, vaginitis, psoriasis
and eczema:
% Base Sodium chlorite (80% .+-. 5%) 0.32 Tetrasodium EDTA 0.19
Glycerol monostearate 4.0 Gincam E-20 disearate 3.0 Poly (sulfonic)
acid 15.0 (16% solution .+-. 1%) Sodium hydroxide 1 N 15.0 Water
q.s. Activator Lactic acid (80% .+-. 5%) 2.64 Natrosol 250 MR 1.25
Isopropyl alcohol U.S.P. 5.0 Giueam E20 disearate 3.0 Glycerol
monostearate 4.0 Cetyl alcohol 8.0 Stearyl alcohol 2.0 Sodium
benzoate 0.04 Water q.s.
EXAMPLE 7
This example illustrates that a composition with the active
ingredient concentration of Example 1, at concentrations greater
than 1:10 dilution with water, inhibits 90% of PMN chemotaxis as
shown in FIG. 1. The chemotaxis inhibiting activity decreases with
increasing dilution. At the 1:20 dilution with water, a composition
with the active ingredient concentration of Example 1 inhibits 60%
PMN chemotaxis, whereas after a 1:50 dilution, very little
anti-inflammatory activity is noted. Similarly, the known
anti-inflammatory agent, ibuprofen, inhibits 50% PMN chemotaxis at
a 0.12 mM concentration. When diluted to 0.048 mM or further,
ibuprofen shows very little anti-inflammatory activity.
PMNs were obtained from rabbit blood and purified as described in
Bandyopadhyay et al., ".sup.111 Indium-Tropolone Labeled Human
PMNs: A Rapid Method of Preparation and Evaluation of Labeling
Parameters," Inflammation 11:13-22, 1987). Rabbit blood was drawn
from the ear vein of four donar rabbits (50 ml each), mixed with
acid citrate dextrose (ACD) anticoagulant and 10 ml of Hespan (6%
HETASTARCH), and stood at room temperature for 45 minutes to allow
spontaneous settling of the Fed blood cells. As rabbit blood
appears to be homologous, blood was pooled for purposes of
obtaining PMN cells for labelling. The upper layer was collected
and centrifuged at 150 g for 8-10 minutes. The upper plasma layer
was saved in a different tube and centrifuged at 450 g for 10
minutes to obtain platelet-poor plasma (PPP) and in the labeling of
PMNs with .sup.111 Inoxine. The pellet was resuspended in 0.9%
saline, and residual red blood cells were lysed by lowering the
tonicity with three volumes ice water for 30 seconds. Tonicity was
restored by adding one volume Hank's Balanced Salt Solution (HBSS)
containing 10 mM buffer, pH 7. The PMNs were then isolated by a
single-step density gradient centrifugation method, using
Ficoll-Hypaque mixture of density 1.114.
Sixty to eighty microcuries of Indium-.sup.111 -oxime (specific
activity greater than 10 mCi/ug) (Mediphysics, Inc., Emeryville,
Calif.) were incubated with PMNs (3.times.10.sup.6) in PPP at
37.degree. C. for 20 minutes. Labeled cells were centrifuged and
washed to remove unbound .sup.111 Inoxine prior to injecting the
PMNs into the ear veins of the rabbits studied. The viability of
the PMSs prior to and following .sup.111 In-labeling was checked in
vitro by the conventional trypan blue dye exclusion method in vitro
leukocyte chemo taxis was accessed using the modified Boyden
Chamber Assay. (Zigmund et al, "Leukocyte Locomotion and
Chemotaxis," J. Exp. Med. 137:387-410, 1983.)
EXAMPLE 8
Both ibuprofen and the composition of Example 1 were able to reduce
the formation of oxygen-free radicals in vivo as indicated by the
concentrations of malondialdehyde and conjugated dienes in tissue
biopsies from wound regions and from nonwound areas. Very little
malondialdehyde and conjugated dienes were noticed in the biopsies
from nonwound regions, while appreciable amounts of these two
compounds were found in the wound biopsy regions. See FIGS. 2 and
3. FIGS. 2 and 3 indicate the formation of free radicals in the
wound area decreases with the duration of the healing process.
Maximum concentrations of malondialdehyde in conjugated dienes were
noticed in 24-hour wound biopsies, with a progressive decline in
later biopsies (days 3 and 6). The activities decreased with time,
suggesting the presence of decreased free radicals with the
duration of healing time.
