The present invention is directed to pharmaceutical compositions that include a therapeutically effective amount of at least one electron active compound, or a pharmaceutically acceptable derivative thereof, that has at least two polyvalent cations, at least one of which has a first valence state and at least one of which has a second, different valence state. Preferred compounds include Bi(III,V) oxide, Co(II,III) oxide, Cu(I,III) oxide, Fe(II,III) oxide, Mn(II,III) oxide, and Pr(III,IV) oxide, and optionally Ag(I,III) oxide. These compounds may be in a crystalline state having metallic cations of two different valences, or electronic states, in the inorganic crystal. In addition, the invention relates to methods for prevention, management, or treatment of a condition using these compounds or pharmaceutical compositions including the same.

The present invention relates to electron active compounds and compositions that have polyvalent cations in their crystal lattices. In addition, the present invention also includes a method of making such electron active compounds. The present invention also relates to methods for the prevention, treatment, or management of conditions, or symptoms thereof, by administering one or more such compounds or compositions.
Tetrasilver tetroxide has been demonstrated to possess unique properties arising from electrostatic concepts of metal cation interaction. Such silver molecules have also been disclosed for various uses, as they are reported to be non-toxic to animals and humans. M. Antelman, xe2x80x9cAnti-Pathogenic Multivalent Silver Molecular Semiconductors,xe2x80x9d Precious Metals, vol. 16:141-149 (1992); M. Antelman, xe2x80x9cMultivalent Silver Bactericides,xe2x80x9d Precious Metals, vol. 16:151-163 (1992). For example, tetrasilver tetroxide activated with an oxidizing agent is disclosed for use in bactericidal, fungicidal, and algicidal use, such as in municipal and industrial water treatment applications and for the treatment of AIDS.
A variety of sources also report the use of certain divalent silver compounds for water treatment, as well as the use of such compounds, typically in combination with certain oxidizing agents, metals, or other compounds, as disinfectants, bactericides, algicides, and fungicides. One source also reports a single in vitro study of the use of such compounds for the treatment of AIDS. These sources include M. Antelman, xe2x80x9cSilver (II, III) Disinfectants,xe2x80x9d Soap/Cosmetics/Chemical Specialties, pp. 52-59 (Mar., 1994), and U.S. Pat. Nos. 5,017,295; 5,073,382; 5,078,902; 5,089,275; 5,098,582; 5,211,855; 5,223,149; 5,336,416; and 5,772,896.
U.S. Patent No. 5,336,499 discloses tetrasilver tetroxide and persulfate compositions having certain in vitro anti-pathogenic properties, i.e., bactericidal, fungicidal, viricidal, and algicidal, in certain concentrations as low as 0.3 ppm, particularly in nutrient broth cultures. The persulfate is disclosed as being an oxidizing agent that activates the tetroxide crystals. Also disclosed are an in vitro study regarding the inhibition of yeast growth in nutrient broth and the formulation of a gynecological cream and douche based on these results, and a report of an in vitro AIDS test with the compositions indicating total suppression of the virus at 18 ppm.
U.S. Pat. No. 5,571,520 discloses the use of molecular crystals of tetrasilver tetroxide, particularly with oxidizing agents to enhance the efficiency of such devices, for killing pathogenic microorganisms, such as staph infections. Amounts of 10 ppm sodium persulfate as an oxidizing agent were used with certain amounts of silver tetroxide in the reported in vitro testing. One human study involved in vivo curing of a gynecological yeast infection with 10 ppm of the silver tetroxide and 40 ppm sodium persulfate. Other in vivo topical studies report in conclusory fashion the cure of a single case of athlete""s foot with a solution of 100 ppm of the composition and the cure of a single case of toenail fungus with a 25% suspension of the composition.
U.S. Pat. No. 5,676,977 discloses intraveneously injected tetrasilver tetroxide crystals used for destroying the AIDS virus, AIDS synergistic pathogens, and immunity suppressing moieties (ISM) in humans. The crystals were formulated for a single injection at about 40 ppm of human blood. This reference also discloses the compositions cause hepatomegaly, also known as enlarged liver, albeit with no reported loss of liver function.
The aforementioned references report detailed descriptions of the mechanism via which the multivalent silver molecular crystal devices were believed to operate. A discussion of such results and concepts was presented at a Seminar entitled xe2x80x9cIncurable Diseases Updatexe2x80x9d (Weizmann Institute of Science, Rehovot, Israel, Feb. 11, 1998). The title of this presentation was xe2x80x9cBeyond Antibiotics, Non Toxic Disinfectants and Tetrasil(trademark) (a composition including tetrasilver tetroxide).xe2x80x9d In this paper, it was reported that the effects of the electron transfer involved with respect to the tetroxide, rendered it a more powerful germicide than other silver entities. Other patents cover multivalent silver antimicrobial compositions, e.g., U.S. Pat. No. 5,017,295 for Ag(II) and U.S. Pat. No. 5,223,149 for Ag (III). These are stronger antimicrobial agents than Ag (I) compounds, but they pale by comparison to tetrasilver tetroxide. Likewise, colloidal silver that derives its germicidal properties from trace silver (I) ions it generates in various environments is also less effective. Accordingly, the oligodynamic properties of these entities may be summarized as follows, which is referred to as the Horsfal series:
Ag4O4 greater than Ag(III) greater than Ag(II) greater than  greater than  greater than  greater than Ag(I)
Another property of the tetrasilver tetroxide is that it does not stain organic matter such as skin in like manner as Ag(I) compounds do. In addition, it is light stable.
Further, synthetic routes for making Bi(III,V) oxide are detailed and reviewed in Gmelins Handbuch DerAnorganischen Chemie, vol. 16:642 (1964). Also, Co(II,III) oxide, Fe(II,III) oxide, Mn(II,III) oxide, and Pr(III,IV) oxide can all be found in nature. These five multivalent metal oxides are also all available commercially.
In view of the beneficial properties of tetrasilver tetroxide, it could be desirable to find other medicinal uses for this compound, as well as to discover other electron active metal oxides that provide similar properties.
The present invention relates to pharmaceutical compositions that include a therapeutically effective amount of at least one electron active compound, or a pharmaceutically acceptable derivative thereof, that has at least two polyvalent cations, at least one of which has a first valence state and at least one of which has a second, different valence state. Advantageously, the pharmaceutical composition may have antipathogenic efficacy. Preferably, the at least one electron active compound includes a metal oxide. In one embodiment, the metal oxide includes at least one of bismuth, cobalt, copper, iron, manganese, praseodymium, or a combination thereof. Preferably, in that embodiment, the metal oxide includes at least one of Bi(III,V) oxide, Co(II,III) oxide, Cu(I,III) oxide, Fe(II,III) oxide, Mn(II,III) oxide, Pr(III,IV) oxide, or a combination thereof. In another embodiment, the metal oxide can include Ag(I,III) oxide. Alternately, the pharmaceutical composition does not include tetrasilver tetroxide. In another alternate embodiment, the pharmaceutical composition does not include tricobalt tetroxide. In one embodiment, the pharmaceutical composition may include at least two different electron active compounds. In another embodiment, the compound may be in powder or granular form.
In a preferred embodiment, the first valence and the second valence of the at least two polyvalent cations differ by at least 1, preferably by 1 or 2. In another preferred embodiment, the first valence and the second valence of the at least two polyvalent cations differ by more than 2. Advantageously, the electron active compound has at least one polyvalent cation which has an EMFox of at least about +0.1 Volts.
In one embodiment, the amount of the at least one electron active compound is present in an amount from about1 ppm to 500,000 ppm, based on the weight of the composition. If desired, the pharmaceutical composition can include a pharmaceutically acceptable carrier. Optionally, the composition can also include an oxidizing agent, preferably present in an amount sufficient to enhance the efficacy of the active compound but insufficient to cause skin irritation. Preferably, the oxidizing agent includes a peroxy acid salt of a persulfate.
In a preferred embodiment, the at least one compound has antimicrobial efficacy, preferably of at least about 20%. In another embodiment, the antimicrobial efficacy is at least about 50%. In yet another embodiment, the antimicrobial efficacy is at least about 80%. In these embodiments, about 100 ppm of the at least one compound is placed in contact for about 10 minutes with microbes having a cell density of approximately 75,000 CFU/mL.
