WO1989010747A1 - Anti-inflammatory and antimicrobial formulations for dermatologic and inflammatory diseases - Google Patents

Anti-inflammatory and antimicrobial formulations for dermatologic and inflammatory diseases Download PDF

Info

Publication number
WO1989010747A1
WO1989010747A1 PCT/US1989/001921 US8901921W WO8910747A1 WO 1989010747 A1 WO1989010747 A1 WO 1989010747A1 US 8901921 W US8901921 W US 8901921W WO 8910747 A1 WO8910747 A1 WO 8910747A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
acid
gel
solution
cream
composition
Prior art date
Application number
PCT/US1989/001921
Other languages
French (fr)
Inventor
Robert D. Kross
Elliott J. Siff
Original Assignee
Alcide Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/40Peroxides
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/825Arthritis
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/931Veneral disease
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/931Veneral disease
    • Y10S514/934Virus

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 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).

Description

ANTI-INFLAMMATORY AND ANTIMICROBIAL FORMULATIONS FOR DERMATOLOGIC AND INFLAMMATORY DISEASES

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of United States patent application Serial No. 190,798, filed May 6 , 1988.

TECHNICAL FIELD

This invention relates generally to topical formulations that are useful for treating various dermatologic disorders, including genita] 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 dermatologic diseases that are thought to be caused by microbial overgrowth or 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 proliferatos in large numbers during acute acne. P. acnes generates a lipase, a protease, and other potentially damaging substances. Follicular contents are known to be chemoattractive 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 normalappearing 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 viral 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 viral 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 of 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 anti-microbial treatments, but is generally not a problem for non-antibiotic treatments.

Topical fungal or yeast diseases represent a large class of diseases. These can include tinea versicolor, 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 jmidazole derivatives miconazol.e and clotrimazole. Fungal lesions on the skin surface are named "tinea" and the Latin name of the particular type of location. For example, "tinea capilis" 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. mentaqrophytes, 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 corporis 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.

Stasis 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 tranmission 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, aspirinlike 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 or histamine have little or no therapeutic effect on inflammation. The inhibition 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, perfused 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 synthetas 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 (s , 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 tissues.

Hypoxia and ischemia are inevitable fates of any kind of tissue injury. Oxygen tension in tissue wounds, when measured by implanted po.larographic 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 and complement cascades. (Weiss et al., "Phagocyte-Generated Oxgen 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 of 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 H2O2 , which ultimately form hypohalite radicals via the myeloperoxidase system [Reaction (iv)].

NADPH i. NADPH + 2O2 oxidate NADP+ + 2O2- + H+ ii. H2O2 + O2- ->-> OH- + OH° + O2 iii. Fe2+ + H2O2 ->-> Fe3+ + OH° + OH- iv. H2O2 + Cl- + H+ myelo H2O + HOCl peroxidase

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 systerns, consisting of such enzymes as superoxide dismutase, catalase, and glutathione peroxidase. However, these anti-oxidative 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, viral, 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 nonsteroidal 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 fo r the topical trea tment of dermatol og ic disorders though t 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, viral 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, intralymphati- cally 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 solu- tions, 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 penetrate 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 of chlorous acid is no more than about 15º 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:

Figure imgf000012_0001
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

Figure 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/m]). The inventive composition is shown by and ibuprofen by

Figure imgf000012_0002
Figure imgf000012_0003

When there is a dotted line, the inventive composition and ibuprofen were reacted with BSA (bovine serum albumin).

Figure 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.

Figure 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.

Figure 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-ill-labeled PMN injection. Images were digitized in a 128 × 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 hyperproli ferative 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 malondi aldehyde 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 malondialdahyde 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 dioxidegenerating 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 is 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 solutions 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 United States Patent 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 chlorite converts to chlorous acid by interacting with hydrogen ions furLher 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:

Figure imgf000016_0001
R1 and R2 may be the same or different and may be selected from the group consisting of hydrogen, methyl, -CH2COOH, -CH2OH, -CHOHCOOH, and -CH2C6H5. Compositions of 3 metal chlorite and the weak organic acids of Formula I are disclosed in copending United States Patent Application Serial Number 850,009, filed on April 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 comp7sition 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 0.01% 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:

Figure imgf000017_0001
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 United States Patent Application Serial Number 038,016, filed April 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 0.001 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, ail 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 (88%± 5%) 2.64

Natrosol 250 MR 1.75

Isopropyl alcohol U.S. P. 5.0 Poloxamer 188 0.4

Sodium Benzoate 0.04

Water q.s.

