CA1328406C - Anti-inflammatory and antimicrobial formulations for dermatalogic and inflammatory diseases - Google Patents
Anti-inflammatory and antimicrobial formulations for dermatalogic and inflammatory diseasesInfo
- Publication number
- CA1328406C CA1328406C CA000598896A CA598896A CA1328406C CA 1328406 C CA1328406 C CA 1328406C CA 000598896 A CA000598896 A CA 000598896A CA 598896 A CA598896 A CA 598896A CA 1328406 C CA1328406 C CA 1328406C
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- Prior art keywords
- acid
- gel
- cream
- solution
- composition
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/40—Peroxides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Abstract
Abstract There is disclosed n 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
- l 13284~6 ANTI-INFLAMMATORY AND ANTIMICROBIAL FORMULATIONS
FOR DERMATOLOGIC AND INFLAMMATORY DISEASES
This invention relates generaLly to topical formu-lations that are useful for treating various dermatologic disorders, includin~ genital herpes lesions, facial and body acne, topical fungal infections, psoriasis, eczema, dandruff, skin ulcers (e.g., decabutus), and other dermato-logic diseases associated with microbial proliferation.
This invention also relates to the anti-inflammatory proper-ties and uses of pharmaceutical compositions.
There are a large number of dermatologic diseases that are thought to be caused by microbial overgrowth or somehow result in a dermatologic inection and/or inflamma-tory reaction. These diseases include acne vulgaris and other pilosebaceous in~lammat~ry disorders, which are thought to be caused in part by an overgrowth of the anaero-bic bacterium ProPion;bacterium acnes (P. acnes), which is normally present in the sebaceous follicles but prolifer-atos in large numbers during acute acne. P. acnes gener-ates 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 inflamma~ory 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 132~40~
surrounding dermis and creating further inflammation. The visible consequence o~ this series of dermal events is a deep inflammatory nodule, ca]led a "cyst." An accumulation of neutrophils in ~he mouth of a follicle produces a S pustule. Deep inflammatoey or cystic lesions may arise from preexisting closed comedones in an area of normal-appearing skin.
Genital herpes is also called ~Herpes Progeni-talis~ and is caused by the herpes simplex virus, usually type 2. Primary genital herpe3 follows an incubation period of 3 to 7 days. The disease can be found by local-ized burning or paresthesia and ollowed by eruption of grouped vesicles, often at multiple sites on tbe 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. Recur-rent genital herpes is common after the primary infection.
Secondary lesions heal within two weeks, and secondary attacks become less frequent with time. Treatments inc]ude drying agents to symptomatically lessen the discomfort of the lesion. Acyclovir, applied topically, tends o decrease pain of the primary lesions, but it ha~ not proven very effective for decreasing viral shedding or lesion dura-~ion. Topical acyclovir has not been shown to be particu-larly effective for-reducing or treatin~ 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 triphospha~e, which can in~erfere with viral VNA replication. Topical acyclovir is applied as a 5% ointment every thr~e hours, or up to ei~ht 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 3 1 3 2 8 ~ ~6 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. Accordin~ly, no backup treat-ments are available for acyclovir-resistant herpes simplex infections. This problem exists wi~h 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 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.
lS Treatments include the use of dandruff shampoos on the affected areas and typical antifungal agents, including the imidazole derivatives miconazole and clotrimazo~ . 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. mentaqrophytes, and Epidermophyton floccsum.
Tinea pedis is commonly called "a~hlete's foot."
It is often caused by Trichophyton rubrum or Trichophyton mentaqrophytes. It often begins as a sca]y lesion between the toes and spreads to produce an acute inflammatory vesicular disease, accompanied by itching, burning and pain.
Tineas corpo~is is also called 'ringworm" and is a dermato-phyte infection involving nonspecific areas of skin. The infection is an erythematous, scaly patch on the skin with sharp, acu-e borders and central clearing. Current treat-ments for topical fungal diseases include the imidazole derivatives, miconazole and clotrimazole. Griseofulvin is ; '. ~
c. _ 5~ .
4 132~4~6 a systemic agent, and ketoconazole is also used systemi-cally 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 erythema~ous, papulovesicular process often accompanied by oozing and crusting and ollowed by a chronic phase o~ 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 character- -ized by chronic periodic remissions and exacerbations.
Lesions usually consist o 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. ~he disease is characterized histologically by accelerated cellular turn-over. 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 ~he disease. However, no single treatment has yet proven to be successful for a wide variety of cases.
Dandruff is a scaling cond;tion 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 leq ulcer and is a form of eczema and often the resu~t o 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.
.. .~7 Acquired Immune Deficiency Syndrome (Al~S) is believed to be spread by sexual con~act, and more specifi-cally, through transmission of the HIV v;rus. 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 ~hat can be used alon~ 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-inflammato~y agents most often function by inhibition of prostaglandin or leukotriene biosynthetic pathways. For example, non-steroidal anti-inflamma~ory drugs such as aspirin (acetylsalicylic acid), indomethacin, and ib~pro~en are known to inhibit the fatty acid cyclooxyqenase enzyme in the prostaglandin pathway from arachidonic acid.
Steroid drugs have an~i-in~lammatory activity but also have numerous side effects, including sodium retention, hepatic deposition of glycogen, and dramatic redistribution o~ ~ody fat. The steroid anti-inf1ammatory properties are m~diated by inhibiting edema, fibrin deposition, capillary dilation, migration of leukocytes, and deposition of collagen.
Steroid anti-inflammatory agents have immunosuppressant side effeçts.
While it is difficult to give an adequate descrip-tion of the inflammatory phenomenon in terms of the under-lying cellular events in the injured tissu~, there are certain features of the process that are generally agreed to be characteris~ic. ~rhese include fenes~ration of the microvasculature, leakage of the elements of blood into the interstitial spaces, and migration of leukocy~es into the inflamed tissue. On a macroscopic level, this is usually accompanied by the clinical signs ery~hema, edema, tender-ness (hyperalgesia), and pain. During this complex response, chemical mediators such as histamine, 5-hydroxy-tryptamine (5-HT), slow-reactiny substance of anaphylaxis 1328~06 (SRS-A), various chemotactic factors, bradykinin, and prostaglandins are liberated locally. Phagocytic cells migrate into the area and cel~ular lysosomal membranes may be ruptured, releasing lytic enzymes. ~11 these events may contribute to ~he inflammatory response. However, aspirin*
like drugs have lit~le or no effect upon ~he release or activity of histamine, S-l~T, SRS-A, or lysosomal enzymes;
and similarly, potent ant~gonis~s of 5-HT or histamine have little or no ~hcrapeutic effect on inElammation.
The inhibi~ion of prostaglandin biosynthesis by aspirin and other non-steroidal anti-inflammatory agents, such as ibuprofcn, has becn demonstrated in three different systems, cell-free homogenates of guinea pig lung, perfused dog spleen, and human platelcts. There are now numerous systems in vitro and ~n vivo in which inhibition of prosta-glandin 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 depend~nt only on ~he drug reaching the enzyme, cyclooxygenasc (pros~aglandin synthetase); the distribution and pharmokinetics of each agent ~hus have an important bearing on the drug's activity.
The migration oE leukocytes into inflamed areas is an important component of in~lammation. Although the classical aspirin-like drugs (sa~icylates, pyrazolone deriva~ives, ibuprofen, indomet~lacin, e~c.) block prosta-glandin biosysthesis, they do not inhibit the formation of the major chemotactic metabolite of arachidonic acid, HL~'E, and may even increase concentrations of this compound in tissues.