Also an aspect of the present invention is a pharmaceutical composition comprising tetracopper tetroxide compound. Advantageously, the tetracopper tetroxide contains two copper(I) ions, two copper(III) ions, and four oxygen atoms in a crystal lattice.
Another aspect of the present invention is a method of preventing, treating, or managing a condition of a patient which includes administering a therapeutically effective amount of at least one of the electron active compounds described herein, or a pharmaceutically acceptable derivative thereof, to prevent, treat, or manage the condition, or a symptom thereof. In one embodiment, the method excludes tetrasilver tetroxide. In a preferred embodiment, the patient is a mammal, preferably, a human. Advantageously, the electron active compound(s) can be administered topically, parenterally, or transdermally, preferably in an amount from about 5 ppm to 500,000 ppm, based on the weight of the composition. In one embodiment, at least two different electron active compounds are administered.
In another embodiment, the method can include administering one or more additional different therapeutic agents, present in an amount sufficient to facilitate the prevention, treatment, or management of the condition. In this embodiment, the one or ore additional therapeutic agents may optionally be administered concurrently with the electron active compound(s).
Another aspect of the present invention relates to a method of facilitating the killing of a pathogen which includes administering a therapeutically effective amount of at least one electron active compound, or a pharmaceutically acceptable derivative thereof, that has at least two polyvalent cations, at least one of which having a first valence state and at least one of which having a second different valence state.
The present invention also involves a method of inhibiting the growth of a pathogen which comprises administering a therapeutically effective amount of at least one electron active compound, or a pharmnaceutically acceptable derivative thereof, that has at least two polyvalent cations, at least one of which having a first valence state and at least one of which having a second different valence state.
In one embodiment, these methods exclude the administration of tetrasilver tetroxide. In either of these methods, the pathogen can include a gram-positive bacillus or coccus; a gram-negative bacillus or coccus; an acid-fast bacterium; another type of bacterium; a fungus; a parasitic microbe; a virus; or a combination thereof.
Tetracopper tetroxide, containing two copper(I) ions, two copper(III) ions, and four oxygen atoms, is one preferred electron active compound, while the administration of tetrasilver tetroxide for treating certain conditions is excluded.
In addition, the present invention relates to a process for preparing tetracopper tetroxide, which includes: combining a copper(I)-containing compound and a caustic solution to form a reactant solution; and heating the reactant solution to a temperature and for a time sufficient to produce a detectable amount of the tetracopper tetroxide compound. Advantageously, the copper(I)-containing compound includes a non-solvated inorganic copper(I) oxide, such as cuprous oxide.
The caustic solution generally contains a strong caustic base and a peroxy acid salt. Preferably, the strong caustic base includes a hydroxide salt, and the peroxy acid salt includes a persulfate.
Another aspect of the invention relates to method water with the compounds or compositions of the present invention.
Some of the terms used in connection with the invention can be defined as follows:
The term xe2x80x9ccondition,xe2x80x9d as used herein, should be understood to refer to a traditionally identified disease, as well as a disorder, an affliction, or an ailment, particularly including those noted herein.
The terms xe2x80x9cprevent,xe2x80x9d xe2x80x9cpreventing,xe2x80x9d and xe2x80x9cprevention,xe2x80x9d as used herein, refer to stopping or hindering a condition, symptom, or pathogen causing a condition, in a patient who is at risk of suffering from such a condition. This also includes reducing the frequency or severity, or both, of the occurrence of such conditions or one or more symptoms thereof.
The terms xe2x80x9cmanage,xe2x80x9d xe2x80x9cmanaging,xe2x80x9d and xe2x80x9cmanagement,xe2x80x9d as used herein, includes controlling those conditions which cannot be cured completely, reducing the time of affliction of such conditions, and the like. Preferably, the compositions prevent, treat, or manage such conditions without superficially discoloring the skin, i.e., no discoloration to the naked eye. In one embodiment, the invention relates to the treatment or management, while in another embodiment the invention relates to the prevention, of the diseases or conditions disclosed and claimed herein. The terms also include the use of the compounds or compositions of the invention to facilitate the halting, diminishing, or inhibiting of the growth or proliferation of pathogens that may accentuate, amplify, exacerbate, or cause, either directly or indirectly, a condition and/or a symptom thereof.
The term xe2x80x9cpatientxe2x80x9d as used herein refers to animals, particularly to mammals. In one preferred embodiment, the term patient refers to humans.
The terms xe2x80x9cadverse effects,xe2x80x9d xe2x80x9cadverse side effects,xe2x80x9d and xe2x80x9cside effects,xe2x80x9d as used herein, include, but are not limited to, cardiac arrhythmia, cardiac conduction disturbances, appetite stimulation, weight gain, sedation, gastrointestinal distress, headache, dry mouth, constipation, diarrhea, drug-drug interactions, superficial discoloration of the skin, dry skin, hepatomegaly, fever, fatigue, and the like. The term xe2x80x9ccardiac arrhythmiaxe2x80x9d includes, but is not limited to, ventricular tachyrhythmia, torsades de pointes, QT prolongation, and ventricular fibrillation.
The phrase xe2x80x9ctherapeutically effective amountxe2x80x9d when used herein in connection with the compositions and methods of the invention, means that amount of electron active metal oxide compound(s) or composition(s), or a derivative thereof, which, alone or in combination with other drugs, provides a therapeutic benefit in the prevention, treatment, or management, of a condition. In one embodiment, the effective amount is one or more metal oxide compounds or compositions as the sole active ingredient. Different therapeutically effective amounts may be applicable for each condition, as will be readily known or determined by those of ordinary skill in the art.
The term xe2x80x9csubstantially freexe2x80x9d means less than about 10 weight percent, preferably less than about 5 weight percent, more preferably less than about 1 weight percent, and most preferably less than about 0.1 weight percent. For example, a composition may be substantially free of added oxidizing agent or of added persulfate according to the invention.
The term xe2x80x9cabout,xe2x80x9d as used herein, should generally be understood to refer to both numbers in a range of numerals. Moreover, all numerical ranges herein should be understood to include each whole integer within the range.
The term xe2x80x9csubstantial,xe2x80x9d as used herein, means at least about 75%, preferably at least about 90%, more preferably at least about 95%, most preferably at least about 99%.
The term xe2x80x9cvalence state,xe2x80x9d as used herein, should be understood to refer to the charge on a given ion or to the charge that may be assigned to a given ion based on its electronic state.
The terms xe2x80x9cinhibit,xe2x80x9d xe2x80x9cinhibiting,xe2x80x9d or xe2x80x9cinhibits,xe2x80x9d as used herein when referring to growth of an item, should be understood to refer to the act of stopping that growth, whether permanently or temporarily, or of reducing the rate of that growth, either permanently or temporarily.
The tetrasilver tetroxide compounds mentioned in the background are one type of electron active compound having multivalent cations in its crystal lattice. Various additional electron active compounds have now also been identified, as well as methods for making and using the same for treating various pathogenic and non-pathogenic conditions or disorders. The electron active compounds of the present invention are believed to have unique crystal structures in that, in the case of the metal oxides, there are generally atoms of the same element in the crystal that have at least two different valences, typically at least one lower-valent metal cation and at least one higher-valent metal cation, for example, such as Co(II) and Co(III), respectively. Exemplary electron active metal oxide compounds according to the invention include, but are not limited to, Ag(I,III), Co(II,III), Pr(III,IV), Bi(III,V), Fe(II,III), Mn(II,III), and Cu(I,III) oxides. In another embodiment, Tb(III,IV) oxide, Tb4O7, or tetraterbium heptoxide, is one electron active metal oxide compound according to the invention. As discussed below, pharmaceutical compositions including one or more of such oxide compounds are useful for treating various conditions. The composition of such exemplary electron active metal oxides is shown in tabular form below:
Without being bound to theory, it is believed that the electron active compounds operate against pathogens by transferring electrons between their lower-valent ions and their higher-valent ions in the crystal, thereby contributing to the death of pathogens by traversing their cell membrane surface. It would seem that this, in effect, xe2x80x9celectrocutesxe2x80x9d the pathogens. While these compounds have also been discovered to be suitable for use in the prevention, treatment, and management of other non-pathogenic conditions and disorders, such as autoimmune disorders, circulatory disorders, neurological disorders, and the like, the mechanism by which such conditions or disorders are prevented, treated, or managed has not yet been fully understood. In any event, the electrons in proximity to pathogens are believed to be perturbed from their balanced crystals by such labile groups as NH, NH2, Sxe2x80x94S, and SH, which can be present, for example, in a pathogen cell membrane. It is believed, however, that normal cells will not be significantly affected because they do not proliferate rapidly enough to expose these labile bonds sufficiently for the bonds to be substantially affected.
