U.S. patent application number 14/173357 was filed with the patent office on 2014-06-26 for tannin formulation for treating gastrointestinal spasms in a subject having diverticulitis.
This patent application is currently assigned to LiveLeaf, Inc.. The applicant listed for this patent is LiveLeaf, Inc.. Invention is credited to Alexander L. HUANG, Gin WU.
Application Number | 20140178495 14/173357 |
Document ID | / |
Family ID | 50552777 |
Filed Date | 2014-06-26 |
United States Patent
Application |
20140178495 |
Kind Code |
A1 |
HUANG; Alexander L. ; et
al. |
June 26, 2014 |
TANNIN FORMULATION FOR TREATING GASTROINTESTINAL SPASMS IN A
SUBJECT HAVING DIVERTICULITIS
Abstract
Methods of treating gastrointestinal spasms are provided. For
example, methods of treating gastrointestinal spasms are provided,
such methods not requiring the use of systemic drugs that have
shown to (i) provide slow relief, (ii) cause adverse side effects,
(iii) limit activities, (iv) worsen existing gastrointestinal
conditions, (v) be unrecommended in several gastrointestinal
conditions that include gastrointestinal spasms, or (vi) be
unrecommended in the absence of diarrhea.
Inventors: |
HUANG; Alexander L.; (Menlo
Park, CA) ; WU; Gin; (San Rafael, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LiveLeaf, Inc. |
San Carlos |
CA |
US |
|
|
Assignee: |
LiveLeaf, Inc.
San Carlos
CA
|
Family ID: |
50552777 |
Appl. No.: |
14/173357 |
Filed: |
February 5, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14142902 |
Dec 29, 2013 |
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14173357 |
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13772264 |
Feb 20, 2013 |
8716352 |
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14142902 |
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13726180 |
Dec 23, 2012 |
8716351 |
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13772264 |
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Current U.S.
Class: |
424/616 |
Current CPC
Class: |
A61K 33/40 20130101;
A61K 36/185 20130101; A61K 31/7028 20130101; A61K 31/192 20130101;
A61K 31/353 20130101; A61K 36/82 20130101; A61K 31/7048 20130101;
A61K 36/185 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 36/82 20130101; A61K 33/40
20130101; A61K 31/352 20130101; A61K 36/22 20130101; A61P 1/04
20180101; A61K 31/353 20130101; A61P 1/00 20180101; A61K 2300/00
20130101; A61K 31/352 20130101; A61K 31/7034 20130101; A61K 31/192
20130101; A61K 45/06 20130101; A61K 31/7048 20130101 |
Class at
Publication: |
424/616 |
International
Class: |
A61K 33/40 20060101
A61K033/40 |
Claims
1. A method of treating a gastrointestinal spasm in a subject
having diverticulitis, the method comprising: administering an
effective amount of a formulation to a subject having a
gastrointestinal spasm, the formulation having a water soluble
tannin combined with hydrogen peroxide in a pharmaceutically
acceptable excipient; wherein, the tannin has a molecular weight
ranging from about 170 Daltons to about 4000 Daltons; the
tannin:peroxide weight ratio ranges from about 1:1000 to about
10:1; and, the formulation relieves a gastrointestinal spasm in the
subject having diverticulitis when compared to a second subject in
a control group also having diverticulitis in which the formulation
was not administered.
2. The method of claim 1, wherein the tannin is a hydrolysable
tannin.
3. The method of claim 1, wherein the tannin is a water soluble
condensed tannin.
4. The method of claim 1, wherein the tannin is a mixture of a
hydrolysable tannin and a water soluble condensed tannin.
5. The method of claim 1, wherein the tannin is a flavanol.
6. The method of claim 1, wherein the tannin is a catechin.
7. The method of claim 1, wherein the tannin is gallic acid,
epigallic acid, or a combination thereof.
8. The method of claim 1, wherein the weight ratio of the
tannin:peroxide ranges from about 1:1 to about 1:50.
9. The method of claim 1, wherein the tannin is combined with the
hydrogen peroxide as a component of a water extract of a plant
tissue.
10. A method of treating a gastrointestinal spasm in a subject
having diverticulitis, comprising: administering an effective
amount of a formulation to a subject having a gastrointestinal
spasm, the formulation produced from a process including combining
a water soluble tannin with hydrogen peroxide at a tannin:peroxide
weight ratio that ranges from about 1:1000 to about 10:1, the
tannin having a molecular weight ranging from about 170 Daltons to
about 4000 Daltons; removing free hydrogen peroxide from the
combination; and, mixing the combination of the tannin and the
hydrogen peroxide with a pharmaceutically acceptable excipient to
create the formulation; wherein, the administering includes
selecting a desired concentration of the formulation for the
administering; and, the formulation relieves a gastrointestinal
spasm in the subject having diverticulitis when compared to a
second subject in a control group also having diverticulitis in
which the formulation was not administered.
11. The method of claim 10, wherein the tannin is a hydrolysable
tannin.
12. The method of claim 10, wherein the tannin is a water soluble
condensed tannin.
13. The method of claim 10, wherein the tannin is a mixture of a
hydrolysable tannin and a water soluble condensed tannin.
14. The method of claim 10, wherein the tannin is a flavanol.
15. The method of claim 10, wherein the tannin is a catechin.
16. The method of claim 10, wherein the tannin is gallic acid,
epigallic acid, or a combination thereof.
17. The method of claim 10, wherein the tannin is combined with the
hydrogen peroxide as a component of a water extract of a plant
tissue.
18. The method of claim 10, wherein the tannin is combined with the
hydrogen peroxide as a component of an alcohol extract of a plant
tissue.
19. The method of claim 1, wherein the tannin is a hydrolysable
tannin having from 3-12 galloyl residues.
20. The method of claim 2, wherein the hydrolysable tannin is a
product of a water extraction of Chinese gall.
21. The method of claim 3, wherein the water soluble condensed
tannin is a product of a water extraction of green tea leaves.
22. The method of claim 1, wherein the tannin is a gallotannin.
23. The method of claim 1, wherein the tannin is an
ellagitannin.
24. The method of claim 23, wherein the tannin is a
punicalagin.
25. A method of treating a gastrointestinal spasm in a subject
having diverticulitis, comprising: administering an effective
amount of a composition to a subject having a gastrointestinal
spasm, the composition produced from a process including combining
a water soluble, hydrolysable tannin with hydrogen peroxide at a
tannin:peroxide weight ratio that ranges from about 1:1000 to about
10:1, the tannin having a molecular weight ranging from about 170
Daltons to about 4000 Daltons; wherein, the administering includes
selecting a desired concentration of the formulation for the
administering; and, the formulation relieves a gastrointestinal
spasm in the subject having diverticulitis when compared to a
second subject in a control group also having diverticulitis in
which the formulation was not administered.
26. The method of claim 25, wherein the water soluble tannin is a
gallotannin or an ellagitannin, and the mixing further comprises
removing free hydrogen peroxide from the combination; and, mixing
the combination of the tannin and the hydrogen peroxide with a
pharmaceutically acceptable excipient to create the
formulation.
27. The method of claim 25, wherein the tannin is an
ellagitannin.
28. The method of claim 27, wherein the tannin is a punicalagin.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/142,902, filed Dec. 29, 29, 2013, which is a continuation of
U.S. application Ser. No. 13/772,264, filed Feb. 20, 2013, which is
a continuation of U.S. application Ser. No. 13/726,180, filed Dec.
23, 2012, each of which is hereby incorporated herein by reference
in its entirety.
BACKGROUND
[0002] 1. Field of the Invention
[0003] The teachings provided herein relate to methods of treating
gastrointestinal spasms.
[0004] 2. Description of Related Art
[0005] Antispasmodics can be used to prevent spasms of the stomach,
intestine, uterus, or urinary bladder. Gastrointestinal spasms, for
example, can be very painful. Abdominal pain and discomfort from
cramping, bloating, forceful vomiting, and forceful defecation are
often the result of spasmodic intestinal contractions. The problem
is that there is no satisfactory treatment to relieve the pain and
suffering that currently exists due to this problem. Spasms can
also be treated using "anticholinergics" that counteract the
effects of the neurohormone acetylcholine. The anticholingergics
decrease both the movements of the stomach and intestine, and also
the secretions of stomach acid and digestive enzymes. Problems with
these drugs include dry mouth and dry eyes because of reduced
salivation and tearing.
[0006] An example of an anticholinergic that is used to treat
cramping is loperamide, an opioid-receptor agonist that slows
peristalsis. As such, it is not directed to relieve cramping from
spasms, per se. Moreover, loperamide crosses the blood-brain
barrier and, although quickly removed from the CNS by
P-glycoprotein, it can be addictive if taken with a drug that
inhibits P-glycoprotein. Moreover, loperamide has several
contraindications, such that it's not recommended for use with
several conditions that can include gastrointestinal spasms. For
example, it is not recommended for treatment with conditions
containing organisms that cross the intestinal walls, such as such
as E. coli O157:H7 or salmonella. And, ironically, although it is
often administered to alleviate abdominal pain and cramping, its
adverse effects can actually include abdominal pain and bloating,
nausea, vomiting and constipation. In fact, loperamide has been
labeled as (i) contraindicated in patients with abdominal pain in
the absence of diarrhea; (ii) not recommended in children below 24
months of age; and (iii) not recommended as the primary therapy in
patients with (a) acute dysentery, which is characterized by blood
in stools and high fever; (b) acute ulcerative colitis; (c)
bacterial enterocolitis caused by invasive organisms including
Salmonella, Shigella, and Campylobacter; or, (d) pseudomembranous
colitis associated with the use of broad-spectrum antibiotics. See,
for example,
http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=4-
1053, Lake Erie Medical DBA Quality Care Products LLC.
[0007] A condition of particular interest in the treatment of
gastrointestinal spasms is irritable bowel syndrome (IBS), a
condition afflicting an estimated 30 million people in the US and
up to 700 million people worldwide. IBS is diagnosed from clinical
symptoms that include abdominal pain, bloating, constipation, and
diarrhea. Treatment options are based upon the predominant symptom,
with diarrhea-predominant IBS receiving antidiarrheal agents, such
as loperamide (IMMODIUM) and pain-predominant IBS patients
receiving antispasmodic agents, such as dicyclomine HCL (BENTRYL)
and hyoscyamine sulfate (LEVSIN). The condition is generally
thought to be the result of spasmodic contractions of the
intestines that interfere with normal peristalsis causing blockages
that lead to bloating and constipation, cause hyperperistaltic
activity leading to frequent need for defecation, or a combination.
Problems with loperamide are discussed above. Dicyclomine has the
problem of some people sweat less, allowing the body to overheat
which can cause heat prostration (fever and heat stroke). As such,
anyone taking this drug should try to avoid extreme heat. Moreover,
dicyclomine can also cause drowsiness and blurred or double vision,
such that people who take this drug should not drive, use machines,
or do anything else that might be dangerous. Hyoscyamine can also
be used but, unfortunately, both dicyclomine and hyoscyamine have
general side effects and, for example, can worsen gastroesophageal
reflux disease. Anticholinergics, generally speaking, are also
known to cause difficulty in passing urine, and children and the
elderly are at a higher risk of developing such side effects.
[0008] One of skill would appreciate having a method of treating
spasms, particularly gastrointestinal spasms, without having to use
systemic drugs that have shown to (i) provide slow relief, (ii)
cause adverse side effects, (iii) limit activities, (iv) worsen
existing gastrointestinal conditions, (v) be unrecommended in
several gastrointestinal conditions that include gastrointestinal
spasms, and (vi) be unrecommended in the absence of diarrhea.
SUMMARY
[0009] The teachings provided herein relate to methods of treating
gastrointestinal spasms. The teachings include methods of treating
gastrointestinal spasms without having to use systemic drugs that
have shown to (i) provide slow relief, (ii) cause adverse side
effects, (iii) limit activities, (iv) worsen existing
gastrointestinal conditions, (v) be unrecommended in several
gastrointestinal conditions that include gastrointestinal spasms,
or (vi) be unrecommended in the absence of diarrhea.
[0010] In some embodiments, the teachings are directed to a method
of treating a gastrointestinal spasm in a subject, the method
comprising administering an effective amount of a composition to a
subject having a gastrointestinal spasm, the composition having a
polyphenol combined with a reactive oxygen species. And, in some
embodiments, the composition can be produced from a process
including combining a polyphenol with a reactive oxygen species;
selecting a desired concentration for the composition; and,
diluting the composition to the desired concentration for the
administering. In these embodiments, the polyphenol can have a
molecular weight ranging from about 170 Daltons to about 4000
Daltons; and, the composition can relieve a gastrointestinal spasm
in the subject either (i) when compared to a second subject in a
control group in which the composition was not administered or (ii)
when compared to a historic baseline of the symptoms present in the
subject. The measurement of relief from gastrointestinal spasms can
be measured using any of a variety of parameters, in some
embodiments. For example, the relief of the spasm can be measured
using a response selected from the group consisting of a reduction
in abdominal pain, a reduction in bloating, a reduction in forceful
defecation, a reduction in forceful vomiting, a reduction in
defecation urgency, a reduction in constipation, and/or a reduction
in incontinence.
[0011] The polyphenol can comprise a single component, a mixture of
components, or a whole extract of a plant tissue, in some
embodiments. In some embodiments, the polyphenol comprises a
tannin. In some embodiments, the polyphenol comprises a
hydrolysable tannin, a condensed tannin, or a combination of a
hydrolysable tannin and a condensed tannin. In some embodiments,
the polyphenol can comprise a pseudotannin selected, for example,
from the group consisting of gallic acid, which can be found in an
extract of a rhubarb plant tissue, for example; flavan-3-ols or
catechins, which can be found in an extract of acacia, catechu,
cocoa, or guarana, for example; chlorogenic acid, which can be
found in coffee, or mate; or, ipecacuanhic acid, which can be found
in carapichea ipecacuanha, for example. As such, it should be
appreciated that, in some embodiments, the polyphenol component can
comprise a flavanol or a catechin. Moreover, the polyphenol can
comprises gallic acid, epigallic acid, or a combination thereof, in
some embodiments.
[0012] The reactive oxygen species can be any such species known to
one of skill to have the ability to combine with the polyphenol as
a composition for the uses taught herein. In some embodiments, the
reactive oxygen species comprises hydrogen peroxide. And, in some
embodiments, the hydrogen peroxide can be combined with the tannin
at a tannin:peroxide weight ratio that ranges from about 1:1000 to
about 10:1. In some embodiments, the weight ratio of the
tannin:peroxide ranges from about 1:1 to about 1:50.
[0013] And, consistent with the above, one of skill will appreciate
that the polyphenol can be combined with the reactive oxygen
species as a component of a water or alcohol extract of a plant
tissue. In some embodiments, the plant tissue can comprise a tannin
or a pseudotannin.