Hypoxia and ischemia are ine~itable fates of any kind o~ tissue injury. Oxygen tension in tissue wounds, when measured by implan~ed polarographic oxygen electrode, was found to be only 5 to 15 mm Hg, as compared to control tissue values of 40 ~o 50 mm Hg. ~Sheffield, "Tissue Oxygen Measurements with Respect to Soft Tissue Wound Healing with Normobaric and Hyperbaric Oxygen," HYPerbaric * tra~e-marks 7 13284~6 Oxyqen Rev. 6:18-46, 1985.) Tissue ischemia is associated with an inflammatory response mediated by stimulated Hagemann factor and complement cascades. (Weiss et al., "Pha~ocyte-Genera~ed Oxgen Metabolites and CelluLar 5 Injury", Lab Invest. 47:5-18, 1982.) These factors activate polymorphonucLear leukocytes (PMNs1 and result in a massive in~lux of phagocytic leukocytes into the wound.
Paradoxically, the antimicromial properties of PMNs are greatly impaired in the ische~ic wound region in vivo because of the lack of molecu]ar oxygen. (Mandell, "Bactericidal Activity of Aerobic and Anaerobic Polymor-phonuclear Neutrophils,~ Infect Immunol. 9-337-41, 1974.) Oxygen therapy, including hyperbaric oxygen treatment, has been suggested to facilitate wound healing and is often lS used as ad;unctive therapy in problem wounds and wound infections. However, the optimal times and mode of oxygen therapy s~ill remain clouded. Oxygen radicals are involved in the phagocytic actions of PMNs, which, upon activation, generate supe~oxide and hydroxyl radicals as well as hydrogen peroxide and hypochlorous acids at the site oE
phagocytosis.
Any wounding, whether surgical or trauma~ic, causes disruption of blood vessels, tissue hemorrhage, acti-vation of Hageman factor, and s~imulation of complement pathways. l'hese morphologic and biochemical events result in the massive influx of PMNs into the wound site and ~he production of superoxide radicals by PMNs as part of the phagocytic response IReaction (i)l. rrhe generated super-oxide radicals undergo the Haber-Weiss reaction lReaction (ii)l or iron-catalyzed Fenton type reactions lReaction ~iii)l, producing cytotoxic OH radicals and H2O2, which u1timately rorm hypohalite radicals via the myeloperoxidase system ¦Reaction (iv)l.
NADYH
i. NADP~ + 202 oxidas>e NADP+ + 202 + E~
ii. H22 + 2 ~>-> OH- + OH + 2 A~
1328~6 iii. Fe2~ ~ H22 ->~> ~'e3~ + OH + O~l iv. H22 ~ Cl- ~ H~ myelo ~ H2O ~ HOCl peroxid se Although the presence of these oxygen-free - radicals is necessary for the oxidative killing of micro-organisms, excessive generation o these cytotoxic radicals may be extremely harmful to native tissues. Tissues are generally equipped wi~h adequ~e an~ioxidative defense sys-tems, consisting o~ such enzymes as superoxide dismutase, catalase, and glutathione peroxidase. ~owever, these anti-oxidative enzymes are known to be reduced during ischemia and hypoxia.
Accordingly, there is a need in the pharmaceuti-cal art for a therapeutic agent that has both strong andbroad spectrum antimicrobial properties for a wide variety of bacterial, fungal, viral, and yeast infections, as well as anti-inflamma~ory 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 lubricat-ing gel that has strong an~iviral 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-inElammatory therapeutic agent that does not possess the side efect problems of the aspicin-like nonsteroidal anti-inflammatory agents or the immunosuppressant proper-ties of the corticosteroids.
The aforementioned therapeutic prob~ems 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, ~' .
13~4~6 the ch~orine 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 inElamma~ory response, or for inflam-maLory conditions. These dermatologic disorders include topical ~ungal diseases, viral lesions such as ~rom genital herpes, and inElammatory/bacterial disorders such as acne.
Additionally, the formulations con~aining the active agents of the present invention are useful for the treatment o~
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 ~ormulations 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 ~o adhere to the epithelial surface and penetrate into ~he dermis. The first solution, gel, or cream contains an amount of me~al chlorite, such that, when combined in equal parts with the first gel, the chlorite ion concerltration in the form of 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 polysulEonic acid wherein the anion of the salt has the formula:
,~ ~
1328~
__ --CH2-CH------- __________________ C=O
Nll CH3 -c-cH2so3 _ CH3 _ X
wherein X has a value such that the mo~.ecular weigbt o~ the ]o anionic portion of the polymer is from about 1,000,000 to about 5,000,000 daItons.
Figure 1 shows the ~n vitro chemotaxis of the inventive composition at the active concentration of Example 1 and the non-steroidal anti-inflammatory agent ibuproÇen (0.5 mg/m]). The inventive composition is shown by ( - _ ) and ibuprofen by ( When there i5 a dottcd line, the inventive composi.tion and ibuprofen were reacted with BSA (bovine serum al.bumi.n).
Figure 2 shows the erfect of the inventive composition (called "~cide~) and i~uprofen on the thiobarbituric acid-reac~ive material production at the wound site during the healing process.
Figure 3 shows the effect of the inventive compo-sition (called "A~cide") and ibuprofen on the conjugated dienes formation at the wound site during the healing process.
Fi.gure 4 is a scintigraphic comparison of Indium-lll-radioactivity accumulation at the wound site during the healing process. The inven~ive composi.tion is termed "~lcide." Gamma-scintigraphy was performed 4 hours following the Indium-lll-labeled ~MN injection. Images were digitized in a 128 x 128 matrix, and regions of interest in wound and nonwound areas were studied.
~.
~284~6 The compositions described herein are useful as topical for~uLations to treat human skin disorders caused by microbial overgrowth or by in~lammation. The skin disordees include facial or ~ody acne, topical fungal infec-tions, gcnital herpes, psoriasis, leg and decubitus ulcers, ec~ema, and dandruE. l'he composition can function as a lubricating barrier gel for the prevention of transmission oE sexually transmitted diseas2s. Dandruf, psoriasis, and eczema are hyperproliferative oc in~lammatory disorders that are believed to be initiated by, or associated with fungal or yeast microbial overgrowth. Accordingly, the skin disorders are oft~n caused by microorganisms, including bacterial, viral, yeast and fungal sources. The compositions or formula~ions are also useful as an~i-in1ammatories.
The tllerapeutic compositions are useEul for the treatment of skin diseases that involve an inflammatory and/or a microbial proliferation component or both compo-nents. Thus, the topical application of the inventivecompositions containing a chlorine dioxide liberating compound in one solution, crcam, or gel and a protic acid in the other solution, cream, or gcl, when mixed, yield chlorine dioxide that is the active antimi~robial or anti-inflammatory agent. A gel composition should have superior skin-adherence properties.
Topical application of the therapeutic composi-tions described herein relates to applica~ion to the surface of the skin and to certain body cavities such as 3~ the mouth, vagina, colon, bladder, nose, and ear.
Systemic application can be localized directly by injection into inflamed issue, 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 . . .
.
.
- 1~284~
]2 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-st~roidal 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 ~ormation of ma~ondialdehyde 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 inflamm~tion 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 in1ux into the wound site during the healing process. The decrease in PMN influx was accompanied by the reduced ~ormation of malondialdahyde and conjugated dienes, i~plying a simultaneous reduction in ~ree radical formation.
Accordingly, the ability of the inventive compositions and formulations to inhibit PMN influx into a wound si~e is evidence of anti-inflammatory ac~ivity.
One aspect of the inven~ive 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 ~rom 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 ormed by the combination of the first ~el, cream, or solution and ;
. .
13 ~328~6 the second gel, cream, or solution. Preferably, the dermatalogic composition is formed by the combining oE 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 concen~rations of chlorite and acid are rela~ively low.