EXAMPLE 2 The composition of Example I 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-epithe lialization 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 times 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

Salicylic 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. Activator

Mandelic acid 2.0

Poloxamer 188 0.4

Sodium benzoate 0.04

Natrosol 250 MR 1.75

Water q.s.

EXAMPLE 6

The following cream can 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

Glucam E-20 distearate 3.0

Poly (sulfonic) acid 15.0 (16% solution ± 1%)

Sodium hydroxide I N 15.0

Water q.s.

Activator

Lactic acid (88% ± 5%) 2.64

Natrosol 250 MR 1.25

Isopropyl alcohol U.S. P. 5.0

Glucam E20 distearate 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 Figure 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., "111Indium-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 red blood cells. As rabbit blood appears to be homologous, blood was pooled for purposes of obtaining PMN cells for labeling. 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 minoxine. 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-Hl-oxine (specific activity greater than 10 mCi/ug) (Mediphysics, Inc., Emeryville, Calif.) were incubated with PMNs (3×106) in PPP at 37°C for 20 minutes. Labeled cells were centrifuged and washed to remove unbound Hlfnoxine prior to injecting the PMNs into the ear veins of the rabbits studied. The viability of the PMNs prior to and following 111In-labeling was checked in vitro by the conventional trypan blue dye exclusion method. in vitro leukocyte chemotaxis 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 concentration 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 Figures 2 and 3. Figures 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 0-5°C in an ice bath. The contents were transferred to screw cap test tubes. One ml of 0.75% thiobarbi turic 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-1cm-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 suspensions containing 5 × 106 cells/ml (PMNs) were introduced into 12 × 75 nm polypropylene test tubes. These cells were activated in the presence of 10-7 M FMLP(formyl-methionylleucyl-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°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-1cm-1 at 550 nm and expressed as nmole of cytochrome C reduced per 106 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 24 hours of surgical incision. See Figure 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 gammascintigraphy 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 ± 0.003 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 111Indium-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.

Claims

ClaimsWHAT IS CLAIMED IS:
1. A use of a composition comprising manufacturing 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 pK of the protic acid is from about 2.8 to about 4.2 for the treatment of dermatologic diseases characterized by microbial overgrowth and/or inflammation.
2. The use of a composition according to claim 1 wherein the dermatologic disease is selected from the group consisting of genital herpes lesions, topical fungal infections, leg ulcers, eczema, acne vulgaris, vaginitis, hemorrhoids, and psoriasis.
3. A use of a composition comprising manufacturing 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 pK of the protic acid is from about 2.8 to 4.2 for the prevention of the sexual transmission of the HIV virus.
4. A use of a composition comprising manufacturing 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 pK of the protic acid is from about 2.8 to about 4.2 for the treatment of tissue inflammation with local or topical administration.
5. The use of a composition according to claims 1, 3 or 4 wherein the chlorine dioxide liberating compound is a metal chlorite and the chlorite ion concentration is the composition in the form of chlorous acid is no more than about 15% by weight of the total amount of chlorite ion concentration.
6. The use of a composition according to claims 1, 3 or 4 wherein the first solution, cream or gel is a gel and contains a polysulfonic acid salt as a thickener.
7. The use of a composition according to claims 1, 3 or 4 wherein the protic acid is selected from the group consisting of lactic acid, citric acid, malic acid and salicylic acid.
PCT/US1989/001921 1988-05-06 1989-05-05 Anti-inflammatory and antimicrobial formulations for dermatologic and inflammatory diseases WO1989010747A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US19079888 true 1988-05-06 1988-05-06
US190,798 1988-05-06
US07202758 US4956184A (en) 1988-05-06 1988-06-03 Topical treatment of genital herpes lesions
US202,758 1988-06-03

Publications (1)

Publication Number Publication Date
WO1989010747A1 true true WO1989010747A1 (en) 1989-11-16

Family

ID=26886461

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1989/001921 WO1989010747A1 (en) 1988-05-06 1989-05-05 Anti-inflammatory and antimicrobial formulations for dermatologic and inflammatory diseases