[0014] One of skill reading the teachings that follow will
appreciate that the concepts can extend into additional embodiments
that go well-beyond a literal reading of the claims, the inventions
recited by the claims, and the terms recited in the claims.
BRIEF DESCRIPTION OF THE FIGURES
[0015] FIGS. 1A-1H are photographs of the dry forms of (A) gallic
acid (a model polyphenol building block) bound to hydrogen
peroxide; (B) gallic acid alone; (C) tannic acid (a model
polyphenol) bound to hydrogen peroxide; (D) tannic acid alone; (E)
pomegranate husk extract bound to hydrogen peroxide; (F)
pomegranate husk extract alone; (G) green tea extract bound to
hydrogen peroxide; and (H) green tea extract alone, according to
some embodiments.
[0016] FIGS. 2A and 2B show that the stability of the hydrogen
peroxide in the combination is consistently, substantially greater
in an aqueous solution than the stability of the hydrogen peroxide
alone in the aqueous solution, according to some embodiments.
DETAILED DESCRIPTION
[0017] Methods of treating gastrointestinal spasms are provided
herein. The methods include treating gastrointestinal spasms
without having to use systemic drugs. Such systemic drugs have been
reported to (i) provide slow relief, (ii) cause adverse side
effects, (iii) limit activities, (iv) worsen existing
gastrointestinal conditions, (v) be unrecommended in several
gastrointestinal conditions that include gastrointestinal spasms,
or (vi) be unrecommended in the absence of diarrhea.
[0018] In some embodiments, the method of treating a
gastrointestinal spasm in a subject comprises administering an
effective amount of a composition to a subject having a
gastrointestinal spasm, the composition having a polyphenol
combined with a reactive oxygen species. And, in some embodiments,
the composition can be produced from a process including combining
a polyphenol with a reactive oxygen species; selecting a desired
concentration for the composition; and, diluting the composition to
the desired concentration for the administering. In these
embodiments, the polyphenol can have a molecular weight ranging
from about 170 Daltons to about 4000 Daltons; and, the composition
can relieve a gastrointestinal spasm in the subject either (i) when
compared to a second subject in a control group in which the
composition was not administered or (ii) when compared to a
historic baseline of the symptoms present in the subject.
[0019] To provide a desired therapeutic relief, the compositions
can be directed to act on tissues at a particular target site,
which can be gastrointestinal tissue, in some embodiments. The term
"target site" can be used to refer to a select location at which
the composition acts to provide a therapeutic effect, or treatment
as described herein. In some embodiments, the target site can be a
tissue of any organ in which control of a spasm is desirable.
Moreover, the target can include any site of action in which the
phenolic compound can be site-activated by an oxidoreductase enzyme
that is available at the site. The oxidoreductase enzyme can be
produced endogeneously by a tissue at a target site, produced
endogeneously by a microbe, introduced exogenously to the target
site, include more than one enzyme, co-enzyme, catalyst, or
cofactor, or a combination thereof. The measurement of relief from
gastrointestinal spasms, for example, can be measured using any of
a variety of parameters. For example, the relief of the spasm can
be measured using a response selected from the group consisting of
a reduction in abdominal pain, a reduction in bloating, a reduction
in forceful defecation, a reduction in forceful vomiting, a
reduction in defecation urgency, a reduction in constipation,
and/or a reduction in incontinence.
[0020] Without intending to be bound by any theory or mechanism of
action, the compositions taught herein can include phenolics, for
example, polyphenols. The phenolic compounds taught herein are
selected to combine with a reactive oxygen species to form a
composition that is deliverable as a stable, or substantially
stable, system. In some embodiments, the compositions can include a
polyphenol component combined with hydrogen peroxide, a combination
of components having an association that offers a stability and
activity, both of which are offered by neither component alone.
Such a composition can be delivered to a target site, for example,
in a polar solution such as water or an alcohol. In some
embodiments, at least a substantial amount of the hydrogen peroxide
can remain bound, or otherwise associated with, and thus stable or
substantially stable, with the phenolic compound. Moreover, in some
embodiments, the composition contains no, or substantially no,
unbound hydrogen peroxide. The teachings also include a
pharmaceutical formulation comprising the compositions taught
herein and a pharmaceutically acceptable excipient.
[0021] The terms "composition," "compound," "binding system,"
"binding pair," and "system" can be used interchangeably in some
embodiments and, it should be appreciated that a "formulation" can
comprise a composition, compound, binding system, binding pair, or
system presented herein. Likewise, in some embodiments, the
compositions taught herein can also be referred to as an "agent," a
"bioactive agent," or a "supplement" whether alone, in a
pharmaceutically acceptable composition or formulation, and whether
in a liquid or dry form. Moreover, the term "bioactivity" can refer
to a treatment that occurs through the use of the compositions
provided herein. One of skill will appreciate that the term "bind,"
"binding," "bound," "attached," "connected," "chemically
connected," "chemically attached," "combined," or "associated" can
be used interchangeably, in some embodiments. Such terms, for
example, can be used to refer to any association between the
polyphenol and reactive oxygen species that has resulted in an
increased stability and/or sustained activity of the composition or
components in the compositions. For example, the terms can be used
to describe a chemical bonding mechanism known to one of skill,
such as covalent, ionic, dipole-dipole interactions, London
dispersion forces, and hydrogen bonding, for example. In some
embodiments, the compositions can comprise a phenolic compound
sharing hydrogen bonds with a reactive oxygen species, for example,
such as hydrogen peroxide. In some embodiments, the phenolic
compound can comprise a polyphenol that covalently binds to an
amino acid or polyol.
[0022] One of skill will appreciate that the compositions should
remain stable, or at least substantially stable, until useful or
activated, and this can relate to a measure of time. Such a measure
of time can include a shelf life, or a time between creation of the
composition and administration of the composition, or some
combination thereof. In some embodiments, the composition is
stable, or substantially stable, when usable as intended within a
reasonable amount of time. In some embodiments, the composition
should be usable within a reasonable time from the making of the
composition to the administration of the composition and, in some
embodiments, the composition should have a reasonable commercial
shelf life. The composition can be considered as "stable" if it
loses less than 10% of it's original oxidation potential, and this
can be measured by comparing it's oxidation potential after making
the composition to the time of administration, and this can include
a reasonable shelf life, in some embodiments. In some embodiments,
the composition can be considered as stable if it loses less than
5%, 3%, 2%, or 1% of it's original oxidation potential when
comparing it's oxidation potential after making the composition to
the time of administration, and this can include a reasonable shelf
life, in some embodiments. The composition can be considered as
"substantially stable" if it loses greater than about 10% of it's
original oxidation potential, as long as the composition can
perform it's intended use to a reasonable degree of efficacy. The
loss can be measured, as above, by measured by comparing it's
oxidation potential after making the composition to the time of
administration, and this can include a reasonable shelf life, in
some embodiments. In some embodiments, the composition can be
considered as substantially stable if a reactive oxygen species
loses greater than about 12%, about 15%, about 25%, about 35%,
about 45%, about 50%, about 60%, or even about 70% of it's original
oxidation potential. The loss may be measured by measured by
comparing it's oxidation potential after making the composition to
the time of administration, and this can include a reasonable shelf
life, in some embodiments. The time to compare the oxidation
potential for a measure of stability can range from about 30
minutes to about one hour, from about one hour to about 12 hours,
from about 12 hours to about 1 day, from about one day to about one
week, from about 1 week to about 1 month, from about 1 month to
about 3 months, from about 1 month to a year, from 3 months to a
year, from 3 months to 2 years, from 3 months to 3 years, greater
than 3 months, greater than 6 months, greater than one year, or any
time or range of times therein, stated in increments of one
hour.
[0023] One of skill will appreciate that the phenolic compound used
in the compositions can be any phenolic compound that functions
consistent with the teachings provided herein, and there are at
least several thousand such phenolic compounds known to those of
skill that can be expected to function as desired. As such, the
teachings provided herein can only include examples of the general
concepts rather than a comprehensive listing of all possibilities
and permutations of the systems that are enabled by the
teachings.
[0024] The phenolic component can be a polyphenol, and the
polyphenol can comprise a single component, a mixture of
components, or a whole extract of a plant tissue, in some
embodiments. In some embodiments, the polyphenol comprises a
tannin. In some embodiments, the polyphenol comprises a
hydrolysable tannin, a condensed tannin, or a combination of a
hydrolysable tannin and a condensed tannin. In some embodiments,
the polyphenol can comprise a pseudotannin selected, for example,
from the group consisting of gallic acid, which can be found in an
extract of a rhubarb plant tissue, for example; flavan-3-ols or
catechins, which can be found in an extract of acacia, catechu,
cocoa, or guarana, for example; chlorogenic acid, which can be
found in coffee, or mate; or, ipecacuanhic acid, which can be found
in carapichea ipecacuanha, for example. As such, it should be
appreciated that, in some embodiments, the polyphenol component can
comprise a flavanol or a catechin. Moreover, the polyphenol can
comprises gallic acid, epigallic acid, or a combination thereof, in
some embodiments.
[0025] In some embodiments, the phenolic compound has at least one
aryl group, or arene moiety, and at least two polar aromatic
groups, such as aromatic hydroxyl groups. In some embodiments, the
polar aromatic groups can be, for example, hydroxyl, amine, amide,
acyl, carboxy, or carbonyl. In some embodiments, the phenolic
compound has at least two aryl groups, and at least two hydroxyl
groups. In some embodiments, the phenolic compounds can be
naturally occurring, such as from a plant or other natural product.
And, in some embodiments, the phenolic compounds can be
synthetically or semi-synthetically produced. The compounds can be
simple monomers, oligomers, or polymers. The polymers can be in the
class of polyphenols or polymeric phenols, where one of skill will
understand that the general difference is typically that
polyphenols generally do not have a repeating unit, whereas
polymeric phenols do. There are exceptions, however, such that
groups of polyphenols and polymeric phenols can overlap. In most
embodiments, the phenolic compound used in the binding system can
be any phenolic compound taught herein, or any prodrugs, codrugs,
metabolites, analogs, homologues, congeners, derivatives, salts,
solvates, and combinations thereof.
[0026] In some embodiments, the phenolic compounds bind to hydrogen
peroxide to form a binding pair and, in some embodiments, the
binding pair remains stable, or substantial stable in water. In
some embodiments, the binding pair remains stable, or substantial
stable in an alcohol. And, in some embodiments, the binding pair
remains stable, or substantial stable, in a polar solvent such as,
for example, a saline solution, an aqueous emulsion, a hydrogel,
and the like.
[0027] In some embodiments, the phenolic compounds are polyphenols
having molecular weights ranging from about 170 to about 4000
Daltons, having from about 12 to about 16 phenolic hydroxyl groups,
and having from about five to about seven aromatic rings, for every
about 1000 Daltons in molecular weight. In some embodiments, the
phenolic compounds function to precipitate alkaloids and proteins.
In some embodiments, the phenolic compounds can bind to cellular
receptors, amino acids, peptides, oligopeptides, polyols,
saccharides, or combinations thereof. In some embodiments, the
phenolic compounds have at least from about 1 to about 20
polyhydroxylated phenolic units and have at least moderate water
solubility.
[0028] The term "solubility" can refer to a concentration of a
solute in a solvent, for example, the phenolic compound in water.
The concentration can be expressed by mass, for example, mg of the
phenolic compound per kg of water at ambient temperature and
pressure. This ratio of mg/kg can be used interchangeably with ppm,
and ng/kg can be used interchangeably with ppb. In some
embodiments, the solubility of the phenolic compound can be higher
than about 500,000 ppm or less than about 1 ppm. In some
embodiments, the solubility of the phenolic compound range from
about 10 ppb to about 500,000 ppm, from about 100 ppb to about
250,000 ppm, from about 1 ppm to about 100,000 ppm, from about 10
ppm to about 50,000 ppm, from about 50 ppm to about 25,000 ppm,
from about 100 ppm to about 10,000 ppm, from about 100 ppm to about
100,000 ppm, from about 200 ppm to about 100,000 ppm, from about
250 ppm to about 50,000 ppm, from about 500 ppm to about 25,000 ppm
from about 250 ppm to about 10,000 ppm, or any range therein. In
some embodiments, the solubility can range from about 1 g/L to
about 10,000 g/L, from about 5 g/L to about 5000 g/L, from about 10
g/L to about 3000 g/L, from about 20 g/L to about 2000 g/L, from
about 50 g/L to about 1000 g/L, from about 100 g/L to about 500
g/L, or any range therein. For purposes of the teachings provided
herein, a compound can be considered to have a low solubility if
the solubility is less than about 50 g/L, a moderate solubility if
the solubility ranges from about 50 g/L to about 1000 g/L, and a
high solubility if the solubility is above about 1000 g/L. In some
embodiments, the phenolic compound can have a low solubility. In
some embodiments, the phenolic compound can have a moderate
solubility. And, in some embodiments, the phenolic compound can
have a high solubility.
[0029] One of skill will appreciate that the phenolic compounds can
still be useful at low solubilities in cases where the solubility
is too low to form a true solution. In some embodiments the
phenolic compounds can be ground into particles to form a colloidal
mixture or suspension that will function consistent with the
teachings provided herein. As such, liquid formulations include
colloids and suspensions in some embodiments. The formulations can
be a dispersed phase mixture in the form of colloidal aerosols,
colloidal emulsions, colloidal foams, colloidal dispersions, or
hydrosols. In some embodiments, the liquid formulation can include
particles having sizes ranging, for example, from about 5 nm to
about 200 nm, from about 5 nm to about 500 nm, from about 5 nm to
about 750 nm, from about 50 nm to about 1 um. In some embodiments,
the liquid formulations can be suspensions, in which the particle
size range from about 1 um to about 10 um, from about 1 um to about
7 um, from about 1 um to about 5 um, or any range therein. In some
embodiments, the liquid formulation can include particles having
sizes ranging from about 1 nm to about 10 um.
[0030] The functionality of a phenolic compound in the teachings
herein can, for at least the reason of solubility, depend on
molecular weight, alone or in addition to other factors discussed
herein such as, for example, extent of hydroxylation, presence and
location of ketone or quinine groups, and the presence of other
functional groups. In some embodiments, the molecular weights of
the phenolic compounds can range from about 110 Daltons to about
40,000 Daltons. In some embodiments, the molecular weights of the
phenolic compounds can range from about 200 Daltons to about 20,000
Daltons, from about 300 Daltons to about 30,000 Daltons, from about
400 Daltons to about 40,000 Daltons, from about 500 Daltons to
about 10,000 Daltons, from about 1000 Daltons to about 5,000
Daltons, from about 170 Daltons to about 4000 Daltons, from about
350 Daltons to about 4,000 Daltons, from about 300 Daltons to about
3,000 Daltons, from about 110 Daltons to about 2,000 Daltons, from
about 200 to about 5000 Daltons, or any range or molecular weight
therein in increments of 10 Daltons.
