US6645531B1

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Page 1

«2) United States Patent

Antelman

US006645531B1

US 6,645,531 B1
Nov. 11, 2003

(10) Patent No.:
(45) Date of Patent:

(54) MULTIVALENT ELECTRON ACTIVE
COMPOSITIONS AND METHODS OF
MAKING AND USING SAME

(75) Inventor: Marvin S. Antelman, Rehovot (IL)

(73) Assignee: Marantech Holding LLC, East
Province, RI (US)

(*) Notice: Subject to any disclaimer, the term of this
patent is extended or adjusted under 35
US.C. 154(b) by 0 days.

(21) Appl. No.: 09/692,126
(22) Filed: Oct. 20, 2000

Related U.S. Application Data

(63) Continuation-in-part of application No. 09/552,172, filed on
Apr. 18, 2000, now Pat, No. 6,258,385.

(60) Provisional application No. 60/214,503, filed on Jun. 28,
2000, provisional application No. 60/184,053, filed on Feb.
22, 2000, and provisional application No. 60/174,793, filed
on Jan. 6, 2000.

(51) Int. C1? veces AGIK 33/34; AGIK 33/24;
A61K 33/26; A61K 33/32
(52) U.S. Cl. . 424/635; 424/617; 424/630;

424/639) 424/646; 424/647; 424/648; 424/653
(58) Field of Search .... 424/600, 617,

424/618, 630, 634, 639, 646, 647, 648,

653
(56) References Cited
U.S. PATENT DOCUMENTS,

3,923,982 A 12/1975 Lamand et al. 424/140
4,447,254 A 5/1984 Hughes et al. 71/67
4,828,832 A 5/1989 De Cuellar et al. 424/618
4,952,411 A 8/1990 Fox, Jr, et al. 424/618
5,017,295 A 5/1991 Antelman 210/764
$,073,382 A 12/1991 Antelman 424/604
5,078,902 A 1/1992 Antelman 210/764
$,089,275 A 2/1992 Antelman 424/602
5,098,582 A 3/1992 Antelman 210/759
5,211,855 A 5/1993 Antelman 210/758
5,223,149 A 6/1993 Antelman 210/764
5,334,588 A 8/1994 Fox, Jr. et al. 514/171
5,336,416 A 8/1994 Antelman 210/764
5,336,499 A 8/1994 Antelman 424/405
5,571,520 A 11/1996 Antelman 424/405
5,612,019 A 3/1997 Gordon et al. 424/9.32
5,676,977 A 10/1997 Antelman 424/618
5,772,896 A 6/1998 Denkewicz, Jr. et al. ... 210/754

FOREIGN PATENT DOCUMENTS

JP 2000060976 2/2000
OTHER PUBLICATIONS

STN/CAS online, file CAPLUS, Acc. No. 1999:748588,
Doc. No. 131:340719 (JP 11322408 A2 (Ohne et al.), Nov.
24, 1999), Abstract.*

STN/CAS online, file CAPLUS, Acc. No. 1997:195107,
Doc. No. 126:182656 (JP 09012415 A2 (Doi et al.), Jan. 14,
1997), Abstract.*

Antelman, Marvin S.; “Silver (II,IM) Disinfectants”; Soap/
Cosmetics/Chemical Specialties, Mar. 1994, pp. 52-59.
Antelman, Marvin S.; Abstracts of American Chemical
Society, 1992(203),

Antelman, Marvin S.; “Anti—Pathogenic Multivalent Silver
Molecular Semiconductors”; Precious Metals; 1992(16); pp.
141-149.

Antelman, Marvin S.; “Multivalent Silver Bactericides”;
Precious Metals; 1992(16); pp. 151-163.

Fung, Man C. and Bowen, Debra L.; “Silver Products for
Medical Indications: Risk—Benefit Assessment”, Clinical
Toxicology, 1996, pp. 119-126.

Dorland et al., Dorland’s Illustrated Medical Dictionary,
Philadelphia: W.B. Saunders Company, 1994, 28” Edition,
p. 351, 759, and 760.

Gennaro, A., Remington’s Pharmaceutical Sciences, Easton,
PA: Mack Publishing Company, 1985, 17% Edition, p.
1573-1575, 1585-1594, and 1601.