Country Status (5)

Country Link
US (3) US4956184A (en)
EP (1) EP0417159A1 (en)
JP (1) JPH03505203A (en)
CA (1) CA1328406C (en)
WO (1) WO1989010747A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993007884A1 (en) * 1991-10-25 1993-04-29 Senju Pharmaceutical Co., Ltd. External preparation for treating hemorrhoidal diseases
EP0561145A1 (en) * 1992-03-19 1993-09-22 Oxo Chemie Ag Use of a chemicallly stabilized chlorite matrix for the manufacture of medicaments for the treatment of HIV infections
WO1997009054A1 (en) * 1995-09-08 1997-03-13 Alcide Corporation Compositions for treatment of skin lesions containing a protic acid and a chlorite ion
US6379685B1 (en) 1997-09-26 2002-04-30 Ecolab Inc. Acidic aqueous chlorite teat dip with improved emollient providing shelf life, sanitizing capacity and tissue protection
US6749869B1 (en) 1997-09-26 2004-06-15 Ecolab Acidic aqueous chlorite teat dip providing shelf life, sanitizing capacity and tissue protection
WO2006132515A1 (en) * 2005-06-09 2006-12-14 Inha-Industry Partnership Institute Agent for the treatment of vaginitis containing mandelic acid as an active ingredient
EP2133083A1 (en) * 2007-03-27 2009-12-16 Taiko Pharmaceutical Co. Ltd. Therapeutic agent for infectious skin or mucosal disease
EP2926819A4 (en) * 2012-11-29 2016-06-29 Xuewu Liu Method for initiating stem cells of mammals and use of chlorine dioxide in preparation of drug for initiating stem cells of mammals