[0031] In some embodiments, the ratio of aromatic rings to
molecular weight of the phenolic compounds can range from about
five to about seven aromatic rings for every about 1000 Daltons. In
some embodiments, the ratio of aromatic rings to molecular weight
of the phenolic compounds can range from about 2 to about 10
aromatic rings for every about 1000 Daltons, from about 3 to about
9 aromatic rings for every about 1000 Daltons, from about 4 to
about 8 aromatic rings for every about 1000 Daltons, from about 5
to about 7 aromatic rings for every about 1000 Daltons, from about
1 to about 5 for every about 500 Daltons, from about 1 to about 4
for every about 500 Daltons, from about 1 to about 3 for every
about 500 Daltons, from about 2 to about 4 for every about 500
Daltons, or any amount or range therein in increments of 1
ring.
[0032] One of skill will appreciate that, in some embodiments the
phenolic compounds can have, or be synthesized or otherwise
designed to contain functional groups that are capable of
releasably bonding to a reactive oxygen species, in a stable or
substantially stable form, until either consumed or released upon
bioactivation at a target site. In some embodiments, a releasable
bond can include any bond other than a covalent bond. In some
embodiments, a releasable bond is a hydrogen bond. As such, the
phenolic compounds should be capable of forming, for example, a
hydrogen bond with a reactive oxygen species upon such
bioactivation. In some embodiments, the phenolic compound shares
hydrogen bonding with hydrogen peroxide and is released through a
bioactivation that occurs when the binding pair comes into contact
with an oxidoreductase enzyme or other reducing agent. In some
embodiments, the phenolic compound can have functional groups that
comprise acyl, amido, amino, carbonyl, carboxyl, hydroxyl, or
peroxyl functionality. In some embodiments, the hydrogen bond
between the reactive oxygen species and the phenolic compound can
include any hydrogen donor and any hydrogen acceptor having an
available lone pair of electrons. In some embodiments, the hydrogen
acceptor can include, for example a N, O, or F atom, or a
combination thereof. In some embodiments, the phenolic compound can
have such a functionality, can be derivatized to have such a
functionality, can be linked to another compound having such a
functionality, can be placed in a carrier having such a
functionality, or some combination thereof.
[0033] In some embodiments, phenolic compounds can include simple
phenols, such as those containing 6 carbons, a C6 structure, and 1
phenolic cycle, such as the benzene alcohols, examples of which
include phenol, benzene diols and it's isomers such as catechol,
and the benzenetriols. In some embodiments, phenolic compounds can
include phenolic acids and aldehydes, such as those containing 7
carbons, a C6-C1 structure, and 1 phenolic cycle, examples of which
include gallic acid and salicylic acids. In some embodiments,
phenolic compounds can include, for example, tyrosine derivatives,
and phenylacetic acids, such as those containing 8 carbons, a C6-C2
structure, and 1 phenolic cycle, examples of which include
3-acetyl-6-methoxybenzaldehyde, tyrosol, and p-hydroxyphenylacetic
acid. In some embodiments, phenolic compounds can include
hydroxycinnamic acids, phenylpropenes, chromones, such as those
containing 9 carbons, a C6-C3 structure, and 1 phenolic cycle,
examples of which include caffeic acid, ferulic acids, myristicin,
eugenol, umbelliferone, aesculetin, bergenon, and eugenin. In some
embodiments, phenolic compounds can include naphthoquinones, such
as those containing 10 carbons, a C6-C4 structure, and 1 phenolic
cycle, examples of which include juglone and plumbagin. In some
embodiments, phenolic compounds can include xanthonoids, such as
those containing 13 carbons, a C6-C1-C6 structure, and 2 phenolic
cycles, examples of which include mangiferin. In some embodiments,
phenolic compounds can include stilbenoids, and anthraquinones,
such as those containing 14 carbons, a C6-C2-C6 structure, and 2
phenolic cycles, examples of which include resveratrol and emodin.
In some embodiments, phenolic compounds can include chalconoids,
flavonoids, isoflavonoids, and neoflavonoids, such as those
containing 15 carbons, a C6-C3-C6 structure, and 2 phenolic cycles,
examples of which include quercetin, myricetin, luteolin, cyanidin,
and genistein. In some embodiments, phenolic compounds can include
lignans and neolignans, such as those containing 18 carbons, a
C6-C3-C6 structure, and 2 phenolic cycles, examples of which
include pinoresinol and eusiderin. In some embodiments, phenolic
compounds can include biflavonoids, such as those containing 30
carbons, a (C6-C3-C6).sub.2 structure, and 4 phenolic cycles,
examples of which include amentoflavone. In some embodiments,
phenolic compounds can include polyphenols, polyphenolic proteins,
lignins, and catechol melanins, such as those containing >30
carbons. In these embodiments, the phenolic compounds can have, for
example, a (C6-C3).sub.n structure, a (C6).sub.n structure, a
(C6-C3-C6).sub.n structure, or some combination thereof, as well as
greater than about 12 phenolic cycles. Examples of such embodiments
can include, for example, the flavolans, in the class of condensed
tannins.
[0034] In some embodiments, the phenolic compounds are natural
phenols that can be enzymatically polymerized. Derivatives of
natural phenols can also be used in some embodiments. These
embodiments can include phenolic compounds having less than 12
phenolic groups, such that they can range from monophenols to
oligophenols. In some embodiments, the natural phenols are found in
plants, have an antioxidant activity, or a combination thereof.
Examples of the natural phenols include, for example, catechol- and
resorcinol-types (benzenediols) with two phenolic hydroxy groups,
and pyrogallol- and phloroglucinol-types (benzenetriols) with three
hydroxy groups. Natural phenols may have heteroatom substituents
other than hydroxyl groups, ether and ester linkages, carboxylic
acid derivatives, or some combination thereof. In some embodiments,
the natural phenols include natural phenol drugs and their
derivatives. Examples of such drugs include, but are not limited
to, anthraquinone drugs, flavone drugs, and flavonol drugs.
Examples of anthraquinone drugs include, but are not limited to,
aloe emodin, aquayamycin, and diacerein. Examples of flavone drugs
include, but are not limited to, ansoxetine and hidrosmin. Examples
of flavonol drugs include, but are not limited to, monoxerutin and
troxerutin.
[0035] In some embodiments, the phenolic compound is a tannin, a
polyphenolic phenylpropanoid, or a combination thereof. In some
embodiments, the tannin is a hydrolysable tannin, a condensed
tannin, or a combination thereof. Hydrolysable tannins can be
found, for example, in chinese gall, which is almost pure in that
it has no or substantially no condensed tannins. Condensed tannins
can be found, for example, in green tea leaf, which is also almost
pure in that it has no or substantially no hydrolysable
tannins.
[0036] Examples of hydrolysable tannin can include gallotannic
acids, quercitannic acids, ellagitannins, gallotannin, pentagalloyl
glucose, galloylquinic acid, galloyl-shikimic acid, and
punicalagin. In some embodiments, the hydrolysable tannin is a
gallotannin or ellagitannin, and isomers thereof, such as isomers
that can precipitate protein. Examples of gallotannins include the
gallic acid esters of glucose in tannic acid
(C.sub.76H.sub.52O.sub.46) and pentagalloyl glucose (PGG), and
isomers thereof, such as the isomers of PGG that function to
precipitate proteins. Examples of an ellagitannin include castalin
and punicalagin. In some embodiments, the tannin is a gallic acid
ester having a molecular weight ranging from about 500 Daltons to
about 3000 Daltons. In some embodiments, the tannin is a
proanthocyanidin having a molecular weight of up to about 20,000
Daltons. In some embodiments, the hydrolysable tannins are
derivatives of gallic acid and characterized by a glucose, quinic
acid or shikimic acid core with its hydroxyl groups partially or
totally esterified with gallic acid or ellagic acid groups. The
compounds can have 3 to 12 galloyl residues but may be further
oxidatively crosslinked and complex. Hydrolysable tannins can be
readily synthesized, for example, to obtain a phenolic compound
with a high number of polar functional groups that form multiple,
stable hydrogen bonds between the tannin and hydrogen peroxide in
the binding system.
[0037] It should be appreciated that, while hydrolysable tannins
and most condensed tannins are water soluble, some very large
condensed tannins are insoluble. In some embodiments, the phenolic
compound can comprise a hydrolysable tannin such as, for example,
burkinabin C, castalagin, castalin, casuarictin, chebulagic acid,
chebulinic acid, corilagin, digallic acid, ellagitannin, gallagic
acid, gallotannin, glucogallin, grandinin, hexahydroxydiphenic
acid, pentagalloyl glucose, punicalagin alpha, punicalagins,
raspberry ellagitannin, roburin A, stenophyllanin A, stenophyllanin
A, tannate, tannic acid, tellimagrandin II, terflavin B, or
3,4,5-tri-O-galloylquinic acid.
[0038] In some embodiments, the phenolic compound can be a
flavonoid which includes several thousand natural phenol compounds.
Examples of the flavonoids include the flavonols, flavones,
flavan-3ol (catechins), flavanones, anthocyanidins, isoflavonoids,
and hybrids of any combination of these compounds. In some
embodiments, the phenolic compounds are the hydrolysable tannins
such as, for example, gallic acid. In some embodiments, the
phenolic compounds are the lignins such as, for example, cinnamic
acid. In some embodiments, the phenolic units can be dimerized or
further polymerized to form any of a variety of hybrids. For
example, ellagic acid is a dimer of gallic acid and forms the class
of ellagitannins, or a catechin and a gallocatechin can combine to
form theaflavin or the large class of thearubigins found in tea. In
another example, a flavonoid and a lignan can combine to form a
hybrid, such a flavonolignans.
[0039] In some embodiments, the phenolic compound can be a
flavan-3ol. Examples include the catechins and the catechin
gallates, where the catechin gallates are gallic acid esters of the
catechins. In some embodiments, the phenolic compound is a catechin
or epicatechin compound (the cis- or trans-isomers). In some
embodiments, the phenolic compound is (-)-epicatechin or
(+)-catechin. In some embodiments, the phenolic compound is
epigallocatechin (EGC) or gallocatechin (EC). In some embodiments,
the phenolic compound is a catechin gallate, such as
epigallocatechin gallate (EGCG)
[0040] In some embodiments, the phenolic compound can be selected
from the group of flavones consisting of apigenin, luteolin,
tangeritin, flavonols, isorhamnetin, kaempferol, myricetin (e.g.,
extractable from walnuts), proanthocyanidins or condensed tannins,
and quercetin and related phenolic compounds, such as rutin.
[0041] In some embodiments, the phenolic compound can be selected
from the group of flavanones consisting of eriodictyol, hesperetin
(metabolizes to hesperidin), and naringenin (metabolized from
naringin).
[0042] In some embodiments, the phenolic compound can be selected
from the group of flavanols consisting of catechin, gallocatechin
and their corresponding gallate esters, epicatechin,
epigallocatechin and their corresponding gallate esters, theaflavin
and its gallate esters, thearubigins, isoflavone phytoestrogens
(found primarily in soy, peanuts, and other members of the Fabaceae
family), daidzein, genistein, glycitein, stilbenoids, resveratrol
(found in the skins of dark-colored grapes, and concentrated in red
wine), pterostilbene (methoxylated analogue of resveratrol,
abundant in Vaccinium berries), anthocyanins, cyanidin,
delphinidin, malvidin, pelargonidin, peonidin, and petunidin. And,
In some embodiments, the phenolic compound can be ubiquinol an
electron-rich (reduced) form of coenzyme Q10.
[0043] In some embodiments, the phenolic compound can be selected
from the group of carotenoid terpenoid consisting of
alpha-carotene, astaxanthin (found naturally in red algae and
animals higher in the marine food chain, a red pigment familiarly
recognized in crustacean shells and salmon flesh/roe),
beta-carotene (found in high concentrations in butternut squash,
carrots, orange bell peppers, pumpkins, and sweet potatoes),
canthaxanthin, lutein (found in high concentration in spinach,
kiwifruit and red peppers), lycopene (found in high concentration
in ripe red tomatoes and watermelons) and zeaxanthin (the main
pigment found in yellow corn, also abundant in kiwifruit).
[0044] In some embodiments, the phenolic compound can be selected
from the group of phenolic acids and their esters consisting of
chicoric acid (another caffeic acid derivative, is found only in
the medicinal herb echinacea purpurea), chlorogenic acid (found in
high concentration in coffee (more concentrated in robusta than
arabica beans, blueberries and tomatoes, and produced from
esterification of caffeic acid), cinnamic acid and its derivatives,
such as ferulic acid (found in seeds of plants such as in brown
rice, whole wheat and oats, as well as in coffee, apple, artichoke,
peanut, orange and pineapple), ellagic acid (found in high
concentration in raspberry and strawberry, and in ester form in red
wine tannins), ellagitannins (hydrolysable tannin polymer formed
when ellagic acid, a polyphenol monomer, esterifies and binds with
the hydroxyl group of a polyol carbohydrate such as glucose),
gallic acid (found in gallnuts, sumac, witch hazel, tea leaves, oak
bark, and many other plants), gallotannins (hydrolysable tannin
polymer formed when gallic acid, a polyphenol monomer, esterifies
and binds with the hydroxyl group of a polyol carbohydrate such as
glucose), rosmarinic acid (found in high concentration in rosemary,
oregano, lemon balm, sage, and marjoram), and salicylic acid (found
in most vegetables, fruits, and herbs; but most abundantly in the
bark of willow trees, from where it was extracted for use in the
early manufacture of aspirin).
[0045] In some embodiments, the phenolic compound can be selected
from the group of nonflavonoid phenolics consisting of curcumin
(has low bioavailability, because, much of it is excreted through
glucuronidation, but bioavailability can be substantially enhanced
by solubilization in a lipid (oil or lecithin), heat, addition of
piperine, or through nanoparticularization, flavonolignans, for
example, silymarin which is a mixture of flavonolignans extracted
from milk thistle), eugenol and xanthones (mangosteen, for example,
is purported to contain a large variety of xanthones, some of
which, like mangostin are believed to be present only in the
inedible shell).
[0046] In some embodiments, the phenolic compound can have a low
molecular weight (less than about 400 Daltons), selected from the
group consisting of caffeic acid, gentisic acid, protocatechuic
acid, phenylacetic acid, gallic acid, phloroglucinol carboxylic
acid, and derivatives thereof. Such compounds can form a
sufficiently soluble binding pair, and their relatively high
hydroxyl group to molecular weight ratio creates favorable
conditions for obtaining the intermolecular hydrogen bonds desired
for the binding systems.