The crystals in the electron active compounds are not believed to be disturbed unless more stable complexes are formed with ligands, for example, such as those comprising a pathogen cell membrane surface in a dynamic state. Indeed, the end result of electron transfer, which is a redox reaction, results in the lower-valent metal ions being oxidized to one valence state higher and the higher-valent metal ions being reduced to one valence state lower. In one embodiment, the oxidation of the lower-valent metal ions and the reduction of the higher-valent metal ions both result in ions having the same oxidation state. Examples of such an embodiment occur when the valence difference between the metal ions in the electron active molecular crystal is 2 and such examples include, but are not limited to, Ag(I,III), Bi(III,V), and Cu(I,III) oxides. In another embodiment, the oxidation of the lower-valent metal ions and the reduction of the higher-valent metal ions result in ions having opposite oxidation states (e.g., ions with a +2 valence state are oxidized to +3, while the ions with a +3 valence state are reduced to +2). Examples of such an embodiment occur when the valence difference between the metal ions in the electron active molecular crystal is 1 and such examples include, but are not limited to, Co(II,III), Fe(II,III), Mn(II,III), and Pr(III,IV) oxides.
The metal ion of certain electron active compounds may exhibit a distinct affinity for certain elements of ligands, for example, such as sulfur, oxygen, or nitrogen, particularly when present in a pathogen""s cell membrane. In many cases, the metal ion will not merely bind to these elements, but will actually form chelate complexes with their ligands. The classic example of this is Ag(I,III) oxide, the monovalent silver ion of which has an affinity for sulfur and nitrogen and the oxidized/reduced divalent ion of which forms chelate complexes with, for example, mercapto or amino groups. Thus, the electron active compound attraction for the cell membrane surfaces, for example, of pathogens, is believed to be driven by powerful electrostatic forces.
Without being bound by theory, the electron exchange may be depicted, for example, by the following series of redox half reactions:
For each redox reaction, there is believed to be an electromotive force, which is the voltage potential of the oxidizing the higher-valent ion in the metal oxide crystal. This is denoted herein as EMFOX. In addition to the electromotive force of oxidation, there is believed to be an associated reduction reaction involving the lower-valent ion in the metal oxide crystal. This reduction reaction may be represented simply, as tabulated above, or may represent the interaction with, for example, a ligand present on a pathogen cell membrane surface, such as one containing sulfur or nitrogen. Associated with the reduction reaction is another electromotive force, or voltage potential of the reducing the lower-valent ion. This is denoted herein as EMFRE.
When the metal ions of the electron active metal oxide interact with, for example, a sulfur-containing ligand, the affinity of the metal ion for sulfur affects EMFRE. The stability of a particular metal sulfide is an approximation of the affinity of a metal ion for sulfur. The following approximate association constants for sulfides indicate the trend in relative affinity of each metal ion for sulfur:
In general, the more stable the compound, the more negative its reduction potential in the reduction reaction, for example, in the case of elemental silver:
2Ag+Sxe2x88x922xe2x88x922exe2x86x92Ag2S EMFRE=xe2x88x920.66
In the case of tetrasilver tetroxide, there is a reduction reaction where Ag(I) is oxidized and an oxidation reaction where Ag(III) is reduced, as follows:             xe2x80x83                                                Ag            +                    -          e          +                      S                          -              2                                      ->                  AgS                                xe2x80x83                                          EMF            RE                              =              -        0.90                                          Ag                      +            3                          +        e            ->                        Ag                      +            2                                            xe2x80x83                                  EMF          OX                      =          +              2.02        .
The voltage that is discharged from a redox reaction of the electron active metal oxides of the present invention, which voltage is denoted herein as the xe2x80x9celectrocution voltage,xe2x80x9d is the combination of the oxidizing cation""s reduction potentials and the reducing cation""s reduction potential (i.e., EMFOXxe2x88x92EMFRE) In the case of tetrasilver tetroxide, the xe2x80x9celectrocution voltagexe2x80x9d is 2.92 volts. The oxidizing cation""s reduction potentials, EMFOX, of exemplary metal oxides according to the present invention are tabulated below:
As noted from the above table, praseodymium-, cobalt-, and copper-based oxides are believed to be stronger antipathogenic agents or to form better pharmaceutical compositions than manganese-, bismuth-, and iron-based oxides, and in one embodiment they are preferred for this reason. Nevertheless, in certain cases, iron exhibits stronger antipathogenic characteristics, particularly antimicrobial characteristics, compared to manganese.
Another factor, however, particularly in antipathogenic or antimicrobial efficacy, can be the sulfur/nitrogen composition, for example, of cell membranes. For example, Staphylococcus aureus bacteria, in a culture having a cell density of 30,000 CFU/mL, exhibit significant mortality from exposure to 100 ppm of Bi(III,V) oxide for about 10 minutes, but no significant mortality from exposure to the same concentrations of Fe(II,III) and Mn(II,III) oxides for the same contact time. This result might be explained by the far greater stability of bismuth(III) sulfide, and thus the far greater affinity of bismuth(III) for sulfur, than either of the iron(II) or manganese(II) analogs.
The electron active metal oxide compounds and compositions of the present invention may be used in any form which sufficiently retains their antipathogenic character, or other non-pathogenic ability, to prevent, treat, or manage one or more of the conditions noted herein.
These compounds or compositions may be used as antipathogenic agents, such as antimicrobial, antibacterial, antiviral, or anti-algal agents, or a combination thereof. In another embodiment, the compounds or compositions may be used for preventing, treating, and/or managing various conditions that are non-pathogenic. For example, non-pathogenic conditions are believed to include certain autoimmune disorders, neurological disorders, and circulatory disorders. While the exact mechanism of the activity of such compounds or compositions is not described herein, nonetheless, suitable prevention, treatment, and/or management of such non-pathogenic conditions may be obtained by administering the compounds or compositions of the invention as described herein and as will be readily apparent to one of ordinary skill in the art.