The final con~entration range o~ chlo~ite concentration is from about ~00 ppm to abou~ 5000 ppm. Preerably, the final range of chlorite con~entration is from about 800 ppm to about 1600 ppm. ~he 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 lS the treatment of inflammatory disorders such as arthritis, interstitial cystitis, and inflamed bowel by specifically localizinq ~he 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 Slates Patent 4,330,531. Thus ~he first and second solutions will mix at the site of injection and locally form chlorous acid for modula~ed release of chlorine dioxide. Alterna~ively, 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-l tract. A fur~her delivery mode is by encapsulation in a specially coa1ed pharmaceutical matrix that is designed to release its contents in the small intestine upon oral administration.
The composition provides a metastable ch~o~ous 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 14 132~06 of ef~ectiveness. As chlorine dioxide forms, more of the chlori~e converts to chlorous acid by interacting with hydrogen ions fur~her genera~ed by i.onization of the organic acid.
Weak organic acids which may be used in the second solut.ion or gel to ~orm the composition of the inventive process include citric, malic, tartaric, glycolic, mandelic and o~her structurally si.milar acids as described in Formula I hereinbelow:
FORMULA I
O
C-OH
Rl and R2 may be the same or difEercnt and may be selected from ~he group consis~ing of hydrogen, methyl, -CH2COOH, -Cl~2OH, -CI~OI~COO~I, and -Cfl2C6H5. Compositions o~
a metal. ch1Orite and the weak organic acids of Formula are disclosed in copending Canadian Patent Applicatlon .S~ri~l Nllmber 476,980, filed on March 20, 1985.
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 ge].ling agent or thick-ener which is nontoxic and nonreactive wi~h the other ingre-dients 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 ~el may be genera]ly from about 0.5% to ., .i 13284~6 about 5~, typically from about 0.8~ to about ~%, and prefer-ably from about ~% ~o about 3îi Of ~lle gel, by weight, of the total composition. l'he amount of preservative in the gel may be generally from about 0.01% to about 0.05%, typically ~rom about O.Ol~ to about 0.04~, and preEcrably from about 0.02% to about 0.03% by weight of the total composition. ~'he chlorine dioxide liberating compound or metal chlori~e ~nd the protic acid are present in separate gels, and the nmount o~ the preservaLive is present in only thst gel containing the protic acid.
The fi~st gel, containing a me~al chlorite, is preferab~y thickened with a polysulfonic acid salt. The amount of polysulfonic acid salt added will depend on the desired use o~ the r~sulting composi~ion. The amount of lS polysulfonic acid salt is generally from about 5% to about 15~, typically Lrom about 5% to about lOS, and preferably from ahout 6% to about 8% by weight of the total composi-tion. The polysulfonic acid is prepared from:
o C1l2=CI~-c-NE~-c(cH3)2-cH2s03l~
or a salt thereof. The polymerization reaction may be accomplished by a solution, emulsion, or suspension polymer-ization process. ~he medium ror the polymerization is uater, an alcohol, or a mixture thereof. The poIymeriza-tion reaction is described in copending Canadian Patent Application Serial Number 563,942, filed April 12, 1~8.
The treatment of certain skin diseases or certain body cavity and joint inflammatory condi~ions can be additional~y accomplished by the synergistic combination of the chlorous acid/chlorine dioxide formed upon admixture or the two gels, creams or solutions and from the protic acicl itself. For example, the composition for acne con~ains salicylic acid 25 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 '''' ~' .S,. ~ ~ .
w 16 1 3 2 8 4 0 ~
is lactic acid, which also functions to form chlorous acid rom ~he metal chlorite, from which chlorine dioxide is formed.
The gel, cream, or solution containing the p~otic acid (second gel, cream, or solution) and he gel, cream, or solution containing the metal chlorite (first ge~, cream, or solution) are mixed either before application to the affected skin area or in situ. After the gels, cceams, or solutions are mixed, the pH of the final mixture composi-tion is generally less tban about 7, typically from about 2to about 5, and preferably from about 2.5 to about 4. In the treatment process, the mixture composition is ordinar-ily applied to ~he affected skin area at a level of about O.OOl gram to abou1- O.l gram pe~ square c~ntimeter of the lS affected substrate.
The present invention also encompasses a method of treatment of certain skin diseases, wherein the mix~ure composi~ion of two creams, solu~ions or gels is ~pplied topically to affected skin at least once dai~y. Prefer-ably, the mixture composition is applied topically toaffected skin twice daily (e.g., b.i.d.). The mix-ure composition shou]d not be applied to affected skin more than eight times a day.
The present invention is illustrated by ~he following examples. Unless otherwise noted, all parts and percentages in the examples as well as the specification and claims are by weight.
EXAMI~L~ 1 This example illustrates a formulation useful fo~
the topical treatment of genital herpes according ~o the methods of the present invention. This formu1ation also can be used for hemorrhoids and has an~i-in1ammatory activi~y, 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 lac~ic acid 17 132~4~6 as the activator protic acid. The ~ormulations on a pe.rcent weight basis are as follows:
First Gel _ s Poly Isulfonic acid) 45.0 (16% solu~ion ~ 1%) Sodium hydroxide 1 N 45.0 Sodium chlorite (80% ~ 5%) 0.32 Tetrasodium EDTA 0.19 Water Second Gel Lactic Acid (88% 1 5~) 2.6~
Natrosol 250 MR ~ . 75 Isopropy~ alcohol U.S.P. 5.0 Poloxamer ~88 0.4 Sodium Benzoate 0.04 Water q.s.
The composition of Example I was prepared for a clinical. trial in a pair of unit dose sachets. ~ 2-gram quantity of gel con~aining 0.16% of ac~ive chlori.te was prepared by mixing the contents of both sachets immediately prior to application. Thirty-five patien~s (30 males and 5 females) were enrolled. ~'hirty-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 t.d.s., and one patient defaulted. Patients were examined daily until the lesions were healed (defined as re-epithe-* tra~e-mark 1.
. ~
1328~06 l.ialization of the original lesions). The resul~s of ~he study were compared to a similar study conducted with topi-cal acyclovir and placebo (Fiddian et al., J. Antimic_ob Chem. 12:Suppl. B:67-77, 1983) and are presented together 5 in Table 1 below:
Median Median Du~ation of Viral Median Recurrence Symptoms Sheddi.ng Healing Rate _ _ _(d)_ _ Time (d) Time (dl %
10 Exsmple 1 3* 1** 8 (1-1') 19.4 (32) Acyclovi~ 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 ti.mes of 1 day or less.
Clinically, 34/35 patients were suffering ~rom firsL
episode (primary) herpes. One patient had a typical lesion (ulcer) which was in~ected with l~aemophYllis ducryiae which crusted over and failed to respond to treatment with the composition of Example 1. The ~reatment was virological~y effective and patient compliance was good. Positive fac-tors mentioned by the patients inf~uencing compliance were:
twice daily dosing (compared with 5 times daily wi~h some treatments su~h as Acyclovir) 35 the formation of a dry protective il~
over the lesions; reduction of odor;
and sanitizing effect.
, -- ....
i lg 132~06 E~AMP~,E 3 The following formulation can be used as a derma-tologic ~el for psoriasis treatment:
s Base %
Sodium chlorite (80~ ~ 5%) 0.32 Tetrasodium E~rA 0.19 Poly (sulfonic acid) 45.0 (16~ solution ~ 1%~ ;
Sodium hydroxide 1 N 40.0 Nacconol 90F 1.8 Water q~
Activator Propy~ene glycol U.S.P. 40.0 Salicylic acid U.S.~. 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
The following formulation can be use as an acne treatment gel:
* tra~e-mark 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 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.
ÆX~MPLE 5 The following gel can be used for ~opical fungal infections, including tinea cruris:
Base %
Sodium ch~orite (80% + 5%) 0.32 Tetrasodium ÆDTA 0.19 Nacconol 90F 1.8 Po]y (sulfonic acid)45.0 (15% solution + 1~) Sodium hydroxide 1 N45 0 Water a.s.
