Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
METHODS FOR THE TREATMENT OF
PERIPHERAL NEURAL AND VASCULAR AILMENTS
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to compositions and methods for the treatment of
to peripheral neural and vascular ailments. In the methods of the present
invention, a
flavonoid is administered to a patient suffering from a peripheral neural or
vascular
ailment.
2. Brief Description of the Prior Art
15 The phrases "peripheral neuropathies" and "small fiber neuropathies" are
used
interchangeably herein to refer to a set of conditions characterized by
functional
changes or pathological changes, or both, in the small, unmyelinated nerve
fibers of
the peripheral nervous system. For the purpose of this application, diabetic
neuropathy is not included among the peripheral small fiber neuropathies.
20 Peripheral or small fiber neuropathies may be caused by any of about a
hundred identified factors that can produce nerve damage. The cause may be
metabolic, for example hypertriglyceridemia or pellagra. ~ Toxic exposures may
also
cause small fiber neuropathies, for example those resulting from alcoholism,
excessive doses of vitamin B6, exposure to toxic metals such as thallium, or
exposure
25 to certain chemotherapeutic agents, such as vinca alkaloids. Certain
congenital
conditions, including amyloidosis, an-a-lipoproteinemia (Tangier's), and a,-
galactosidase (Fabry's), are known to cause small fiber neuropathies. Small
fiber
neuropathies may result from infections such as leprosy, or diseases such as
AIDS,
herpes simplex, herpes zoster (shingles), cytomegalovirus, hepatitis B and C,
Lyme
3o disease, autoimmune diseases, Fabry disease, diphtheria, vasculitis, and
porphyria. In
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
2
approximately 15% of cases, the cause of the small fiber neuropathy cannot be
determined. The neuropathy is then referred to as idiopathic.
Patients afflicted with peripheral neuropathies have pain in their
extremities.
The pain may at first be perceived as a tingling sensation in the fingers or
toes.
Decreased sensitivity to heat or cold is also a common early symptom.
Frequently,
however, a physical examination will show that the patient's reflexes,
strength,
sensory levels, and electrophysiology are normal. This has historically
complicated
the diagnosis of peripheral neuropathies, or led to underdiagnosis, especially
in the
early stages of the neuropathies. Recent technology, however, including skin
biopsies
l0 and measurement of the density of different nerve fiber types in the
epidermis, has
improved the likelihood of detecting peripheral neuropathies.
Small fiber or peripheral neuropathies tend to progress by spreading upward,
and patients may develop intense pain and/or a burning sensation that can be
so severe
as to be debilitating. Other symptoms of these neuropathies include cold hands
or
15 feet, cramps, muscle weakness and/or atrophy, eventual loss of perception
of pressure,
pain and/or temperature, neuropathic ulcers, lack of sweating, dry eyes, dry
mouth,
impotence, and restless leg syndrome.
In some cases, treatment of the underlying cause may also reverse or alleviate
small fiber neuropathies. When the underlying cause is unidentifiable or
otherwise
2o untreatable, however, treatment consists of reducing the symptoms of the
neuropathies, typically by administering medications known to decrease pain
from
neuropathy and related conditions. These medications include tricyclic
antidepressants, anticonvulsants, opioid medications, and local anesthetics
applied to
the painful area. An afflicted patient may also undergo physical and
occupational
25 therapy to improve mobility and function.
Often, the symptoms of peripheral neuropathies do not vary due to their
underlying causes. For example, a neuropathy caused by exposure to
chemotherapeutic agents may present symptoms almost identical to those of a
neuriopathy caused by Lyme disease. As a further example, diabetic neuropathy,
is a
30 fairly common long-term complication of diabetes mellitus that shares many
of the
symptoms of peripheral neuropathies. The cause of diabetic neuropathy,
however, is
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
3
believed to be a chronic systemic excess of the glucose metabolite sorbitol.
Further,
treating the underlying cause of diabetic neuropathy, that is, improving
glycemic
control, will often prevent the symptoms from worsening. Diabetic neuropathy
is
also known to be reversible, if good glycemic control is instituted while the
condition
is in its early stages.
Peripheral Neuropathies including diabetic neuropathies, can also impair
circulation in the affected area. Impaired circulation can adversely affect
the
appearance of the skin. Adverse effects on the appearance of the skin caused
by
radiation iniury can include for example, redness, discoloration, dryness of
the skin.
l0 "Peripheral vascular diseases" are diseases of the blood vessels outside
the
heart that lead to restriction or blockage of the blood vessels.
Atherosclerosis, when it
affects the extremities rather than the coronary arteries, is an example of a
peripheral
vascular disease. Peripheral vascular diseases may also be long-term
complications of
other diseases, such as Raynaud's disease, Raynaud's phenomenon, hypertension,
or
Buerger's disease (thromboangitis obliterans).
An early symptom of peripheral vascular disease includes pain upon
exercising that is relieved by rest. These diseases are progressive, however,
and
patients may also experience numbness, muscle weakness or pain, loss of hair
on the
affected extremities, cyanosis, weak or absent pulse in the affected
extremities, gait
abnormalities, pain when resting, skin ulcers, and, eventually gangrene.
Impaired
circulation caused by peripheral vascular disease can also adversely affect
the
appearance of the skin. Adverse effects on the appearance of the skin caused
by
radiation injury can include, for example, redness, discoloration, dryness of
the skin.
In general, an agent that promotes or induces angiogenesis, or one that at
least
partially clears blocked or restricted vessels, or one that will facilitate
peripheral
circulation by other means, i.e. by decreasing cellular adhesion, will be
effective to
treat peripheral vascular diseases.