In this example malondialdehyde was assayed as described in Das et
al., "Affects of Superoxide Anions on The (Na+K)ATPase System in
Rat Lung," Clin. Physiol. Biochem. 2:32-38, 1984. Each tissue
sample was weighed and added to 15% trichloroacetic acid (TCA) (30
mg/ml). Tissue was homogenized using a Polytron homogenizer at
0.degree.-5.degree. C. in an ice bath. The contents were
transferred to screw cap test tubes. One ml of 0.75% thiobarbituric
acid solution in 0.5% sodium acetate was then added to each tube.
The tubes were boiled in a water bath for 20 minutes. The samples
were centrifuged. Absorbance of supernatants was read at 535 nm.
The molar extinction coefficient at 535 nm equaled 156 mM.sup.-1
cm.sup.-1. The results are expressed as nmoles of thiobarbituric
acid reactive material formed per gram of tissue.
The assay for superoxide generation was done according to the
modified method of McCord et al, "The Reduction of Cytochrome C by
Milk Xanthine Oxidase," J. Biol. Chem. 243:5733-60, 1968. Aliquots
of cell suspension containing 5.times.10.sup.6 cells/ml (PMNs) were
introduced into 12.times.75 nm polypropylene test tubes. These
cells were activated in the presence of 1.0.sup.-7 M
FMLP(formyl-methionyl-leucyl-phenylalanine, chemotactic factor).
The cells plus the activator were incubated for 20 minutes in the
presence of 75 uM horse heart ferricytochrome C (Type III, Sigma).
Incubation was terminated by placing the tubes on ice, following
which they were centrifuged at 800 g for 10 minutes at 4.degree. C.
To determine cytochrome C reduced by the presence of superoxide
anion during the incubation, 0.2 ml of cell free of supernatant was
mixed with 2.2 ml of buffer (pH 7.9), and the absorbance measured
at 550 nm in a Beckman recording spectrophotometer. The amount of
cyctochrome C in the reaction mixture was calcuated using an
absorbance coefficient of 21.1 mM.sup.-1 cm.sup.-1 at 550 nm and
expressed as nmole of cytochrome C reduced per 10.sup.6 cells. The
reagent blank contained the same mixture without the cells, and the
absorbance of the nonreduced cytochrome C was subtracted from the
total reaction mixture.
The assay for conjugated diene is described by Recknagel et al,
"Lipoperoxidation As a Vector in Carbon Tetrachloride
Hepatotoxicity," Lab. Invest. 15:132-46, 1966.
EXAMPLE 9
This example illustrates that significant influx of radiolabeled
PMNs into the wound region occurred within hours of surgical
incision. See FIG. 4. The influx of PMNs decreased with the
duration of the healing process, and very little PMN occurred after
three days of wound healing. The results by noninvasive, whole-body
gamma-scintigraphy was confirmed by counting the radioactivity
incorporated in wound and nonwound regions of tissue biopsies. See
Table 2 below:
TABLE 2 Effects of the Composition of Example 1 and Ibuprofen on
the In Vivo PMN Influx in the Wound Biopsies Evaluated by Organ
Counting Day 1 Day 3 Day 6 (% of injected dose/gram tissue wt)
Control 7.165 .+-. 1.121 0.906 .+-. 1.003 0.007 .+-. 0.007 Example
1 0.011 .+-. 0.005 0.034 .+-. 0.022 0.006 .+-. 0.002 Ibuprofen
0.020 .+-. 0.010 0.007 .+-. 0.002 0.008 .+-. 0.009
A significantly higher amount of radioactivity was found in the
wound biopsies compared to nonwound biopies. A reduced amount of
radioactivity was found in the ibuprofen and Example 1 composition
treated wounds. The amount of .sup.111 Indium-radioactivity was
maximum in the 24-hour wounds, confirming the results of whole-body
gamma-scintigraphy.
The principles, preferred embodiments, and modes of operation of
the invention have been described in the foregoing specification.
However, the invention herein which is intended to be protected is
not to be construed as limited to the particular forms disclosed,
since these are to be regarded as illustrative rather than
restrictive. Variations and changes may be made by those skilled in
the art without departing from the spirit and scope of the
invention.
* * * * *