U.S. patent application number 12/350427 was filed with the patent office on 2009-07-09 for method and compositions for administering resveratrol and pterostilbene.
Invention is credited to David RUBIN, Tal Rubin.
Application Number | 20090175803 12/350427 |
Document ID | / |
Family ID | 40844736 |
Filed Date | 2009-07-09 |
United States Patent
Application |
20090175803 |
Kind Code |
A1 |
RUBIN; David ; et
al. |
July 9, 2009 |
METHOD AND COMPOSITIONS FOR ADMINISTERING RESVERATROL AND
PTEROSTILBENE
Abstract
Resveratrol and/or pterostilbene are added to a chewable
carrier, to enhance absorption of resveratrol and/or pterostilbene
buccally or through the mucous membranes of the mouth. The
composition containing the resveratrol and/or pterostilbene is
designed to be retained in the mouth for at least 20 seconds and up
to 20 minutes to ensure absorption of the resveratrol and/or
pterostilbene through the mucous membranes of the mouth.
Inventors: |
RUBIN; David; (San Diego,
CA) ; Rubin; Tal; (San Diego, CA) |
Correspondence
Address: |
BROWDY AND NEIMARK, P.L.L.C.;624 NINTH STREET, NW
SUITE 300
WASHINGTON
DC
20001-5303
US
|
Family ID: |
40844736 |
Appl. No.: |
12/350427 |
Filed: |
January 8, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61019745 |
Jan 8, 2008 |
|
|
|
Current U.S.
Class: |
424/48 ; 514/719;
514/729 |
Current CPC
Class: |
A61K 9/006 20130101;
A23G 4/068 20130101; A61K 9/0058 20130101; C12H 1/14 20130101; A23K
20/111 20160501; A61K 31/047 20130101; C12G 2200/21 20130101; A61K
31/09 20130101; C12G 1/02 20130101; A23G 3/364 20130101; A23G 4/12
20130101; A61K 9/0056 20130101; A61K 9/0095 20130101; A61P 35/00
20180101; A23G 3/48 20130101 |
Class at
Publication: |
424/48 ; 514/729;
514/719 |
International
Class: |
A61K 9/68 20060101
A61K009/68; A61K 31/047 20060101 A61K031/047; A61K 31/09 20060101
A61K031/09 |
Claims
1. A composition for administering at least one compound selected
from the group consisting of resveratrol and, pterostilbene
comprising adding the at least one compound to a carrier that
requires chewing or retention in the mouth for from about 20
seconds to about twenty minutes.
2. The composition according to claim 1 wherein the carrier is
selected from the group consisting of chewing gum, gummi candy,
taffy, caramel candy, fudge, degradable thin films, nondegradable
thin films and hard candy.
3. The composition according to claim 1 wherein the at least one
compound is present in an amount to provide a dose of from about 1
g to about 5 g per piece of carrier.
4. A method for administering at least one compound selected from
the group consisting of resveratrol and pterostilbene, their esters
or any such conjugate that does not eliminate their bio activity,
that are absorbable via the mouth mucosa membranes to an individual
in need thereof comprising: a. incorporating the at least one
compound into a carrier that requires chewing or retention in the
mouth; b. administering the carrier to the individual so that the
individual retains the carrier in the mouth; c. whereby the at
least one compound is absorbed through the mucous membranes of the
mouth.
5. The method according to claim 4 wherein the carrier is retained
in the mouth over a period of from about 20 seconds to about 20
minutes.
6. The method according to claim 4 wherein the carrier is selected
from the group consisting of chewing gum, gummy candy, taffy,
caramel, candy, fudge, degradable thin films, nondegradable thin
films, and hard candy.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority from provisional
application 61/019,745, filed Jan. 8, 2008.
FIELD OF THE INVENTION
[0002] The present invention relates to methods and compositions
for administering resveratrol and pterostilbene.
BACKGROUND OF THE INVENTION
[0003] Resveratrol and its analogs, pterostilbene
(3,5-dimethoxy-4'-hydroxy-trans-stilbene), TMS
(3,4',5-reimwrhoxzy-trans-stilbene), 3,4',4-DH-5-MS
(3,4'-dihydroxy5-methoxy-trans-stilbnene) and
3,5-DH-4'MS(3,5-dihydroxy-4'-,ethoxy-trans-stilbene), have been
shown to have chemopreventaive activity against cardiovascular
disease and a variety of cancers in model systems. However, it is
not clear whether the drugs reach the proposed sites of action in
vivo after oral administration, especially in humans.
