U.S. patent application number 10/811828 was filed with the patent office on 2005-10-06 for composition for protection against superficial vasodilator flush syndrome.
Invention is credited to Theoharides, Theoharis C..
Application Number | 20050220909 10/811828 |
Document ID | / |
Family ID | 35054620 |
Filed Date | 2005-10-06 |
United States Patent
Application |
20050220909 |
Kind Code |
A1 |
Theoharides, Theoharis C. |
October 6, 2005 |
Composition for protection against superficial vasodilator flush
syndrome
Abstract
Compositions with synergistic anti-inflammatory effects in
inflammatory diseases resulting from activation and consequent
degranulation of mast cells and followed by secretion of
inflammatory biomolecules from the activated mast cells, composed
of a heavily sulfated, non-bovine proteoglycan such as shark
cartilage chondroitin sulfate C, an unrefined olive kernel
oil/extract that increases absorption of these compositions in
various routes of administration, and one or more of a hexosamine
sulfate such as D-glucosamine sulfate, a flavone such as quercetin,
S-adenosylmethionine, a histamine-1 receptor antagonist, a
histamine-3 receptor agonist, an antagonist of the actions of CRH,
caffeine, and a polyamine.
Inventors: |
Theoharides, Theoharis C.;
(Brookline, MA) |
Correspondence
Address: |
DR. MELVIN BLECHER
4329 VAN NESS ST., NW
WASHINGTON
DC
20016
US
|
Family ID: |
35054620 |
Appl. No.: |
10/811828 |
Filed: |
March 30, 2004 |
Current U.S.
Class: |
424/769 ;
514/263.31; 514/27; 514/54; 514/62 |
Current CPC
Class: |
A61K 31/737 20130101;
A61K 31/4965 20130101; A61K 36/76 20130101; A61K 31/473 20130101;
A61K 31/7008 20130101; A61K 31/55 20130101; A61K 8/735 20130101;
A61K 31/353 20130101; A61K 36/63 20130101; A61Q 11/00 20130101;
A61Q 17/04 20130101; A61K 8/60 20130101; A61K 31/522 20130101; A61K
8/498 20130101; A61K 8/9789 20170801; A61K 36/63 20130101; A61K
2300/00 20130101; A61K 31/353 20130101; A61K 2300/00 20130101; A61K
31/473 20130101; A61K 2300/00 20130101; A61K 31/4965 20130101; A61K
2300/00 20130101; A61K 31/55 20130101; A61K 2300/00 20130101; A61K
31/737 20130101; A61K 2300/00 20130101; A61K 36/76 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
424/769 ;
514/054; 514/027; 514/062; 514/263.31 |
International
Class: |
A61K 035/78; A61K
031/522; A61K 031/737; A61K 031/7008 |
Claims
I claim:
1. A composition with synergistic anti-inflammatory properties in
conditions induced by the activation of mast cells, consequent
degranulation of said cells and secretion of inflammatory
biomolecules, comprising a non-bovine proteoglycan sulfate and an
unrefined olive kernel extract ("OKE"), and one or more of a
hexosamine sulfate, a flavone, S-adenosylmethionine ("SAM"), a
histamine-1 receptor antagonist, a histamine-3 agonist, an
antagonist of the actions of Corticotropin Releasing Hormone
("CRH"), a hyaluronate salt, a rutin, a polyamine, and caffeine, in
an appropriate excipient or vehicle.
2. The composition according to claim 1, wherein said sulfated
proteoglycan is selected from the group consisting of non-bovine
chondroitin sulfate, keratan sulfate, dermatan sulfate and sodium
hyaluronate.
3. The composition according to claim 2, wherein said chondroitin
sulfate is chondroitin sulfate C derived from shark cartilage.
4. The composition according to claim 1, wherein said hexosamine
sulfate is D-glucosamine sulfate.
5. The composition according to claim 1, wherein said flavone is
selected from the group consisting of quercetin, myricetin,
genistein and kaempferol.
6. The composition according to claim 1, wherein said unrefined
kernel extract contains polyphenols and alpha-tocopherol.