[0047] In some embodiments, the phenolic compounds can be from a
natural extract, such as an extract of a plant or other natural
product. See, for example, U.S. Published Patent Application Nos.
20100158885 and 20110070198, each of which is hereby incorporated
by reference herein in its entirety. Those skilled in the art of
such extracts will understand that extracts of plant materials are
not typically pure in one type of phenolic compound. Plant tannin
extracts, for example, typically comprise heterogenous mixtures and
derivatives of the above classes.
[0048] One of skill will appreciate, given the teachings provided
herein, that the polyphenol can be combined with the reactive
oxygen species as a component of a water or alcohol extract of a
plant tissue. In some embodiments, the plant tissue can comprise a
tannin or a pseudotannin. In some embodiments, the phenolic
compound is extracted from a whole or partial plant tissue selected
from the group consisting of seeds and fruits; ovaries; juice;
pulp; galls; husks; bark; stems; leaves; flowers; sheaths; hulls;
sprouts; bulbs; hips; tubers; roots of grains; grasses; legumes;
trees; vegetables; medicinal herbs; tea leaves; algaes; marine
plants; and, forages. One of skill will appreciate that the type
and content of phenolic compound obtained can be expected to vary
with the species, season, geographical location, cultivation, and
storage. Examples of plant tissues include, but are not limited to,
plant tissues from the species of Aloe, Pachycereus, and Opuntia.
Other examples can include, but are not limited to, Agavaceae,
Cactaceae, Poaceae, Theaceae, Leguminosae, and Lythraceae. In some
embodiments, the plant tissues can be selected from the group
consisting of pomegranate husk, aloe vera leaves, and green tea
leaves. Other examples of plant tissues can include, but are not
limited to Aloe (Aloe vera), Angelica (Angelica archangelica),
Barberry (Berberis vulgaris) Root Bark, Bilberry (Vaccinium
myrtillus), Calendula (Calendula officinalis), Cramp bark (Viburnum
opulus), Eleutherococcus root (Eleutherococcus senticosus), Kidney
wood (Eysenhardtia orththocarpa), Mimosa tenuiflora, Papaya (Carica
papaya) leaves, Pau D' Arco (Tabebuia avellanedae), Sassafras
albidum root bark, Saw Palmatto (Serenoa repens), St John's wort
(Hypericum perforatum), Valerian (Valeriana officinalis), Apple
(Malus domestica), Grape (Vitis vinifera), Echinacea purpurea,
Grape seed extract, and Blueberry (Vaccinium corymbosum). In some
embodiments, the plant tissues are selected from the group
consisting of barley germ, green tea leaves, aloe vera leaves, mung
beans, carrot, cereal grains, seeds, buds, and sprouts.
[0049] Likewise, one of skill will appreciate that there are
numerous reactive oxygen species that can be used in the systems
taught herein, as long as the reactive oxygen species function
consistent with such teachings. Hydrogen peroxide, and precursors
of hydrogen peroxide, are merely examples. In some embodiments, the
phenolic compounds in the compositions (i) have phenolic hydroxyl
groups that are oxidizable in the presence of a reactive oxygen
species and an oxidoreductase enzyme, and (ii) are soluble in a
polar liquid, such as water or an alcohol, for example, or at least
moderately soluble. The phenolic compounds should also be (iii)
non-toxic to a subject upon administration. And, in some
embodiments, the phenolic compounds should also (iv) crosslink or
polymerize with itself or other phenolic compounds in the
compositions taught herein.
[0050] The reactive oxygen species can be any such species known to
one of skill to have the ability to combine with the polyphenol as
a composition for the uses taught herein. For example, the reactive
oxygen species can include, but is not limited to, the reactive
oxygen species includes a component selected from the group
consisting of hydrogen peroxide, superoxide anion, singlet oxygen,
and a hydroxyl radical. In some embodiments, the reactive oxygen
species comprises hydrogen peroxide. And, in some embodiments, the
hydrogen peroxide can be combined with the tannin at a
tannin:peroxide weight ratio that ranges from about 1:1000 to about
10:1. In some embodiments, the weight ratio of the tannin:peroxide
ranges from about 1:1 to about 1:50. In some embodiments, the
exogeneous reactive oxygen species can be generated, as hydrogen
peroxide for example, from a solid hydrogen peroxide generating
material selected from the group consisting of sodium percarbonate,
potassium percarbonate, a carbamide peroxide, and urea
peroxide.
[0051] In some embodiments, the reactive oxygen species is hydrogen
peroxide or materials that release or generate hydrogen peroxide
including, but not limited to, hydration of adducts of hydrogen
peroxide such as carbamide peroxide, magnesium peroxide, and sodium
percarbonate; amino perhydrates; superoxide dismutase decomposition
of ozone, superoxides or superoxide salts; glucose oxidase and
glucose, aqueous dilution of honey; H.sub.2O.sub.2 production by
lactobacillus; catalytic quinone hydrogenation; superoxides; and,
superoxide dismutase. In some embodiments, the reactive oxygen
species can include peroxide ion, organic peroxides, organic
hydroperoxides, peracid superoxides, dioxygenyls, ozones, and
ozonides. hydrogen peroxide or materials that generate hydrogen
peroxide can be obtained or derived synthetically or from plant
tissues or combinations of plant tissues.
[0052] Enzymes can activate the compositions for the methods taught
herein, and the systems for the methods of treatment can be
designed accordingly. And, generally speaking, one of skill will
appreciate that there are a wide variety of enzymes are possible
and can be target site dependent. Generally, the enzymes fall into
the classes of oxidoreductases. As such, there are several enzymes
and isozymes that will be present at a target site and capable of
bioactivating the binding systems. In some embodiments, the
oxidoreductases can be categorized into about 22 classes, and the
selectivity of the bioactivation of the binding system at a target
site depends, at least in part, on the selectivity of the
oxidoreductase at the target site. In some embodiments, the
oxidoreductase can include those oxidoreductases that act on the
CH--OH group of donors (alcohol oxidoreductases, for example; EC
Number class 1.1). In some embodiments, the oxidoreductase can
include those oxidoreductases that act on diphenols and related
substances as donors (catechol oxidase, for example, EC Number
class 1.10). In some embodiments, the oxidoreductase can include
those oxidoreductases that act on peroxide as an acceptor
(peroxidases, such as horseradish peroxidase and catalase; EC
Number class 1.11). In some embodiments, the oxidoreductase can
include those oxidoreductases that act on phenols as an acceptor
(tyrosinases, for example; EC Number class 1.14). Examples of other
useful enzymes for the teachings provided herein include, but are
not limited to, glutathione peroxidase 1 and 4 (in many mammalian
tissues), glutathione peroxidase 2 (in intestinal and extracellular
mammalian tissues), glutathione peroxidase 3 (in plasma mammalian
tissues), lactoperoxidase, myeloperoxidase (in salivary &
mucosal mammalian tissues), myeloperoxidase (in neutrophil
mammalian tissues), cytochrome peroxidase (in yeasts such as
Candida albicans) and horseradish peroxidase (common to show in
vitro activity). One of skill will appreciate that oxidoreductases
are selective and, in some embodiments, the oxidoreductase can
include an alternate enzyme that are selective for a binding system
having a phenolic compound that acts as a substrate for the
alternative enzyme.
[0053] In some embodiments, the oxidoreductases include
mono-oxygenases such as, for example, phenylalaning monooxygenase,
tyrosine monooxygenase, and tryptophan monooxygenase. In some
embodiments, the oxidoreductases include dioxygenases such as, for
example, tryptophan dioxygenase, homogentisate dioxygenase,
trimethyl lysine dioxygenase, and nitric oxide synthase. In some
embodiments, the oxidoreductases include peroxidases such as, for
example, catalase, myeloperoxidase, thyroperoxidase. In some
embodiments, the oxidoreductases act in the presence of a co-factor
or co-enzyme, such as nicotinamide adenine dinucleotide phosphate
(NADP) or nicotinamide adenine dinucleotide (NAD).
Methods of Making the Compositions
[0054] The design of the binding systems include (i) selecting the
phenolic compound, (ii) selecting the reactive oxygen species,
(iii) selecting the ratio of phenolic compound to reactive oxygen
species, and (iv) selecting a carrier. In some embodiments, the
phenolic compound can be derivatized or attached to another
chemical moiety via a linker, or another known method such as, for
example, esterification to facilitate or improve an association
between the phenolic compound and the reactive oxygen species, as
well as to potentially modify, solubility, tissue absorption, or
toxicity.
[0055] One of skill will appreciate that, at least from the
teachings provided herein, there are a vast number of components
that can be selected, the selection of which is, at least in part,
dependent on type of enzyme, co-enzymes, cofactors or catalysts
present at the target site for the bioactivation of the system. The
design of the system can include for example, (i) identifying the
target site; (ii) identifying an enzyme, co-enzymes, cofactors, or
catalysts present at the target site but not present at tissue
surrounding the target site; (iii) selecting a binding pair for
activation at the target site by the enzyme, co-enzymes, cofactors,
or catalysts; and, (iv) selecting a carrier in which the binding
pair is stable or substantially stable. Identifying the target site
can include, for example, select a target tissue for treatment,
such as a spastic tissue at which the enzyme, co-enzymes, cofactors
or catalysts present. In some embodiments, the target site is a GI
tissue, at which peroxidase or oxidase may be present. Identifying
an enzyme, co-enzymes, cofactors, or catalysts present at the
target site but not present at tissue surrounding the target site
can include, for example, identifying the tissue type, as well as
the presence of a microbe. Anaerobic pathogens such as Pseudomonas
and Vibrio, for example, can express a peroxide or an oxidase,
making these enzymes available at the target site.
[0056] After the system and environment of use are known, one of
skill can select a carrier in which the composition is stable or
substantially stable. In one example, the binding system can
comprise a mixture of phenolic compounds in a desired ratio with
hydrogen peroxide. For example, the phenolic compounds can include
a mixture of a pomegranate extract and a green tea extract, and the
ratio of phenolic compound to hydrogen peroxide can range from
about 1:2 to about 1:20 on a wt/wt basis, which can include molar
weight bases. In some embodiments, the hydrogen peroxide can be
added to the phenolic compound using a concentration of about 0.01%
to about 10% hydrogen peroxide solution, and any free hydrogen
peroxide can remain or be removed using the teachings provided
herein. One of skill can easily select the dose for a particular
use, which will vary according to factors that include the
environmental conditions at the site of use. In another example,
the compositions can comprise a mixture of phenolic compounds in a
desired ratio with hydrogen peroxide. For example, the phenolic
compounds can include a mixture of a pomegranate extract and a
green tea extract, and the ratio of phenolic compound to hydrogen
peroxide can range from about 3:1 to about 1:3 on a wt/wt basis
(e.g., molar weight). The hydrogen peroxide can be added to the
phenolic compound using a concentration of about 0.01% to about 10%
hydrogen peroxide. In some embodiments, a 35% hydrogen peroxide
stock solution can be used as a source of hydrogen peroxide, which
can be obtained from a commercially available stock solution, for
example. In some embodiments, up to 60% hydrogen peroxide stock
solution can be used as a source of hydrogen peroxide. In fact,
higher concentrations are available, and could be used in some
embodiments if handled properly. One of skill will be able to
readily select, obtain and/or produce desired concentrations of
hydrogen peroxide. Again, one of skill can easily select the dose
for a particular use, which will vary according to factors that
include environmental conditions at the site of use. In some
embodiments, this formulation has worked well for uses in animals
that are non-humans.
[0057] The compositions can include, for example, a weight (molar
or mass) ratio of phenolic compound to reactive oxygen species that
ranges from about 1:1000 to about 1000:1. In some embodiments, the
ratio of phenolic compound to reactive oxygen species can range
from about 1:1000 to about 500:1, from about 1:500 to about 500:1,
from about 1:250 to about 500:1, from about 1:500 to about 250:1,
from about 1:250 to about 250:1, from about 1:100 to about 250:1,
from about 1:250 to about 100:1, from about 1:100 to about 100:1,
from about 1:100 to about 50:1, from about 1:50 to about 100:1,
from about 1:50 to about 50:1, from about 1:25 to about 50:1, from
about 1:50 to about 25:1, from about 1:25 to about 25:1, from about
1:10 to about 10:1, from about 1:1000 to about 250:1, from about
1:1000 to about 100:1, from about 1:1000 to about 50:1, from about
1:1000 to about 25:1, from about 1:1000 to about 10:1, from about
1:1000 to about 5:1, from about 1:10 to about 1:20, from about 1:10
to about 1:30, from about 1:10 to about 1:40, from about 1:10 to
about 1:50, from about 1:10 to about 1:60, from about 1:10 to about
1:70, from about 1:10 to about 1:80, from about 1:10 to about 1:90,
from about 1:20 to about 1:30, from about 1:20 to about 1:40, from
about 1:20 to about 1:50, from about 1:20 to about 1:60, from about
1:20 to about 1:70, from about 1:20 to about 1:80, from about 1:20
to about 1:90, from about 1:30 to about 1:90, or any range
therein.
[0058] In some embodiments, the composition comprises a ratio of a
tannin and hydrogen peroxide, a phenylpropanoid and a hydrogen
peroxide, a catechin and hydrogen peroxide, an epigallic acid and a
hydrogen peroxide, or a combination thereof an of these phenolic
compounds with hydrogen peroxide.
[0059] In some embodiments, the compositions include a stable
hydrogen bonded complex between the phenolic compound and the
reactive oxygen species. For example, a highly hydroxylated
polyphenol compound can be combined with a high concentration of
hydrogen peroxide, the combination leading to binding the hydrogen
peroxide to the phenolic compound to produce the binding system.
The binding system can be intended for dilution in water or a solid
excipient. One of skill will appreciate that such a complex can be
referred to as a polyphenol peroxysolvate, in some embodiments,
when in a liquid form for storage or administration to a subject,
and a phenolic perhydrate when in an anhydrous, or substantially
anhydrous, form for storage or administration to a subject.
[0060] The compositions can be carried in a liquid, powder,
capsule, tablet, or gas for administration to a subject. The
selection of the phenolic compound should take into consideration
the manner in which the reactive oxygen species will bind to the
phenolic compound to form a stable, or substantially stable,
binding pair. The binding pair can be considered substantially
stable where the reactive oxygen species retains all, most, or at
least a predictable amount of oxidation strength for the uses and
functions recited herein.
[0061] One of skill will appreciate that a phenolic compound can be
derivatized to introduce or enhance a desired function. The
phenolic compound can be derivatized, for example, to increase it's
functionality for binding to the reactive oxygen species,
maintaining stability or miscibility in a carrier, or binding to a
target site, using any method known to one of skill. In some
embodiments, the phenolic compound can be bound to a polyol,
pegylated, attached to a saccharide, or attached to glucose, for
example.