Decreased inicrocirculation is also a long-term complication of diabetes. In
general, a therapy that is effective for peripheral vascular diseases will
also be
effective to counter decreased microcirculation caused by diabetes.
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
4
There remains a need for a treatment for small fiber neuropathies that is
clinically effective when the underlying cause of the neuropathy is unknown. A
need
also remains for an effective treatment for small fiber neuropathies that does
not
suffer from the disadvantage of causing severe side effects.
In addition, there remains a need for a clinically effective treatment of
peripheral vascular ailments.
Accordingly, it is an object of certain embodiments of the present invention
to
provide a method that is effective for the treatment of small fiber
neuropathies and
peripheral vascular ailments.
l0 It is another object of certain embodiments of the present invention to
provide
a method for the treatment of small fiber neuropathies or peripheral vascular
ailments
by administering a composition that does not cause severe side effects in the
patient.
It is another object of certain embodiments of the present invention to
provide
a composition for the treatment of peripheral neuropathies or peripheral
vascular
15 ailments.
These and other objects of the present invention will be apparent from the
summary and detailed descriptions of the invention that follow.
SUMMARY OF THE INVENTION
20 The present invention provides a method for the treatment of peripheral
neural
and vascular ailments by administering a composition including a
therapeutically
effective amount of a flavonoid having antioxidant properties, and,
optionally, an
acceptable carrier.
In another embodiment, the invention relates to a composition for treating
25 peripheral neural and vascular ailments. The composition comprises a
therapeutically
effective amount of a mixture of a flavonoid having antioxidant properties, a
therapeutically effective amount of a non-flavonoid antioxidant compound, and,
optionally, an acceptable Garner.
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The compositions and methods of the invention provide significant, effective
relief of symptoms of peripheral neural and vascular ailments, as well as
partial
recovery of lost microcirculation or neurological function in some cases.
Surprisingly, the efficacy of the invention is not dependent on the underlying
causes
of the peripheral neural and vascular ailments. In addition, the composition
used in
the method of the invention, when administered in a therapeutically effective
amount
to treat peripheral neural and vascular ailments, does not cause severe side
effects.
The topical compositions and methods of the invention also treat adverse
l0 effects on the appearance of the skin caused by peripheral neuropathies
and/or
peripheral vascular disease. These cosmetic benefits are obtained in patients
having
such disorders. Adverse effects on the appearance of the skin include, for
example,
redness, discoloration, dryness. Such cosmetic effects are intended to be
included
within the meaning of "treating ailments," although the effects relate to the
appearance of skin in people using the composition and methods, Thus, the
invention
treats or cosmetically improves the appearance of persons having peripheral or
neural
vascular ailments by, for example, reducing or preventing redness of skin,
reducing or
preventing discoloration of skin, beautifying skin, improving appearance of
skin,
promoting attractiveness of skin, cleansing skin, removing dead or damaged
skin or
skin cells from skin and moisturizing skin.
The oral compositions and methods of the invention also provide nutritional
and/or dietary benefits. These nutritional or dietary cosmetic benefits are
obtained in
patients having peripheral neuropathies and/or peripheral vascular disease.
Such
nutritional or dietary effects are also intended to be included within the
meaning of
"treating ailments." Thus, the invention offers dietary or nutritional
benefits in
supporting and/or maintaining neural, vascular and muscular health, maintains
sensory integrity, i.e. sensations of hot and cold, and supports the
maintenance of skin
health.
The term "derivatives," as used herein, refers to structurally similar
compounds that exhibit a common activity (e.g., antioxidant) and contain at
least one
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
6
significant, common structural element with the compound from which it is
derived,
which common structural element provides the common activity.
The expression "therapeutically effective amount," as used herein, refers to a
nontoxic amount of a compound which is sufficient to provide the desired
therapy to
counteract small fiber neuropathies or peripheral vascular diseases. A
therapeutic
amount may, for example, reduce pain, reverse sensory fiber loss or
demyelination,
promote angiogenesis, increase microcirculation, or increase sensory
perception. The
exact amount required may vary, depending on the species, age, and general
condition
of the patient, the nature of the complications, the particular combination of
l0 compounds, the mode of administration, and the like. The term
"therapeutically" is
intended to encompass beneficial cosmetic effects and effects of improved
nutrition as
well as medical effects.
The compositions used in the method of the present invention include at least
one flavonoid. Flavonoids are small organic compounds having a phenyl
15 benzopyrone structure. They are found in the leaves, fruits; seeds, stems,
or flowers
of all vascular plants. Citrus fruits are a prominent source of flavonoids,
over 4000 of
which have been identified as deriving from plant sources. On average, the
daily
Western diet contains about one gram of mixed flavonoids.
Examples of flavonoids include, without limitation, flavonones, flavonols,
20 anthocyanidins, proanthocyanidins, procyanidolic oligomers, biflavans,
polyphenols,
rutinosides, hydroxyethylrutinosides, and leucoanthocyanins.
Suitable flavonoids for use in the present invention include those that do not
induce significant, adverse side effects when administered to a mammal in a
therapeutically effective amount, and that do not react with any of the other
25 ingredients of the composition used in the present invention to cause a
substantial loss
of activity of one or more compounds of the composition. Preferred flavonoids
are
obtained from natural sources. However, derivatives of such compounds may also
be
suitable for use in the present invention. Preferred flavonoids may be
administered to
humans without significant, adverse side effects when used in therapeutically
30 effective amounts.