21 132~4~6 ~ctivator Mandelic acid 2.0 Poloxamer 1~8 0.4 Sodium benzoate 0.04 Natrosol 250 MR l.75 Water q-S~
EX~MPL~ 6 The Eollowing cream can be used for the topical treatment of leg or decubitus ulcers, topical fungal infec-tions, vagini.tis, psoriasis and eczema:
8ase %
Sodium chlori~e (80% ~ 5~ 0.32 Tetrasodium EDrA 0.19 Glycerol monostearate 4.0 Glucam E-20 distearate 3.0 Poly (sulfonic) acid 15.0 (16% solution + 1%) Sodium hydroxide l N 15.0 Water q.s.
Activator Lactic acid (88~ + 5~-) 2.64 Natrosol 250 MR 1.25 Isopropyl alcohol U.S.P. S.0 Glucam E20 distearate 3.0 Glycerol monostearate ~n , 22 1~28406 Ce~yL alcohol 8.0 Stearyl alcohol 2.0 Sodium benzoate 0.04 Water q.s.
This example illus~rates that a composi~ion with the active ingredient concentration o~ F.xample 1, at concen-trations greater ~han 1:~0 dilution wi~h water, inhibits 90~ of PMN chemotaxis as shown in Figure 1. The chemotaxis inhibiting activity decreases with increasing dilution. At the 1:20 dilution uith water, a composition with the active ingredient concentration o~ Example 1 inhibits 60% PMN
chemotaxis, whereas sEter a 1:50 dilution, very little anti-inElammato~y activity is noted. Similarly, the known anti-inflammatory agent, ibupro~en, inhibits 50% rMN chemo-taxis at a 0.12 ~M concen~ration. When diluted to 0.048 mMor further, ibuprofen shows very lit~le anti-inflammatory activity.
PMNs were obtained ~rom rabbit blood and pueified as described in Bandyopadhyay et al., "~ ndium-Tropolone Labeled ~uman PMNs: A Rapid Method of Preparation and Evaluation of Labeling Parameters,~ lnflammation 11:13-22, 1987~. Rabbit blood was drawn from ~he ear vein of four donar rabbits (50 ml each), mixed with acid citrate dextrose (~CD~ anticoagulant and 10 ml of llespan (6~
HETASTMCI~), and stood at room temperature ~or 45 minutes to allow spontaneous settling of ~he red blood cells. As rabbit b~ood a~pears to be homologous, L~lood was pooled for purposes of obtaining ~MN cells for labeling. The upper layer was collected and centrifuged at 150 9 for 8-10 minutes. The upper plasma layee was saved in a different tube and centrifuged at 450 9 ~or ~0 minutes to obtain platelet-poor plasma (rPP) and in the labeling of PMNs with * tra~e-m2rk .
1111noxine. The pelLet was resuspended in 0.9% saline, and residua~ 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 1.11~.
Sixty to eighty microcuries of Indium-lll-oxine (specific activity greater than 10 mCi/ug)(Mediphysics, Inc., Emeryville, Calif.) were incubated with eMNs ~3x106) in PPP at 37C for 20 minutes. Labeled cells were centri-fuged and washed to remove unbound llllnoxine prior to injecting the PMNs into the ear veins of the rabbits studied. The viability of the ~MNs prior to and Eollowing lllIn-labeling was checked in vitro by the conventional trypan blue dye exclusion me~hod. ln vitro leukocyte chemo-~axis was acccssed using the modiied Boyden Chamber ~ssay (Zigmund et al., ~J.eukocyte Locomotion and Chemotaxis,"
J. Exp. Med. 137:387-410, 1983.) EXAMeLE 8 Both ibuprofen and the composition of Example 1 were able to reduce the formation of oxygen-~ree radicals ln vivo as indicated by the concentration of ma~ondialde-hyde and conjugated dienes in tissue biopsies from woundregions and from nonwound areas. Very little malondialde-hyde and conjugated dienes were noticed in ~he 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 or free radica~s in the wound area decreases with the duraLion of the healing process. Maximum concentrations of malon-dialdehyde in conjugated dienes were noticed in 2~-ho~r wound biopsies, with a progressive decline in later biopsies (days 3 and 6). The activities decreased with ~J
1328~6 time, suggesting the presence of decreased free radicals with the dura~ion of healin~ 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 wei~hed and added to 15% trichloroacetic acid ('rCA) (30 mg/ml). Tissue was homogenized using a Polytron homogenizer at 0-5C in an ice bath. The contents were transferred to screw cap test tubes. One ml of 0.75% ~hioba~bi~uric acid solution in 0.5% sodium acetate was then added to each tube. The tubes were boiled in a wa~er bath for 20 minutes. The samples were centri~uged. Absorbance of supernatan~s was read at 535 nm. The molar extinction coeEficient at 535 nm equaled 156 mM~lcm~l, The results are expressed as nmoles of thiobarbituric acid reactive material formed per gram of tissue.
1'he assay for superoxide genera~ion 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 suspen-sions containing S x 106 cells/ml (PMNs) were in~roduced into 12 x 75 nm polypropylene test tubes. These cells were activated in the presence of 10-7 M FMLP~formyl-methionyl-leucyl-phenylalanine, chemotactic factor). The cells plus the activator were incuba~ed for 20 minutes in the presence of 75 uM horse heart ferricytochrome C (T~pe lII, Sigma).
Incuba~ion was terminated by placing the tubes on ice, following which they were centrifuged at 800 g for 10 minutes at 4C. To determine cytochrome C reduced by the presence oE superoxide anion during the incubation, 0 2 mJ
of cell free o~ superna~ant was mixed wi~h 2.2 ml o~ buffer (pH 7.9), and ~he absorbance measured at 550 nm in a Beckman recording spec~rophotometer. The amount of cyctochrome C in the reaction mixture was calcuated using an absorbance coefficient of 21.1 mM~lcm~l at 550 nm and expressed as nmole of cytochrome C reduced per lo6 cells.
, 1 3 2 8 4 0 ~
l'he 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 ~ecknagel et al., ~r.ipoperoxidation As a Vector in Carbon Tetrachloride Hepatotoxicity,~ Lab. I vest. 15:132-46, 1966.
This example illustrates that significant influx oE radio1abe1ed 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 heal-ing. The results by noninvasive, uhole-body gamma-scintigraphy was confirmed by counting the radioactivity incorporated in wound and nonwound regions of tissue biopsies. See Table 2 below:
Effects o~ the ComPosition of Example_l and IbuProfen on the In Vivo PMN Influx in the Wound Biopsies Evaluated by Orqan Countinq 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 signiEicantly 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 ~ . ...
26 . . 132~6 lllIndi.um-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.
Vari~tions and chan~es may be made by those skilled in the art without departing from the spirit and scope of the inven~ion.
. ~
,
FOR DERMATOLOGIC AND INFLAMMATORY DISEASES
This invention relates generaLly to topical formu-lations that are useful for treating various dermatologic disorders, includin~ genital herpes lesions, facial and body acne, topical fungal infections, psoriasis, eczema, dandruff, skin ulcers (e.g., decabutus), and other dermato-logic diseases associated with microbial proliferation.
This invention also relates to the anti-inflammatory proper-ties and uses of pharmaceutical compositions.
There are a large number of dermatologic diseases that are thought to be caused by microbial overgrowth or somehow result in a dermatologic inection and/or inflamma-tory reaction. These diseases include acne vulgaris and other pilosebaceous in~lammat~ry disorders, which are thought to be caused in part by an overgrowth of the anaero-bic bacterium ProPion;bacterium acnes (P. acnes), which is normally present in the sebaceous follicles but prolifer-atos in large numbers during acute acne. P. acnes gener-ates 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 inflamma~ory 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 132~40~
surrounding dermis and creating further inflammation. The visible consequence o~ this series of dermal events is a deep inflammatory nodule, ca]led a "cyst." An accumulation of neutrophils in ~he mouth of a follicle produces a S pustule. Deep inflammatoey or cystic lesions may arise from preexisting closed comedones in an area of normal-appearing skin.