[0004] Walle et al., in Drug Metabolism and Disposition 32:
1377-1382, 2004, examined the absorption, bioavailability and
metabolism of 14C-resveratrol after oral and intravenous doses in
six human volunteers. When healthy men and women took an oral dose
of 2 grams of trans-resveratrol, only traces of the unchanged
resveratrol were detected in plasma. However, the resveratrol is
rapidly transformed in the liver to the glucurunide, which makes
the resveratrol not bioavailable.
[0005] Resveratrol is found in limited quantities in wine and some
foods. The amount of resveratrol in wines ranges from about 0.05
mg/liter to about 7.13 mg/L, with red wines having the most
resveratrol. Other sources of resveratrol are peanuts and peanut
butter (about 1 mg per cup (about 150 g), and red grapes, which
[0006] Resveratrol and pterostilbene have been shown to have
chemopreventive activity against cardiovascular disease and a
variety of cancers in model systems. However, it is not clear if
the drug reaches the proposed sites of action in vivo after oral
ingestion, especially in humans. Unfortunately, as reported by
Walle et al., Drug Metabolism and Disposition 32:1377-1382, 2004,
absorption of a dietary relevant 25-mg oral dose was at least 70%
with peak plasma levels of resveratrol and metabolites of 491.+-.90
ng/ml (about 2 microM) and a plasma half-life of 9.2.+-.0.6 hours.
However, only trace amounts of unchanged resveratrol (<5 ng/ml)
could be detected in plasma. Most of the oral dose was recovered in
urine, and liquid chromatography/mass spectrometry analysis
identified three metabolic pathways: sulfate and glucuronic acid
conjugation of the phenolic groups and hydrogenation of the
aliphatic double bond, the latter likely produced by intestinal
microflora. Extremely rapid sulfate conjugation by the
intestine/liver appears to be the rate-limiting step in the
bioavailability of resveratrol and related compounds such as
pterostilbene.
[0007] In order to avoid this entero-hepatic first exposure, an
exposure that deactivates resveratrol, it was discovered that
absorption through the buccal mucosa could bypass the enter-hepatic
circulation and thus enable the resveratrol to be absorbed
unchanged. Indeed, non-conjugated resveratrol levels were
substantially increased in the serum in this way. It was also found
that ethanol and DMSO in concentrations from 5% to about 50% could
be used as vehicles or as transfer agents for resveratrol, which
can increase absorption up to ten-fold.
SUMMARY OF THE INVENTION
[0008] Accordingly, Resveratrol, pterostilbene, and related
compounds can be administered transmucosally or buccally by
incorporating one or more of these compounds into any foodstuff
that remains in the mouth for a period of time of at least five
seconds or more, and preferably up to twenty minutes, such as
chewing gum, taffy, hard candy, jerky, etc. Detailed Description of
the Invention
[0009] Significant reductions in cardiovascular disease risk have
been associated with moderate consumption of alcoholic beverages
(43). This "French Paradox", the observation that mortality from
coronary heart disease is relatively low in France despite
relatively high levels of dietary saturated fat and cigarette
smoking, suggested that the regular consumption of red wine could
provide additional protection from cardiovascular disease (44, 45).
Red wine contains resveratrol and even higher levels of flavonoids.
These polyphenolic compounds have antioxidant, anti-inflammatory,
and other potentially anti-atherogenic effects in the test tube and
in some animal modes of atherosclerosis (46). Results of
epidemiological studies addressing the value of these polyphenolic
compound has been inconsistent. While some large prospective
studies found that wine drinkers were at lower risk of
cardiovascular disease than been or liquor drinkers (47-49), others
fond no difference (50-52). Several studies have discovered that
people who drink wine have higher incomes, more education, smoke
less, and eat more fruits and vegetables and less saturated fat
than people who prefer beer or liquor (53-55). This may explain
some of the differences.