The compositions and methods of the invention advantageously prevent, treat, or manage dermatological diseases or conditions. The conditions against which the electron active compounds, such as metal oxides, of the present invention have utility include, but are not limited to, Madura foot, actinomycosis, oral actinomycosis, anthrax, food poisoning, botulism, wound infections, pseudomembranous colitis, colitis, gas gangrene, gangrene, tetanus, diphtheria, pharyngeal diphtheria, pleomorphic laryngeal diphtheria, cutaneous diphtheria, endocarditis, bacteremia, urinary tract infections, listerosis, meningitis, miscarriage, narcodiosis, acne, skin lesions, abscesses, toxic shock syndrome, prosthesis contamination, dental caries, plaque, gum disease, gingivitis, subacute endocarditis, bacterial pneumonia, otitis, sinusitis, cat scratch fever, septicemia, abdominal and pelvic abscesses, Oroya fever, systemic Oroya fever, verruga peruana, cutaneous verruga peruana, whooping cough, Lyme disease, epidemic relapsing fever, brucellosis, granuloma inguinale granulomatic, donovanosis, gastroenteritis, nosocomial infections, tularemia, bacterial vaginitis, urethritis, bacterial conjunctivitis, chancroid, otitis media, chronic gastritis, peptic ulcer, diarrhea, Legionnaires"" disease, leptospirosis, gonorrhea, arthritis, periodontal disease, salmonellosis, typhoid fever, shigellosis, rat bite fever, pharyngitis, scarlet fever, syphilis, cholera, Asiatic cholera, Yersina arthritis, bubonic plague, chronic pulmonary disease, Hansen""s disease, leprosy, tuberculosis, dermal tuberculosis, psittachosis, ornithosis, conjunctivitis, trachoma, lymphogranuloma venereum, genital tract infections, Q fever, primary atypical pneumonia, rickettsial pox, typhus, epidemic typhus, Rocky Mountain spotted fever, tsutsugamushi fever, nongonococcal urethritis, human erlichiosis, meningococcal meningitis, skin infections, corneal infections, external ear infections, candidiasis, monoiliasis, thrush, candidosis, mucositis, bacteremia, hepatitis, hepatitis A, hepatitis B, hepatitis C, hepatitis E, coccidiomycosis, lymphadenitis, balantidiasis cryptosporidosis, amoebiasis, amoebic dysentery, giardiasis, giardia enteritis, leishmaniasis, Kala-azar, malaria, toxoplasmosis, trypanosomiasis, Chagas disease, African sleeping sickness, dengue, Japanese encephalitis, Rift Valley fever, Ebola hemorrhagic fever, Venezuelan hemorrhagic fever, hantavirus pulmonary syndrome, hemorrhagic fever with renal syndrome, cytomegalovirus infection, poliomyelitis, West Nile virus disease, influenza, measles, condyloma, encephalitis, ankylosing spondylitis, arteritis, inflammatory bowel disease, polyarteritis nodosa, rheumatic fever, systemic Lupus erythematosus, Alzheimer""s disease, multiple sclerosis, osteoporosis, Crohn""s disease, strep throat, yellow fever, eczema, psoriasis, dernatitis, disease-induced skin ulcers, undefined tropical diseases, shingles, rashes, heat rashes, bedsores, cold sores, blisters, boils, herpes simplex, acne, pimples, skin chafing, skin cracking, itchiness, skin peeling, warts, one or more symptoms thereof, or any combination thereof. In another embodiment, the condition includes HIV (AIDS), or one or more symptoms. It should be understood that the invention includes the use of the compounds or compositions to prevent, treat, or manage each of these conditions individually or multiple conditions concurrently or sequentially. Thus, the prevention, treatment, or management of each condition should be understood as a separate embodiment.
The pathogens which may be killed by, or the growth or proliferation of which may be halted, diminished, or inhibited by, the electron active metal oxides of the present invention include, but are not limited to, gram-positive bacilli and cocci; gram-negative bacilli and cocci; acid-fast bacteria; other bacteria; fungi; parasitic microbes, e.g., protozoa; and viruses.
Examples of gram-positive bacilli and cocci include, but are not limited to, Actinomedurae, Actinomyces israelii, Bacillus anthracis, Bacillus cereus, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Corynebacterium, Enterococcusfaecalis, Listeria monocytogenes, Nocardia, Propionibacterium acnes, Staphylococcus aureus, Staphylococcus epiderm, Streptococcus mutans, Streptococcus pneumoniae, and combinations thereof.
Examples of gram-negative bacilli and cocci include, but are not limited to, Afipia felis, Bacteriodes, Bartonella bacilliformis, Bortadella pertussis, Borrelia burgdorferi, Borrelia recurrentis, Brucella, Calymmatobacterium granulomatis, Campylobacter, Escherichia coli, Francisella tularensis, Gardnerella vaginalis, Haemophilius aegyptius, Haemophilius ducreyi, Haemophilius influenziae, Heliobacter pylori, Legionella pneumophila, Leptospira interrogans, Neisseria meningitidia, Porphyromonas gingivalis, Providencia sturti, Pseudomonas aeruginosa, Salmonella enteridis, Salmonella typhi, Serratia marcescens, Shigella boydii, Streptobacillus moniliformis, Streptococcus pyogenes, Treponema pallidum, Vibrio cholerae, Yersinia enterocolitica, Yersinia pestis, and combinations thereof.
Examples of acid-fast bacteria include, but are not limited to, Myobacterium avium, Myobacterium leprae, Myobacterium tuberculosis, and combinations thereof.
Examples of other bacteria not falling into the other three categories include, but are not limited to, Bartonella henseiae, Chlamydia psittaci, Chlamydia trachomatis, Coxiella bumetii, Mycoplasma pneumoniae, Rickettsia akari, Rickettsia prowazekii, Rickettsia rickettsii, Rickettsia tsutsugamushi, Rickettsia typhi, Ureaplasma urealyticum, Diplococcus pneumoniae, Ehrlichia chafensis, Enterococcusfaecium, Meningococci, and combinations thereof.
Examples of fungi include, but are not limited to, Aspergilli, Candidae, Candida albicans, Coccidioides immitis, Cryptococci, and combinations thereof.
Examples of parasitic microbes include, but are not limited to, Balantidium coli, Cryptosporidium parvum, Cyclospora cayatanensis, Encephalitozoa, Entamoeba histolytica, Enterocytozoon bieneusi, Giardia lamblia, Leishmaniae, Plasmodii, Toxoplasma gondii, Trypanosomae, trapezoidal amoeba, and combinations thereof.
Examples of viruses include, but are not limited to, Arboviruses, Ebola virus, Guanarito virus, Hanta virus, Hantaan virus, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis E, other Hepatitis viruses, Herpes-type viruses, Poliovirus, West Nile virus, Echo virus, and combinations thereof.
The antipathogenic or non-pathogenic compositions of the present invention may optionally further include the use of one or more additional therapeutic agents known to treat a condition, or a symptom thereof. Examples of such additional therapeutic agents include, but are not limited to, chelating agents, vitamins, minerals, silica hydride microclusters, analgesics, Sambucol(trademark), aspirin, and the like.
The electron active metal oxide compounds of the present invention may also be used for water treatment, for example, as disclosed in U.S. Pat. No. 5,223,149 and 5,336,416. Optionally but preferably, the electron active metal oxides used for treating a body of water are any listed above, more preferably provided that the metal oxide does not include tetrasilver tetroxide. It is also more preferable, in the previous embodiment, that the metal oxide does not include tetracopper tetroxide.
The administration of one or more active ingredients and/or optional therapeutic agent(s), in accordance with the methods of the invention may occur together, concurrently but separately, sequentially, or a combination thereof. The optional additional therapeutic agent is generally a compound other than an electron active metal oxide compound.
The antipathogenic or antimicrobial performance of certain metal oxides may be improved or enhanced by the presence of an oxidizing agent. This is particularly the case when the metal oxide compounds or compositions are present in low amounts, i.e., typically less than 45 ppm, and more commonly when present in an amount less than about 40 ppm, based on the weight of the composition. In such situations, an oxidizing agent may be included in certain compositions of the invention in small amounts when the compositions are administered by certain routes. In such an embodiment, the oxidizing agent includes a peroxy acid salt, preferably a Group I salt of a persulfate, more preferably potassium persulfate. In another embodiment, the oxidizing agent includes the same peroxy acid salt which was present as a starting material in the reaction to form the particular electron active metal oxide. The oxidizing agent may advantageously be present in the composition in amounts from about 1 ppm to 500 ppm, based on the weight of the composition. In alternate embodiments, there may be from about 5 ppm to 200 ppm or from about 10 ppm to 100 ppm of oxidizing agent, based on the weight of the composition.
It is believed that the additional presence of certain types or amounts of oxidizing agent(s) may tend to irritate the skin, particularly when the compound or composition including metal oxide(s) is present in large amounts, such as greater than 50 ppm, based on the weight of the composition. In one embodiment, as more compound or composition is administered, a correspondingly smaller amount of undesirable oxidizing agent is required. Thus, in some embodiments, it has been found that the additional oxidizing agent is unnecessary and in fact undesirable for the purpose of treating certain conditions described herein, since the additional oxide may have or contribute to an undesirable side effect, for example, such as skin irritation when applied topically. For those embodiments, the compositions minimize the amount of additional oxidizing agent, such as persulfate, or are substantially or completely free of added persulfates or other oxidizing agents.