Genital herpes is also called ~Herpes Progeni-talis~ and is caused by the herpes simplex virus, usually type 2. Primary genital herpe3 follows an incubation period of 3 to 7 days. The disease can be found by local-ized burning or paresthesia and ollowed by eruption of grouped vesicles, often at multiple sites on tbe 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. Recur-rent genital herpes is common after the primary infection.
Secondary lesions heal within two weeks, and secondary attacks become less frequent with time. Treatments inc]ude drying agents to symptomatically lessen the discomfort of the lesion. Acyclovir, applied topically, tends o decrease pain of the primary lesions, but it ha~ not proven very effective for decreasing viral shedding or lesion dura-~ion. Topical acyclovir has not been shown to be particu-larly effective for-reducing or treatin~ 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 triphospha~e, which can in~erfere with viral VNA replication. Topical acyclovir is applied as a 5% ointment every thr~e hours, or up to ei~ht 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 3 1 3 2 8 ~ ~6 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. Accordin~ly, no backup treat-ments are available for acyclovir-resistant herpes simplex infections. This problem exists wi~h 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 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.
lS Treatments include the use of dandruff shampoos on the affected areas and typical antifungal agents, including the imidazole derivatives miconazole and clotrimazo~ . 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. mentaqrophytes, and Epidermophyton floccsum.
Tinea pedis is commonly called "a~hlete's foot."
It is often caused by Trichophyton rubrum or Trichophyton mentaqrophytes. It often begins as a sca]y lesion between the toes and spreads to produce an acute inflammatory vesicular disease, accompanied by itching, burning and pain.
Tineas corpo~is is also called 'ringworm" and is a dermato-phyte infection involving nonspecific areas of skin. The infection is an erythematous, scaly patch on the skin with sharp, acu-e borders and central clearing. Current treat-ments for topical fungal diseases include the imidazole derivatives, miconazole and clotrimazole. Griseofulvin is ; '. ~
c. _ 5~ .
4 132~4~6 a systemic agent, and ketoconazole is also used systemi-cally 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 erythema~ous, papulovesicular process often accompanied by oozing and crusting and ollowed by a chronic phase o~ 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 character- -ized by chronic periodic remissions and exacerbations.
Lesions usually consist o 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. ~he disease is characterized histologically by accelerated cellular turn-over. 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 ~he disease. However, no single treatment has yet proven to be successful for a wide variety of cases.
Dandruff is a scaling cond;tion 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 leq ulcer and is a form of eczema and often the resu~t o 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.
.. .~7 Acquired Immune Deficiency Syndrome (Al~S) is believed to be spread by sexual con~act, and more specifi-cally, through transmission of the HIV v;rus. 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 ~hat can be used alon~ 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-inflammato~y agents most often function by inhibition of prostaglandin or leukotriene biosynthetic pathways. For example, non-steroidal anti-inflamma~ory drugs such as aspirin (acetylsalicylic acid), indomethacin, and ib~pro~en are known to inhibit the fatty acid cyclooxyqenase enzyme in the prostaglandin pathway from arachidonic acid.
Steroid drugs have an~i-in~lammatory activity but also have numerous side effects, including sodium retention, hepatic deposition of glycogen, and dramatic redistribution o~ ~ody fat. The steroid anti-inf1ammatory properties are m~diated by inhibiting edema, fibrin deposition, capillary dilation, migration of leukocytes, and deposition of collagen.
Steroid anti-inflammatory agents have immunosuppressant side effeçts.
While it is difficult to give an adequate descrip-tion of the inflammatory phenomenon in terms of the under-lying cellular events in the injured tissu~, there are certain features of the process that are generally agreed to be characteris~ic. ~rhese include fenes~ration of the microvasculature, leakage of the elements of blood into the interstitial spaces, and migration of leukocy~es into the inflamed tissue. On a macroscopic level, this is usually accompanied by the clinical signs ery~hema, edema, tender-ness (hyperalgesia), and pain. During this complex response, chemical mediators such as histamine, 5-hydroxy-tryptamine (5-HT), slow-reactiny substance of anaphylaxis 1328~06 (SRS-A), various chemotactic factors, bradykinin, and prostaglandins are liberated locally. Phagocytic cells migrate into the area and cel~ular lysosomal membranes may be ruptured, releasing lytic enzymes. ~11 these events may contribute to ~he inflammatory response. However, aspirin*
like drugs have lit~le or no effect upon ~he release or activity of histamine, S-l~T, SRS-A, or lysosomal enzymes;
and similarly, potent ant~gonis~s of 5-HT or histamine have little or no ~hcrapeutic effect on inElammation.
The inhibi~ion of prostaglandin biosynthesis by aspirin and other non-steroidal anti-inflammatory agents, such as ibuprofcn, has becn demonstrated in three different systems, cell-free homogenates of guinea pig lung, perfused dog spleen, and human platelcts. There are now numerous systems in vitro and ~n vivo in which inhibition of prosta-glandin 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 depend~nt only on ~he drug reaching the enzyme, cyclooxygenasc (pros~aglandin synthetase); the distribution and pharmokinetics of each agent ~hus have an important bearing on the drug's activity.
The migration oE leukocytes into inflamed areas is an important component of in~lammation. Although the classical aspirin-like drugs (sa~icylates, pyrazolone deriva~ives, ibuprofen, indomet~lacin, e~c.) block prosta-glandin biosysthesis, they do not inhibit the formation of the major chemotactic metabolite of arachidonic acid, HL~'E, and may even increase concentrations of this compound in tissues.
Hypoxia and ischemia are ine~itable fates of any kind o~ tissue injury. Oxygen tension in tissue wounds, when measured by implan~ed polarographic oxygen electrode, was found to be only 5 to 15 mm Hg, as compared to control tissue values of 40 ~o 50 mm Hg. ~Sheffield, "Tissue Oxygen Measurements with Respect to Soft Tissue Wound Healing with Normobaric and Hyperbaric Oxygen," HYPerbaric * tra~e-marks 7 13284~6 Oxyqen Rev. 6:18-46, 1985.) Tissue ischemia is associated with an inflammatory response mediated by stimulated Hagemann factor and complement cascades. (Weiss et al., "Pha~ocyte-Genera~ed Oxgen Metabolites and CelluLar 5 Injury", Lab Invest. 47:5-18, 1982.) These factors activate polymorphonucLear leukocytes (PMNs1 and result in a massive in~lux of phagocytic leukocytes into the wound.
Paradoxically, the antimicromial properties of PMNs are greatly impaired in the ische~ic wound region in vivo because of the lack of molecu]ar oxygen. (Mandell, "Bactericidal Activity of Aerobic and Anaerobic Polymor-phonuclear Neutrophils,~ Infect Immunol. 9-337-41, 1974.) Oxygen therapy, including hyperbaric oxygen treatment, has been suggested to facilitate wound healing and is often lS used as ad;unctive therapy in problem wounds and wound infections. However, the optimal times and mode of oxygen therapy s~ill remain clouded. Oxygen radicals are involved in the phagocytic actions of PMNs, which, upon activation, generate supe~oxide and hydroxyl radicals as well as hydrogen peroxide and hypochlorous acids at the site oE
phagocytosis.