[0010] In vitro, resveratrol effectively scavenges (neutralizes)
free radicals an other oxidants (11) and inhibits oxidation of low
density lipoprotein (12, 13). However, there is little evidence
that resveratrol is an important antioxidant in vivo (14) because
resveratrol is very quickly conjugated in the
gastrointestinal/liver system, and intracellular concentrations of
resveratrol in humans are likely to be much lower than that of
other important antioxidants, such as vitamin C, vitamin E and
glutathione. It is believed that the antioxidant activity of
resveratrol metabolites, which comprise most of the circulating
resveratrol, may be lower than that of resveratrol.
[0011] The chemical structure of resveratrol is very similar to
that of the synthetic estrogen agonist, diethylstilbestrol,
suggesting that resveratrol might also function as an estrogen
agonist. However, in cell culture experiments resveratrol acts as
an estrogen agonist under some condition, and an estrogen
antagonist under other conditions (16, 17). In estrogen
receptor-positive breast cancer cells, resveratrol acted as an
estrogen agonist in the absence of the endogenous estrogen
17-beta-estradiol, but acted as an estrogen antagonist in the
presence of 17-beta estradiol (18, 19). At present it appears that
resveratrol has the potential to act as an estrogen agonist or
antagonist, depending upon factors such as cell type, estrogen
receptor isoform (ER alpha or ER beta), and the presence of
endogenous estrogens (15).
[0012] Resveratrol, 3,4'-dihydroxystilbene, also known as
3,4'5-stilbenetriol, is a phytoalexin produced naturally by several
plants when under attack by bacteria or fungi. Resveratrol has also
been produced synthetically [see Farina et al., Nat. Prod. Res.
20(3): 247-252 2006]. A number of beneficial health effects of
resveratrol have been reported, including anti-cancer, antiviral,
neuroprotective, anti-aging, anti-inflammatory, and life-prolonging
effects, although most of the studies used animal subjects rather
than humans.
[0013] Resveratrol is found in widely varying amounts in grapes
(primarily the skins of red grapes), raspberries, mulberries,
plums, peanuts, berries of the Vaccinium species, including
blueberries, bilberries, cranberries, some pines such as Scotch
pine and eastern white pine, and the roots and stalks of giant
knotweed and Japanese knotweed. Resveratrol was first isolated from
an extract of the Peruvian legume Cassia quinquangulata in
1974.
[0014] In grapes, resveratrol is found primarily in the skin and
seeds. The amount found in grape skins also varies with the grape
cultivar, its geographic origin, and exposure to fungal infection.
The amount of fermentation time a wine spends in contact with grape
skins is an important determinant of its resveratrol content.
[0015] Pterostilbene is a stilbenoid compound chemically related to
resveratrol. Other names for pterostilbene are
4-[(E)-2-(3,5-dimethoxyphenyl)ethenyl]phenol;
3',5'-dimethoxy-4-stilbenol; and
3,5-dimethoxy-4'-hydroxy-trans-stilbene.
[0016] Pterostilbene has been found to be equal in potency to
resveratrol as a cancer-preventive agent (Rimando et al., Cancer
Chemopreventive and Antioxidant Activities of Pterostilbene, a
Naturally Occurring Analogue of Resveratrol, Ars.usda.gov).
Antioxidants destroy free radicals, highly reactive molecules whose
excess has been linked to cancer, which may account for the
effectiveness of resveratrol and pterostilbene against cancer.
Animal studies have also found that pterostilbene can lower blood
glucose and may be a potent antidiabetic agent.
[0017] Quantitative studies have shown that for every ten parts
resveratrol, there are only one to two parts pterostilbene. The
relationship between the two compounds and their unequal content in
plants is unclear, but remains the subject of ongoing studies.
Dark-skinned grapes are likely to contain the most pterostilbene.
For reasons that are not clear, pterostilbene is normally not found
in wine. This may be because it is unstable in light and air, which
makes it less likely to survive the wine-making process.
[0018] For administration, the resveratrol and/or pterostilbene can
be natural or synthetic. They may also be in the form of a
pharmacologically acceptable salt, ester, amide, prodrug or analog
or as a combination thereof. Salts, esters, amides, prodrugs and
analogs of resveratrol and/or pterostilbene may be prepared using
standard procedures known to those skilled in the art of synthetic
organic chemistry and pharmaceutical formulation.