* cited by examiner

Primary Examiner—Jose’ G. Dees
Assistant Examiner—¥rank Choi

(57) ABSTRACT

The present invention is directed to pharmaceutical compo-
sitions 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(ILIIH)
oxide, Cu(II) oxide, Fe(II,IID oxide, Mn(IL,ID oxide, and
Pr(IILIV) oxide, and optionally Ag(I,III) oxide. These com-
pounds may be in a crystalline state having metallic cations
of two different valences, or electronic states, in the inor-
ganic 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.

7 Claims, No Drawings

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US 6,645,531 B1

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MULTIVALENT ELECTRON ACTIVE
COMPOSITIONS AND METHODS OF
MAKING AND USING SAME

CROSS-REFERENCE TO RELATED
APPLICATIONS

This application is a continuation-in-part of Application
No. 09/552,172, filed Apr. 18, 2000, now USS. Pat. No.
6,258,385 and claims benefit of Provisional Application No.
60/174,793, filed Jan. 6, 2000, No. 60/184,053, filed Feb. 22,
2000, and No. 60/214,503, filed Jun. 28, 2000.

FIELD OF THE INVENTION

The present invention relates to electron active com-
pounds and compositions that have polyvalent cations in
their crystal lattices. In addition, the present invention also
includes a method of making such electron active com-
pounds. 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.

BACKGROUND OF THE INVENTION

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, “Anti-
Pathogenic Multivalent Silver Molecular Semiconductors,”
Precious Metals, vol. 16:141-149 (1992); M. Antelman,
“Multivalent Silver Bactericides,” Precious Metals, vol.
16:151-163 (1992). For example, tetrasilver tetroxide acti-
vated with an oxidizing agent is disclosed for use in
bactericidal, fungicidal, and algicidal use, such as in munici-
pal 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, “Silver (II, II) Disinfectants,” 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.

US. Patent No. 5,336,499 discloses tetrasilver tetroxide
and persulfate compositions having certain in vitro anti-
pathogenic properties, i.¢., 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.

USS. 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

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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.

USS. Pat. No. 5,676,977 discloses intraveneously injected
tetrasilver tetroxide crystals used for destroying the AIDS
virus, AIDS synergistic pathogens, and immunity suppress-
ing 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 descrip-
tions of the mechanism via which the multivalent silver
molecular crystal devices were believed to operate. A dis-
cussion of such results and concepts was presented at a
Seminar entitled “Incurable Diseases Update” (Weizmann
Institute of Science, Rehovot, Israel, Feb. 11, 1998). The
title of this presentation was “Beyond Antibiotics, Non
Toxic Disinfectants and Tetrasil™ (a composition including
tetrasilver tetroxide).” 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 anti-
microbial compositions, ¢.g., U.S. Pat. No. 5,017,295 for
Ag(ID and USS. 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:

Ag,O.>Ag(ID>Ag()>>>>Ag)

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 DerAnorganis-
chen Chemie, vol. 16:642 (1964). Also, Co(ILIID oxide,
Fe(III) oxide, Mn(ILII) oxide, and Pr(III,1V) 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.

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical compo-
sitions 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

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metal oxide includes at least one of Bi(III,V) oxide, Co(II,
III) oxide, Cu(I,IID) oxide, Fe(ILII) oxide, Mn(ILII) oxide,
Pr(IIL,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 pharma-
ceutical 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 EMF 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
aboutl 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, pref-
erably present in an amount sufficient to enhance the efficacy
of the active compound but insufficient to cause skin irrita-
tion. 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 pharmaceu-
tical composition comprising tetracopper tetroxide com-
pound. 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 deriva-
tive 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 admin-
istering 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 elec-
tron 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

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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 deriva-
tive 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 adminis-
tration 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(II) ions, and four oxygen atoms, is one preferred
electron active compound, while the administration of tet-
rasilver 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 detect-
able 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 inven-
tion.

DEFINITIONS

Some of the terms used in connection with the invention
can be defined as follows:

The term “condition,” as used herein, should be under-
stood to refer to a traditionally identified disease, as well as
a disorder, an affliction, or an ailment, particularly including
those noted herein.