Any wounding, whether surgical or trauma~ic, causes disruption of blood vessels, tissue hemorrhage, acti-vation of Hageman factor, and s~imulation of complement pathways. l'hese morphologic and biochemical events result in the massive influx of PMNs into the wound site and ~he production of superoxide radicals by PMNs as part of the phagocytic response IReaction (i)l. rrhe generated super-oxide radicals undergo the Haber-Weiss reaction lReaction (ii)l or iron-catalyzed Fenton type reactions lReaction ~iii)l, producing cytotoxic OH radicals and H2O2, which u1timately rorm hypohalite radicals via the myeloperoxidase system ¦Reaction (iv)l.
NADYH
i. NADP~ + 202 oxidas>e NADP+ + 202 + E~
ii. H22 + 2 ~>-> OH- + OH + 2 A~
1328~6 iii. Fe2~ ~ H22 ->~> ~'e3~ + OH + O~l iv. H22 ~ Cl- ~ H~ myelo ~ H2O ~ HOCl peroxid se Although the presence of these oxygen-free - radicals is necessary for the oxidative killing of micro-organisms, excessive generation o these cytotoxic radicals may be extremely harmful to native tissues. Tissues are generally equipped wi~h adequ~e an~ioxidative defense sys-tems, consisting o~ such enzymes as superoxide dismutase, catalase, and glutathione peroxidase. ~owever, these anti-oxidative enzymes are known to be reduced during ischemia and hypoxia.
Accordingly, there is a need in the pharmaceuti-cal art for a therapeutic agent that has both strong andbroad spectrum antimicrobial properties for a wide variety of bacterial, fungal, viral, and yeast infections, as well as anti-inflamma~ory 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 lubricat-ing gel that has strong an~iviral 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-inElammatory therapeutic agent that does not possess the side efect problems of the aspicin-like nonsteroidal anti-inflammatory agents or the immunosuppressant proper-ties of the corticosteroids.
The aforementioned therapeutic prob~ems 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, ~' .
13~4~6 the ch~orine 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 inElamma~ory response, or for inflam-maLory conditions. These dermatologic disorders include topical ~ungal diseases, viral lesions such as ~rom genital herpes, and inElammatory/bacterial disorders such as acne.
Additionally, the formulations con~aining the active agents of the present invention are useful for the treatment o~
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 ~ormulations 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 ~o adhere to the epithelial surface and penetrate into ~he dermis. The first solution, gel, or cream contains an amount of me~al chlorite, such that, when combined in equal parts with the first gel, the chlorite ion concerltration in the form of 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 polysulEonic acid wherein the anion of the salt has the formula:
,~ ~
1328~
__ --CH2-CH------- __________________ C=O
Nll CH3 -c-cH2so3 _ CH3 _ X
wherein X has a value such that the mo~.ecular weigbt o~ the ]o anionic portion of the polymer is from about 1,000,000 to about 5,000,000 daItons.
Figure 1 shows the ~n vitro chemotaxis of the inventive composition at the active concentration of Example 1 and the non-steroidal anti-inflammatory agent ibuproÇen (0.5 mg/m]). The inventive composition is shown by ( - _ ) and ibuprofen by ( When there i5 a dottcd line, the inventive composi.tion and ibuprofen were reacted with BSA (bovine serum al.bumi.n).
Figure 2 shows the erfect of the inventive composition (called "~cide~) and i~uprofen on the thiobarbituric acid-reac~ive material production at the wound site during the healing process.
Figure 3 shows the effect of the inventive compo-sition (called "A~cide") and ibuprofen on the conjugated dienes formation at the wound site during the healing process.
Fi.gure 4 is a scintigraphic comparison of Indium-lll-radioactivity accumulation at the wound site during the healing process. The inven~ive composi.tion is termed "~lcide." Gamma-scintigraphy was performed 4 hours following the Indium-lll-labeled ~MN injection. Images were digitized in a 128 x 128 matrix, and regions of interest in wound and nonwound areas were studied.
~.
~284~6 The compositions described herein are useful as topical for~uLations to treat human skin disorders caused by microbial overgrowth or by in~lammation. The skin disordees include facial or ~ody acne, topical fungal infec-tions, gcnital herpes, psoriasis, leg and decubitus ulcers, ec~ema, and dandruE. l'he composition can function as a lubricating barrier gel for the prevention of transmission oE sexually transmitted diseas2s. Dandruf, psoriasis, and eczema are hyperproliferative oc in~lammatory disorders that are believed to be initiated by, or associated with fungal or yeast microbial overgrowth. Accordingly, the skin disorders are oft~n caused by microorganisms, including bacterial, viral, yeast and fungal sources. The compositions or formula~ions are also useful as an~i-in1ammatories.
The tllerapeutic compositions are useEul for the treatment of skin diseases that involve an inflammatory and/or a microbial proliferation component or both compo-nents. Thus, the topical application of the inventivecompositions containing a chlorine dioxide liberating compound in one solution, crcam, or gel and a protic acid in the other solution, cream, or gcl, when mixed, yield chlorine dioxide that is the active antimi~robial or anti-inflammatory agent. A gel composition should have superior skin-adherence properties.
Topical application of the therapeutic composi-tions described herein relates to applica~ion to the surface of the skin and to certain body cavities such as 3~ the mouth, vagina, colon, bladder, nose, and ear.
Systemic application can be localized directly by injection into inflamed issue, 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 . . .
.
.
- 1~284~
]2 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-st~roidal 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 ~ormation of ma~ondialdehyde 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 inflamm~tion 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 in1ux into the wound site during the healing process. The decrease in PMN influx was accompanied by the reduced ~ormation of malondialdahyde and conjugated dienes, i~plying a simultaneous reduction in ~ree radical formation.
Accordingly, the ability of the inventive compositions and formulations to inhibit PMN influx into a wound si~e is evidence of anti-inflammatory ac~ivity.
One aspect of the inven~ive 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 ~rom 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 ormed by the combination of the first ~el, cream, or solution and ;
. .
13 ~328~6 the second gel, cream, or solution. Preferably, the dermatalogic composition is formed by the combining oE 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 concen~rations of chlorite and acid are rela~ively low.
The final con~entration range o~ chlo~ite concentration is from about ~00 ppm to abou~ 5000 ppm. Preerably, the final range of chlorite con~entration is from about 800 ppm to about 1600 ppm. ~he 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 lS the treatment of inflammatory disorders such as arthritis, interstitial cystitis, and inflamed bowel by specifically localizinq ~he 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 Slates Patent 4,330,531. Thus ~he first and second solutions will mix at the site of injection and locally form chlorous acid for modula~ed release of chlorine dioxide. Alterna~ively, 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-l tract. A fur~her delivery mode is by encapsulation in a specially coa1ed pharmaceutical matrix that is designed to release its contents in the small intestine upon oral administration.
The composition provides a metastable ch~o~ous 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 14 132~06 of ef~ectiveness. As chlorine dioxide forms, more of the chlori~e converts to chlorous acid by interacting with hydrogen ions fur~her genera~ed by i.onization of the organic acid.
Weak organic acids which may be used in the second solut.ion or gel to ~orm the composition of the inventive process include citric, malic, tartaric, glycolic, mandelic and o~her structurally si.milar acids as described in Formula I hereinbelow:
FORMULA I
O
C-OH
Rl and R2 may be the same or difEercnt and may be selected from ~he group consis~ing of hydrogen, methyl, -CH2COOH, -Cl~2OH, -CI~OI~COO~I, and -Cfl2C6H5. Compositions o~
a metal. ch1Orite and the weak organic acids of Formula are disclosed in copending Canadian Patent Applicatlon .S~ri~l Nllmber 476,980, filed on March 20, 1985.