7. The composition according to claim 1, said composition being for
oral use, comprising 10-3,000 mg per capsule or tablet of each of
non-bovine chondroitin sulfate C, quercetin and D-glucosamine
sulfate, with 900-1200 mg unrefined olive kernel extract.
8. The composition according to claim 7, further supplemented with
3-1,000 mg of SAM per capsule or tablet.
9. A composition according to claim 1, wherein said inflammatory
diseases are selected from the group consisting of: arthritis,
cancers, fibromyalgia, inflammatory bowel disease, interstitial
cystitis, irritable bowel syndrome, migraines, angina, chronic
prostatitis, eczema, multiple sclerosis, psoriasis, sun burn, tooth
decay, periodontal disease, stressed-induced migraines,
stress-induced opening of bladder mucosa, stress-induced opening of
the blood-brain barrier, superficial vasodilator (flush} syndrome,
medical devices and hormonally-dependent cancers.
10. The composition according to claim 9, wherein said inflammatory
disease is arthritis and said composition is for oral
administration, comprising non-bovine chondroitin sulfate, OKE,
quercetin, D-glucosamine sulfate, and, optionally, sodium
hyaluronate.
11. The composition according to claim 9, wherein said inflammatory
disease is arthritis and said composition is for topical use,
comprising, non-bovine chondroitin sulfate, OKE, D-glucosamine
sulfate, quercetin, sodium hyaluronate, and bitter willow bark
extract.
12. The composition according to claim 9 for oral or aerosol use in
allergic conditions, comprising non-bovine chondroitin sulfate, OKE
and a flavonoid selected from the group consisting of quercetin,
myricetin and kaempferol, and, optionally, a histamine-1 receptor
antagonist.
13. The composition according to claim 9, for topical use in
allergic conditions, comprising non-bovine chondroitin sulfate,
OKE, myricetin, alpha-tocopherol, and, optionally, a
histamine-1-receptor antagonist.
14. The composition according to claim 13, wherein said antagonist
is diphenhydramine, hydroxyzine, azatadine, azelastine or
cyproheptadine.
15. The composition according to claim 9 wherein said inflammatory
disease is superficial vasodilator "flush" syndrome, said
composition comprising a non-bovine proteoglycan, OKE, a flavonoid,
bitter willow bark extract, and, optionally, cyproheptadine or
azatadine.
16. The composition according to claim 9, wherein said inflammatory
disease is multiple sclerosis, said composition comprising
non-bovine chondroitin sulfate, OKE, quercetin or myricetin,
hydroxyzine, and, optionally, caffeine, SAM and
interferon-beta.
17. The composition according to claim 9, wherein said inflammatory
disease is migraine headaches, and said composition comprises
non-bovine chondroitin sulfate, OKE, quercetin, and azatadine.
18. The composition according to claim 1, said composition being
for oral use, comprising 150-300 mg per capsule or tablet of each
of non-bovine chondroitin sulfate, quercetin and D-glucosamine
sulfate, with 900-1200 mg of OKE, and, optionally, 100-200 mg
sodium hyaluronate and/or 100 mg SAM.
19. The composition according to claim 1, said composition
consisting of an ointment or cream for topical application,
comprising, in % by weight, non-bovine chondroitin sulfate, 5; OKE,
15; D-glucosamine sulfate, 5; quercetin, 3; sodium hyaluronate-5;
and, bitter willow bark extract 5.
20. The composition according to claim 19 supplemented by at least
one of the histamine-1 receptor antagonists diphenhydramine,
hydroxyzine, azelastine, azatadine, cyproheptadine, each 1-5 mg
%.
21. The composition according to claim 1, said composition
compromising a mouth wash composition, consisting of non-bovine
chondroitin sulfate and quercetin, each 0.3-0.4 M; OKE, 1% (v/v);
and, optionally, at least one of D-glucosamine sulfate, 0.4 M and
SAM, 0.15 M, in a mouth wash vehicle.
22. The composition according to claim 1, said composition
consisting of a tooth paste, comprising, in mg %, non-bovine
chondroitin sulfate, 5; OKE,1; quercetin, 3, and, optionally,
D-glucosamine sulfate, 5, in a tooth paste vehicle.