The terms “prevent,” “preventing,” and “prevention,” 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 “manage,” “managing,” and “management,” 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 superfi-
cially discoloring the skin, i.e., no discoloration to the naked
eye. In one embodiment, the invention relates to the treat-
ment or management, while in another embodiment the
invention relates to the prevention, of the diseases or con-
ditions 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,

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amplify, exacerbate, or cause, either directly or indirectly, a
condition and/or a symptom thereof.

The term “patient” as used herein refers to animals,
particularly to mammals. In one preferred embodiment, the
term patient refers to humans.

The terms “adverse effects,” “adverse side effects,” and
“side effects,” as used herein, include, but are not limited to,
cardiac arrhythmia, cardiac conduction disturbances, appe-
tite 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
“cardiac arrhythmia” includes, but is not limited to, ven-
tricular tachyrhythmia, torsades de pointes, Q; prolongation,
and ventricular fibrillation.

The phrase “therapeutically effective amount” 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 thera-
peutically 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 “substantially free” 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 “about,” 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 “substantial,” 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 “valence state,” 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 “inhibit,” “inhibiting,” or “inhibits,” 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.

DETAILED DESCRIPTION OF THE
INVENTION

The tetrasilver tetroxide compounds mentioned in the
background are one type of electron active compound hav-
ing multivalent cations in its crystal lattice. Various addi-
tional 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 condi-
tions or disorders. The electron active compounds of the
present invention are believed to have unique crystal struc-
tures 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(II), respectively.

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Exemplary electron active metal oxide compounds accord-
ing to the invention include, but are not limited to, Ag(LIID,
Co(ILI), Pr(IILIV), Bi(III,V), Fe(III), Mn(ILIII), and
Cu(LII) oxides. In another embodiment, Tb(IILTV) oxide,
Tb,O,, or tetraterbium heptoxide, is one electron active
metal oxide compound according to the invention. As dis-
cussed 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:

Lower-valent Higher-valent

© Formula Metal cations ion # ion #
2 AgO, — Agi) Agt 2 Ag? 2
1 C030, Co(II) Cot? 1 Cot? 2
2 Prey, PrCLILIV) Pr? 2 Prt 4
2 Bi,O, Bi(II,V) Bit* 1 Bit> 1
1 FeO, Fe(III) Fe? 1 Pe? 2
1 Mn30, — Mn(IL,tI1) Mn"? 1 Mn‘? 2
2 @,O, cu(LI, cut 2 an 2

¢ - total number of electrons believed to be exchanged;
#- number of particular ion type per formula unit.

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, “electrocutes” the
pathogens. While these compounds have also been discov-
ered 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 mecha-
nism 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, NH,, S—S, 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 substan-
tially 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 oxi-
dized 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(IH,V), and Cu(II) 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

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include, but are not limited to, Co(II,II), Fe(II), Mn(II,
II), and Pr(III,1'V) 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(LIII) 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:

metal(LIL[V)  metal(III,V)
metal(LI) oxides metal(IL[ID oxides oxides oxides
Cot - ¢ = Cot Pr -¢ = Prt Bits - ¢ = Bi™*

Co +e=Co* — Prit+e=Pr? Bi +e = Bi"
Fe*? — e = Fet?

Fe"? + @ = Fe’?

Mn*? - e = Mn**

Mn"? += Mn"?

Cute = Cu?
Cut +e = Cu?

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 EMF®*. In addition to the elec-
tromotive 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 EMF”.

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 EMF*”. The
stability of a particular metal sulfide is an approximation of
the affinity of a metal ion for sulfur. The following approxi-
mate association constants for sulfides indicate the trend in
relative affinity of each metal ion for sulfur:

Agi) 49
cat) 47
Co(IL) 26
Fe(II) 19
Mn(I1) 15

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+S ?-2e—-Ag.S EMF" =-0.66

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:

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Agt-e+S? Ags — EMFRE =-0.90

Ag? tes Ag? EMF = 42,02.