[0062] Moreover, one of skill will appreciate that the compositions
should, in some embodiments, be produced free of compounds that can
lead to degradation of the otherwise stable, or substantially
stable, combinations. As such, in some embodiments, the
compositions comprise solutes that are substantially free of
transition metals, metal ions, heavy metals, oxidoreductase
enzymes, other strong oxidizers, reactive halogen compounds,
hydrogen halides, and other compounds that can cause a
decomposition of the reactive oxygen species, or its disassociation
from the phenolic compound with which it forms a binding pair.
[0063] The compositions can be made using ingredients from
commercially available chemical providers, or they can be made
directly from whole, plant extracts, for example, water extracts or
alcohol extracts.
[0064] A Commercially Available Source of the Phenolic
Component
[0065] Commercially available chemical providers, for example
Sigma-Aldrich, can provide phenolic and polyphenolic chemicals for
use with the methods of treatment taught herein. In the example set
forth below, (i) gallic acid (a model polyphenol building block) is
combined with hydrogen peroxide; and, (ii) tannic acid (a model
polyphenol component) is combined with hydrogen peroxide. Both
gallic acid and tannic acid are commercially available from
Sigma-Aldrich. One of skill will appreciate that a wide variety of
polyphenolics are commercially available.
[0066] A Whole, Plant Extract as a Source of the Phenolic
Component
[0067] The method of obtaining the phenolic component, e.g, the
polyphenol component, from a plant tissue can be produced using the
following process: [0068] i. Harvest plant tissue comprising a
polyphenol component, for example, the polyphenol comprising a
tannin. It is desirable to harvest while minimizing physical damage
to the plant tissue. For example, whole leaf extractions can be
performed to avoid physical damage to the leaves, but it may be
desirable to reduce the size of the leaves by cutting them, for
example, to increase the speed and yield of the extraction in some
embodiments. [0069] ii. Denaturing all, or substantially all, of
the oxidoreductase enzymes in the plant. This can be done through
drying, for example, using heating in the range of about 60.degree.
C. to about 150.degree. C., or a combination of such heating and
dessication. Alcohols can also be used to denature the enzymes.
[0070] iii. Extracting the polyphenols from the plant tissue using
a suitable solvent including, but not limited to, water or an
alcohol. Water extractions have been used in this example. Since
we're after water soluble plant materials, a simple water
extraction is sufficient to provide the plant extract containing
polyphenols for the compositions.
[0071] The plant extraction procedures are simple, although they
can be modified for efficiency in product yield and activity.
Although inefficient, the simplest extraction procedure, for
example, would be to merely harvest the plant tissue, denature the
endogeneous enzymes, and soak the tissue in water to isolate the
water soluble extract of the plant tissue. Another simple
extraction method would be to harvest the plant tissue, and isolate
the water soluble extract of the tissue in water at temperatures
greater than about 80.degree. C. to steam. An even simpler process
would not include denaturing the enzymes, but the stability and
activity of the extract in the composition suffers greatly.
Additional steps can be added, however, to increase the efficiency
of the extraction, although such steps are not required. For
example, the harvesting can include cutting into as large of pieces
as practical to the size of the plant to preserve the metabolic
activity in the plant tissue can be done. The plant tissue can be
pulverized after denaturing the enzymes, and the water can be
heated at temperatures ranging from about 25.degree. C. to about
100.degree. C., from about 30.degree. C. to about 95.degree. C.,
from about 35.degree. C. to about 90.degree. C., from about
40.degree. C. to about 85.degree. C., from about 45.degree. C. to
about 80.degree. C., from about 45.degree. C. to about 75.degree.
C., from about 45.degree. C. to about 70.degree. C., from about
45.degree. C. to about 65.degree. C., or any amount or range
therein in increments of 1.degree. C., to make the process of
extraction more efficient.
[0072] In some embodiments, the endogeneous enzymes include a
catalase or peroxidase that is at least substantially inactivated.
In some embodiments, the endogeneous enzymes can be inactivated
through heating, cooling, boiling, freezing, dessicating, freezing
and thawing cycles, blanching, or a combination thereof. In some
embodiments, the endogeneous enzymes can be inactivated using a
process that includes allowing natural degradation over time,
adding at least 1% salt, radiating, or adding an exogeneous
chemical enzymatic inhibitor.
[0073] In some embodiments, the plant extract is produced from a
process comprising: harvesting the plant tissue; at least partially
inactivating an endogeneous enzyme; optionally reducing particle
size of the plant tissue through cutting, avulsing, or pulverizing;
creating the extracted component through a process that includes
combining the plant tissue with water or alcohol for an effective
time and at an effective temperature; optionally removing particles
from the mixture; and, adding the reactive oxygen species to the
effective, or otherwise desired, amount.
[0074] In some embodiments, the water soluble plant extract can
then be optionally filtered, for example, using a filter, for
example a 5 um filter in some embodiments, and hydrogen peroxide
can then be added to the filtered extract to a concentration of 1%
by weight of the total composition. In some embodiments, the
hydrogen peroxide can be added to the extract in an amount ranging
from about 0.01% to about 10% by weight of the total composition.
Increasing the concentration of hydrogen peroxide added has been
observed to increase the potency and stability of the resulting
compositions.
[0075] After combining the reactive oxygen species with the
polyphenol component, the free reactive oxygen species in the
compositions can be left in the composition, or it can be removed
using an enzyme, catalyst, or reducing agent. In this example, the
reactive oxygen species is hydrogen peroxide, and the free hydrogen
peroxide can be removed from the composition in a subsequent step
contacting the free hydrogen peroxide with a hydrogen peroxide
degrading enzyme, such catalase; a catalyst such as manganese
dioxide, platinum, iron, or copper; or, a reducing agent such as
ferric chloride, copper sulfate, or sodium hypochlorite. In some
embodiments, the composition having the free hydrogen peroxide can
be contacted with a metal catalyst or catalase bound to a solid
non-soluble substrate. In some embodiments, the solid substrate can
be a bead column or screen, for example. Likewise, the catalysts
and reducing agents can be used in a similar manner to remove the
free hydrogen peroxide, or any other free reactive oxygen
species.
[0076] As such, the concentration of free reactive oxygen species,
such as free hydrogen peroxide, remaining in the composition can
range from about 0 to about 10% based on total dry weight of the
composition. Moreover, in some embodiments, the total hydrogen
peroxide concentration can range from about 0.001% to about 1%,
from about 0.001% to about 0.1%, from about 0.01% to about 0.05%,
from about 0.005% to about 5%, from about 0.007% to about 2%, from
about 0.01% to about 5%, from about 0.05% to about 5%, from about
0.1% to about 5%, from about 0.2% to about 4.5%, from about 0.3% to
about 4%, from about 0.4% to about 3.5%, from about 0.5% to about
3%, from about 0.6% to about 2.5%, from about 0.7% to about 2%,
from about 0.001% to about 1.5%, about 1%, or any amount or range
therein in increments of 0.001%. And, it should be appreciated that
the concentration of free hydrogen peroxide, for example, can also
be reduced, or further reduced, by dilution of the composition in
various commercial formulations.
[0077] Moreover, precipitates of protein or other impurities can
form at this point and can optionally be removed by additional
filtration, and we often filter after we allow the solution to
react for about an hour. Although not necessary, additional
reactive oxygen species can be added to ensure complete saturation
of hydrogen peroxide on the binding sites of the polyphenols in the
extract. In this example, hydrogen peroxide was used as the
reactive oxygen species, keeping track of the total hydrogen
peroxide concentration.
[0078] The plant extract is combined with the reactive oxygen
species, and the solution can be allowed to react for a period of
time ranging from about 10 minutes to about 72 hours, in some
embodiments, before diluting the composition to a desired
concentration. In some embodiments, the solution can be allowed to
react for a period of time ranging from about 1 minute to about 96
hours, from about 5 minutes to about 48 hours, from about 10
minutes to about 36 hours, from about 10 minutes to about 24 hours,
from about 10 minutes to about 12 hours, from about 10 minutes to
about 8 hours, or from about 10 minutes to about 1 hour, or any
range therein in increments of 1 minute. In this example, the
extracts were allowed to react with the hydrogen peroxide for a
minimum of 2 hours. The dilution can be desirable, for example, (i)
to control the concentration of the composition in solution, and/or
(ii) to accelerate degradation of the unbound reactive oxygen
species to limit the composition to having no, or substantially no,
free reactive oxygen species. In this example, the hydrogen
peroxide is more susceptible to degradation when free in solution,
and one of skill will appreciate that the degradation will increase
in rate when the composition is diluted.
[0079] In some embodiments, dry compositions are provided. For
example, the system can be in the form of a powder, pill, tablet,
capsule, or as separate dry components for mixing into a liquid
form. In these embodiments, both the phenolic compound and the
reactive oxygen species are in a dry form either before or after
creation of the binding pair, and the binding system can be used in
the dry form, or converted to a liquid form, for any of the uses
taught herein. The advantages of the dry compositions can include,
for example, the ease of storage and transport. In some
embodiments, the binding systems, whether in liquid or dry form,
can be combined with vitamins, electrolytes, and/or other nutrients
in either liquid or dry form. The dry form of the binding system
can be manufactured using any drying process known to one of skill,
such as solvent exchange, vacuum drying, critical point drying,
heating, dessication, or a combination thereof. In some
embodiments, the phenolic compound is dried as a single component.
In some embodiments, the binding pair is formed, and the binding
pair is dried together. And, in some embodiments, the reactive
oxygen species can be, independently, in any dry form known to one
of skill, such as the dry forms taught herein. In embodiments
having the reactive oxygen species in an independent dry form, the
dry phenolic compound and the dry reactive oxygen species can be
combined in a polar solvent, for example, to create the binding
pair prior to use.
[0080] Methods of Using the Compositions
[0081] Methods of treating gastrointestinal spasms are provided.
This can include reducing or eliminating abdominal pain, bloating,
forceful defecation, forceful vomiting, defecation urgency,
constipation, and/or incontinence. Causes of gastrointestinal
cramping can range from mild conditions to serious conditions, such
as food poisoning, constipation, gastroenteritis, viral infections,
bacterial infections, lactose intolerance, excessive flatulence and
bloating, indigestion, diverticulitis, autoimmune disease,
intestinal inflammation and even colorectal cancer, adhesions, and
the like. In some embodiments, stress and/or dehydration can even
trigger gastrointestinal cramps, for example.
[0082] The disorders treated can be self-induced. In some
embodiments, gastrointestinal spasms can be self-induced through
overindulging, such as through overeating and/or overdrinking. In
some embodiments, gastrointestinal spasms can be due to
deficiencies, such as deficiencies in nutrition or hydration, for
example. The compositions taught herein can be used in treating
such conditions, either alone or in co-administrations with
nutritional therapy or rehydration therapies. The disorders might
also be induced through environmental conditions, exercise, or
socioeconomic conditions. In some embodiments, the composition can
be co-administered with at least one other nutritional and/or
rehydrating agent for aiding recovery from a health imbalance, or
to maintain a health balance. Examples of rehydrating agents can
include, but are not limited to, GATORADE and other electrolyte
drinks, oral rehydration solutions (ORSs) generally, new oral
rehydration solution (N-ORS), SEURO ORAL, PEDIAONE, and PEDIALYTE.
Examples of nutritional supplements can include, but are not
limited to, zinc sulfate, salted rice water, salted yogurt-based
drinks, and vegetable or chicken soup with salt. Such health
imbalances can include, but is not limited to, dehydration,
malnutrition, electrolyte imbalance, vitamin deficiency, food
hypersensitivities, stress induced diarrhea, abdominal cramping,
and alcohol hangover, or a combination thereof. In some
embodiments, the methods taught herein can further include the
administration of oral rehydrating or nutritional agents such as
sodium, potassium, dextrose, fructose, glucose, magnesium, zinc,
selenium, vitamin A, Vitamin D, Vitamin C, dietary fiber, and
combinations thereof. The amounts and ratios of the agents to the
composition can be substantially varied to provide prophylaxis,
therapy or maintenance of healthful balance. Ratios of the
compositions herein to the nutritional agents or rehydration agents
can range, for example, from about 1:100 to about 100:1, from about
1:50 to about 50:1, from about 1:40 to about 40:1, from about 1:30
to about 30:1, from about 1:20 to about 20:1, from about 1:10 to
about 10:1, from about 1:5 to about 5:1, from about 1:4 to about
4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1, from
about 1:1.5 to about 1.5:1, about 1:1, or any range therein. The
ratios can be based on volume:volume, mass:volume, volume:mass,
mass:mass, or molar:molar. It should be appreciated that the
concentrations of the compositions taught herein can be the same or
different than the concentrations of the nutritional agents or
rehydration agents. And, it should also be appreciated that the
concentrations and ratios of concentrations can be subjective to a
particular administration, such that they can be independently
selected according to the condition treated, objective sought,
desired effect, and/or personal preference. The combinations can be
administered under any regime taught herein for the administration
of an agent or combination of agents.
[0083] Irritable bowel syndrome (IBS) is a problem of particular
interest and includes, for example, chronic or frequent
gastrointestinal spasms. IBS is often diagnosed as a set of these
symptoms, such as diarrhea, constipation, and bloating, in addition
to, perhaps, a measured food sensitivity. The compositions taught
herein, however, can generally be used for this and other medicinal
purposes, as a health supplement, or a nutritional composition. The
compositions can provide a therapeutic and/or prophylactic effect
in the treatment of a condition in a subject, particularly in the
treatment of a gastrointestinal spasm. The targeted action of the
binding systems allows for the administration of surprisingly low
effective doses of the phenolic compounds. As a result, the
compositions also improve safety by substantially increasing the
separation between an effective dose and any toxic/side
effects.
[0084] The terms "treat," "treating," and "treatment" can be used
interchangeably and refer to the administering or application of
the binding systems taught herein, including such administration as
a health or nutritional supplement, and all administrations
directed to the prevention, inhibition, amelioration of the
symptoms, or cure of a condition taught herein. The terms
"disease," "condition," "disorder," and "ailment" can be used
interchangeably in some embodiments. The term "subject" and
"patient" can be used interchangeably and refer to an animal such
as a mammal including, but not limited to, non-primates such as,
for example, a cow, pig, horse, cat, dog, rat and mouse; and
primates such as, for example, a monkey or a human. As such, the
terms "subject" and "patient" can also be applied to non-human
biologic applications including, but not limited to, veterinary,
companion animals, commercial livestock, aquaculture, and the like.