[0019] The resveratrol and/or pterostilbene can be incorporated
into a chewable or other type of food or delivery vehicle that is
retained in the mouth for about five seconds to about twenty
minutes. Types of foods that require long chewing or that remain in
the mouth for a period of time of up to twenty minutes include
chewing gum, taffy, hard candies that are sucked, gummy candies,
fudge, lozenges, and the like. Alternatively, the resveratrol
and/or pterostilbene can be incorporated in a thin film that can be
retained in the mouth and from which the active ingredient is
delivered across the oral mucous membranes.
[0020] Some compounds are not carcinogenic until they have been
metabolized in the body by cytochrome P450 enzymes (2). By
inhibiting the expression and activity of certain cytochrome P450
enzymes (20,21), resveratrol could help prevent cancer by
decreasing exposure to these activated carcinogens. In contrast,
increasing the activity of phase II biotransformation enzymes
generally promotes the excretion of potentially toxic or
carcinogenic chemicals. Resveratrol has been found to increase the
expression and activity of the phase II enzyme NAD(P)H:quinine
reductase in cultured cells (5, 22).
[0021] Following DNA damage, the cell cycle can be transiently
arrested to allow for DNA repair or activation of pathways leading
the apoptosis if the damage is irreparable (23). Defective cell
cycle regulation may result in the propagation of mutations that
contribute to the development of cancer. Resveratrol has been found
to induce cell cycle arrest when added to cancer cells grown in
culture (24).
[0022] Unlike normal cells, cancer cells proliferate rapidly and
lose the ability to respond to cell death signals which initiate
apoptosis. Resveratrol has been found to inhibit proliferation and
induce apoptosis in a number of cancer cell lines (21).
[0023] Cancerous cells invade normal tissue with the aid of matrix
metalloproteinases. Resveratrol has been found to inhibit the
activity of at least one type of matrix metalloproteinase (25).
Invasive tumors must also develop new blood vessels to fuel their
rapid growth by angiogenesis. Resveratrol has been found to inhibit
angiogenesis in vitro (26, 27).
[0024] Inflammation promotes cellular proliferation and
angiogenesis and inhibits apoptosis (28). Resveratrol has been
found to inhibit the activity of several inflammatory enzymes in
vitro, including cyclooxygenase and lipoxygenase (29, 30).
[0025] Atherosclerosis is now recognized as an inflammatory
disease, and several measures of inflammation are associated with
increased risk of myocardial infarction (31). One of the earliest
events in the development of atherosclerosis is the recruitment of
inflammatory while blood cells from the blood to the artery wall by
vascular cell adhesion molecules (32). Resveratrol has been found
to inhibit the expression of adhesion molecules in cultured
endothelial cells (33, 34).
[0026] eNOS catalyzes the formation of nitric oxide (NO) by
vascular endothelial cells. NO is required to maintain
vasodilation, and impaired NO-dependent vasodilation is associated
with increased risk of cardiovascular disease (38). Resveratrol has
been found to stimulate eNOS activity in cultured endothelial cells
(39, 40).
[0027] Platelet aggregation is one of the first steps in forming a
blood clot that can occlude a coronary or cerebral artery,
eventually resulting in myocardial infarction or stroke.
Resveratrol has been found to inhibit platelet aggregation in vitro
(41, 42).
[0028] Resveratrol has been found to exert a number of potentially
cardioprotective effects in vitro, as discussed above, including
inhibition of platelet aggregation (41, 42, 56), promotion of
vasodilation by enhancing the production of NO (40, 57) and
inhibiting inflammatory enzymes (30, 58, 59). However, the
concentrations of resveratrol required to produce these effects are
higher than those that have been measured in human plasma after
oral consumption of resveratrol (7). Although the presence of
resveratrol in red wine has stimulated a great deal of interest in
the potential for resveratrol to prevent cardiovascular diseases,
there is currently no convincing evidence that resveratrol has a
cardioprotective effecting humans, particularly in the amounts
present in one or two glasses of red wine daily.
[0029] When added to cells in vitro, resveratrol has been found to
inhibit the proliferation of a variety of human cancer cell lines,
including those from breast, prostate, stomach, colon, pancreatic
and thyroid cancers (2). In animal models, oral administration of
resveratrol inhibited the development of esophageal (63),
intestinal (64) and mammary cancer (18, 55) induced by chemical
carcinogens. It is not known whether high intakes of resveratrol
can help prevent cancer in humans. Studies of human metabolism of
orally ingested resveratrol may not result in tissue levels that
are high enough to realize most of the protective effects
demonstrate in vitro studies (7, 10). It is likely that the tissue
levels of resveratrol result from the conjugation of resveratrol
shortly after ingestion, which produces conjugated resveratrol that
is not useful for any of the known activities of resveratrol.