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 “electrocution voltage,” is
the combination of the oxidizing cation’s reduction poten-
tials and the reducing cation’s reduction potential (ie.,
EMF?*-EMF**) In the case of tetrasilver tetroxide, the
“electrocution voltage” is 2.92 volts. The oxidizing cation’s
reduction potentials, EMF°*, of exemplary metal oxides
according to the present invention are tabulated below:

Formula Metal cations EME
Ag,Ox Ag(LLID) 2.02
C0304 Co(II) 181
PrOn, Pr(LLLV) 2.86
Bi,O, Bi(III,V) 1.59
Fe,O, Fe(IL UID) 0.77
Mn;04 Mn (IL IID, 154
CuO, Cu(II) 1.80

As noted from the above table, praseodymium-, cobalt-,
and copper-based oxides are believed to be stronger
antipathogenic agents or to form better pharmaceutical com-
positions 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(III) and Mn(ILIII) oxides for
the same contact time. This result might be explained by the
far greater stability of bismuth(IIJ) 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 compo-
sitions 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 circula-
tory disorders. While the exact mechanism of the activity of
such compounds or compositions is not described herein,
nonetheless, suitable prevention, treatment, and/or manage-
ment of such non-pathogenic conditions may be obtained by
administering the compounds or compositions of the inven-
tion as described herein and as will be readily apparent to
one of ordinary skill in the art.

The compositions and methods of the invention advanta-
geously prevent, treat, or manage dermatological diseases or

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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, pharyn-
geal diphtheria, pleomorphic laryngeal diphtheria, cutane-
ous diphtheria, endocarditis, bacteremia, urinary tract
infections, listerosis, meningitis, miscarriage, narcodiosis,
acne, skin lesions, abscesses, toxic shock syndrome, pros-
thesis 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, granu-
loma 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 pulmo-
nary 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, cor-
neal 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 symp-
toms. 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 inhib-
ited 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, ¢.g., pro-
tozoa; and viruses.

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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, Sta-
phylococcus 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, Helio-
bacter 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 com-
binations thereof.

Examples of acid-fast bacteria include, but are not limited

5 to, Myobacterium avium, Myobacterium leprae, Myobacte-

rium 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, Cox-
iella bumetii, Mycoplasma pneumoniae, Rickettsia akari,
Rickettsia prowazekii, Rickettsia rickettsii, Rickettsia
tsutsugamushi, Rickettsia typhi, Ureaplasma urealyticum,
Diplocaeccus 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 lim-
ited to, Balantidium coli, Cryptosporidium parvum,
Cyclospora cayatanensis, Encephalitozoa, Entamoeba
histolytica, Enterocytozoon bieneusi, Giardia lamblia,

Leishmaniae, Plasmodii, Toxoplasma gondii,
Trypanosomae, trapezoidal amoeba, and combinations
5 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, Hepa-
titis 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

5 a condition, or a symptom thereof. Examples of such addi-

tional therapeutic agents include, but are not limited to,
chelating agents, vitamins, minerals, silica hydride
microclusters, analgesics, Sambucol™, 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 pre-
vious embodiment, that the metal oxide does not include
tetracopper tetroxide.

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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 com-
pound other than an electron active metal oxide compound.

The antipathogenic or antimicrobial performance of cer-
tain 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 advan-
tageously 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 SO ppm, based on the weight of the composition.
In one embodiment, as more compound or composition is
administered, a correspondingly smaller amount of undesir-
able 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 mini-
mize 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 discolora-
tion 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 compara-
tively non-toxic compared to silver salts, such as conven-
tional 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, com-
mercial concentrates were formulated with 2% of the tet-
rasilver tetroxide. For acceptance of the oxide in commerce,
for which EPA registration No. 3432-64 was obtained, it was
necessary for the Ag,O, to undergo a series of toxicity tests.
A 3% concentrate was used and evaluated by a certified
laboratory employing good laboratory practice (GLP)

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according to the Code of Federal Regulations for this
purpose. The results were as follows:

Acute Oral Toxicity
Acute Dermal Toxicity
Primary Eye Irritation
Primary Skin Irritation
Skin Sensitization

LDso Greater than 5,000 mg/Kg
LDso Greater than 2,000 mg/Kg
Mildly irritating

No irritation

Non-Sensitizing

Subsequent evaluations conducted according to the inven-
tion showed that unless persons were prone to silver
allergies, the pure tetrasilver tetroxide compositions accord-
ing 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 mani-
fested by the K, of the tetrasilver tetroxide compositions,
which is approximately 7.9x10-".