Many of the applications can include control environmental
pathogens that are on or in plants, as well as places not
necessarily in living hosts, such as those that are in water and
water systems, for example, as well as soil, air, and food for
microbial control, alteration of surface characteristics, or
anywhere that can benefit from a supply of a stable oxidizer
source.
[0085] In some embodiments, the composition includes (i) a phenolic
compound selected from the group consisting of condensed tannins,
hydrolysable tannins, complex tannins, phlorotannins,
psuedotannins, and derivatives thereof; and, (ii) hydrogen peroxide
in a stable, or substantially stable, non-covalent association.
[0086] In some embodiments, the compositions taught herein can be
used to protect, maintain, improve, or restore a digestive health
of a subject when administered orally in an effective amount. In
some embodiments, the effectiveness can be measured by comparing to
a control group that did not receive the binding system. And, in
some embodiments, the effectiveness can be measured according to a
historical baseline for the subject being treated. The binding
systems can be used to prevent, inhibit, or ameliorate the symptoms
associated with a loss of digestive tract homeostasis. In some
embodiments, the binding systems can be used to prevent, treat,
ameliorate the symptoms of, or even cure, a chronic
gastrointestinal condition. Such conditions can include, but are
not limited to, hyperacidity, colitis, irritable bowel syndrome,
crohn's disease, necrotic enteritis, functional colonic diseases,
malabsorption, a peptic ulcer, gastro-esophageal reflux disease,
ulcerative colitis, and diverticulitis. In some embodiments, the
binding systems can be used to reduce mucosal tissue inflammation,
dysfunction, or damage. Such conditions can be induced, for
example, by drug side effects, chemotherapy, dysbiosis, radiation,
changes in normal flora, hyperimmunity, autoimmune reactions,
immune deficiencies, nervousness, allergies, chemical irritation,
and stress. In some embodiments, the binding systems can be
administered for selectively inhibiting the growth of
gastrointestinal pathogens. It should be appreciated that there may
be lesser inhibition of non-pathogenic strains, particularly common
probiotic bacteria such as bifidobacteria and lactobacilli. And, in
some embodiments, administration of the binding systems can produce
short term immune modulation effects as well as potentially change
the chronic expression of the activating enzymes associated with
some conditions with longer term use of the binding systems.
[0087] In some embodiments, the symptoms of a gastrointestinal
condition can include, for example, diarrhea, dehydration,
malnutrition, constipation, nausea, and/or cramping. And, in some
embodiments, the symptoms of a gastrointestinal condition can be
temporary and include acid irritation, indigestion, bloating,
cramps, spasmodic peristalsis, diarrhea, and constipation.
Administering the binding systems for the treatment and/or
management of gastrointestinal conditions can be considered a
nutritional or health supplement, in some embodiments. In some such
embodiments, for example, the binding pair can be administered to
prevent, inhibit, or ameliorate the effect, infectivity, and
virulence of pathogens including bacteria, virus, fungi, yeast,
prions, protozoa and parasites in a subject orally taking an
effective amount of the supplement.
[0088] As described herein, the binding systems can be used in a
method of treating acute diarrhea in a subject. In some
embodiments, the methods comprise orally administering an effective
amount of a binding system taught herein to the subject. The
binding system can prevent, inhibit, or ameliorate a symptom of
acute diarrhea in the subject when compared to a second subject in
a control group in which the binding system was not administered.
In some embodiments, the symptom is selected from the group
consisting of a stool score, heartburn, indigestion, urgency of
defecation, nausea, vomiting, stomach pain, and bloating.
[0089] As described herein, the binding systems can be used in a
method of treating irritable bowel syndrome in a subject. In some
embodiments, the method comprises orally administering an effective
amount of a binding system taught herein to the subject. The
binding system can prevent, inhibit, or ameliorate the symptoms of
irritable bowel syndrome in the subject when compared to a second
subject in a control group in which the binding system was not
administered. In some embodiments, the symptom is selected from the
group consisting of a stool score, heartburn, indigestion, urgency
of defecation, nausea, vomiting, stomach pain, and bloating.
[0090] As described herein, the binding systems can be used in a
method of treating an inflammatory bowel disease in a subject. In
some embodiments, the method comprises orally administering an
effective amount of a binding system taught herein to the subject.
The binding system can prevent, inhibit, or ameliorate the symptoms
of inflammatory bowel disease in the subject when compared to a
second subject in a control group in which the binding system was
not administered. In some embodiments, the symptom is selected from
the group consisting of a stool score, heartburn, indigestion,
urgency of defecation, nausea, vomiting, stomach pain, and
bloating.
[0091] As described herein, the binding systems can be used in a
method of treating food poisoning in a subject. In some
embodiments, the method comprises orally administering an effective
amount of a binding system taught herein to the subject. The
binding system can prevent, inhibit, or ameliorate the symptoms of
food poisoning in the subject when compared to a second subject in
a control group in which the binding system was not administered.
In some embodiments, the symptom is selected from the group
consisting of a stool score, heartburn, indigestion, urgency of
defecation, nausea, vomiting, stomach pain, and bloating.
[0092] Methods of Administering the Compositions
[0093] The terms "administration" or "administering" can be used to
refer to a method of incorporating a composition into the cells or
tissues of a subject, either in vivo or ex vivo to test the
activity of a system, as well as to diagnose, prevent, treat, or
ameliorate a symptom of a disease. In one example, a compound can
be administered to a subject in vivo using any means of
administration taught herein. In another example, a compound can be
administered ex vivo by combining the compound with cell tissue
from the subject for purposes that include, but are not limited to,
assays for determining utility and efficacy of a composition. And,
of course, the systems can be used in vitro to test their
stability, activity, toxicity, efficacy, and the like. When the
compound is incorporated in the subject in combination with one or
active agents, the terms "administration" or "administering" can
include sequential or concurrent incorporation of the compound with
the other agents such as, for example, any agent described above. A
pharmaceutical composition of the invention can be formulated, in
some embodiments, to be compatible with its intended route of
administration.
[0094] Any administration vehicle known to one of skill to be
suitable for administration of the compounds, compositions, and
formulations taught herein can be used. A "vehicle" can refer to,
for example, a diluent, excipient or carrier with which a compound
is administered to a subject. A "pharmaceutically acceptable
carrier" is a diluent, adjuvant, excipient, or vehicle with which
the composition is administered. A carrier is pharmaceutically
acceptable after approval by a state or federal regulatory agency
or listing in the U.S. Pharmacopeial Convention or other generally
recognized sources for use in subjects. The pharmaceutical carriers
include any and all physiologically compatible solvents, dispersion
media, coatings, antibacterial and antifungal agents, isotonic and
absorption delaying agents, and the like. Examples of
pharmaceutical carriers include, but are not limited to, sterile
liquids, such as water, oils and lipids such as, for example,
phospholipids and glycolipids. These sterile liquids include, but
are not limited to, those derived from petroleum, animal, vegetable
or synthetic origin such as, for example, peanut oil, soybean oil,
mineral oil, sesame oil, and the like. Suitable pharmaceutical
excipients include, but are not limited to, starch, sugars, inert
polymers, glucose, lactose, sucrose, gelatin, malt, rice, flour,
chalk, silica gel, sodium stearate, glycerol monostearate, talc,
sodium chloride, dried skim milk, glycerol, propylene, glycol,
water, ethanol, and the like. The composition can also contain
minor amounts of wetting agents, emulsifying agents, pH buffering
agents, or a combination thereof. The compositions can take the
form of solutions, suspensions, emulsion, tablets, pills, capsules,
powders, sustained-release formulations and the like. Oral
formulations can include standard carriers such as, for example,
pharmaceutical grades mannitol, lactose, starch, magnesium
stearate, sodium saccharine, cellulose, magnesium carbonate, and
the like. See Martin, E. W. Remington's Pharmaceutical Sciences.
Supplementary active compounds can also be incorporated into the
compositions. In some embodiments, the carrier can be a solvent or
dispersion medium including, but not limited to, water; ethanol; a
polyol such as for example, glycerol, propylene glycol, liquid
polyethylene glycol, and the like; and, combinations thereof. The
proper fluidity can be maintained in a variety of ways such as, for
example, using a coating such as lecithin, maintaining a required
particle size in dispersions, and using surfactants.
[0095] The compositions can be administered to a subject orally or
rectally, for example, in the treatment of a gastrointestinal
spasm. Oral administration can include digestive tract, buccal,
sublingual, and sublabial, and a carrier such as a solid or liquid
can be used. A solid can include, for example, a pill, capsule,
tablet, or time-release technology in some embodiments; and, for
buccal or sublingual, a solid can include an orally disintegrating
tablet, a film, a lollipop, a lozenge, or chewing gum; and, a
liquid can include a mouthwash, a toothpaste, an ointment, or an
oral spray. A liquid can include, for example, a solution, soft
gel, suspension, emulsion, syrup, elixir, tincture, or a
hydrogel.
[0096] Tablets, pills, capsules, troches liquids and the like may
also contain binders, excipients, disintegrating agent, lubricants,
glidants, chelating agents, buffers, tonicity modifiers,
surfactants, sweetening agents, and flavoring agents. Some examples
of binders include microcrystalline cellulose, gum tragacanth or
gelatin. Some examples of excipients include starch or
maltodextrin. Some examples of disintegrating agents include
alginic acid, corn starch and the like. Some examples of lubricants
include magnesium stearate or potassium stearate. An example of a
chelating agent is EDTA. Some examples of buffers are acetates,
citrates or phosphates. Some examples of tonicity modifiers include
sodium chloride and dextrose. Some examples of surfactants for
micellation or increasing cell permeation include coconut soap,
anionic, cationic or ethoxylate detergents. An example of a glidant
is colloidal silicon dioxide. Some examples of sweetening agents
include sucrose, saccharin and the like. Some examples of flavoring
agents include peppermint, chamomile, orange flavoring and the
like. It should be appreciated that the materials used in preparing
these various compositions should be pharmaceutically pure and
non-toxic in the amounts used
[0097] Rectal administrations can be made using any method known to
one of skill. For example, a suppository formulation can be
prepared by heating glycerin to about 120.degree. C., combining the
binding system with the heated glycerin, mixing the combination,
adding purified water to a desired consistency, and pouring the
desired consistency into a mold to form the suppository.
[0098] The compositions may be administered as suspensions or
emulsions. Lipophilic solvents or vehicles include, but are not
limited to, fatty oils such as, for example, sesame oil; synthetic
fatty acid esters, such as ethyl oleate or triglycerides; and
liposomes. Suspensions that can be used for injection may also
contain substances that increase the viscosity of the suspension
such as, for example, sodium carboxymethyl cellulose, sorbitol, or
dextran. Optionally, a suspension may contain stabilizers or agents
that increase the solubility of the compounds and allow for
preparation of highly concentrated solutions. In some embodiments,
an administration, such as an oral or rectal administration, for
example, may include liposomes. In some embodiments, the liposome
may assist in a targeted delivery system. The liposomes can be
designed, for example, to bind to a target protein and be taken up
selectively by the cell expressing the target protein.
[0099] In some embodiments, isotonic agents can be used such as,
for example, sugars; polyalcohols that include, but are not limited
to, mannitol, sorbitol, glycerol, and combinations thereof; and
sodium chloride. Sustained absorption characteristics can be
introduced into the compositions by including agents that delay
absorption such as, for example, monostearate salts, gelatin, and
slow release polymers. Carriers can be used to protect against
rapid release, and such carriers include, but are not limited to,
controlled release formulations in implants and microencapsulated
delivery systems. Biodegradable and biocompatible polymers can be
used such as, for example, ethylene vinyl acetate, polyanhydrides,
polyglycolic acid, collagen, polyorthoesters, polylactic acid,
polycaprolactone, polyglycolic copolymer, and the like. Such
formulations can generally be prepared using methods known to one
of skill in the art.
[0100] In some embodiments, the composition is administered in a
sustained release formulation, and the formulation can include one
or more agents in addition to the composition. In some embodiments,
the sustained release formulations can reduce the dosage and/or
frequency of the administrations of such agents to a subject. In
some embodiments, an exogenous catalyst or enzyme is introduced to
a target and one or more of the reactive oxygen species, phenolic
compound, or the exogeneous catalyst or enzyme are segregated by
encapsulation or micellation to delay the bioactivation until
target site is reached by all components.
[0101] One of skill understands that the amount of the agents
administered can vary according to factors such as, for example,
the type of disease, age, sex, and weight of the subject, as well
as the method of administration. For example, an administration can
call for substantially different amounts to be effective. Dosage
regimens may also be adjusted to optimize a therapeutic response.
In some embodiments, a single bolus may be administered; several
divided doses may be administered over time; the dose may be
proportionally reduced or increased; or, any combination thereof,
as indicated by the exigencies of the therapeutic situation and
factors known one of skill in the art. It is to be noted that
dosage values may vary with the severity of the condition to be
alleviated, as well as whether the administration is prophylactic,
such that the condition has not actually onset or produced
symptoms. Dosage regimens may be adjusted over time according to
the individual need and the professional judgment of the person
administering or supervising the administration of the
compositions, and the dosage ranges set forth herein are exemplary
only and do not limit the dosage ranges that may be selected by
medical practitioners. The compounds can be administered in dosage
units. The term "dosage unit" can refer to discrete, predetermined
quantities of a compound that can be administered as unitary
dosages to a subject. A predetermined quantity of active compound
can be selected to produce a desired therapeutic effect and can be
administered with a pharmaceutically acceptable carrier. The
predetermined quantity in each unit dosage can depend on factors
that include, but are not limited to, (a) the unique
characteristics of the active compound and the particular
therapeutic effect to be achieved, and (b) the limitations inherent
in the art of creating and administering such dosage units.
[0102] An "effective amount" of a compound can be used to describe
a therapeutically effective amount or a prophylactically effective
amount. An effective amount can also be an amount that ameliorates
the symptoms of a disease. A "therapeutically effective amount" can
refer to an amount that is effective at the dosages and periods of
time necessary to achieve a desired therapeutic result and may also
refer to an amount of active compound, prodrug or pharmaceutical
agent that elicits any biological or medicinal response in a
tissue, system, or subject that is sought by a researcher,
veterinarian, medical doctor or other clinician that may be part of
a treatment plan leading to a desired effect. In some embodiments,
the therapeutically effective amount should be administered in an
amount sufficient to result in amelioration of one or more symptoms
of a disorder, prevention of the advancement of a disorder, or
regression of a disorder. In some embodiments, for example, a
therapeutically effective amount can refer to the amount of an
agent that provides a measurable response of at least 5%, at least
10%, at least 15%, at least 20%, at least 25%, at least 30%, at
least 35%, at least 40%, at least 45%, at least 50%, at least 55%,
at least 60%, at least 65%, at least 70%, at least 75%, at least
80%, at least 85%, at least 90%, at least 95%, or at least 100% of
a desired action of the composition.