[0030] As described by Rimando et al., Agric. Food Chem., 2002,
50(12):3453-3457, pterostilbene was evaluated for antioxidant
potential. The peroxyl-radical scavenging activity of pterostilbene
was the same as that of resveratrol, having total reactive
antioxidant potentials of 237.+-.58 and 253.+-.53 microM,
respectively. Pterostilbene exhibited significant inhibition of
carcinogen-induced preneoplastic lesions using a mouse mammary
organ culture model.
[0031] Accordingly, resveratrol and/or pterostilbene can be
formulated in an alcoholic beverage that is retained in the mouth
prior to swallowing such that the resveratrol and/or pterostilbene
is absorbed through the mucous membranes of the mouth, thus
bypassing the gastrointestinal/liver systems and passing directly
into the blood stream. Alternatively, the resveratrol and/or
ptersostilbene can be incorporated into a vehicle such as food,
candy, chewing gum, films, or the like, that can be retained in the
mouth for a sufficient time to deliver the resveratrol and/or
ptersostilbene through the oral mucous membranes.
[0032] Rimando et al., in Agric. Food Chem., 2005, 53(9):3403-3407,
reported that pterostilbene acts as a PPARA agonist and may be a
more effective PPARA agonist and hypolipidemic agent than
resveratrol. In vivo studies have demonstrated that pterostilbene
possesses lipid and glucose lowering effects.
[0033] Hougee et al., in Planta Med, 2005, 781(5): 387-392, note
that an extract of Pterocarpus marsupium Roxbn (PM) containing
pterostilbene was evaluated for its PGE-2 inhibitory activity in
LPS-stimulated PBMC in healthy human volunteers. The biological
activity and safety of the PM extract were evaluated. It was found
that PM extract, pterostilbene and resveratrol inhibited PGE2
production from LPS-stimulated human peripheral blood mononuclear
cells.
[0034] Pan et al., Agric. Food Chem. 2007 September
19:55(19):7777-7785. demonstrated that pterostilbene was able to
inhibit cell proliferation and induce apopotosis in a
concentration- and time-dependent manner, which may provide an
improved treatment of human gastric cancer.
[0035] As resveratrol and pterostilbene are rapidly conjugated when
administered orally, it is desirable to administer these compounds
transmucosally or buccally to avoid conjugation in the
gastric-hepatic system.
[0036] Resveratrol and/or pterostilbene can be administered
transmucosally or buccally by adding the resveratrol and/or
pterostilbene to chewing gums or candies, or other edible
substances that remain in contact with the mucous membranes of the
mouth for a period of time of from about five seconds to about two
minutes. The concentration should be 1-5 mg per candy or the
equivalent to chewing gum or chocolate. Among the types of candies
are hard candies that remain in the mouth for a prolonged period of
time, and chewy candies such as taffy, gummi candies, confectionary
starch and caramels, that require a long period of chewing.
[0037] One method of incorporating resveratrol and/or pterostilbene
in a chewable product is to provide a consumable center and a
compressible composition including the resveratrol and/or
pterostilbene that is compressed around the consumable center. The
resveratrol or pterostilbene may be encapsulated. The chewable
center may be, by way of example and not of limitation, a gummi
candy, confectionary starch, hard candy, licorice-type candy, or a
tableted excipient such as dextrose, sucrose, or other saccharides,
sorbitol, mannitol, iso-maltol, other sugar alcohols, or
combinations thereof. The product may be in any shape and size
suitable for chewing, such as a disk shape, a pellet shape, a
spherical shape, or a tube shape.