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 under-
stood 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 pre-
ferred 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 about! to 3 times.
per day until the condition is suitably cured or satisfactorily
controlled. In one embodiment, the composition may gen-
erally be topically applied at a dosage level of from about 1
mg to 1000 mg per cm” of skin surface, preferably about 10
mg to 500 mg per cm* 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 accord-
ing to the invention have been commercially sold under the
poorly named “Ag(II) OXIDE” 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,
“Anti-Pathogenic Multivalent Silver Molecular
Semiconductors,” Precious Metals, vol. 16:141-149 (1992)
by reacting silver nitrate with potassium peroxydisulfate
according to the following equation in alkali solutions:

4AgNO+2K,8,0g+8NaOH>Ag,O ,+3Na,SO,K,SO,+2NaNO3+
2KNO,+4H,0

To the extent necessary to understand the present invention,
the disclosure of Antelman is hereby incorporated herein by
express reference thereto.

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Tetracopper tetroxide, also referred to herein as Cu(LIID)
oxide or Cu,O,, 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 limit-
ing 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 stoichiom-
etry 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 80° C., most preferably about
90° C. to 95° 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 45° 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

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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 fil-
tered 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(III) oxide and Mn(II,III) oxide are
commercially available from Aldrich Company of
Milwaukee, Wis., and Co(ILII) 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 Anorga-
nischen Chemie, vol. 16:642 (1964), and the oxide is avail-
able 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 ingre-
dient 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 neces-
sary 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 physi-
cian will know how and when to interrupt, adjust, or
terminate therapy in conjunction with individual patient
response.

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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 man-
aged.

In practical use, the metal oxide, or a derivative thereof,
can be combined as the active ingredient in intimate admix-
ture 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 inven-
tion may include, but are not limited to, suspensions, solu-
tions and elixirs; aerosols; or carriers, including, but not
limited to, starches, sugars, microcrystalline cellulose,
diluents, granulating agents, lubricants, binders, disintegrat-
ing 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, prefer-
ably 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, ¢.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 viscos-
ity 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 thixo-
tropic 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 prepara-
tions 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 prepa-
rations may also contain emollients, perfumes, and/or pig-
ments 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 admin-
istration may be in the form of suspensions, solutions,

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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 com-
position 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 car-
rier 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 con-
tains from about! 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 propylpara-
bens 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.

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US 6,645,531 B1

17

Thus, in one embodiment, the invention includes a compo-
sitions 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 adminis-
tered 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,
hydropropylmethy! cellulose in varying proportions to pro-
vide 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 inven-
tion. 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 inven-
tion.

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 medi-
cal 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 ini-
tially 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 condi-
tions or compounds. The term “controlled-release compo-
nent” 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 composi-
tion.

The pharmaceutical compositions for use in the present
invention include electron active metal oxides, or a deriva-
tive thereof, as the active ingredient, and may also contain
a pharmaceutically acceptable carrier, and optionally, other

20

30

40

60

18

therapeutic ingredients. Suitable derivatives include any
available “pharmaceutically acceptable salts,” 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. Par-
ticularly 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.

EXAMPLES

‘These and other aspects of the present invention may be
more fully understood with reference to the following non-
limiting examples, which are merely illustrative of the
preferred embodiments of the present invention, and are not
to be construed as limiting the invention, the scope of which
is defined by the appended claims.

EXAMPLES 1-16
Antipathogenic Efficacy of Compositions
EXAMPLES 1-2

In Vitro Treatment of Salmonella with
Compositions of Invention

Acculture of Salmonella of cell density 500,000 CFU/mL
was contacted for 10 minutes with approximately 4 ppm
hexapraseodymium undecoxide (Pr¢0,,), which is believed
to contain two distinct oxidation states of praseodymium,
Pr(III) and Pr(IV), in its erystal lattice, at a pH of about 9,
followed with a culture adjusted to a pH of about 10. The
percentages of bacterial colonies killed by this treatment
were 96.4% and 93.8%, respectively. The experiment was
repeated with the same cell density of Salmonella using
about 5 ppm of tricobalt tetroxide (Co;0,), which is
believed to contain two distinct oxidation states of cobalt,
Co(II) and Co(II), in its crystal lattice, at a pH of about 10.
The percentage of bacterial colonies killed by this treatment
was 92.8% after 10 minutes of contact with the oxide-
containing composition.