Families Citing this family (87)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5151415A (en) * 1991-05-23 1992-09-29 Dallas Sirany Method of treating a papova-type viral infection
DE69328635D1 (en) * 1992-01-21 2000-06-15 Howard Alliger Use of a substance mixture containing alpha hydroxy organic acid for the manufacture of a medicament for the treatment of small aphthous ulcers
US5407656A (en) * 1992-03-04 1995-04-18 Arco Research Co., Inc. Method and compositions for the production of chlorine dioxide
US5622725A (en) * 1992-03-20 1997-04-22 Alcide Corporation Wound disinfection and repair
US5667817A (en) * 1992-03-20 1997-09-16 Alcide Corporation Method and composition for prevention and treatment of female lower genital tract microbial infections
US5252343A (en) * 1992-03-20 1993-10-12 Alcide Corporation Method and composition for prevention and treatment of bacterial infections
FR2695034B1 (en) 1992-09-01 1994-10-07 Oreal Cosmetic or pharmaceutical composition comprising in combination a peroxidase and an antioxidant agent singlet.
EP0663958A4 (en) * 1992-09-25 1999-10-20 Woo David D L The Regents Of T Inhibition of cyst formation by cytoskeletal specific drugs.
US5585379A (en) * 1992-12-30 1996-12-17 Agis Industries (1983) Ltd. Acyclovir antiviral gel composition
US6046243A (en) * 1993-02-12 2000-04-04 Bernard Technologies, Inc. Compositions for sustained release of a gas
US5980826A (en) * 1993-02-12 1999-11-09 Bernard Technologies Inc. Methods of deodorizing and retarding contamination or mold growth using chlorine dioxide
US5505948A (en) * 1993-06-01 1996-04-09 Dermatology Home Products, Inc. Home skin peel composition for producing healthy and attractive skin
WO1995016454A1 (en) * 1993-12-17 1995-06-22 Kligman Albert M Method for treatment of papulo-pustules and comedones of the skin
CN1106259A (en) * 1994-02-05 1995-08-09 日东制药株式会社 Antiphlogistic and analgesic gel agent for external use containing propanoic acid non steroid pharmaceutical as effective composition
CA2184813C (en) * 1994-03-04 2000-01-04 Robert D. Kross Wound disinfection and repair
US5489260A (en) * 1994-10-20 1996-02-06 Striano; James S. Lumbar spine support
US5597561A (en) * 1994-12-14 1997-01-28 Alcide Corporation Adherent disinfecting compositions and methods of use in skin disinfection
US5651977A (en) * 1994-12-14 1997-07-29 Alcide Corporation Adherent disinfecting compositions and methods relating thereto
US5639295A (en) * 1995-06-05 1997-06-17 Southwest Research Institute Method of making a composition containing a stable chlorite source
US5707739A (en) * 1995-06-05 1998-01-13 Southwest Research Institute Powdered biocidal compositions
US5705092A (en) * 1995-06-05 1998-01-06 Southwest Research Institute Multilayered biocidal film compositions
US5914120A (en) * 1995-06-05 1999-06-22 Southwest Research Institute Amine-containing biocidal compositions containing a stabilized chlorite source
EP0774899B1 (en) * 1995-06-12 2006-04-05 Bernard Technologies, Inc. Sustained release, transparent biocidal compositions
FR2738150B1 (en) * 1995-09-01 1997-10-31 Synthelabo Use of sulphasalazine and its metabolites for the manufacture of a medicament useful in the treatment of venous insufficiency and venous ulcers
US6096350A (en) * 1995-09-08 2000-08-01 Alcide Corporation Compositions and methods for prevention and treatment of diseases associated with honey bees
US5855922A (en) * 1995-12-07 1999-01-05 Bio-Cide International, Inc. Antiseptic composition and process for prophylaxis and therapeutic treatment of dermal disorders
US5730965A (en) * 1996-06-13 1998-03-24 Dermatology Home Products, Inc. Shampoo for treating seborrheic dermatitis, dandruff or psoriasis