Certain of the electron active metal oxides may be black in color, such that care must be taken when formulating suitable topical pharmaceutical compositions according to the invention to inhibit blackening or superficial discoloration of the skin. Without being bound by theory, it is believed that larger amounts of such compositions promote increased superficial discoloration. Thus, in one embodiment, the pharmaceutical compositions preferably have an insufficient amount of metal oxide composition to cause visible skin discoloration.
Additionally, it was found by rigorous testing that certain silver tetroxide-containing compositions were comparatively non-toxic compared to silver salts, such as conventional formulations of silver nitrate, silver sulfadiazine, and benzoyl peroxide. Since these silver tetroxide compositions were effective at certain ppm concentrations in killing pathogens in nutrient broth and for water treatment, commercial concentrates were formulated with 2% of the tetrasilver tetroxide. For acceptance of the oxide in commerce, for which EPA registration No. 3432-64 was obtained, it was necessary for the Ag4O4 to undergo a series of toxicity tests. A 3% concentrate was used and evaluated by a certified laboratory employing good laboratory practice (GLP) according to the Code of Federal Regulations for this purpose. The results were as follows:
Subsequent evaluations conducted according to the invention showed that unless persons were prone to silver allergies, the pure tetrasilver tetroxide compositions according to the invention could be applied to the skin without any ill effects or evidence of irritation, despite the fact that the compositions of the invention can be a powerful oxidizing agent. This can perhaps be explained by the stability manifested by the KA of the tetrasilver tetroxide compositions, which is approximately 7.9xc3x9710xe2x88x9213.
Where the electron active compositions according to the invention are applied to the skin, they may be combined with a carrier in an amount from about 5 ppm to 500,000 ppm, more preferably from about 50 ppm to 250,000 ppm of the electron active metal oxide composition, based on the weight of the composition. In various embodiments, the compositions are provided in amounts from about 400 ppm to 100,000 ppm, from about 1,000 ppm to 70,000 ppm, from about 10,000 ppm to 50,000 ppm, or from about 20,000 ppm to 40,000 ppm, based on the weight of the composition. In one preferred embodiment, the compositions are formulated with about 25,000 ppm to 35,000 ppm of metal oxide, based on the weight of the composition. It will be readily understood by those of ordinary skill in the art that the ppm concentration of electron active compound(s), such as metal oxide, in the composition is based on the total weight of the composition.
When prevent, treating, or managing conditions, a preferred embodiment employs amounts of about 0.1 to 10 percent by weight, about 0.25 to 5 percent by weight, or about 2 to 4 percent by weight of the compounds or compositions of the invention. The compositions, when applied topically, can be applied to the skin about1 to 3 times per day until the condition is suitably cured or satisfactorily controlled. In one embodiment, the composition may generally be topically applied at a dosage level of from about 1 mg to 1000 mg per cm2 of skin surface, preferably about 10 mg to 500 mg per cm2 of skin surface. When applied topically, a preferred carrier includes petroleum jelly, such as white petroleum jelly. For example, a suitable white petroleum jelly is available from Penreco of Houston, Tex.
Most of the metal oxide compounds for use according to the invention are commercially available from various sources. Tetrasilver tetroxide compositions for use according to the invention have been commercially sold under the poorly named xe2x80x9cAg(II) OXIDExe2x80x9d tradename. They may be obtained from Aldrich Chemical Co., Inc., having a place of business in Milwaukee, Wis. The chemical synthesis of tetrasilver tetroxide compounds can be performed according to the method described on page 148 in M. Antelman, xe2x80x9cAnti-Pathogenic Multivalent Silver Molecular Semiconductors,xe2x80x9d Precious Metals, vol. 16:141-149 (1992) by reacting silver nitrate with potassium peroxydisulfate according to the following equation in alkali solutions:
4AgNO3+2K2S2O8+8NaOHxe2x86x92Ag4O4+3Na2SO4K2SO4+2NaNO3+2KNO3+4H2O
To the extent necessary to understand the present invention, the disclosure of Antelman is hereby incorporated herein by express reference thereto.
Tetracopper tetroxide, also referred to herein as Cu(I,III) oxide or Cu4O4, is a preferred electron active compound in accordance with the invention. This compound may be prepared as follows.
Suitable copper-based starting materials for this reaction include at least one copper(I)-containing material. In one embodiment, a water soluble copper(I) salt can be used. Typically, a water soluble copper(I) salt can be prepared by dissolving an inorganic copper(I) compound, for example, such as cuprous oxide, in an appropriate acid, for example, an organic acid, such as acetic acid. Since soluble copper(I) salts are not readily commercially available at the present time, however, a non-solvated inorganic copper(I) compound, such as cuprous oxide itself, can be used as the copper(I)-containing starting material. In addition, other copper(I)-containing materials, either inorganic, such as a copper(I) oxide, or organic, such as an organometallic copper(I) compound, or both, may be used, where the copper(I)-containing material(s) are sufficiently soluble in an aqueous or organic solution to allow reaction with other materials to form an electron active copper oxide compound.
The copper(I)-containing starting material is combined with an aqueous caustic solution. This caustic solution preferably contains two components: a strong caustic base and a peroxy acid salt. Examples of suitable strong caustic bases include Group I and Group II hydroxides, preferably sodium hydroxide or potassium hydroxide. Examples of suitable peroxy acid salts include Group I salts of persulfates, preferably potassium persulfate.
The copper-based starting material is typically the limiting reagent in such a preparation. The ratio of each of the components in the caustic solution to that of the copper-based starting material is theoretically set by the stoichiometry of the particular reaction. In one preferred embodiment, there is a relative molar excess, i.e., an amount more than stoichiometrically necessary, of each of the components in the caustic solution with respect to the copper-based starting material. When a strong caustic base and a peroxy acid salt are present in the caustic solution, the relative molar excesses of the components may be at least about 50% and at least about 10%, respectively, preferably at least about 100% and at least about 20%, respectively, more preferably, at least about 250% and at least about 40%, respectively, most preferably at least about 500% and at least about 75%, respectively.
Generally, the reactants may be added together in any manner that comports with typical laboratory procedure. In one embodiment, the copper(I)-containing starting material is placed in a reactor, to which the strong caustic base and the peroxy acid salt are added, each typically in their own solutions. The solution containing the reactants is then typically heated to a temperature sufficient to activate a reaction, preferably sufficient to activate a reaction with no major undesirable side reactions or other undesirable effects, more preferably above about 80xc2x0 C., most preferably about 90xc2x0 C. to 95xc2x0 C. The solution is heated for a time sufficient to facilitate the reaction, preferably to provide substantial completion of the reaction, preferably for at least about 5 minutes, more preferably for at least about 15 minutes, after which time the solution is allowed to cool or is cooled, preferably to below about 45xc2x0 C., more preferably to about room temperature.
The color change of the solution, from its original color, red, to a color indicating a reaction has occurred, in this case black, may occur at the heated temperature or during or after cooling.
The purification and isolation of the desired product can be accomplished by any suitable method available to those of ordinary skill in the art. In the majority of situations, the desired reaction product is primarily a solid, but may be dissolved or dispersed in at least part of the solution. In one preferred embodiment, the solution is carefully decanted off, and then the remaining product is washed multiple times with distilled water, before being sufficiently dried. In another preferred embodiment, the solution is vacuum filtered to remove the filtrate, and the remaining product is sufficiently dried.
The yield of solid tetracopper tetroxide material, based on the reactants, is typically at least about 10%, preferably at least about 45%, more preferably at least about 75%, most preferably at least about 80%.
In addition, Fe(II,III) oxide and Mn(II,III) oxide are commercially available from Aldrich Company of Milwaukee, Wis., and Co(II,III) oxide and Pr(III,IV) oxide are commercially available from Noah Technologies of San Antonio, Tex. Also, Bi(III,V) oxide synthetic routes are detailed and reviewed in Gmelins Handbuch Der Anorganischen Chemie, vol. 16:642 (1964), and the oxide is available commercially from City Chemicals of New York, N.Y.