EXAMPLES 3-4

Antipathozenic Effect of Compositions in Water
Purification

The praseodymium oxide crystals of Example 1 were
tested against the standard AOAC coliform culture used in
water purification studies and having a 375,000 CFU/mL
density. The results of this study are tabulated below:

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US 6,645,531 B1

19 20
ppm PrgQ,; Contact time (mins.) pH Bacteria mortality (%) Composition of the Invention % Bacteria Killed
4 5 7 68 5 Bi (ILLV) oxide, Bi,O, 38%
4 10 7 nh Fe (ILUD oxide, Fe3O, 32%
10 5 7 65 Mn (ILI) oxide, MnO, 28%
10 10 7 16
5 5 9 84
10 10 9 88

The experiment of Example 3 was repeated with about 4
ppm of tricobalt tetroxide (Co,O0,) according to Example 2,
at a contact time of about 5 minutes at a pH of about 7. The
percentage of bacterial colonies killed by this treatment was
75%.

EXAMPLE 5

In vitro Treatment of Stayhylococcus aureus with
Compositions

1 gram of Pr (ILIV) oxide (Pr;0,,) was dissolved in 20
mL of 85% phosphoric acid, which underwent substantially
no redox reaction with the praseodymium oxide, such that an
active solution was formed. The solution was subsequently
diluted to yield a 100 ppm solution, based on the oxide
component. The Pr (III,ITV) oxide solution, when put in
contact with Staphylococcus aureus at 220,000 CFU/mL cell
density, served to kill substantially all the bacteria (100%
mortality) after 10 minutes of contact with the oxide-
containing composition.

EXAMPLES 6-9

In vitro Treatment of £. coli with Compositions of
the Invention

A culture of E. coli bacteria having a cell density of
420,000 CFU/mL was contacted for about 10 minutes with
about 6 ppm of Co (ILII) oxide, Co30,, at a pH of about 7,
also in the presence of 10 ppm potassium monopersulfate,
which is commercially available under the trademark
OXONE from DuPont De Nemours, Inc., of Wilmington,
Del. The percentage of bacteria killed by this contact was
47.6%. When repeating the previous experiment using a
culture having a cell density of 380,000 CFU/mL and with
about 5 ppm of Pr (IILIV) oxide in the presence of about 50
ppm OXONE™, the percentage of bacteria killed was
39.5%.

A culture of F. cofi bacteria having a cell density of
160,000 CFU/mL was contacted for about 10 minutes with
about 100 ppm of Cu (1,111) oxide, Cu,O,. The percentage
of bacteria killed by this contact was 63.8%. When repeating
the previous experiment using only about half the Cu (LID)
oxide concentration, i.¢., about 50 ppm, in the presence of
about 200 ppm OXONE™, the percentage of bacteria killed
was 97.8%.

EXAMPLES 10-13

In vitro Treatment of E£. coli with Compositions of
the Invention

Cultures of E. coli bacteria, each having a cell density
around 100,000 CFU/mL, were each contacted for about 10
minutes with various electron active molecular metal oxide
crystals according to the invention, resulting in the follow-
ing percentages of bacteria killed:

10

20

30

66

These experiments were repeated using reduced triiron
tetroxide, Fe;0,, concentrations and E. coli cultures, each
having a reduced cell density of 75,000 CFU/mL, with
variable OXONE™ concentrations. When Fe (II, III) oxide
was used in about 50 ppm concentration in the presence of
about 200 ppm OXONE™,, the percentage of bacteria killed
was about 73.3%. When Fe (IL,IID) oxide was used in about
20 ppm concentration, in the presence of about 100 ppm
OXONE™, the percentage of bacteria killed was about
49.3%.