US6024980A (en) * 1996-06-28 2000-02-15 Mcneil-Ppc, Inc. Multiphase soft gelatin dosage form
DE69732913T2 (en) * 1996-09-18 2006-05-04 Bernard Technologies, Inc., Chicago Powder for the controlled release of a gas
US5888528A (en) * 1997-05-19 1999-03-30 Bernard Technologies, Inc. Sustained release biocidal powders
WO1999017787A3 (en) * 1997-10-06 1999-06-17 Oxo Chemie Ag Use of a chemically-stabilized chlorite solution for inhibiting an antigen-specific immune response
DE19802708A1 (en) * 1998-01-24 1999-07-29 Hoechst Marion Roussel De Gmbh Use of 1-hydroxy-2-pyridone compounds with powder base for treatment of lower leg ulcers and decubitus ulcers
US6277408B1 (en) 1998-02-09 2001-08-21 Southwest Research Institute Silicate-containing powders providing controlled, sustained gas release
US6605304B1 (en) 1998-02-09 2003-08-12 Bernard Technologies, Inc. Silicate-containing powders providing controlled, sustained gas release
US6114398A (en) * 1998-03-03 2000-09-05 Ratcliff; Perry A. Personal lubricant to prevent and stop itching
US6123966A (en) * 1998-09-03 2000-09-26 Alcide Corporation Stabilized two-part disinfecting system and compositions and methods related thereto
WO2001013956A3 (en) * 1999-08-26 2001-10-04 Ganeden Biotech Inc Use of emu oil a carrier for antifungal, antibacterial, and antiviral medications
US20070104798A1 (en) 1999-10-04 2007-05-10 S.K. Pharmaceuticals, Inc. Synergistic antimicrobial preparations containing chlorite and hydrogen peroxide
US6663902B1 (en) 2000-09-19 2003-12-16 Ecolab Inc. Method and composition for the generation of chlorine dioxide using Iodo-Compounds, and methods of use
US7086403B2 (en) * 2000-12-05 2006-08-08 Church & Dwight Co., Inc. Condom with male genital desensitizer lubricant
US20050177892A1 (en) * 2001-02-12 2005-08-11 Pioneer Hi-Bred International, Inc. Maize Rar1-interactor polynucleotides and methods of use
CA2440687A1 (en) * 2001-03-15 2002-09-26 Agis Industries (1983) Ltd. Dermatological preparations
US6599432B2 (en) 2001-05-02 2003-07-29 Robert D. Kross Methods for disinfecting small diameter water lines
US7223909B2 (en) * 2002-03-21 2007-05-29 Ball Horticultural 4-ketocarotenoids in flower petals
US6746667B2 (en) * 2001-07-05 2004-06-08 Closure Medical Corporation Adhesive treatment for tinea pedis
US6835536B2 (en) 2001-08-21 2004-12-28 Micrologix Biotech Inc. Antimicrobial cationic peptides and formulations thereof
EP1421108A2 (en) 2001-08-24 2004-05-26 Dale Cameron Antimicrobial and anti-inflammatory peptides
US20050142215A1 (en) * 2002-03-27 2005-06-30 Kling William O. Antimicrobial compositions and methods of use
CA2483448C (en) 2002-04-25 2011-01-25 William O. Kling Anti-acne compositions and methods of use
JP2005524708A (en) 2002-05-08 2005-08-18 アメリカン バイオフィジックス コーポレイション Apparatus for trapping insects fly attractant object
US8067469B2 (en) 2002-05-08 2011-11-29 Woodstream Corporation System for trapping flying insects with attractant lures
WO2003105804A1 (en) * 2002-06-17 2003-12-24 Taro Pharmaceuticals U.S.A, Inc. Ibuprofen suspension
US7477941B2 (en) * 2003-06-30 2009-01-13 Johnson & Johnson Consumer Companies, Inc. Methods of exfoliating the skin with electricity
US7479133B2 (en) * 2003-06-30 2009-01-20 Johnson & Johnson Consumer Companies, Inc. Methods of treating acne and rosacea with galvanic generated electricity
US7477938B2 (en) * 2003-06-30 2009-01-13 Johnson & Johnson Cosumer Companies, Inc. Device for delivery of active agents to barrier membranes
US8734421B2 (en) 2003-06-30 2014-05-27 Johnson & Johnson Consumer Companies, Inc. Methods of treating pores on the skin with electricity
US7477939B2 (en) * 2003-06-30 2009-01-13 Johnson & Johnson Consumer Companies, Inc. Methods of treating a wound with galvanic generated electricity