[0103] In some embodiments, the desired action of the composition
is relief of a gastrointestinal spasm. The relief can include, for
example, reducing or eliminating abdominal pain, bloating, forceful
defecation, forceful vomiting, defecation urgency, constipation,
and/or incontinence. In these embodiments, at least 10% relief can
be obtained in a time ranging from 1 minute to 24 hours, from about
5 minutes to about 18 hours, from about 10 minutes to about 12
hours, from about 20 minutes to about 8 hours, from about 30
minutes to about 6 hours, from about 1 hours to about 4 hours, from
about 2 hours to about 10 hours, from about 3 hours to about 9
hours, or any range or amount therein in increments of 5
minutes.
[0104] A "prophylactically effective amount" can refer to an amount
that is effective at the dosages and periods of time necessary to
achieve a desired prophylactic result, such as prevent the onset of
an inflammation, allergy, nausea, diarrhea, infection, and the
like. Typically, a prophylactic dose is used in a subject prior to
the onset of a disease, or at an early stage of the onset of a
disease, to prevent or inhibit onset of the disease or symptoms of
the disease. A prophylactically effective amount may be less than,
greater than, or equal to a therapeutically effective amount.
[0105] In some embodiments, a therapeutically or prophylactically
effective amount of a composition may range in concentration from
about 0.01 nM to about 0.10 M; from about 0.01 nM to about 0.5 M;
from about 0.1 nM to about 150 nM; from about 0.1 nM to about 500
.mu.M; from about 0.1 nM to about 1000 nM, 0.001 .mu.M to about
0.10 M; from about 0.001 .mu.M to about 0.5 M; from about 0.01
.mu.M to about 150 .mu.M; from about 0.01 .mu.M to about 500 .mu.M;
from about 0.01 .mu.M to about 1000 nM, or any range therein. In
some embodiments, the compositions may be administered in an amount
ranging from about 0.005 mg/kg to about 100 mg/kg; from about 0.005
mg/kg to about 400 mg/kg; from about 0.01 mg/kg to about 300 mg/kg;
from about 0.01 mg/kg to about 250 mg/kg; from about 0.1 mg/kg to
about 200 mg/kg; from about 0.2 mg/kg to about 150 mg/kg; from
about 0.4 mg/kg to about 120 mg/kg; from about 0.15 mg/kg to about
100 mg/kg, from about 0.15 mg/kg to about 50 mg/kg, from about 0.5
mg/kg to about 10 mg/kg, or any range therein, wherein a human
subject is often assumed to average about 70 kg.
[0106] The amount of the composition administered may vary widely
depending on the type of formulation, size of a unit dosage, kind
of excipients, and other factors well known to those of ordinary
skill in the art. A formulation may comprise, for example, an
amount of the composition ranging from about 0.0001% to about 6%
(w/w), from about 0.01% to about 1%, from about 0.1% to about 0.8%,
or any range therein, with the remainder comprising the excipient
or excipients. In some embodiments, the compositions can be
administered, for example, in an amount of ranging from about 0.1
.mu.g/kg to about 1 mg/kg, from about 0.5 .mu.g/kg to about 500
.mu.g/kg, from about 1 .mu.g/kg to about 250 .mu.g/kg, from about 1
.mu.g/kg to about 100 .mu.g/kg from about 1 .mu.g/kg to about 50
.mu.g/kg, or any range therein. One of skill can readily select the
frequency and duration of each administration. For example,
depending on the gastrointestinal disorder treated, whether a
prophylactic treatment or a treatment of an existing disorder,
variables such as the age and size of the subject can be
considered, as well as the source and type of the polyphenol
component and the intensity of the symptoms. In these embodiments,
the compositions can be administered orally in daily doses ranging
from about 5 .mu.g to about 5000 .mu.g dry weight, for example. In
such embodiments, the compositions can be administered orally in
amounts ranging from about 5 .mu.g to about 5000 .mu.g, from about
10 .mu.g to about 4000 .mu.g, from about 20 .mu.g to about 3000
.mu.g, from about 50 .mu.g to about 2000 .mu.g, from about 100
.mu.g to about 1000 .mu.g, from about 250 .mu.g to about 500 .mu.g,
or any range therein, in dry weight. In some embodiments, the
compositions can be administered orally in daily doses of about 100
.mu.g, about 200 .mu.g, about 300 .mu.g, about 400 .mu.g, about 500
.mu.g, about 600 .mu.g, about 700 .mu.g, about 800 .mu.g, about 900
.mu.g, about 1000 .mu.g, about 2000 .mu.g, about 3000 .mu.g, about
4000 .mu.g, about 5000 .mu.g, about 6000 .mu.g, about 7000 .mu.g,
about 8000 .mu.g, about 9000 .mu.g, or any range therein in
increments of 50 .mu.g dry weight.
[0107] In some embodiments, the composition can be administered in
conjunction with at least one other therapeutic agent for the
condition being treated. The amounts of the agents can be reduced,
even substantially, such that the amount of the agent or agents
desired is reduced to the extent that a significant response is
observed from the subject. A significant response can include, but
is not limited to, a reduction or elimination of nausea, a visible
increase in tolerance, a faster response to the treatment, a more
selective response to the treatment, or a combination thereof. In
some embodiments, the methods taught herein can further include the
administration of an antibiotic, an anti-emetic, an
anticholinergic, an antispasmodic, or an anticancer agent.
[0108] Antibiotics can include, for example, aminoglycosides,
ansamycins, carbacephem, carbapenems, cephalosporins (first through
fifth generation), glycopeptides, lincosamides, macrolides,
monobactams, penicillins, penicillin combinations, polypeptides,
quinolones, sulfonamides, tetracyclines, and drugs against
mycobacteria. In some embodiments, the antibiotic is selected from
the group consisting of natural penicillin, cephalosporin,
amoxicillin, ampicillin, clavamox, polymyxin, tetracycline,
chlortetracycline, doxycycline, chloramphenicol, erythromycin,
oleandomycin, streptomycin, gentamicin, kanamycin, tombramycin,
nalidixic acid, rifamycin, rifampicin, prontisil, gantrisin,
trimethoprim, isoniazid, para-aminosalicylic acid, and ethambutol.
One of skill will appreciate that subgroups of this group can be
desired in some embodiments. Anti-emetics can include, for example,
anticholinergic agents, antidopaminergic agents, 5-HT3 antagonists,
H1 antihistamines, cannabinoids, corticosteroids, and
benzodiazepines. In some embodiments, the anti-emetics can be
selected from the group consisting of benzodiazepines such as
diazepam or lorazepam; 5-HT.sub.3 receptor antagonists such as
ondansetron, tropisetron, granisetron, and dolasetron.
Antispasmodics can include, for example, anticholinergics such as
dicyclomine and hyoscyamine, as well as mebeverine and papaverine,
for example. Anticancer agents can include, for example, alkylating
agents, antimetabolites, anthracyclines, plant alkaloids,
topoisomerase inhibitors, and other antitumor agents. One of skill
will appreciate that the agents listed above can be used alone, or
in combination, in some embodiments. For example, chemotherapy and
anti-emetics can be administered together. And, anti-emetics can be
administered together, such as a combination of corticosteroids and
a second anti-emetic such as an antihistamine, anticholinergic,
benzodiazepine, cannabinoid, or an antidopaminergic agent.
[0109] Combinations therapies can be administered, for example, for
30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 18 hours,
1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9
days, 10 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 3 months, 6
months 1 year, any combination thereof, or any amount of time
considered necessary by one of skill. The agents can be
administered concomitantly, sequentially, or cyclically to a
subject. Cycling therapy involves the administering a first agent
for a predetermined period of time, administering a second agent or
therapy for a second predetermined period of time, and repeating
this cycling for any desired purpose such as, for example, to
enhance the efficacy of the treatment. The agents can also be
administered concurrently. The term "concurrently" is not limited
to the administration of agents at exactly the same time, but
rather means that the agents can be administered in a sequence and
time interval such that the agents can work together to provide
additional benefit. Each agent can be administered separately or
together in any appropriate form using any appropriate means of
administering the agent or agents.
[0110] The compositions taught herein can be used in
co-administrations with nutritional therapy or rehydration
therapies. In some embodiments, the composition can be
co-administered with at least one other nutritional and/or
rehydrating agent for aiding recovery from a health imbalance, or
to maintain a health balance. Examples of rehydrating agents can
include, but are not limited to, GATORADE and other electrolyte
drinks, oral rehydration solutions (ORSs) generally, new oral
rehydration solution (N-ORS), SEURO ORAL, PEDIAONE, and PEDIALYTE.
Examples of nutritional supplements can include, but are not
limited to, zinc sulfate, salted rice water, salted yogurt-based
drinks, and vegetable or chicken soup with salt. Such health
imbalances can include, but is not limited to, dehydration,
malnutrition, electrolyte imbalance, vitamin deficiency, food
hypersensitivities, stress induced diarrhea, abdominal cramping,
and alcohol hangover, or a combination thereof. In some
embodiments, the methods taught herein can further include the
administration of oral rehydrating or nutritional agents such as
sodium, potassium, dextrose, fructose, glucose, magnesium, zinc,
selenium, vitamin A, Vitamin D, Vitamin C, dietary fiber, and
combinations thereof. The amounts and ratios of the agents to the
composition can be substantially varied to provide prophylaxis,
therapy or maintenance of healthful balance. Ratios of the
compositions herein to the nutritional agents or rehydration agents
can range, for example, from about 1:100 to about 100:1, from about
1:50 to about 50:1, from about 1:40 to about 40:1, from about 1:30
to about 30:1, from about 1:20 to about 20:1, from about 1:10 to
about 10:1, from about 1:5 to about 5:1, from about 1:4 to about
4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1, from
about 1:1.5 to about 1.5:1, about 1:1, or any range therein. The
ratios can be based on volume:volume, mass:volume, volume:mass,
mass:mass, or molar:molar. It should be appreciated that the
concentrations of the compositions taught herein can be the same or
different than the concentrations of the nutritional agents or
rehydration agents. And, it should also be appreciated that the
concentrations and ratios of concentrations can be subjective to a
particular administration, such that they can be independently
selected according to the condition treated, objective sought,
desired effect, and/or personal preference. The combinations can be
administered under any regime taught herein for the administration
of an agent or combination of agents.
Articles of Manufacture
[0111] Articles of manufacture that encompass finished, packaged
and labelled products are provided. The articles of manufacture
include the appropriate unit dosage form in an appropriate vessel
or container such as, for example, a glass vial or other container
that is hermetically sealed. In the case of dosage forms suitable
for oral administration, the active ingredient, e.g. one or more
agents including a dosage form taught herein, may be suitable for
administration orally, rectally, or the like.
[0112] As with any such product, the packaging material and
container are designed to protect the stability of the product
during storage and shipment. In addition, the articles of
manufacture can include instructions for use or other information
material that can advise the user such as, for example, a
physician, technician or patient, regarding how to properly
administer the composition as a prophylactic, therapeutic, or
ameliorative treatment of the disease of concern. In some
embodiments, instructions can indicate or suggest a dosing regimen
that includes, but is not limited to, actual doses and monitoring
procedures.
[0113] In some embodiments, the articles of manufacture can
comprise one or more packaging materials such as, for example, a
box, bottle, tube, vial, container, sprayer, insufflator,
intravenous (I.V.) bag, envelope, and the like; and at least one
unit dosage form of an agent comprising an extract taught herein
within the packaging material. There can be a first composition
comprising at least one unit dosage form of an agent comprising a
binding system as taught herein within the packaging material, and
optionally, a second composition comprising a second agent such as,
for example, any other bioactive agent that may be administered in
combination with the binding system, or any prodrugs, codrugs,
metabolites, analogs, homologues, congeners, derivatives, salts,
solvates, and combinations thereof. In some embodiments, the
articles of manufacture may also include instructions for using the
composition as a diagnostic, prophylactic, therapeutic, or
ameliorative treatment for the condition of concern. In some
embodiments, the instructions can include informational material
indicating how to administer the systems for a particular use or
range of uses, as well as how to monitor the subject for positive
and/or negative responses to the systems.
[0114] In some embodiments, the article of manufacture can include
a substantially anhydrous binding system. For example, a kit can be
assembled which includes the anhydrous binding system comprising an
anhydrous tannin with instructions combining the tannin with and an
anhydrous reactive species generating component that forms a
therapeutically, prophylactically, or nutritionally useful
composition upon hydration.
[0115] Kits for the treatment of gastrointestinal spasms are
provided herein. In these embodiments, the kits can include the
polyphenol component and/or the reactive oxygen species in a wet or
dry form. Optionally, the kits can include instructions for use in
treating a subject. The instructions can include, for example,
instructions on diluting the composition to a desired concentration
and administration according to suggested dilution factors on the
basis of ages and weights of subjects, as well as known conditions
and target sites. The suggested dilution factors can be selected
from the ranges taught herein. In some embodiments, the kits
comprise a dry, stable form of the composition components. For
example, the kits can comprise a dry form of a polyphenol
component, such as one polyphenol, a combination of polyphenols, or
an extract of a plant tissue having polyphenols. Moreover, the kits
can also comprise a dry form of a hydrogen peroxide generating
material that functions to generate an effective amount of an
exogeneous reactive oxygen species, wherein the reactive oxygen
species includes a component selected from the group consisting of
hydrogen peroxide, superoxide anion, singlet oxygen, and a hydroxyl
radical. In these embodiments, the composition can be at least
substantially free of active endogeneous oxidative enzymes and
catalytic substances that cause degradation of the composition.
Example 1
Making and Testing an Antispasmodic Composition
[0116] This experiment includes the use of gallic acid, tannic
acid, a pomegranate husk extract, and a green tea extract.
[0117] Measuring the Amount of Hydrogen Peroxide that Remains Bound
to the Polyphenol
[0118] One of skill knows that hydrogen peroxide does not exist in
a pure, solid form under normal conditions, for example, ambient
conditions. However, this example shows that the hydrogen peroxide
can exist in dry form when in association with the model compounds
and plant extracts, and the compositions have been isolated in a
dry form as proof. Art-recognized procedures, such as those
set-forth at least in U.S. Pat. Nos. 3,860,694; 3,864,454;
4,171,280; and 4,966,762, were used as a guide for this study.
[0119] The model compounds were used to show that the compounds
include hydrogen peroxide, the reactive oxygen species component,
in a relatively stable association with the polyphenol component.