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
7
The selection of the flavonoid(s) included in the composition may be
determined by factors such as toxicity, bioavailability, solubility or
dispersability, and
the like. Examples of flavonoids suitable for use in the present invention
include,
without limitation, (-)-epigallocatechin; (-)-epigallocatechin-gallate;1,2,3,6-
tetra-o-
gallyol-(3-d-glucose; 2'-o-acetylacetoside; 3,3',4-tri-o-methyl-ellagic acid;
6,3',4'-
trihydroxy-5,7,8-trimethoxyflavone; 6-hydroxy-luteolin; 6-hydroxykaempferol-
3,6-
dimethyl ether; 7-o-acetyl-8-epi-loganic acid; acacetin; acetoside; acetyl
trisulfate
quercetin; amentoflavone; apigenin; apiin; astragalin; avicularin; axillarin;
baicalein;
brazilin; brevifolin carboxylic acid; caryophyllene; catechin; chrysin;
chrysin-5,7-
to dihydroxyflavone; chrysoeriol; chrysosplenol; chrysosplenoside-a;
chrysosplenoside-
d; cosmosiin; ~-cadinene; curcumin; cyanidin; dihydroquercetin;
dimethylmussaenoside; diacerylcirsimaritin; diosmin; diosmetin; dosmetin;
ellagic
acid; ebinin; epicatechin; ethyl brevifolin carboxylate; flavocannibiside;
flavosativaside; galangin; gallic acid; genistein; ginkgo flavone glycosides;
ginkgo
heterosides; gossypetin; gossypetin-8-glucoside; haematoxylin; hesperidine;
hispiduloside; hyperin; indole; iridine; isoliquiritigenin; isoliquiritin;
isoquercitrin;
jionoside; juglanin; kaempferol; kaempferol-3-rhamnoside; kaempferol-3-
neohesperidoside; kolaviron; licuraside; linariin; linarin; lonicerin;
luteolin; luteolin-
7-glucoside; luteolin-7-glucoronide; macrocarpal-a; macrocarpal-b; macrocarpal-
d;
macrocarpal-g; maniflavone; morin; methyl scutellarein; monoHER, diHER,
triHER,
tetraHER, myricetin; naxingenin; naringin; nelumboside; nepetin; nepetrin;
nerolidol;
oligomeric proanthocyanidins; oxyayanin-a; pectolinarigenin; pectolinarin;
pelargonidin; phloretin, phloridzin, polyphenols, including green tea
polyphenols;
quercetagetin; quercetin; quercimertrin; quercitrin; quercitryl-2" acetate;
reynoutrin;
rhamnetin; rhoifolin; rutin; scutellarein; sideritoflavone; silibin;
silydianin;
silychristine; silymarin; sophoricoside; sorbarin; spiraeoside; taxufolin;
trifolin;
vitexin; and wogonin, and the pharmaceutically acceptable salts ; solvates;
and
derivatives of these compounds.
Preferred flavonoids are those that also have strong antioxidant properties.
Examples of preferred flavonoids include, without limitation, (-)-
epigallocatechin-3-
gallate, catechin, rutin, quercetin, quercitrin, myricetin, kaempferol,
myrecetrin
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
8
luteolin, morin, fisetin, silymarin, apigenin, hesperitin, hesperidin, citrin,
gossypetin,
chrysin, oligomeric proanthocyanidins, biacalein, curcumin, gallic acid,
epicatechin,
dihydroquercetin, ginkgo flavone glycosides, ginkgo heterosides, silibin,
silydianin
silychristine, galangin, monoHER, diHER, triHER, tetraHER, naringenin,
naringin,
taxifolin, diosmin, phloretin, phloridzin, cyanidin, pelargonidin and
derivatives
thereof, and the pharmaceutically acceptable salts of these compounds.
More preferred flavonoids include, without limitation, quercetin, quercitrin,
myricetin, rutin, kaempferol and myrecetrin. These compounds exhibit good
antioxidant properties in combination with relatively low toxicity.
to Advantageously, flavonoids and flavonoid derivatives may provide additional
beneficial effects in the composition of the present invention. For example,
quercetin
acts as a chelator for transition metals. Flavonoids are also believed to
possess anti-
inflammatory activity and to assist in the stabilization of cell membranes,
both
activities that promote the treatment of small fiber neuropathies. Quercetin
is also
believed to have anticlastogenic properties. In addition, some flavonoids and
flavonoid derivatives act as radical scavengers, reducing the concentration of
hydroxyl radicals, for example, and thereby further enhancing the antioxidant
effect
of the composition used in the present invention.
Suitable non-flavonoid antioxidants for use in the present invention include
those that exhibit antioxidant activity without causing any severe adverse
side affects
when administered in a therapeutically effective amount, and that do not react
with
any of the other ingredients of the composition used in the present invention
to cause
a substantial loss of activity of one or more compounds. Preferred
antioxidants
include those that occur naturally in the human body and materials obtained
from
plants or animals, or derivatives of such compounds.
Preferred non-flavonoid antioxidants include, without limitation, ascorbyl
palmitate, ascorbic acid (vitamin C), vitamin A, vitamin E and its
pharmaceutically
acceptable esters (including but not limited to the acetate), a-lipoic acid,
especially
DL- a-lipoic acid, coenzyme Q10, glutathione (GSH), galangin, gingkolides,
tocotrienols, carotenoids, cyanidin, curcuminoids, and derivatives thereof
which
exhibit antioxidant activity.
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
9
More preferably, mixtures of two or more antioxidants are employed in the
composition used in the present invention. Derivatives of one or more of these
compounds that exhibit antioxidant activity when administered in the
compositions of
the present invention may also be employed. The antioxidants may also be used
in
the form of their pharmaceutically acceptable salts. The salts may be
preferred in
some cases, for example to increase solubility or dispersability, or to reduce
adverse
side effects.