US7486989B2 (en) * 2003-06-30 2009-02-03 Johnson & Johnson Consumer Companies, Inc. Device for delivery of oxidizing agents to barrier membranes
US7507228B2 (en) * 2003-06-30 2009-03-24 Johnson & Johnson Consumer Companies, Inc. Device containing a light emitting diode for treatment of barrier membranes
US7476222B2 (en) * 2003-06-30 2009-01-13 Johnson & Johnson Consumer Companies, Inc. Methods of reducing the appearance of pigmentation with galvanic generated electricity
US7480530B2 (en) 2003-06-30 2009-01-20 Johnson & Johnson Consumer Companies, Inc. Device for treatment of barrier membranes
US7477940B2 (en) * 2003-06-30 2009-01-13 J&J Consumer Companies, Inc. Methods of administering an active agent to a human barrier membrane with galvanic generated electricity
US20040265395A1 (en) * 2003-06-30 2004-12-30 Ying Sun Device for delivery of reducing agents to barrier membranes
WO2005076829A3 (en) * 2004-02-05 2005-11-24 Satish Asotra Stable loratadine spill resistant formulation
CA2572895A1 (en) 2004-07-13 2006-01-19 Mediwound, Ltd. Compositions and methods for dermatological wound healing
US20070264226A1 (en) * 2006-05-10 2007-11-15 Karagoezian Hampar L Synergistically enhanced disinfecting solutions
EP2517713A3 (en) 2007-06-01 2013-01-30 Nuvo Research AG A method of treating allergic asthma, allergic rhinitis and atopic dermatitis
EP2200619B1 (en) * 2007-09-28 2015-08-12 Johnson & Johnson Consumer Companies, Inc. Electricity-generating particulates and the use thereof
WO2009093540A1 (en) * 2008-01-23 2009-07-30 Taiko Pharmaceutical Co., Ltd. Chlorine dioxide liquid preparation composition
US20100012894A1 (en) * 2008-07-15 2010-01-21 Basf Catalysts Llc Tooth Whitening Compositions and Methods
US20100015252A1 (en) * 2008-07-15 2010-01-21 Basf Catalysts Llc Tooth Polishing Compositions and Methods of Tooth Polishing Without Mechanical Abrasion
KR20110039461A (en) * 2008-07-15 2011-04-18 바스프 코포레이션 Methods, systems and devices for administration of chlorine dioxide
US8150525B2 (en) * 2008-08-27 2012-04-03 Johnson & Johnson Consumer Companies, Inc. Treatment of hyperhydrosis
US20100082088A1 (en) * 2008-08-27 2010-04-01 Ali Fassih Treatment of sweating and hyperhydrosis
US20100196512A1 (en) * 2009-02-04 2010-08-05 Basf Catalyst Llc Treatment of Non-Oral Biological Tissue with Chlorine Dioxide
US20120089232A1 (en) 2009-03-27 2012-04-12 Jennifer Hagyoung Kang Choi Medical devices with galvanic particulates
US8744567B2 (en) * 2009-11-13 2014-06-03 Johnson & Johnson Consumer Companies, Inc. Galvanic skin treatment device
KR20110091461A (en) * 2010-02-05 2011-08-11 존슨 앤드 존슨 컨수머 캄파니즈, 인코포레이티드 Lip compositions comprising galvanic particulates
CN101785786B (en) 2010-02-20 2012-09-05 北京欧凯纳斯科技有限公司 Chlorine dioxide ointment used for treating dermatophytosis
US20110212042A1 (en) * 2010-03-01 2011-09-01 Prithwiraj Maitra Skin care composition having desirable bulk color
US20110236491A1 (en) * 2010-03-25 2011-09-29 Jeannette Chantalat Topical anti-inflammatory composition
US20130225529A1 (en) * 2012-02-27 2013-08-29 Basil Rigas Phospho-ester derivatives and uses thereof
JP2015071581A (en) * 2013-05-20 2015-04-16 本部三慶株式会社 Virus disinfectant containing chlorous acid water
CN105263327A (en) * 2013-05-20 2016-01-20 本部三庆株式会社 Drug-resistant microbe and variant microbe disinfectant containing chlorous acid aqueous solution
CA2979730A1 (en) * 2015-03-16 2016-09-22 Kantian Sciences Corporation Treatment of acne vulgaris with sequential topical formulations comprising antimicrobial organic acid anions in alkaline phase
US9474768B1 (en) 2016-05-18 2016-10-25 Reoxcyn Discoveries Group, Inc. Lubricant formulations
US9833471B1 (en) 2016-09-15 2017-12-05 Reoxcyn Discoveries Group, Inc. Hypochlorous acid-based hand sanitizer