[0038] Another method of incorporating resveratrol and/or
pterostilbene into a chewable form for transmucosal delivery is by
incorporating the resveratrol and/or pterostilbene into a
dissolvable matrix material. This dissolvable matrix material may
include carbohydrates, fats, proteins such as gelatin, waxes
(natural and synthetic), hydrocarbons and other materials that
safely dissolve in the oral cavity. The combination of resveratrol
and/or pterostilbene and the matrix material can be compressed,
poured into a mold cavity, dehydrated, freeze dried or otherwise
formed into an integral delivery system. Specific confectionery
components can be combined in order for the mixture to form an
integral solid mass. These components include, for example,
compressible confectioner's sugar, sorbitol, mannitol and
maltodextrin. Any food-safe flavoring and/or coloring materials may
be incorporated into the product.
[0039] In the formulations of resveratrol and/or pterostilbene the
dissolution of the matrix material can be controlled by adding a
hydrophobic agent such as calcium stearate to slow dissolution.
Dissolution can also be slowed by mechanically compressing the
mixture to a greater extent.
[0040] Another method for administering the resveratrol and/or
pterostilbene orally by maintaining the resveratrol and/or
pterostilbene in contact with the mucous membranes of the mouth is
by incorporating these active ingredients in an orally
nondissolvable matrix. The resveratrol and/or pterostilbene may be
incorporated into a sponge-like matrix, the resveratrol and/or
pterostilbene may be microencapsulated and held within a
microsponge, the resveratrol and/or pterostilbene may be contained
within a permeable membrane or screen-like barrier, or the
resveratrol and/or pterostilbene may be held within other
nondissolvable containment vehicles capable of releasing the
resveratrol and/or pterostilbene for transmucosal
administration.
[0041] When the resveratrol and/or pterostilbene is incorporated
into a sponge-like matrix, the matrix may be designed to release
the resveratrol and/or pterostilbene in response to pressure,
either negative or positive, or other similar release trigger. The
matrix may be held within a screen or permeable membrane which
allows the resveratrol and/or pterostilbene to permeate the screen
when exposed to conditions of the mouth, pharynx, or esophagus.
Suitable screen-like materials include woven nylon, polypropylene
or polyethylene mesh, with varying apertures or pore sizes, and
porous sheet materials. A preferred screen or membrane material is
preferably flexible with no or low absorption of resveratrol and/or
pterostilbene and that is free of interaction with the oral mucous
membranes, palatable in taste and texture, non-irritating,
nontoxic, hypoallergenic and does not leach out plasticizers.
[0042] Alternatively, a sponge-like matrix may be held together
with a suitable biocompatible adhesive, either dissolvable or
nondissolvable. Typical adhesives include sodium
carboxymethylcellulose, sodium alginate, and tragacanth.
[0043] Compositions containing resveratrol and/or pterostilbene as
an active ingredient include all compositions wherein the active
ingredient is contained in an amount effective to achieve its
intended purpose. While individual needs vary, determination of
optimal ranges of effective amounts of each compound is within the
skill of the art. Typical dosages comprise 0.01 to 100 mg/kg body
weight. The preferred dosages comprising 0.1 to 100 mg/kg body
weight. The most preferred dosages comprise 1 to 50 mg/kg body
weight.
[0044] Another vehicle for administering resveratrol and/or
pterostilbene is by incorporating the resveratrol and/or
pterostilbene in a thin film that dissolves slowly in the oral
cavity so that the resveratrol or pterostilbene is slowly released
through the mucous membranes of the mouth. These thin film products
are generally formed by combining a properly selected polymer and
polar solvent, as well as resveratrol and/or pterostilbene and any
desired fillers.
[0045] The film-forming polymer may be water soluble, water
insoluble, or a combination of one or more either water soluble or
water insoluble polymers. The polymer may include cellulose or a
cellulose derivative. Specific examples of useful water soluble
polymers include, but are not limited to, pullulan,
hydroxypropylmethylcelluilose, hydroxyethylcellulose,
hydroxypropylcellulose, polyvinyl pyrrollidone, carboxymethyl
cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol,
xanthan gum, gum Arabic, gum tragacanth, guar gum, gum acacia,
polyacrylic acid, methyl methacrylate copolymers, carboxyvinyl
polymers, starch, and combinations thereof. Specific examples of
useful water insoluble polymers include, but are not limited to,
ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate
phthalate, hydroxypropyl methyl cellulose phthalate and
combinations thereof.
[0046] Other polymers that can be used in films for administering
resveratrol and/or pterostilbene include biodegradable polymers,
copolymers, block polymers and combinations thereof. Suitable
polymers are described in detail in Yang et al., US Published
Application No. 2003/0107149, the entire contents of which are
incorporated herewith by reference. The films are preferably
designed for controlled release of the resveratrol and/or
pterostilbene.