As discussed, one of skill will appreciate that hydrogen peroxide
in a free form, for example, would otherwise quickly degrade. The
polyphenols were provided from model compounds or plant extracts. A
dry form of the compositions was made between (i) gallic acid (a
model polyphenol building block from Sigma-Aldrich) and hydrogen
peroxide; (ii) tannic acid (a model polyphenol component from
Sigma-Aldrich) and hydrogen peroxide; (iii) pomegranate husk
extract and hydrogen peroxide; and, (iv) green tea extract and
hydrogen peroxide, using the procedures taught herein, including:
[0120] i. adding a solution of 35% hydrogen peroxide slowly into
each of the gallic acid powder, tannic powder, pomegranate husk
extract powder, or green tea extract powder. The adding is done in
a glass dish or beaker at 45-65.degree. C. under constant, gentle
mixing; [0121] ii. creating a dry form of the composition by
continuing the heating under the constant, gentle mixing until fine
dry granules or hard amorphous chunks form; [0122] iii. crushing
the granules or chunks into a powder, which is the dry form;
dissolving the powder into water, knowing that the dry forms will
not have stable, free hydrogen peroxide, such that the dissolved
powder will carry only the stabilized hydrogen peroxide associated
with the model compounds or extracts; and, [0123] iv. measuring the
total hydrogen peroxide concentration associated with the model
compounds or extracts in the dry form.
[0124] The hydrogen peroxide concentration measurements were taken
using standard methods to determine the amount of hydrogen peroxide
that bound to the model compounds or extracts in the dry form. It
was found that (i) about 3.0% hydrogen peroxide bound to the gallic
acid (a model polyphenol building block) by total dry wt; (ii)
about 2.5% hydrogen peroxide bound to the tannic acid (a model
polyphenol component) by total dry wt; (iii) about 1.8% hydrogen
peroxide bound to the pomegranate husk extract by total dry wt;
and, (iv) about 2.0% hydrogen peroxide bound to the green tea
extract by total dry wt. To measure the hydrogen peroxide levels, a
standard, WATERWORKS peroxide test strip method was used having a
test sensitivity of 0.5, 2, 5, 10, 25, 50, 100 ppm, available from
Industrial Test Systems, Inc., Rock Hill, S.C. 29730.
[0125] FIGS. 1A-1H are photographs of the dry forms of (A) gallic
acid (a model polyphenol building block) bound to hydrogen
peroxide; (B) gallic acid alone; (C) tannic acid (a model
polyphenol) bound to hydrogen peroxide; (D) tannic acid alone; (E)
pomegranate husk extract bound to hydrogen peroxide; (F)
pomegranate husk extract alone; (G) green tea extract bound to
hydrogen peroxide; and (H) green tea extract alone, according to
some embodiments. As can be seen, the dry compositions exist and do
contain a stable amount of hydrogen peroxide in an amount ranging
from about 1.8% to about 3.0%, indicating the stabilizing
association between the combined model compounds and extracts with
the hydrogen peroxide. One of skill will appreciate that,
surprisingly, the compositions contain a substantial amount of a
stabilized hydrogen peroxide that is carried with the model
compounds or extracts as a dry form.
[0126] The Stability of the Hydrogen Peroxide in the Combination is
Greater in an Aqueous Solution than the Stability of the Hydrogen
Peroxide Alone in the Aqueous Solution
[0127] This method tests the stability of the hydrogen peroxide in
the combination. The testing methods used follow the standard
procedures set-forth by the Clinical and Laboratory Standards
Institute (CLSI) and US Pharmacopeia. [0128] i. E. coli was chosen
as the bacteria to challenge the stability of the bound
compositions and the free hydrogen peroxide. [0129] ii. The
hydrogen peroxide concentration was matched to the selected
bacteria in order to form a useful curve representing hydrogen
peroxide degradation over time for the samples. As such, the
hydrogen peroxide was varied from 62.5 ppm to 500 ppm on a fixed E.
coli concentration of 10.sup.6 CFU/ml, and a concentration of 125
ppm was chosen as the initial hydrogen peroxide level used to
challenge the E. coli over time. [0130] iii. A ratio of 1:1 of the
hydrogen peroxide to each of the model compounds and plant extracts
was used to form each bound composition, such that 125 ppm of each
plant extract was combined with the 125 ppm of the hydrogen
peroxide. [0131] iv. The free hydrogen peroxide was added at a
concentration of 125 ppm as a control to show the relative
stability of the hydrogen peroxide alone in the aqueous solution as
compared to the bound compositions.
[0132] FIGS. 2A and 2B show that the stability of the hydrogen
peroxide in the combination is consistently, substantially greater
in an aqueous solution than the stability of the hydrogen peroxide
alone in the aqueous solution, according to some embodiments. FIG.
2A compares stabilities of free hydrogen peroxide to hydrogen
peroxide bound to each of: gallic acid (a model polyphenol building
block), tannic acid (a model polyphenol), pomegranate husk extract,
green tea extract, and Blessed thistle extract. FIG. 2B shows very
similar and consistent stabilities when comparing free hydrogen
peroxide to hydrogen peroxide bound to a wide variety of species of
plants: Aloe, Angelica, Barberry Root Bark, Bilberry, Calendula,
Cramp bark, Eleutherococcus root, Kidney wood, Mimosa tenuiflora,
Papaya leaves, Pau D'Arco, Sassafras albidum root bark, Saw
Palmatto, St. John's wort, Valerian, Apple, Grape, Echinacea
purpurea, Grape seed extract, and Blueberry. In both FIGS. 2A and
2B, there are curves that cannot be identified well individually,
as they are identical and overlapping. The free hydrogen peroxide
curve does not overlap with any of the bound compositions beyond
the 4 hour mark. Table 1 provides data used to produce the curves
in the overlap for clarity.
TABLE-US-00001 TABLE 1 Hours 0 4 8 12 16 20 24 Aloe (Aloe vera) 125
30 25 20 15 15 10 Angelica (Angelica archangelica) 125 16 15 12 10
10 12 Barberry (Berberis vulgaris) 125 30 20 15 10 10 12 Root Bark
Bilberry (Vaccinium myrtillus) 125 30 25 20 15 12 15 Calendula
(Calendula officinalis) 125 16 15 12 10 10 10 Cramp bark (Viburnum
opulus) 125 16 12 10 10 12 12 Eleutherococcus root 125 16 12 10 10
10 10 (Eleutherococcus senticosus) Kidney wood 125 16 12 10 10 10
10 (Eysenhardtia orththocarpa) Mimosa tenuiflora 125 30 25 15 10 12
15 Papaya (Carica papaya) leaves 125 16 12 10 10 12 15 Pau D' Arco
(Tabebuia avellanedae) 125 20 15 10 10 12 10 Sassafras albidum root
bark 125 20 15 10 10 10 12 Saw Palmatto (Serenoa repens) 125 15 12
10 10 10 12 St John's wort 125 40 25 20 12 15 12 (Hypericum
perforatum) Valerian (Valeriana officinalis) 125 20 15 12 10 10 12
Apple (Malus domestica) 125 15 11 10 10 10 10 Grape (Vitis
vinifera) 125 30 20 15 15 12 12 Echinacea purpurea 125 16 15 12 12
10 10 Grape seed extract 125 30 20 15 10 10 10 Blueberry (Vaccinium
corymbosum) 125 20 15 12 10 10 10 H2O2 125 15 0 0 0 0 0
[0133] The results were quite impressive and surprising, as the
free hydrogen peroxide degraded quickly to near 0.0 ppm each time
within about the first 8 hours, whereas each of the bound
compositions maintained at least 10 ppm or greater for the total
duration of the study, which was limited due to time constraints.
As such, it was observed that the stabilities were maintained at a
concentration of at least 10 ppm or greater for at least 24 hours,
a concentration sufficient to maintain bactericidal activity in
water. FIG. 2A shows that at least 7 days of stability remained
present in at least the samples that were afforded the at least 7
days of testing. In fact, potencies have been observed to remain in
the compositions when challenged for at least 30 days, and the
original batches have shown to remain potent for at least 90 days,
in some cases.
Example 2
Treating Gastrointestinal Spasms in Patients Having Irritable Bowel
Syndrome
[0134] A physician-controlled, open-label pilot study of 29
patients was performed. The patients suffered chronic
gastrointestinal symptoms, including gastrointestinal spasms, and
were selected because they were either non-responsive, or merely
partially responsive, to standard treatments. The patients had been
diagnosed with irritable bowel syndrome (IBS) and ranged in age
from 29 years old to 79 years old, having a mean age of 51 years
old. 83% of the patients were female. The patients were provided
with sufficient volume of the composition for five days of
consumption and asked to note any response or effects of the
extract. Each of the patients received a 25 ml bottle of the test
composition and instructed to take 5 ml per day with water at least
1 hour before meals for a 5 day period. The patients had been under
treatment for chronic GI distress for an extended period and were
asked to compare the performance of the test composition against
their own subjective baseline health.
[0135] The Test Composition
[0136] The test solution ("the composition" or "the test
composition") contained approximately 1100 micrograms total dry
weight of dessicated pomegranate and green tea extract dissolved in
a solution of 0.05% hydrogen peroxide in purified water. 25 ml was
of the solution was then further diluted in 250 ml of oral
rehydration solution to a final concentration of 0.0045% hydrogen
peroxide and 100 micrograms of polyphenols before administration.
Unused and undiliuted solutions of the composition from the same
lot were tested for hydrogen peroxide concentration using standard
methodologies, described herein, verifying an unchanged ratio of
peroxide to polyphenols. The free hydrogen peroxide at the fully
diluted oral concentration was well below its conventionally
accepted minimum inhibitory concentration for most bacteria.
[0137] The composition was tested for stability. Consistent with
the methods taught herein, the composition was dessicated to a
gummy solid with slow heating in a glass dish or beaker at
45-65.degree. C. under constant, gentle mixing, along with vacuum
dessication to degrade free hydrogen peroxide. The composition was
then rehydrated to its original liquid volume to determine the
amount of hydrogen peroxide that was stable enough to remain in the
composition. And, to compare the composition to those prepared from
other plant tissues, the same test was performed with a variety of
polyphenol extracts including grape skin extract, guava leaf
extract, green tea extract only, pomegranate rind only, Aloe vera
skin extract, and knotweed extract. All of the compositions
retained a substantial concentration of a stable, hydrogen peroxide
through the dessication and rehydration cycle, providing evidence
that water extracts from different plant sources provide a source
of polyphenols that form similar stable compositions with hydrogen
peroxide.
[0138] The Study
[0139] Significant responses to administration of the composition
were observed. Of the 29 patients, 4 complained of constipation and
2 showed improvement. The 6 out of the 13 with gluten sensitivity
(a test used in the diagnosis of IBS) reported reduced incidence of
bloating, abdominal pain, bowel urgency or soft/water stools
following gluten intake, suggesting that the composition is an
effective treatment for irritable bowel syndrome. 19 out of the 29
(65%) subjects generally reported an improved health and relief of
symptoms. 11 out of 16 (69%) of the subjects, a rather high
percentage, reported improvement in gastrointestinal spasm
symptoms. It has been observed, generally, that subjects receiving
the composition have reported significant improvements over their
historic baseline health within 24 hours.
[0140] A Literature Comparison
[0141] As described above, loperamide can be used to treat symptoms
of IBS. As an agent for IBS patients, loperamide has been reported
to resolve abdominal pain symptoms in 56% to 59% of patients in one
study but to be no different from placebo in other studies. See,
for example, Kaplan M A, et al. Arch Fam Med 8: 243-248 (1999);
Efskind, P S, et al. Scand J Gastroenterol 31: 463-468 (1996); Cann
P A, et al. Dig Dis Sci 29(3): 239-247 (1984); and, Jailwala J, T F
Imperiale, K Kroenke. Ann Intern Med 133: 136-147 (2000).
Antispasmotic medications have been reported to result in a higher
level of relief of abdominal pain than placebo, with up to 56% of
patients experiencing a result that was clinically meaningful. See,
for example, Trinkley K E, et al. J Clin Pharm Thera 36: 275-282
(2011); and, Page J G, et al. J Clin Gastroenterol 3: 153-156
(1981).
[0142] In comparison, the results to date suggest that the
compositions taught herein offer a significant improvement over the
results that have been observed in the literature for loperamide,
for example, at least with regard to the treatment of IBS.
[0143] Other Studies
[0144] Other compositions using polyphenols derived from water
extractions from other plants have been tested and shown to provide
similar results. In one study, grape skin extract and guava leaf
extract have been combined with commercial food grade hydrogen
peroxide and plant extracted hydrogen peroxide from aloe vera gel.
This composition was administered to human subjects suffering from
abdominal cramps. In all cases, the administration provided
effective relief, evidence that other sources of water soluble
polyphenol extracts provide commercially valuable and effective
antispasmodic compositions.
[0145] In another study, 46 adults (including 6 having IBS)
experiencing vomiting, abdominal pain, cramps, and bloating were
given the 25 ml solution of the combination of composition (green
tea/pomegranate/H2O2) and reported near-immediate relief with a
significant reduction in symptoms remaining after 24 hours of
treatment when compared to a placebo group. 78% reported
significant benefit.
Example 3
Prophylactic Inhibition or Prevention of Alcohol Overindulgence
[0146] Experimental prophylactic use of the compositions has shown
in a variety of subjects that it can inhibit or prevent
gastrointestinal symptoms of the over consumption of alcohol.
Surprisingly, it was also effective at inhibiting or preventing
other symptoms of excess alcohol consumption. For example, the
symptoms that have been prevented or inhibited have been measured
against the historic baseline of the subject, including an
alcohol-induced headache; and, alcohol-induced dermal and other
tissue reactions such as apparent immune-type, allergenic reactions
that included itchiness, blotchiness, flushing, red eyes, and runny
nose.
[0147] Prior to the consumption of alcohol at a social event, each
of the subjects consumed approximately 2000 ug-5000 ug of a green
tea/pomegranate composition (dry weight) with water. The green
tea/pomegranate that was administered was from a variety of lots
and varied in ratio from 1:1 to 4:1 wt/wt. The subjects consumed
approximately 2-10 alcoholic drinks, mixed and/or straight, ranging
in content from about 5% to about 60% alcohol. The drinks ranged in
content from wine to beer to liqueurs to liquors, and combinations
thereof. Each of the subjects expressed that the composition
provided a substantial prophylactic effect to inhibit or prevent
the effects of the alcohol consumption, using their own, personal
historic baselines of what they expected to experience without
consuming the composition prior to drinking.
[0148] The experiments shown herein are for illustration and
example only. One of skill can vary the experimental conditions and
components to suit a particular or alternate experimental design.
The experimental conditions can be in vitro or in vivo, or designed
for any subject, for example, human or non-human. For example,
animal testing can be varied to suit a desired experimental method.
As such, one of skill will appreciate that the concepts can extend
well-beyond the examples shown, a literal reading of the claims,
the inventions recited by the claims, and the terms recited in the
claims.
* * * * *
References