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0287074A2 (en) * 1987-04-14 1988-10-19 Alcide Corporation Disinfecting compositions

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4330531A (en) * 1976-03-26 1982-05-18 Howard Alliger Germ-killing materials
US4084747A (en) * 1976-03-26 1978-04-18 Howard Alliger Germ killing composition and method
GB1555796A (en) * 1976-10-15 1979-11-14 Unilever Ltd Composition for treating acne
US4381296A (en) * 1980-06-23 1983-04-26 Tinnell James E Treatment for herpes virus
US5185161A (en) * 1984-03-21 1993-02-09 Alcide Corporation Disinfection method and composition therefor
US4690772A (en) * 1985-06-03 1987-09-01 National Medical Care Sterilant compositions
EP0315627B1 (en) * 1986-08-01 1992-08-19 RUBINSTEIN, Alan I. A method to treat blood

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0287074A2 (en) * 1987-04-14 1988-10-19 Alcide Corporation Disinfecting compositions

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993007884A1 (en) * 1991-10-25 1993-04-29 Senju Pharmaceutical Co., Ltd. External preparation for treating hemorrhoidal diseases
EP0561145A1 (en) * 1992-03-19 1993-09-22 Oxo Chemie Ag Use of a chemicallly stabilized chlorite matrix for the manufacture of medicaments for the treatment of HIV infections
US6086922A (en) * 1992-03-19 2000-07-11 Oxo Chemie Ag Use of a chemically-stabilized chlorite matrix for the parenteral treatment of HIV infections
WO1997009054A1 (en) * 1995-09-08 1997-03-13 Alcide Corporation Compositions for treatment of skin lesions containing a protic acid and a chlorite ion
US5772985A (en) * 1995-09-08 1998-06-30 Alcide Corporation Method for treating bovine hairy heel warts
US6699510B2 (en) 1997-09-26 2004-03-02 Ecolab Inc. Acidic aqueous chlorite teat dip with improved visual indicator stability, extended shelf life, sanitizing capacity and tissue protection
US6436444B1 (en) 1997-09-26 2002-08-20 Ecolab Inc. Acidic aqueous chlorite teat dip providing shelf life sanitizing capacity and tissue protection
US6379685B1 (en) 1997-09-26 2002-04-30 Ecolab Inc. Acidic aqueous chlorite teat dip with improved emollient providing shelf life, sanitizing capacity and tissue protection
US6749869B1 (en) 1997-09-26 2004-06-15 Ecolab Acidic aqueous chlorite teat dip providing shelf life, sanitizing capacity and tissue protection
USRE41279E1 (en) 1997-09-26 2010-04-27 Ecolab Inc. Acidic aqueous chlorite teat dip with improved visual indicator stability, extended shelf life, sanitizing capacity and tissue protection
WO2006132515A1 (en) * 2005-06-09 2006-12-14 Inha-Industry Partnership Institute Agent for the treatment of vaginitis containing mandelic acid as an active ingredient
EP2133083A1 (en) * 2007-03-27 2009-12-16 Taiko Pharmaceutical Co. Ltd. Therapeutic agent for infectious skin or mucosal disease
EP2133083A4 (en) * 2007-03-27 2012-02-15 Taiko Pharmaceutical Co Ltd Therapeutic agent for infectious skin or mucosal disease
EP2926819A4 (en) * 2012-11-29 2016-06-29 Xuewu Liu Method for initiating stem cells of mammals and use of chlorine dioxide in preparation of drug for initiating stem cells of mammals

Also Published As

Publication number Publication date Type
US4956184A (en) 1990-09-11 grant
EP0417159A1 (en) 1991-03-20 application
CA1328406C (en) 1994-04-12 grant
JPH03505203A (en) 1991-11-14 application
US5384134A (en) 1995-01-24 grant
USRE37263E1 (en) 2001-07-03 grant

Similar Documents

Publication Publication Date Title
Tranquada et al. Irreversible Lactic Acidosis Associated With Phenformin Therapy: Report of Three Cases
Jacob et al. Dimethyl sulfoxide (DMSO) toxicology, pharmacology, and clinical experience
RUNDLES et al. Allopurinol in the treatment of gout
US5753270A (en) Topical treatment of diseased skin disorders
US6488965B1 (en) Synergistic antimicrobial preparations containing chlorite and hydrogen peroxide
US5693676A (en) Nitric oxide donor composition and method for treatment of anal disorders
US4708965A (en) Method of treating herpes virus infections with N,N'-diacetylcystine and derivatives
US5459135A (en) Composition comprising indomethacin [non-steroidal anti-inflammatory agent] and effectively non-antibacterial tetracycline to reduce bone loss
US5658956A (en) Bioadhesive-wound healing compositions and methods for preparing and using same
US4507281A (en) Interferon-containing compositions
Senagore et al. Short-chain fatty acid enemas: a cost-effective alternative in the treatment of nonspecific proctosigmoiditis
US5466680A (en) Method and compositions for enhancing white blood cell functioning on a mucosal or cutaneous surface
US5037810A (en) Medical application for heparin and related molecules
US4512978A (en) Dermatological composition useful in the treatment of psoriasis
US4879282A (en) Medical application for heparin and related molecules
US4309989A (en) Topical application of medication by ultrasound with coupling agent
US5504117A (en) Pharmacologic preparation for the treatment of anal disorders
US4512977A (en) Therapeutic selenium compositions and the use thereof
US4025645A (en) Non-steroid topical agent for alleviating inflammation in mammals
US5308839A (en) Composition comprising non-steroidal anti-inflammatory agent tenidap and effectively non-antibacterial tetracycline
US5439685A (en) Pharmaceutical composition for the prevention of sexually transmitted diseases
US4256763A (en) Treatment of herpes simplex infections and acne
Wales et al. The spermicidal activity of hydrogen peroxide in vitro and in vivo
US20030004143A1 (en) Use of NSAIDs for prevention and treatment of cellular abnormalities of the female reproductive tract
US4847083A (en) Two-step procedure for indolent wound healing and aqueous medium and topical ointment used in connection therewith

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LU NL SE

WWE Wipo information: entry into national phase

Ref document number: 1989906234

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1989906234

Country of ref document: EP

WWR Wipo information: refused in national office

Ref document number: 1989906234

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1989906234

Country of ref document: EP