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 ge].ling agent or thick-ener which is nontoxic and nonreactive wi~h the other ingre-dients 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 ~el may be genera]ly from about 0.5% to ., .i 13284~6 about 5~, typically from about 0.8~ to about ~%, and prefer-ably from about ~% ~o about 3îi Of ~lle gel, by weight, of the total composition. l'he amount of preservative in the gel may be generally from about 0.01% to about 0.05%, typically ~rom about O.Ol~ to about 0.04~, and preEcrably from about 0.02% to about 0.03% by weight of the total composition. ~'he chlorine dioxide liberating compound or metal chlori~e ~nd the protic acid are present in separate gels, and the nmount o~ the preservaLive is present in only thst gel containing the protic acid.
The fi~st gel, containing a me~al chlorite, is preferab~y thickened with a polysulfonic acid salt. The amount of polysulfonic acid salt added will depend on the desired use o~ the r~sulting composi~ion. The amount of lS polysulfonic acid salt is generally from about 5% to about 15~, typically Lrom about 5% to about lOS, and preferably from ahout 6% to about 8% by weight of the total composi-tion. The polysulfonic acid is prepared from:
o C1l2=CI~-c-NE~-c(cH3)2-cH2s03l~
or a salt thereof. The polymerization reaction may be accomplished by a solution, emulsion, or suspension polymer-ization process. ~he medium ror the polymerization is uater, an alcohol, or a mixture thereof. The poIymeriza-tion reaction is described in copending Canadian Patent Application Serial Number 563,942, filed April 12, 1~8.
The treatment of certain skin diseases or certain body cavity and joint inflammatory condi~ions can be additional~y accomplished by the synergistic combination of the chlorous acid/chlorine dioxide formed upon admixture or the two gels, creams or solutions and from the protic acicl itself. For example, the composition for acne con~ains salicylic acid 25 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 '''' ~' .S,. ~ ~ .
w 16 1 3 2 8 4 0 ~
is lactic acid, which also functions to form chlorous acid rom ~he metal chlorite, from which chlorine dioxide is formed.
The gel, cream, or solution containing the p~otic acid (second gel, cream, or solution) and he gel, cream, or solution containing the metal chlorite (first ge~, cream, or solution) are mixed either before application to the affected skin area or in situ. After the gels, cceams, or solutions are mixed, the pH of the final mixture composi-tion is generally less tban about 7, typically from about 2to about 5, and preferably from about 2.5 to about 4. In the treatment process, the mixture composition is ordinar-ily applied to ~he affected skin area at a level of about O.OOl gram to abou1- O.l gram pe~ square c~ntimeter of the lS affected substrate.
The present invention also encompasses a method of treatment of certain skin diseases, wherein the mix~ure composi~ion of two creams, solu~ions or gels is ~pplied topically to affected skin at least once dai~y. Prefer-ably, the mixture composition is applied topically toaffected skin twice daily (e.g., b.i.d.). The mix-ure composition shou]d not be applied to affected skin more than eight times a day.
The present invention is illustrated by ~he following examples. Unless otherwise noted, all parts and percentages in the examples as well as the specification and claims are by weight.
EXAMI~L~ 1 This example illustrates a formulation useful fo~
the topical treatment of genital herpes according ~o the methods of the present invention. This formu1ation also can be used for hemorrhoids and has an~i-in1ammatory activi~y, 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 lac~ic acid 17 132~4~6 as the activator protic acid. The ~ormulations on a pe.rcent weight basis are as follows:
First Gel _ s Poly Isulfonic acid) 45.0 (16% solu~ion ~ 1%) Sodium hydroxide 1 N 45.0 Sodium chlorite (80% ~ 5%) 0.32 Tetrasodium EDTA 0.19 Water Second Gel Lactic Acid (88% 1 5~) 2.6~
Natrosol 250 MR ~ . 75 Isopropy~ alcohol U.S.P. 5.0 Poloxamer ~88 0.4 Sodium Benzoate 0.04 Water q.s.
The composition of Example I was prepared for a clinical. trial in a pair of unit dose sachets. ~ 2-gram quantity of gel con~aining 0.16% of ac~ive chlori.te was prepared by mixing the contents of both sachets immediately prior to application. Thirty-five patien~s (30 males and 5 females) were enrolled. ~'hirty-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 t.d.s., and one patient defaulted. Patients were examined daily until the lesions were healed (defined as re-epithe-* tra~e-mark 1.
. ~
1328~06 l.ialization of the original lesions). The resul~s of ~he study were compared to a similar study conducted with topi-cal acyclovir and placebo (Fiddian et al., J. Antimic_ob Chem. 12:Suppl. B:67-77, 1983) and are presented together 5 in Table 1 below:
Median Median Du~ation of Viral Median Recurrence Symptoms Sheddi.ng Healing Rate _ _ _(d)_ _ Time (d) Time (dl %
10 Exsmple 1 3* 1** 8 (1-1') 19.4 (32) Acyclovi~ 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 ti.mes of 1 day or less.
Clinically, 34/35 patients were suffering ~rom firsL
episode (primary) herpes. One patient had a typical lesion (ulcer) which was in~ected with l~aemophYllis ducryiae which crusted over and failed to respond to treatment with the composition of Example 1. The ~reatment was virological~y effective and patient compliance was good. Positive fac-tors mentioned by the patients inf~uencing compliance were:
twice daily dosing (compared with 5 times daily wi~h some treatments su~h as Acyclovir) 35 the formation of a dry protective il~
over the lesions; reduction of odor;
and sanitizing effect.
, -- ....
i lg 132~06 E~AMP~,E 3 The following formulation can be used as a derma-tologic ~el for psoriasis treatment:
s Base %
Sodium chlorite (80~ ~ 5%) 0.32 Tetrasodium E~rA 0.19 Poly (sulfonic acid) 45.0 (16~ solution ~ 1%~ ;
Sodium hydroxide 1 N 40.0 Nacconol 90F 1.8 Water q~
Activator Propy~ene glycol U.S.P. 40.0 Salicylic acid U.S.~. 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
The following formulation can be use as an acne treatment gel:
* tra~e-mark 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 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.
ÆX~MPLE 5 The following gel can be used for ~opical fungal infections, including tinea cruris:
Base %
Sodium ch~orite (80% + 5%) 0.32 Tetrasodium ÆDTA 0.19 Nacconol 90F 1.8 Po]y (sulfonic acid)45.0 (15% solution + 1~) Sodium hydroxide 1 N45 0 Water a.s.
21 132~4~6 ~ctivator Mandelic acid 2.0 Poloxamer 1~8 0.4 Sodium benzoate 0.04 Natrosol 250 MR l.75 Water q-S~
EX~MPL~ 6 The Eollowing cream can be used for the topical treatment of leg or decubitus ulcers, topical fungal infec-tions, vagini.tis, psoriasis and eczema:
8ase %
Sodium chlori~e (80% ~ 5~ 0.32 Tetrasodium EDrA 0.19 Glycerol monostearate 4.0 Glucam E-20 distearate 3.0 Poly (sulfonic) acid 15.0 (16% solution + 1%) Sodium hydroxide l N 15.0 Water q.s.
Activator Lactic acid (88~ + 5~-) 2.64 Natrosol 250 MR 1.25 Isopropyl alcohol U.S.P. S.0 Glucam E20 distearate 3.0 Glycerol monostearate ~n , 22 1~28406 Ce~yL alcohol 8.0 Stearyl alcohol 2.0 Sodium benzoate 0.04 Water q.s.
This example illus~rates that a composi~ion with the active ingredient concentration o~ F.xample 1, at concen-trations greater ~han 1:~0 dilution wi~h water, inhibits 90~ of PMN chemotaxis as shown in Figure 1. The chemotaxis inhibiting activity decreases with increasing dilution. At the 1:20 dilution uith water, a composition with the active ingredient concentration o~ Example 1 inhibits 60% PMN
chemotaxis, whereas sEter a 1:50 dilution, very little anti-inElammato~y activity is noted. Similarly, the known anti-inflammatory agent, ibupro~en, inhibits 50% rMN chemo-taxis at a 0.12 ~M concen~ration. When diluted to 0.048 mMor further, ibuprofen shows very lit~le anti-inflammatory activity.