The magnitude of a prophylactic or therapeutic dose of electron active composition(s), or a derivative thereof, in the acute or chronic management of diseases and disorders described herein will vary with the severity of the condition to be prevented, treated, or managed and the route of administration. For example, oral, mucosal (including rectal and vaginal), parenteral (including subcutaneous, intramuscular, bolus injection, and intravenous, such as by infusion), sublingual, transdermal, nasal, buccal, and like may be employed. In one embodiment, a patient may gargle using the composition of the present invention. Dosage forms include tablets, troches, lozenges, dispersions, suspensions, suppositories, solutions, capsules, soft elastic gelatin capsules, patches, and the like. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. Suitable dosing regimens can be readily selected by those of ordinary skill in the art with due consideration of such factors. In general, the total daily dosage for the conditions described herein, is from about 0.1 mg to 1,000 mg of the active ingredient, i.e., one of the metal oxides described herein, or a derivative thereof. In another embodiment, the daily dosage can be from about 1 mg to 500 mg, while in another embodiment, the daily dosage can be from about 2 mg to 200 mg of the metal oxide composition. A unit dosage can include, for example, 30 mg, 60 mg, 90 mg, 120 mg, or 300 mg of metal oxide composition. Preferably, the active ingredient is administered in single or divided doses from one to four times a day, such as by topical administration. In another embodiment, the compositions are administered by an oral route of administration. The oral dosage forms may be conveniently presented in unit dosage forms and prepared by any methods available to those of ordinary skill in the art of pharmacy.
In managing the patient, the therapy may be initiated at a lower dose, e.g., from about 1 mg, and increased up to the recommended daily dose or higher depending on the patient""s global response. It is further recommended that children, patients over 65 years, and those with impaired renal or hepatic function, initially receive low doses when administered systemically, and that they be titrated based on individual response(s) and blood level(s). It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
Any suitable route of administration may be employed for providing the patient with an effective dosage of electron active metal oxide, or a derivative thereof. The most suitable route in any given case will depend on the nature and severity of the condition being prevented, treated, or managed.
In practical use, the metal oxide, or a derivative thereof, can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms and may include a number of components depending on the form of preparation desired for administration. The compositions of the present invention may include, but are not limited to, suspensions, solutions and elixirs; aerosols; or carriers, including, but not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.
Suitable forms in which the electron active compounds or compositions of the present invention may be used include, but are not limited to, powder, granule, flake, solution, suspension, emulsion, slurry, aerosol spray, gel, paste, and combinations thereof. In one preferred embodiment, the form is a powder or solution. When the electron active compounds are in the form of a solution, the solution may be aqueous, non-aqueous, or a combination thereof, preferably at least partially aqueous, more preferably substantially aqueous. In a preferred embodiment, the metal oxides are in an aqueous solution.
The compositions of the invention may be applied topically, e.g., either directly as a powder or in non-sprayable or sprayable form. Non-sprayable forms can be semi-solid or solid forms including a carrier indigenous to topical application and preferably having a dynamic viscosity greater than that of water. Suitable formulations include, but are not limited to, suspensions, emulsions, creams, ointments, powders, liniments, salves and the like. If desired, these may be sterilized or mixed with any available auxiliary agents, carriers, or excipients, e.g., thixotropes, stabilizers, wetting agents, and the like. One or more thixotropic agents can be included in types and amounts sufficient to increase adhesion of topically applied compositions of the invention to the skin, so as to inhibit or prevent runoff or other loss of the composition from the treatment zone on the skin. Preferred vehicles for non-sprayable topical preparations include ointment bases, e.g., polyethylene glycol-1000 (PEG-1000); conventional ophthalmic vehicles; creams; and gels, as well as petroleum jelly and the like. In one more preferred embodiment, the carrier includes a petroleum jelly. In another preferred embodiment, the carrier is formulated as a cream, gel, or lotion. In another preferred embodiment, the carrier is 3 weight percent active ingredient, 36 weight percent heavy mineral oil, 47 weight percent petroleum jelly, and 14 weight percent Tivawax P, which is available from Tivian Laboratories, Inc., of Providence, R.I. In yet another preferred embodiment, the composition may be a dry powder, such as with 5 weight percent active ingredient and 95 weight percent bismuth subgallate. These topical preparations may also contain emollients, perfumes, and/or pigments to enhance their acceptability for various usages.
The compositions may also be formulated for parenteral administration by injection (subcutaneous, bolus injection, intramuscular, or intravenous, such as by infusion), and may be dispensed in a unit dosage form, such as a multidose container or an ampule. Compositions of the electron active metal oxide, or a derivative thereof, for parenteral administration may be in the form of suspensions, solutions, emulsions, or the like, in aqueous or oily vehicles, and in addition to the active ingredient may contain one or more formulary agents, such as dispersing agents, suspending agents, stabilizing agents, preservatives, and the like.
In the case where an intravenous injection or infusion composition is employed, a suitable dosage range can be, e.g., from about 0.5 mg (0.1 ppm) to about 1,000 mg (200 ppm) total dose, preferably from about 5 mg (1 ppm) to 400 mg (80 ppm). In one preferred embodiment, the total dose can be from about 50 mg (10 ppm) to 200 mg (40 ppm). It should be understood that any suitable amount of the composition according to the invention may be administered if effective to prevent, treat, or manage one or more conditions described herein.
Pharmaceutical compositions of the present invention may be orally administered in discrete pharmaceutical unit dosage forms, such as capsules, cachets, soft elastic gelatin capsules, tablets, or aerosols sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the pharmaceutically acceptable carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. Suitable types of oral administration include oral solid preparations, such as capsules or tablets, or oral liquid preparations. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
For example, a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, granulating agent, surface active agent, dispersing agent, or the like. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. In one embodiment, each tablet, capsule, cachet, or gel cap contains from about 0.5 mg to about 500 mg of the active ingredient, while in another embodiment, each tablet contains from about1 mg to about 250 mg of the active ingredient. The amount of active ingredient found in the composition, however, may vary depending on the amount of active ingredient to be administered to the patient.
Another suitable route of administration is transdermal delivery, for example, via an abdominal skin patch.
The metal oxide(s), or a derivative thereof, may be formulated as a pharmaceutical composition in a soft elastic gelatin capsule unit dosage form by using conventional methods well known in the art, such as in Ebert, Pharm. Tech, 1(5):44-50 (1977). Soft elastic gelatin capsules have a soft, globular gelatin shell somewhat thicker than that of hard gelatin capsules, wherein a gelatin is plasticized by the addition of plasticizing agent, e.g., glycerin, sorbitol, or a similar polyol. The hardness of the capsule shell may be changed by varying the type of gelatin used and the amounts of plasticizer and water. The soft gelatin shells may contain an additional preservative, such as methyl- and propylparabens and sorbic acid, to prevent the growth of fungi, although this is not necessary since the compounds and compositions of the invention provide anti-fungal efficacy. Thus, in one embodiment, the invention includes a compositions formulated as a gelatin shell with an electron active metal oxide compound of the present invention, completely free of added preservatives. The active ingredient may be dissolved or suspended in a liquid vehicle or carrier, such as vegetable or mineral oils, glycols such as polyethylene glycol and propylene glycol, triglycerides, surfactants such as polysorbates, or a combination thereof.
In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release means, delivery devices, or both, as are well known to those of ordinary skill in the art, such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, the disclosures of which are hereby incorporated herein by express reference thereto. These pharmaceutical compositions can be used to provide slow or controlled-release of the active ingredient therein using, for example, hydropropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or the like, or a combination thereof. Suitable controlled-release formulations available to those of ordinary skill in the art, including those described herein, may be readily selected for use with the tetrasilver tetroxide compositions of the invention. Thus, single unit dosage forms suitable for topical or oral administration, such as gels, lotions, cremes, tablets, capsules, gelcaps, caplets, and the like, that are adapted for controlled-release are encompassed by the present invention.
All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of the active ingredient being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations may include: 1) extended activity of the active ingredient; 2) reduced dosage frequency; and 3) increased patient compliance.