In a preferred embodiment, the antioxidant used in the composition of the
present invention may comprise one or more antioxidant enzymes. The
antioxidant
l0 enzymes useful in the present invention are those capable of scavenging
radicals, of
promoting radical scavengers or preventing radical formation. One or more of
these
antioxidant enzymes may act synergistically with one or more of the other
antioxidants in the composition to scavenge free radicals more effectively and
thereby
aid in the prevention of cell damage in the skin. In a more preferred
embodiment, the
antioxidant enzyme used in the present invention is capable of absorption
through the
skin. Preferred antioxidant enzymes for use in the present invention include
superoxide dismutase, catalase, glutathione peroxidase, methionine reductase,
and the
like.
In a more preferred embodiment, both quercetin and an antioxidant are
included in the composition of the present invention. This combination of
quercetin
and an antioxidant results in an enhanced anti-oxidative effect. The
antioxidant may
be a flavonoid or a non-flavonoid.
Other compounds may also be included in the composition of the present
invention to provide additional benefits, such as absorbability when applied
topically,
free radical scavenging, transition metal chelation, nitric oxide
stabilization,
analgesia, and anti-inflammatory activity. Some of these properties may have a
beneficial effect on the pain of other related disorders such as fibromyalgia.
Additional materials that may optionally be included in the compositions used
in the
present invention include inositol and other B-complex vitamins.
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
Some preferred compositions used in the invention also contain vitamin D3, a.
vitamin D3 analog, a compound that may be converted, or metabolized into
vitamin D3
in the human body, or a metabolite of vitamin D3.
Vitamin D3, also known as cholecalciferol, may be further converted into
5 another vitamin D intermediate, 25-hydroxycholecalciferol, in the liver by
mitochondrial hydroxylase, in the presence of NADPH, and molecular oxygen.
OH
CH2
24
z
HO ~~~I 25-hydroxycholecalciferol
When a more active form of vitamin D3 is required, 25-hydroxycholecalciferol
is
l0 transported to the kidney where a new hydrolase enzyme is synthesized. This
enzyme
introduces another hydroxyl group at position 1, and the bioactive form of
vitamin D3,
calcitriol, is produced.
OH
OH CH2~ ~~ 24
11 ~~
2
I I Biologically Active Vitamin D
HO , ~~ 1,25-dihydroxycholecalciferol
Calcitriol
An exemplary vitamin D3 analog is 1(S), 3(R)-dihydroxy-20(R)-(1-ethoxy-5-
ethyl-5-hydroxy-2-heptyn-1-yl)-9, 10-seco-pregna-5(Z), 7(E), 10 (19)-triene.
An
exemplary vitamin D3 metabolite is 1, 25-dihydroxyvitamin D3. Pharmaceutically
acceptable salts of vitamin D3 and its derivatives and metabolites may be
employed in
. the methods of the present invention. Vitamin D3 is particularly preferred
for use in
2o the present invention.
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
11
A dispersant may be necessary to facilitate the formulation of the vitamin D3
or related compound. Suitable dispersants are well known to persons skilled in
the
art. Corn oil is one dispersant that is well suited for vitamin D3 and related
compounds. Also advantageously, corn oil is a natural product. The corn oil is
used
in an amount sufficient to disperse the vitamin D3 or related compound.
The compositions used in the present invention may provide one or more of
the following localized or systemic beneficial effects to a patient when
administered
in therapeutically effective amounts: relief of pain, burning, tingling,
electrical
sensations and/or hyperalgesia; increased microcirculation; nitric oxide
stabilization;
to promotion of healing of skin ulcers and lesions; protein kinase C
inhibition; decreased
oxidative stress; anti-inflammatory activity; blockage of the formation of
leukotrienes; stabilization of cell membranes; and promotion of the synthesis
of nerve
growth factor.
Compositions in accordance with the invention can provide additional effects
of improving the appearance of the skin. Skin appearance may be adversely
affected
by peripheral neuropathies, including diabetic neuropathy, and/or peripheral
vascular
disease, or by other causes unrelated to the peripheral neuropathies and/or
peripheral
vascular disease being treated. One or more of the following beneficial
properties
may be realized when compositions of the invention axe topically applied in an
2o effective amount: reducing or preventing redness of skin, reducing or
preventing
discoloration of skin, beautifying skin, improving appearance of skin,
promoting
attractiveness of skin, cleansing skin, removing dead or damaged skin or skin
cells
from skin and moisturizing skin.
Without wishing to be held to a particular theory, there are several
physiological processes that might be affected by an effective treatment for
small
fiber neuropathies. For example, an effective treatment might cause the
degeneration
of peripheral nerves to slow or to stop. Alternatively, an effective treatment
might
induce healing or regeneration of the damaged nerves. An effective treatment
might
also cause the generation of new nerves to replace the damaged nerves.
3o It is therefore expected that effective treatments for small fiber
neuropathies
will be applicable to other diseases or conditions affecting peripheral
nerves. A
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
12
method of regenerating nerves is beneficial to treat any patient suffering
from nerve
damage, for example, a skin graft patient or a victim of a nerve-severing
trauma. In
fact, many flavonoids are potent aldose reductase inhibitors. It has been
shown that
the oral administration of aldose reductase inhibitors increases the diameter
of
peripheral nerve bundles. Thus, it is expected that the methods of the present
invention extend to the generation and regeneration of nerves. .
Although the underlying cause of diabetic neuropathy is specifically known to
be distinct from the other causes of small fiber neuropathies, the symptoms
and
pathologies are shared. It is therefore expected that an effective treatment
for small
l0 fiber neuropathies will arrest, reverse, or alleviate certain symptoms of
diabetic
neuropathy. It has also been found that for treatment of diabetic neuropathy,
the
optional component, vitamin D3 or a derivative or metabolite thereof, may be
excluded from the composition and the composition will still provide a
beneficial
effect, provided the composition includes other suitable components.