EXAMPLES 14-16

In vitro Treatment of Staphylococcus aureus Using
Compositions

Compositions containing about 100 ppm of Bi (III,V)
oxide, Bi,O,, Fe (ILIII) oxide, Fe,;0,, or Mn (ILIII) oxide,
Mn,0,, were tested for antimicrobial efficacy by contacting
cultures of Staphylococcus aureus bacteria having cell den-
sities of 75,000 CFU/mL for about 10 minutes. The iron and
manganese oxide compositions were observed to kill sub-
stantially no bacteria, whereas the composition containing
dibismuth tetroxide was observed to kill about 37.3% of the
bacteria.

EXAMPLE 17

Preparation of Tetracopper Tetroxide

2.4 grams each of sodium hydroxide and potassium
persulfate were dissolved, each in 25 mL of distilled water,
each in its own 50 mL beaker. These solutions were mixed
together in another beaker, to which 700 mg of red cuprous
oxide was added. This beaker was heated to approximately
90° C. and was maintained from about 90° C. and 95° C. for
about 15 minutes before being allowed to cool to room
temperature. The heating of the solution caused a color
change from red to black, indicating a reaction of the oxide.

The solid product was purified and isolated by one of two
methods: a) decanting off the solution, washing the remain-
ing product at least seven times with distilled water, and
drying the product; or b) vacuum filtering the solution and
drying the product. The experimental yield was similar using
either isolation method.

The average theoretical yield of Cu(LIID oxide, or Cu,0,,
was 83%, based on the following equation:

ANaOH+2Cn,0+2K,S,02—Cu 0 ,+2Na,$O,+2K,S$0,2H,0

Based on all of the test data described above, the healing
mechanism associated with the use of the metal oxides of the
invention to treat and manage at least some skin diseases,
without being bound by theory, appears to involve mecha-
nisms other than merely inhibiting or killing pathogens and
curing infections that tend to aggravate disease and retard
the natural healing process. The data indicate that healing is
brought about even in cases where no abnormal bacteria
counts or infection is evident. This suggests that the electron
active compound(s) may also act against auto-antibodies

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US 6,645,531 B1

21

that trigger autoimmune reactions associated with diseased
tissue, as well as against other non-pathogenic conditions or
diseases, such as circulatory or neurological conditions or
diseases.

Although preferred embodiments of the invention have
been described in the foregoing Detailed Description, it will
be understood that the invention is not limited to the
embodiments disclosed, but is capable of numerous rear-
rangements and modifications of parts and elements without
departing from the spirit of the invention. It will be under-
stood that the chemical and pharmaceutical details of every
design may be slightly different or modified by one of
ordinary skill in the art without departing from the compo-
sitions and methods taught by the present invention.

What is claimed is:

1. A method of halting, diminishing, or inhibiting the
growth of at least one of a bacterium, a fungus; a parasitic
microbe, and a virus, which method comprises administer-
ing to a human being a therapeutically effective amount of
at least one electron active compound 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, wherein the at least one electron active compound
comprises a metal oxide selected from the group consisting
of Bi(III,V) oxide, Co(II,III) oxide, Cu(II) oxide, Mn(II,
IID) oxide, Pr(III,IV) oxide, Tb,O,, or a mixture thereof.

15

20

22

2. Tetracopper tetroxide, which comprises two copper(I)
ions, two copper(II), ions and four oxygen atoms in a
crystal lattice.

3. A process for preparing tetracopper tetroxide, having
two copper(I) ions, two copper(II) ions, and four oxygen
atoms in a crystal lattice, which process comprises:

combining a copper(I)-containing compound and a caus-
tic 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 a
tetracopper tetroxide.

4. The process of claim 3, wherein the copper(I)-
containing compound comprises a non-solvated inorganic
copper(I) oxide.

5. The process of claim 4, wherein non-solvated inorganic
copper(I) oxide comprises cuprous oxide.

6. The process of claim 3, wherein the caustic solution
comprises a strong caustic base and a peroxy acid salt.

7. The process of claim 3, wherein the strong caustic base
comprises a hydroxide salt, and wherein the peroxy acid salt
comprises a persulfate.

+ * 8