Most controlled-release formulations are designed to initially release an amount of active ingredient that promptly produces the desired therapeutic effect, and gradual and continual release of other amounts of active ingredient to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of active ingredient in the body, the active ingredient should be released from the dosage form at a rate that will replace the amount of active ingredient being metabolized and excreted from the body.
The controlled-release of the active ingredient may be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term xe2x80x9ccontrolled-release componentxe2x80x9d in the context of the present invention is defined herein as a compound or compounds, including polymers, polymer matrices, gels, permeable membranes, liposomes, microspheres, or the like, or a combination thereof, that facilitates the controlled-release of the active ingredient (e.g., tetrasilver tetroxide) in the pharmaceutical composition.
The pharmaceutical compositions for use in the present invention include electron active metal oxides, or a derivative thereof, as the active ingredient, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients. Suitable derivatives include any available xe2x80x9cpharmaceutically acceptable salts,xe2x80x9d which refer to a salt prepared from pharmaceutically acceptable non-toxic acids including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. Examples of such inorganic acids are nitric, sulfuric, lactic, glycolic, salicylic, and phosphoric. Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like. Particularly preferred acids are lactic, glycolic, and salicylic acids. The pharmaceutically acceptable salts preferably do not include halide-containing salts when tetrasilver tetroxide is present, as these salts are believed to facilitate breakdown of the oxide lattice present in the silver oxide compositions of the invention.

Multivalent electron active compositions and methods of making and using same


An embolization device for positioning in a blood vessel comprises an elongated wire body (1) which in its unloaded condition has a predetermined shape and has an elongated shape with a substantially straight center line during its insertion through a catheter (18) to a placement site in the blood vessel and after its release from the catheter assumes a complexly curved shape which depends on the predetermined shape and on the blood vessel impact on the wire body. In its predetermined shape the wire body has at least one section (4) located, between its front and back ends in which the center line has substantially no curvature or such a small curvature that along a length of at least 20 mm it follows a helix-free path. The front end section (2, 2xe2x80x3, 2xe2x80x2xe2x80x3) of the wire body is adapted to be frictionally locked to the vessel wall when discharged from the catheter, before said helix-free section (4) has been discharged from the catheter. When the helix-free section (4) is discharged it will bend sideways and seek towards the middle of the vessel lumen and continue towards the opposite vessel wall where it is frictionally locked. At continued pushing out many such vessel-crossing wire portions (20) occur, which provides efficient occlusion of the vessel.

The present invention relates to an embolization device for positioning in a blood vessel, comprising an elongated wire body which in its unloaded condition has a predetermined shape and has an elongated shape with a substantially straight center line during its insertion through a catheter to a placement site in the blood vessel and after its release from the catheter assumes a complexly curved shape which depends on the predetermined shape and on the blood vessel impact on the wire body, which wire body preferably has a coupling means at its back end.
Embolization devices in the form of coils where the wire body is formed by a thread extending helically around the center line of the wire body are well-known within radiology, where embolization coils are used for a number of different purposes all with the common feature that it is desired to limit or stop the free flow of blood in an area of a blood vessel. One example of an endovascular field of application for embolization devices for percutaneous, transluminal insertion using minimally invasive techniques, can be mentioned occlusion of an aneurism to prevent rupture of the vessel wall with resulting bleeding. Aneurisms may occur anywhere in the vascular system, but particularly cerebral and abdominal aneurisms require treatment to avoid life-threatening conditions. Another application is occlusion of arteriovenous malformations (AVM), where short-circuiting of arteries and veins looking like skeins of wool may occur, or occlusion of arteriovenous shunts or fistulas, which are major short-circuits between the artery side and the vein side in the vascular system with resulting heavy undesired blood flow. A fourth example of an application is blocking of the blood flow to a tumor, and a fifth, closure of traumatically conditioned blood flows owing to incised wounds or other bodily injuries or gastrointestinal bleeding.
Since embolization devices can be used in many different places in the vascular system and in vessels with very differing sizes, many different coils have been specially designed with various basic designs of the predetermined shape, and each basic design is usually made in a number of different sizes. To treat emergency patients, radiologists today have to stock a large number of different coils, and in the endovascular repair normally many coils are used which are inserted individually and are placed in a pile at the site of placement to be occluded. Considerable expertise is required to select the correct coil sizes for the relevant application, and the risk of unintended migration of a coil to other vessel sites owing to insufficient fitting within the vessel cannot be disregarded.
Conventionally, the predetermined shape of the embolization devices is made so that the wire body is helical with a helix diameter of the same size or slightly larger than the relevant vessel lumen, so that the wound wire body exerts an abutment pressure against the vessel wall. If the helix diameter is too large, the pressure against the vessel wall may become injuriously high, and if it is too small, the wire body can easily be released and drift away. Embolization coils with a regular helical shape or irregular coil shape are known from, for example, U.S. Pat. Nos. 4,994,069, 5,122,136, WO094/11051 and WO94/11051; SU-1777842-A1 discloses a coil with a single helix, WO95/25480 describes a spiral coil, DE-295 18 932-U1 a spherical coil, and WO96/18343 and U.S. Pat. No. 4,994,069 coils with a random matrix shape.
Before insertion of the embolization device, a catheter is placed transluminally in the vascular system having its distal catheter end at the site of placement, whereupon a guidewire mounted with the embolization device is pushed in through the catheter. When the wire body leaves the distal end of the catheter, it seeks to assume the predetermined shape. If the size and shape of the device are deemed suitable for the vessel geometry at the site of placement, the wire body is disconnected from the guidewire. A number of applicable types of coupling means in the back end of the guidewire with associated corresponding part on the guidewire are known, see for example EP-A-720 838 disclosing a screw thread, U.S. Pat. No. 5,217,484 disclosing a prehensile claw, WO94/06503 disclosing a pin connection, WO94/06502 disclosing a clamp connection, WO96/00104 disclosing a conical thread connection and EP-A 717 969 disclosing an inflatable holder.
The object of the present invention is to provide an embolization device which is applicable for a number of different vessel geometries and sizes and which at its placement in the vessel assumes a complexly curved shape which provides effective occlusion by means of the wire body itself. It is also desirable to achieve the occlusion with a smaller number of devices than is possible in the known art in order thus to reduce the risk of travel of a device away from the site of placement and to reduce the time spent on performing the occlusion.
In view of this the embolization device according to the invention is characterized in that the wire body in its predetermined or first or unloaded shape has at least one section located between its front and back ends in which the center line has substantially no curvature or such a small curvature that along a length of at least 20 mm it follows a helix-free path, and that the front end section of the wire body is adapted to be frictionally locked to the vessel wall at its discharge from the catheter, before said helix-free section has been discharged from the catheter. Of course, while the wire body is within the catheter, it is constrained in a generally linear shape.
The distal end of the catheter is usually located immediately at or at a short distance from the site of placement when the front end section of the wire body is discharged from the catheter as the wire body is pushed at its back end. During the discharging, the end section will approach and abut the vessel wall. At the continued discharge, the end section will arrange itself along the vessel wall over a length that causes the end section to frictionally lock with the vessel wall. Frictional locking in the present context means that the frictional forces between the distal end section and the vessel wall reach a magnitude at which the column loading from the free end of the wire body located between the catheter opening and the closest point of abutment with the vessel wall is unable to move the end section in relation to the vessel wall. As the helix-free section has a length of at least 20 mm, at least part of the section will still be inside the catheter when the end section becomes frictionally locked. At the subsequent release of the helix-free section, the free portion thereof will bend sideways away from the closest point of abutment with the vessel wall and seek towards an opposite area of the vessel wall, as seen in relation to the closest point of abutment, where a frictional locking will also occur. Then discharge of a further portion of the helix-free section of the catheter will lead to renewed bending of the wire body in a new direction, etc. The length of the helix-free section can be adapted to the vessel geometry at the site of placement to be occluded, a longer helix-free section for the same vessel geometry making the embolization device arrange itself with more portions of the wire across the vessel lumen, thereby making the occlusion denser, and a shorter helix-free section producing a more open occlusion, should this be desired.