Flavonoids promote microcirculation and therefore can also be used to treat
peripheral vascular diseases. For example, the flavonoid quercetin supports
vascular
functioning in general, and therefore is an effective treatment for peripheral
vascular
diseases. Decreased microcirculation is believed to be caused at least in part
by
oxidative stress resulting from an excess of free radicals. Quercetin, an
example of a
2o flavonoid with antioxidant properties, is therefore an effective treatment
for this
condition. The chelating properties of flavonoids such as quercetin contribute
to its
effectiveness. The overabundance of sorbitol in the bloodstream of diabetic
patients
attracts metal ions, which are sequestered by chelation.
The compositions used in the present invention are preferably formulated with
an acceptable carrier. The non-carrier ingredients may be combined with the
Garner
materials to produce a particular dosage form, or be customized for a
particular
treatment regimen. Thus, the amount of each ingredient may vary depending on
such
factors as the particular mode of administration, the activity of the
particular
compounds employed, the age, bodyweight, general health, sex, and diet of the
3o patient, time of administration, rate of excretion, the combination of
compounds, or
the severity of the illness, among other potential factors. .
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
13
A standard reference text on pharmaceutical formulations, Remington's
Pharmaceutical Sciences, 1 ~~' Ed., Mack Publishing Co. 1990, is incorporated
herein
by reference in its entirety.
It is well known in the art that the individual ingredients in formulated
products may interact with each other. These interactions include, for
example,
chemical equilibria and other chemical or physical processes. These
interactions may
cause the original individual components of a formulated product to change
over time.
Such changes may be chemical or physical. For example, an acidic component may
become deprotonated in a formulation that also contains a basic component.
Alternatively, one or more components may precipitate or crystallize from a
formulated product. Equilibria and other processes may be expected to increase
in
number and complexity with increasing numbers of components in a given
formulation. Such equilibria and other processes may be either innocuous or
deleterious to the activity of the formulated product.
The term "stable" as used herein refers to the property of retaining at least
a
portion of the intended activity over a certain period of time.
The terms "mixture," "composition" and "formulation" as used herein refer to
stable mixtures, compositions, and formulations, respectively. Preferred
mixtures,
compositions, and formulations are stable over a period of at least about
three months.
In the method of the present invention, the composition may be administered
via several routes, including, without limitation, topically, orally, via an
implanted
reservoir, or by inhalation.
In a method of the invention, the composition is administered orally. An oral
composition for use in the invention may be administered one to six times
daily, or as
needed to relieve pain and other symptoms of the small fiber neuropathies.
Preferably, when administered orally, the composition is administered two to
four
times daily, as needed for pain. A sufficient amount should be administered to
provide one or more of the beneficial effects of the compositions described
above.
The method initially treats acute symptoms but may be continued indefinitely
to
3o relieve pain, prevent symptoms from returning and possibly restore some
nerve and/or
skin function.
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
14
The oral compositions and methods of the invention also function as dietary or
nutritional supplements. In this aspect of the invention, oral compositions
and
methods can maintain and/or support neural health, maintain and/or support
vascular
health and circulation, maintain and/or support muscular health, maintain
sensory
integrit, i.e. sensations of hot and cold, and support the health of the skin.
The oral-compositions used in the present invention may be orally
administered in any acceptable dosage form including, but not limited to,
capsules,
tablets, lozenges, troches, hard candies, powders, sprays, elixirs, syrups,
and
suspensions or solutions.
l0 Suitable acceptable earners for tablets include lactose and corn starch,
for
example. Lubricating agents may also be added to the tablets, including, for
example,
magnesium stearate, sodium lauryl sulfate and talc. Tablets may also contain
excipients such as sodium citrate, calcium carbonate and calcium phosphate.
Disintegrants such as starch, alginic acid and complex silicates, may also be
employed. Tablets may also include binding agents such as
polyvinylpyrrolidone,
gelatin and gum acacia.
The composition used in the invention may be administered in capsule form,
with or without diluents. Useful diluents for capsules include, without
limitation,
lactose and dried cornstarch. In addition, solid compositions similar to those
of the
tablets described above may be administered in soft and hard gelatin capsules.
The compositions used in the invention may be administered orally as
encapsulated or unencapsulated suspensions, and they may comprise emulsifying
and/or suspending agents such as are well known to those of skill in the art.
Ancillary
ingredients such as sweeteners, flavorants, coloring agents, dyes, and
diluents such as
water, ethanol, propylene glycol, glycerin and various combinations thereof
may also
be included in the oral formulations.
The compositions used in the present invention may also be administered by
nasal aerosol or by inhalation. Appropriate formulations may be prepared using
well-
known techniques. For this method of administration, suitable carriers
include, for
3o example, saline and/or other conventional solubilizing or dispersing
agents, optionally
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
formulated with one or more preservatives, absorption promoters to enhance
bioavailability, andlor fluorocarbons.
In a preferred method of the present invention, the composition is applied
topically to an area of the skin in the vicinity of tissue that suffers from
small fiber
neuropathy in order to relieve pain and other symptoms of the small fiber
neuropathy.
Such areas typically include the patients' extremities, such as the fingers,
toes, hands
and feet, where neuropathy is often most pervasive.
Preferably, a suitable amount of the topical composition of the invention is
applied one to six times daily, as needed. More preferably, the topical
composition is
l0 applied two to four times daily, as needed. Also preferably, a sufficient
amount of the
topical composition is applied to cover the afflicted area with a thin layer
of the
composition and the composition is rubbed into the skin until little or no
residue
remains on the skin. The treatment is almost immediately effective to
alleviate acute
symptoms, and may be continued, for a predetermined period or indefinitely, to
15 relieve pain, prevent the return of symptoms of small fiber neuropathies,
and possibly
restore some nerve and/or skin function.