PMNs were obtained ~rom rabbit blood and pueified as described in Bandyopadhyay et al., "~ ndium-Tropolone Labeled ~uman PMNs: A Rapid Method of Preparation and Evaluation of Labeling Parameters,~ lnflammation 11:13-22, 1987~. Rabbit blood was drawn from ~he ear vein of four donar rabbits (50 ml each), mixed with acid citrate dextrose (~CD~ anticoagulant and 10 ml of llespan (6~
HETASTMCI~), and stood at room temperature ~or 45 minutes to allow spontaneous settling of ~he red blood cells. As rabbit b~ood a~pears to be homologous, L~lood was pooled for purposes of obtaining ~MN cells for labeling. The upper layer was collected and centrifuged at 150 9 for 8-10 minutes. The upper plasma layee was saved in a different tube and centrifuged at 450 9 ~or ~0 minutes to obtain platelet-poor plasma (rPP) and in the labeling of PMNs with * tra~e-m2rk .
1111noxine. The pelLet was resuspended in 0.9% saline, and residua~ 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 1.11~.
Sixty to eighty microcuries of Indium-lll-oxine (specific activity greater than 10 mCi/ug)(Mediphysics, Inc., Emeryville, Calif.) were incubated with eMNs ~3x106) in PPP at 37C for 20 minutes. Labeled cells were centri-fuged and washed to remove unbound llllnoxine prior to injecting the PMNs into the ear veins of the rabbits studied. The viability of the ~MNs prior to and Eollowing lllIn-labeling was checked in vitro by the conventional trypan blue dye exclusion me~hod. ln vitro leukocyte chemo-~axis was acccssed using the modiied Boyden Chamber ~ssay (Zigmund et al., ~J.eukocyte Locomotion and Chemotaxis,"
J. Exp. Med. 137:387-410, 1983.) EXAMeLE 8 Both ibuprofen and the composition of Example 1 were able to reduce the formation of oxygen-~ree radicals ln vivo as indicated by the concentration of ma~ondialde-hyde and conjugated dienes in tissue biopsies from woundregions and from nonwound areas. Very little malondialde-hyde and conjugated dienes were noticed in ~he 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 or free radica~s in the wound area decreases with the duraLion of the healing process. Maximum concentrations of malon-dialdehyde in conjugated dienes were noticed in 2~-ho~r wound biopsies, with a progressive decline in later biopsies (days 3 and 6). The activities decreased with ~J
1328~6 time, suggesting the presence of decreased free radicals with the dura~ion of healin~ 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 wei~hed and added to 15% trichloroacetic acid ('rCA) (30 mg/ml). Tissue was homogenized using a Polytron homogenizer at 0-5C in an ice bath. The contents were transferred to screw cap test tubes. One ml of 0.75% ~hioba~bi~uric acid solution in 0.5% sodium acetate was then added to each tube. The tubes were boiled in a wa~er bath for 20 minutes. The samples were centri~uged. Absorbance of supernatan~s was read at 535 nm. The molar extinction coeEficient at 535 nm equaled 156 mM~lcm~l, The results are expressed as nmoles of thiobarbituric acid reactive material formed per gram of tissue.
1'he assay for superoxide genera~ion 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 suspen-sions containing S x 106 cells/ml (PMNs) were in~roduced into 12 x 75 nm polypropylene test tubes. These cells were activated in the presence of 10-7 M FMLP~formyl-methionyl-leucyl-phenylalanine, chemotactic factor). The cells plus the activator were incuba~ed for 20 minutes in the presence of 75 uM horse heart ferricytochrome C (T~pe lII, Sigma).
Incuba~ion was terminated by placing the tubes on ice, following which they were centrifuged at 800 g for 10 minutes at 4C. To determine cytochrome C reduced by the presence oE superoxide anion during the incubation, 0 2 mJ
of cell free o~ superna~ant was mixed wi~h 2.2 ml o~ buffer (pH 7.9), and ~he absorbance measured at 550 nm in a Beckman recording spec~rophotometer. The amount of cyctochrome C in the reaction mixture was calcuated using an absorbance coefficient of 21.1 mM~lcm~l at 550 nm and expressed as nmole of cytochrome C reduced per lo6 cells.
, 1 3 2 8 4 0 ~
l'he 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 ~ecknagel et al., ~r.ipoperoxidation As a Vector in Carbon Tetrachloride Hepatotoxicity,~ Lab. I vest. 15:132-46, 1966.
This example illustrates that significant influx oE radio1abe1ed 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 heal-ing. The results by noninvasive, uhole-body gamma-scintigraphy was confirmed by counting the radioactivity incorporated in wound and nonwound regions of tissue biopsies. See Table 2 below:
Effects o~ the ComPosition of Example_l and IbuProfen on the In Vivo PMN Influx in the Wound Biopsies Evaluated by Orqan Countinq 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 signiEicantly 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 ~ . ...
26 . . 132~6 lllIndi.um-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.
Vari~tions and chan~es may be made by those skilled in the art without departing from the spirit and scope of the inven~ion.
. ~
,
Claims (7)
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.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US19079888A | 1988-05-06 | 1988-05-06 | |
| US190,798 | 1988-05-06 | ||
| US202,758 | 1988-06-03 | ||
| US07/202,758 US4956184A (en) | 1988-05-06 | 1988-06-03 | Topical treatment of genital herpes lesions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1328406C true CA1328406C (en) | 1994-04-12 |
Family
ID=26886461
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000598896A Expired - Lifetime CA1328406C (en) | 1988-05-06 | 1989-05-05 | Anti-inflammatory and antimicrobial formulations for dermatalogic and inflammatory diseases |
Country Status (6)
| Country | Link |
|---|---|
| US (3) | US4956184A (en) |
| EP (1) | EP0417159A1 (en) |
| JP (1) | JPH03505203A (en) |
| AU (1) | AU3696889A (en) |
| CA (1) | CA1328406C (en) |
| WO (1) | WO1989010747A1 (en) |
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| GB1555796A (en) * | 1976-10-15 | 1979-11-14 | Unilever Ltd | Composition for treating acne |
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| EP0315627B1 (en) * | 1986-08-01 | 1992-08-19 | RUBINSTEIN, Alan I. | A method to treat blood |
| US4891216A (en) * | 1987-04-14 | 1990-01-02 | Alcide Corporation | Disinfecting compositions and methods therefor |
-
1988
- 1988-06-03 US US07/202,758 patent/US4956184A/en not_active Ceased
-
1989
- 1989-05-05 CA CA000598896A patent/CA1328406C/en not_active Expired - Lifetime
- 1989-05-05 EP EP89906234A patent/EP0417159A1/en not_active Ceased
- 1989-05-05 JP JP1505975A patent/JPH03505203A/en active Pending
- 1989-05-05 AU AU36968/89A patent/AU3696889A/en not_active Abandoned
- 1989-05-05 WO PCT/US1989/001921 patent/WO1989010747A1/en not_active Application Discontinuation
-
1993
- 1993-09-01 US US08/115,461 patent/US5384134A/en not_active Expired - Lifetime
-
1997
- 1997-01-22 US US08/787,144 patent/USRE37263E1/en not_active Expired - Lifetime
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|---|---|
| AU3696889A (en) | 1989-11-29 |
| USRE37263E1 (en) | 2001-07-03 |
| US5384134A (en) | 1995-01-24 |
| US4956184A (en) | 1990-09-11 |
| EP0417159A1 (en) | 1991-03-20 |
| WO1989010747A1 (en) | 1989-11-16 |
| JPH03505203A (en) | 1991-11-14 |
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