The embolization device provides the considerable advantage that the helix-free section itself automatically adapts to the vessel geometry in question, and is fastened securely to it without any risk of unintended release from the site of placement. The various fields of application of the embolization device display different specific problems, for example that the wire body should only exert a relatively limited pressure on the vessel wall at placement in an aneurism where the vessel wall may be in danger of rupturing, but has to exert a substantially larger pressure on the vessel wall at placement in a vessel to be occluded for blocking of the blood supply to a tumor or an AVM, where the vessel wall is strong and the certainty against release of the wire body has to be high. All these different desired properties of the device can be taken into consideration by designing the wire body with a rigidity adapted to the desired application, a greater rigidity providing a heavier abutment pressure against the vessel wall.
The device according to the invention has the further advantage that the cavity in the vessel is crossed by the wire body suitably many times in different directions. The wire body has its own property of rigidity effectively counteracting recanalization at the site of occlusion, and the crossing wire portions also abut the vessel wall at each end of the crossing portions, which also contributes to the long-term stability of the occlusion. The placement is furthermore conducted in such an orderly manner that the risk of knotting or locking filtration of the wire body is extremely low. This provides the advantage that if desired the wire body can always be repositioned in the catheter by retraction of the proximal end of the member.
Preferably at its back end the wire body has a coupling means so that at insertion and placement the embolization device is mounted on the guidewire, thus rendering it possible directly to reposition the device in the catheter in case of problems in connection with the occlusion. It is also possible to manufacture the embolization device without any coupling means and to push out the device from the catheter by means of a stylet-shaped pusher.
In some applications the front end section may constitute a substantially rectilinear extension of the helix-free section, and at its distal extreme end the end section may be provided with a guide means, which may, for example, be umbrella-shaped. Alternatively the device in a preferred embodiment may be formed so that the helix-free section of the wire body extends to the front end section, which is curved at its front end, the center line of the section here turning at least 90xc2x0, preferably from 120xc2x0 to 320xc2x0, in relation to the course of the center line in the helix-free section when the wire body assumes its predetermined shape.
Firstly, the curved end section gives the wire body a soft and flexible front end with an extremely low risk of injuring the vessel wall when the front end meets it. This embodiment is therefore suitable for embolization of aneurisms. If, at the time of placement, the catheter end is positioned so that the pushing-out direction of the wire body is at right angles to the vessel wall in the aneurism, the vessel wall is touched by the curved front end which, owing to its curvature, is resiliently deformed without applying any risky pressure to the vessel wall, and at the same time the wire body is maneuvered: to the side to follow the vessel wall. If the pushing-out direction forms an oblique angle with the vessel wall, the curved end section results in a turn of the wire body so as to follow the curvature of the vessel wall.
Secondly, the curved end section is an integral part of the wire body, and transverse forces acting on the end section when it meets the vessel wall may therefore via the end section be partially transmitted to the section of the wire body located further behind, so that it is maneuvered to fit with the shape of the vessel wall before it has been advanced all the way to the vessel wall. For application in aneurisms, the center line in the front end of the wire body preferably turns through an angle ranging from 120xc2x0 to 320xc2x0. Keeping the angle below 320xc2x0 prevents the end section in the predetermined shape from forming a full helical line which may, after placement in the aneurism, exert a greater pressure against the vessel wall than the pressure of the helix-free section, which is determined by the rigidity of the wire, as mentioned above. The angle of at least 120xc2x0 provides great certainty that the end section will nestle up along the vessel wall in the advantageously atraumatical manner.
For applications in aneurisms, the embolization device may further advantageously be formed so that the back end section of the wire body with the coupling means is curved, the center line of the end section turning at least 120xc2x0, and preferably from 140xc2x0 to 340xc2x0 when the wire body assumes it predetermined shape. When the embolization device has been placed in the aneurism in the complexly curved shape, the curved back end section causes the coupling means to lie protected inside the cavity of the aneurism, surrounded by the wire portions crossing the cavity. With this location, the coupling means is prevented from sticking out through the access opening to the aneurism and from abutting the vessel wall of the aneurism. An angle smaller than 120xc2x0 or larger than 340xc2x0 in some cases entails the risk that the coupling means sticks out.
When the embolization device is intended for placement at sites where the vessel has a relatively large lumen and a suitably strong wall, for example in vessels with AVM, shunts or fistulas, the front end section of the wire body is preferably curved and forms several helices, suitably in the form of a spiral with a decreasing helix diameter towards the front end when the wire body assumes its predetermined shape. When the front end section is discharged through the catheter opening, it assumes the helical shape immediately outside the catheter opening and can thereby be frictionally locked to the vessel wall in a very well-defined position in the vessel. The catheter can then be slightly retracted so that the helix-free section has a suitable free length between the end section and the catheter opening, whereupon the whole wire body can be pushed out of the catheter so that it automatically adapts to the vessel geometry in the manner described above. If the distal helices have a small diameter, they will be placed centrally in the lumen of the vessel and here prevent the outward curving wire body portions from being pressed centrally through and out on the other side of the already placed distal end section. Thus, in addition to an accurate positioning, the embodiment also renders it possible to achieve a compactly placed device that only extends over a short vessel length.
In a particularly simple embodiment the helix-free section extends from the front to the back end sections. Thus, the whole wire body can have homogeneous properties except in the two end sections. Such an embolization device has a wide field of application. For special applications, the device may alternatively be designed so that between the front and the back end sections there are several helix-free sections with intermediate sections which may be helical and/or may produce breakpoints in the curvature of the wire body when it assumes its predetermined shape. With a single embolization device of this design it is possible to occlude two or more mutually separated places in a vessel, for example on both sides of a fistula. When the front section of the wire body is positioned at the first site in the vessel, and the front helix-free section(s) is/are placed, the catheter can be retracted in the vessel to a position at the desired second site of occlusion, whereupon an intermediate section of the wire body is placed and frictionally locked to the vessel, and finally the remainder of the device is placed. The sections of the wire body placed at individual sites of occlusion are mutually connected via a portion of the wire body, which prevents travel of the embolization device away from one occlusion site. Furthermore the insertion procedures for provision of two separate occlusions are considerably facilitated.
The wire body can be formed in different ways. One possibility is to use a single solid thread of wire which is bent in the end sections to the desired predetermined shape. In the front end section the wire may have a smaller diameter and be wound helically around the center line of the section to increase the flexibility of the wire body front end. Another possibility is to construct the wire body from several thin threads which are laid, woven or braided together into a body of a larger diameter than the thin threads. From the manufacture of ropes or wires it is known that the laying, weaving or braiding can be effected in a pattern that imparts resilient properties to the resulting wire body. Owing to the extremely small outer diameter of the threads, this method of manufacture is costly, however. A third and preferred possibility is to form the wire body from a thread that extends helically around the center line of the wire body. This design involves several advantages. From the manufacture of conventional embolization coils it is well-known to wind a thin thread around a mandrel in order to provide an embolization coil, and in terms of manufacturing it is an advantage to manufacture the wire body by this well-tried technique. For a specific desired rigidity (or rather flexibility) of the wire body, the wire body may be given a rather large diameter with a helically wound thread, which gives the radiologist a better possibility of seeing the wire body during its positioning in the vessel, because the larger diameter makes the wire body more radiopaque.
In a preferred embodiment, in the helix-free section the wire body has a spring constant which, measured on a 50 mm long portion of the wire body, is of at least c=P/exe2x89xa70.0008 N/mm, P being an axially acting applied force measured in N, and e being the change in length measured in mm, preferably of 0.0015 N/mmxe2x89xa6cxe2x89xa60.08 N/mm, suitably in the interval of 0.0008 N/mmxe2x89xa6cxe2x89xa60.2 N/mm. The preferred spring constant depends on the relevant application, on the method of insertion and on the intended pressure of the device against the vessel wall. If the spring constant becomes substantially lower than 0.0008 N/mm, the ability of the device to lock against the vessel wall will become poor. For application in aneurisms having a diameter of up to 6 mm, the spring constant preferably ranges from 0.0015 N/mm to 0.08 N/mm, and for applications where the vessel wall is stronger, the spring constant preferably ranges from 0.008 N/mm to 0.2 N/mm.

Embolization device for positioning in a blood vessel