[0047] Other carriers for pterostilbene and/or resveratrol are
chews impregnated with an emulsion of the active ingredients.
Examples of such chews can be found in Brown et al., U.S. Pat. No.
7,147,888, the entire contents of which are hereby incorporated by
reference.
[0048] Pharmaceutical compositions for administering the active
ingredients transmucosally or buccally as described above
preferably contain, in addition to the pharmacologically active
compound, suitable pharmaceutically acceptable carriers comprising
excipients and auxiliaries which facilitate processing of the
active compounds into preparations which can be used transmucosally
or buccally.
[0049] Preferably, the dosage forms, contain from about 0.01 to
about 99 percent by weight, preferably from about 20 to 75 percent
by weight, active compound(s), together with the excipients. For
purposes of the present invention, all percentages are by weight
unless otherwise indicated. In addition to the following described
pharmaceutical composition, the resveratrol and/or pterostilbene
can be formulated as inclusion complexes, such as cyclodextrin
inclusion complexes.
[0050] In determining the dosages of the resveratrol and/or
pterostillbene to be administered, the dosage and frequency of
administration is selected in relation to the pharmacological
properties of the specific active ingredients. Normally, at least
three dosage levels should be used. In toxicity studies in general,
the highest dose should reach a toxic level but be sub lethal for
most animals in the group. If possible, the lowest dose should
induce a biologically demonstrable effect. These studies should be
performed in parallel for each compound selected.
[0051] Additionally, the ID.sub.50 level of the active ingredient
in question can be one of the dosage levels selected, and the other
two selected to reach a toxic level. The lowest dose that dose not
exhibit a biologically demonstrable effect. The toxicology tests
should be repeated using appropriate new doses calculated on the
basis of the results obtained. Young, healthy mice or rats
belonging to a well-defined strain are the first choice of species,
an the first studies generally use the preferred route of
administration. Control groups given a placebo or which are
untreated are included in the tests. Tests for general toxicity, as
outlined above, should normally be repeated in another non-rodent
species, e.g., a rabbit or dog. Studies may also be repeated using
alternate routes of administration.
[0052] Singe dose toxicity tests should be conducted in such a way
that signs of acute toxicity are revealed and the mode of death
determined. The dosage to be administered is calculated on the
basis of the results obtained in the above-mentioned toxicity
tests. It may be desired not to continue studying all of the
initially selected compounds. Data on single dose toxicity, e.g.,
ID.sub.50, the dosage at which half of the experimental animals
die, is to be expressed in units of weight or volume per kg of body
weight and should generally be furnished for at least two species
with different modes of administration. In addition to the
ID.sub.50 value in rodents, it is desirable to determine the
highest tolerated dose and/or lowest lethal dose for other species,
i.e., dog and rabbit.
[0053] The amount of resveratrol and/or pterostilbene to be
administered to any given patient must be determined empirically,
and will differ depending upon the condition of the patients.
Relatively small amounts of the active ingredient can be
administered at first, with steadily increasing dosages if no
adverse effects are noted. Of course, the maximum safe toxicity
dosage as determined in routine animal toxicity tests should never
be exceeded.
[0054] The foregoing description of the specific embodiments will
so fully reveal the general nature of the invention that others
can, by applying current knowledge, readily modify and/or adapt for
various applications such specific embodiments without undue
experimentation and without departing from the generic concept,
and, therefore, such adaptations and modifications should and are
intended to be comprehended within the meaning and range of
equivalents of eth disclosed embodiments.
[0055] It is to be understood that the phraseology or terminology
employed herein is for the purpose of description and not of
limitation. The means and materials for carrying out various
disclosed functions may take a variety of alternative forms without
departing from the invention.
[0056] Thus, the expressions "means to . . . " and "means for . . .
" as may be found in the specification above and/or in the claims
below, followed by a functional statement, are intended to define
and cover whatever structural, physical, chemical, or electrical
element or structures which may now or in the future exist for
carrying out the recited function, whether or nor precisely
equivalent to the embodiment or embodiments disclosed in the
specification above. It is intended that such expressions be given
their broadest interpretation.
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