A topical formulation of the composition used in the invention preferably
includes an acceptable topical carrier. Many acceptable topical carriers are
known to
those of skill in the art. The compounds in the composition maybe dissolved,
dispersed and/or suspended in the topical carrier.
Suitable hydrophilic ointment bases are known to persons skilled in the art.
Exemplary hydrophilic ointment bases suitable for use in the present invention
are
non-U.S.P. hydrophilic ointment bases such as those made by Fougera, Inc., a
division of Altana, Inc. of Melville, NY. Sufficient hydrophilic ointment base
is
employed to act as a carrier for the compounds of the composition. Typically
the
hydrophilic ointment base will make up more than 80% of the total composition
and
more preferably 80-90% of the composition is the hydrophilic ointment base.
The
hydrophilic ointment base functions as a carrier and preferably enhances
penetration
of the compounds into the skin.
One preferred topical carrier comprises hydroxymethyl cellulose. Another
preferred acceptable carrier includes a solution of an acrylic copolymer in a
non-
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
16
aqueous solvent system. The non-aqueous solvent system preferably contains a
polyethylene glycol such as, for example, methoxy polyethylene glycol 550
(MPEG).
One preferred MPEG is Sentry Carbowax MPEG 550 (Dow Corp., Midland, MI),
which is suitable for use in foods, pharmaceuticals, and cosmetics. The
acrylic
copolymer is preferably present in a concentration range of 3-6% by weight of
solution. Also preferably, the acrylic copolymer has a molecular weight of
more than
20,000. More preferably, the acrylic copolymer has a molecular weight of more
than
100,000, to substantially prevent absorption of the acrylic copolymer by the
human
body through the skin.
to Preferably, the acceptable topical Garner independently provides benefits
to
the patient. For example, the topical Garner may comprise panthenol or a
panthenol
derivative. The panthenol derivatives useful in the present invention include
at least
D-panthenol, DL-panthenol, and mixtures thereof. Panthenol provides skin
moisturizing properties, acts as a quick, deep penetrating component of the
carrier,
-helps deliver the compounds through the skin to the area to be treated, and
may impart
a healing effect to damaged tissue. The amount of panthenol or panthenol
derivative
preferably ranges from 0.25 to 10 weight percent, more preferably from 0.5 to
5
weight percent, and, still more preferably, from 1 to 2 weight percent, based
on the
total weight of the topical composition.
The topical carrier of the present invention may employ other penetrants in
addition to panthenol or as an alternative to panthenol. Exemplary penetrants
include
ethanol, oleic acid, sodium lauryl sulfate, isopropyl myristate, glycerol
monooleate,
caprylic/capric triglyceride, Crodamol GTC/C, glyceryl tricaprylate/caprate,
Miglyol
810, Miglyol 812, MCT oil, Neobee M5, Nesatol, oleum neutrale, oleum vegetable
tenue, thin vegetable oil, light mineral oil, stearyl alcohol and lanolin
mixed with
suitable vegetable oils or with soft paraffin. These penetrants may have an
emollient
effect and facilitate the absorption of ingredients of the topical composition
of the
present invention into the skin.
Preferably, the topical carrier of the present invention contains at least a
hydrophilic ointment base, panthenol or a panthenol derivative, and one or
more
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
17
dispersants, if needed to disperse an insoluble or partially insoluble
compounds in the
carrier.
The topical carrier of the present invention may also include additional
ingredients well known to persons skilled in the art, such as other carrier
materials,
other moisturizers, humectants, emollients, radiation blocking compounds,
particularly UV-blockers, as well as other suitable materials that do not have
a
significant adverse effect on the activity of the topical composition in the
amount
used. A preferred additional ingredient for inclusion in the carrier is sodium
acid
phosphate, a moisturizer.
l0 The topical composition of the present invention is preferably made by cold
compounding, when one or more of the compounds employed in the topical
composition are known to be sensitive to heat. Thus, in some cases, the
stability or
activity of the composition may be detrimentally affected as a result of other
formulation methods. Preferably, a sufficient amount of the topical carrier is
used, to
provide a substantially homogeneous cream or ointment. It may be necessary to
dissolve, disperse or suspend one or more of the ingredients prior to
formulation in
order to ensure substantially homogeneous distribution of one or more of the
ingredients in the composition.
As noted above, dosages may vary with the manner of formulating the
2o compounds. In general, the components of the composition, which include the
flavonoid and the optional antioxidant, will make up from 0.5-90% by weight of
the
total composition to provide the desired daily dosage. The body weight dosages
herein, when not normalized, are based on a patient having a body weight of 70
kg.
The appropriate unit dosage may be determined by dividing the daily dosage by
the
number of unit doses per day.
The at least one flavonoid of the present invention is administered in a safe
and effective amount. Every pound of a preferred topical composition of the
present
invention preferably includes about 1 to about 150 grams of one or more
flavonoids,
about 0.1 to about 50 grams of non-flavonoid antioxidants, and other suitable
ingredients such as topical carriers.
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
18
Preferably, the flavonoid is used in an amount of about 2 to about 100 grams
per pound of the composition. More preferably, the flavonoid is employed in an
amount of about to about 10-50 grams per pound of the composition, and, still
more
preferably, about 15 to about 40 grams per pound of the composition.
When vitamin D3 or a derivative or metabolite thereof is used in the
composition, the ratio of the amount of that compound to the amount of the
flavonoid
employed in the compositions of the present invention is from about 200 IU per
gram
of antioxidant to about 3 million IU per gram of flavonoid. More preferably,
the
composition contains about 1800 IU to about 1 million IU of nerve growth
factor
to synthesis promoter per gram of flavonoid, and, still more preferably, about
5000 IU to
about 200,000 IU of nerve growth factor synthesis promoter per gram of
flavonoid.
When the composition includes both vitamins A and D3, they are preferably
formulated together in a corn oil dispersion. Generally, each cubic centimeter
(cc) or
milliliter (mL) of the corn oil dispersion contains about 500,000 to about
2,000,000
15 IU of vitamin A and about 50,000 to about 200,000 IU of vitamin D3.
Preferably,
every milliliter of the corn oil contains about 800,000 to about 1,200,000 IU
of
vitamin A and about 80,000 IU to about 120,000 IU of vitamin D3. More
preferably,
the composition used in the invention contains about 1,000,000 IU and about
100,000
IU of vitamins A and D3, respectively.
2o When a composition including vitamin D3 or derivative or metabolite of
vitamin D3 is administered, the vitamin D3 or derivative or metabolite of
vitamin D3 is
used in a safe and effective amount. More preferably, an amount of about 6 to
about
14.3 IU per kg of body weight of the patient for each administration. More
preferably, an amount of about 8 to about 14.3 IU per kg body weight of the
patient,
25 ' and, still more preferably, an amount of about 10 to about 13 IU is
employed per kg
of body weight of the patient, is administered.
The flavonoid is preferably used in an amount that provides substantially the
same level of activity as a daily dose of about 13 to about 22 mg/kg
bodyweight of
quercetin. More preferably, the flavonoid is administered in an amount that
provides
30 substantially the same level of activity as a daily dose of about 17.2 to
about 21.4 mg/
kg bodyweight of quercetin, and, still more preferably, an amount that
provides
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
19
substantially the same level of activity as a daily dose of about 18 to about
21 mg/kg
bodyweight of quercetin.
About 11 to about 29 mg/kg bodyweight/day of ascorbyl palinitate may be
administered. More preferably, about 14.3 to about 28.6 mg/kg bodyweight/day
is
administered.
When vitamin E is administered in the form of mixed tocopherols, the daily
dosage is preferably about 4 to about 12 IU per kg bodyweight. More
preferably, the
daily dosage is about 5.7 to about 11.4 IU per kg bodyweight. Still more
preferably,
the daily dosage of mixed tocopherols is about 6 to about 10 IU per kg
bodyweight.
to When vitamin E is administered in another form, an amount is administered
that
provides an equivalent effect as the above-described amounts of mixed
tocopherols.
When vitamin A is administered, the daily dosage is preferably about 170 to
about 360 IU per kg bodyweight per day. More preferably, the dosage is about
214.3
to about 357.1 IU per kg bodyweight per day. Still more preferably, the dosage
is
15 about 220 to about 340 IU per kg bodyweight per day.
Every pound of a preferred topical composition of the present invention
preferably includes about 2 to about 50 grams of one or more flavonoids, about
1 to
about 50 grams of non-flavonoid antioxidants, as well as other suitable
ingredients
such as topical carriers.
20 The witch hazel extract may be used in an amount of about 2.5 - 40 cc, more
preferably of about 5 - 30 cc, and most preferably of about 10 - 20 cc per
pound of
topical base. The glycerine humectant may be used in an amount of about 2-20
cc,
more preferably of about 3.5 - 15 cc, and most preferably of about 5 - 10 cc
per pound
of topical base. The apricot kernel oil may be used in an amount of about 0.5 -
5 cc,
25 more preferably of about 0.5 - 4 cc, and most preferably of about 1 - 3 cc
per pound of
topical base. The AJIDEW NL-50 NaPCA (50% aqueous solution) may be used in an
amount of about 15 - 45 cc, more preferably of about 20 - 40 cc, and most
preferably
of about 25 - 35 cc per pound of topical base.
A more preferred topical composition of the invention can be made using the
30 following ingredients: about 25 to about 35 cc of a 50% aqueous solution of
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
AJIDEW NL-50 NaPCA (50% aqueous solution) moisturizing agent, about 5 to about
10 cc of D- or DL-panthenol, and about 10 to about 50 grams of quercetin
powder.
The above amounts are appropriate for combination with one pound of
hydrophilic ointment base. As is well known in the art, larger amounts of one
or more
components, e.g. an antioxidant, can be employed while reducing the amount of
another component of the same type or having a similar type of activity.
In a preferred embodiment, about l Og/kg bodyweight of quercetin is used. In
another preferred embodiment, about Sg/kg bodyweight to about 25g/kg
bodyweight,
more preferably about Sg/kg bodyweight, of rutin are added to the composition.
In
to another preferred embodiment, about l Og to about SOg/kg bodyweight, more
preferably about l Og/kg bodyweight, of glutathione are added to the
composition.
In one embodiment of the present invention, the compositions are substantially
free of cinnamic acid derivatives of the formula:
COOR
O
X'
Y O
~O
15 wherein the groups X, Y and R, independently of one another, can be chosen
from the
group consisting of H and branched or unbranched alkyl having 1-18 carbon
atoms,
acids thereof, and physiologically tolerated salts thereof.
The following examples are provided to describe the invention in further
detail. These examples, which set forth a preferred mode presently
contemplated for
2o carrying out the invention, are intended to illustrate and not to limit the
invention.
RXAMPT,R 1
A topical composition including a mixture of an hydrophilic ointment base,
sodium acid phosphate moisturizing agent, and DL-panthenol, formulated
together as
the acceptable carrier, and further including quercetin was prepared by cold
compounding. The formulation of the composition is given in Table 1. The
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
21
formulation may optionally be supplemented with coenzyme Q10 (SOOmg) and may
optionally contain another antioxidant,.
The composition was prepared by first placing the hydrophilic ointment base
in a stainless steel bowl and mixing briskly until the ointment became creamy.
The
sodium acid phosphate, panthenol, quercetin, and other anti-oxidant, if any,
were next
added in that order. After each ingredient was added, mixing was continued
until no
traces of dry ingredients were visible and a substantially homogeneous mixture
was
obtained. The final color was a consistent yellow and the cream had the
consistency
of cake frosting. The mixture was stored in a sterile container. All
containers and
to tools that contact the composition during mixing must also be sterilized
with, for
example, zephiran chloride, a bleach solution, or betadine.
This composition can be topically administered, under the supervision of a
physician, to patients diagnosed with small fiber neuropathies. The topical
composition may be applied, for example, twice daily in the morning and
afternoon,
or up to six times daily, as needed for pain relief, over a period of a few
days. Treated
patients are predicted to experience positive results that will last up to a
day or two
after treatment is discontinued.
Table 1
2o I~edient Amount
Hydrophilic ointment base ~ llb
50% aqueous solution of Sodium acid phosphate 25cc
DL-panthenol 5cc
Quercetin powder l Og-SOg
Other Antioxidant l Og-50g
Other combinations of compounds suitable for use in the methods of the
invention are set forth in Examples 2 through 7. The compounds may be combined
with about l lb of hydrophilic ointment base for topical administration.
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
22
EXAMPLE 2
A topical composition was formulated using the ingredients listed in Table 2
below.
Table 2
Ingredient Amount
White Petrolatum 5,760.0
g
Stearyl Alcohol 4,030.0
g
Isopropyl Palmitate 1,730.0
g
Apricot Kernal Oil 140.5
g
to Vitamin A Palmitate and Vitamin D3 in corn 140.5
oil dispersion g
DL-a-tocopheryl acetate 47.7
g
Butylated Hydroxy Anisole 13.25
g
Methylparaben 5.83
g
Propylparaben 3.45
g
Sodium Lauryl Sulfate ~ 230.6
g
Propylene Glycol 2,766.6
g
DL-Panthenol, 50% in water 304.8
g
Sodium L-Pyrrolidone Carboxylic Acid (50% in 1,598.0
water) g
Purified Water 8,500.0
g .
Glycerin 318.0
g
Ascorbyl Palmitate 100.7
g
Quercetin Dihydrate 204.1
g
Witch Hazel Extract 598.9
g
The composition of Table 2 was topically administered three times per day
over a period of 4 weeks to 24 patients suffering from diabetic neuropathy in
at least
one foot as a result of having Type 1 or Type 2 diabetes mellitus in a placebo-
controlled, double blind proof of concept study conducted in France. 12
patients
received a placebo consisting of the composition of Table 2 except that the
ascorbyl
palmitate and quercetin dihydrate were left out. Eligible patients were
screened using
the Michigan Neuropathy Screening Instrument (MNSI), Feldman, E.L., et al., "A
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
23
Practical Two-Step Quantitative Clinical and Electrophysiological Assessment
for the
Diagnosis and Staging of Diabetic Neuropathy," Diabetes Cage, 1994, pp. 1281-
1289.
5.3 ml of the topical ointment was topically administered to the affected area
three times per day. Treatment was assessed using both a detailed symptom
assessment and a quality of life questionnaire.
The results of the test were positive. The formulation produced a significant
decrease of diabetic peripheral neuropathy pain and discomfort, and an
improvement
in the appearance and texture of the skin, including reduced dryness. A
similar
formulation without ascorbyl pahnitate was also effective on diabetic skin and
aging
to skin, as well as providing relief from the discomfort of diabetic
peripheral neuropathy
and small fiber peripheral neuropathy.
EXAMPLE 3
Ingredient Amount
Hydrophilic ointment base llb
50% aqueous solution
of Sodium acid phosphate 25cc
DL-panthenol 5cc
Quercetin powder l Og-SOg
2o Glutathione l Og-SOg
EXAMPLE 4
In egr diem Amount
Hydrophilic ointment base l lb
50% aqueous solution
of Sodium acid phosphate 25cc
DL-panthenol 5cc
Quercetin powder lOg-SOg
Rutin Sg-25g
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
24
EXAMPLE 5
Ingredient Amount
Ascorbyl Palmitate 2g
Hesperidine 2g
Rutin 20g
Vitamins A and D3 3cc
Vitamin E acetate 1 cc
DL Panthenol 50-L Scc
EXAMPLE 6
I~edient Amount
Ascorbyl Palmitate 2g
Ascorbyl glucosamine lg
Luteolin 15g
Vitamins A and D3 3cc
Vitamin E acetate 1 cc
DL-Panthenol 50-L 5cc
EXAMPLE 7
In e~. diem Amount
Ascorbyl glucosamine . 2g
Apigenin 1 Sg
Vitamins A and D3 3cc
Vitamin E acetate 1 cc
DL Panthenol SO-L Scc
CA 02470603 2004-06-16
WO 03/053336 PCT/US02/35654
EXAMPLE 8
In~-redient Amount
Ascorbyl palmitate 2g
Gamma linolenic acid l Og
5 Rutin 15g
Vitamins A and D3 3cc
Vitamin E acetate 1 cc
DL Panthenol 50-L Scc
l0 Although the present invention has been described and exemplified in terms
of
certain preferred embodiments, other embodiments will be apparent to those
skilled in
the art. The invention is, therefore, not limited to the particular
embodiments
described and exemplified, but is capable of modification or variation. The
full scope
of the invention is delineated by the appended claims.