23. The composition according to claim 1, said composition
consisting of a sunscreen composition, comprising, in mg %,
non-bovine chondroitin sulfate, 5; OKE, 10; quercetin 3; and at
least one of D-glucosamine sulfate, 5, and titaniun dioxide, 5, in
a sun screen vehicle.
24. The composition according to claim 1, for use in treating
migraine headaches, said composition comprising, in mg, non-bovine
chondroitin sulfate, 50; OKE, 150; guercetin, 100; azatadine, 4;
and, optionally, a CRH antagonist.
25. The composition according to claim 1, said composition
comprising, in mg, non-bovine chondroitin sulfate, 50: quercetin,
400; hydroxyzine, 50; and, optionally, a CRH antagonist.
26. The composition according to claim 1, said composition
comprising, in mg, non-bovine chondroitin sulfate, 100; OKE,
900-1200; D-glucosamine sulfate, 50; and quercetin, 100.
27. The composition according to claim 1, comprising, in mg %,
non-bovine chondroitin sulfate, 5; OKE, 900-1200; D-glucosamine
sulfate, 5; and quercetin, 3.
28. The composition according to claim 1, wherein said inflammatory
disease is cancer and wherein said composition is designed for oral
use, comprising 25-50 mg of genistein and 150-300 mg of quercetin,
and 900-1200 mg OKE.
29. The composition according to claim 1, wherein said inflammatory
disease is atherosclerosis with or without myocardial ischemia,
comprising 100-300 mg each of non-bovine chondroitin sulfate,
myricetin, folic acid and SAM, and 900-1200 mg OKE, in a vehicle
for oral use.
30. The composition according to claim 1, wherein said inflammatory
disease is interstitial cystitis or prostatitis, said composition
comprising, in mg, 100-300 of non-bovine chondroitin sulfate,
900-1200 of OKE, 50-300 D-glucosamine sulfate, 100-300 of sodium
hyaluronate, 100-400 quercetin, in a vehicle for oral use.
31. The composition according to claim 1, wherein said inflammatory
disease is multiple sclerosis, said composition comprising, in mg,
50-300 each of non-bovine chondroitin sulfate, myricetin,
hydroxyzine and SAM, 900-1200 of OKE, and, optionally,
interferon-beta, in a vehicle for oral use.
32. The composition according to claim 1, said composition
comprising, in mg, non-bovine chondroitin sulfate 200; OKE, 450;
myricetine, 200; and diphenhydramine, 5 mg.
33. The composition according to claim 1, said composition
comprising, in mg, non-bovine chondroitin sulfate, 50; OKE,
900-1200; kaempferol, 100; SAM, 50; folic acid, 50; and niacin,
100.
34. The composition according to claim 1, wherein said inflammatory
disease is superficial vasodilation flush syndrome, said
composition comprising 50 mg non-bovine chondroitin sulfate; OKE,
450 mg; 350 mg quercetin, 5% by weight bitter willow bark extract,
and, optionally, 4 mg cyproheptadine or azatadine.
35. The composition according to claim 1, wherein said inflammatory
disease is skin allergy, said composition comprising, in % by
weight, 5 each of aloe vera, non-bovine chondroitin sulfate and
alpha-tocopherol, 15 of OKE, and, optionally, azelastine.
36. The composition according to claim 1, wherein said inflammatory
disease in allergy or allergic asthma, comprising 200 mg of
myricetin, 200 mg of non-bovine chondroitin sulfate, and,
optionally, azelastine or hydroxyzine.
38. The composition according to claim 1, wherein said inflammatory
disease is a hormonally-dependent cancer, comprising, in mg,
non-bovine chondroitin sulfate, 150; OKE, 450; quercetin, 250;
genistein, 50; and, optionally, 10 tamoxifen or raloxifen.
39. The composition according to claim 1, wherein said inflammatory
disease is allergic conjunctivitis, comprising quercetin, 0.05%;
non-bovine chondroitin sulfate, 2.0%; OKE, 0.001%; and, optionally,
azelastine 0.05%.
Description
BACKGROUND OF THE INVENTION
[0001] The invention is generally related to the treatment of
inflammatory conditions. More specifically, the invention is
related to compositions containing inhibitors of mast cell
activation and secretion such as a proteoglycan that are designed
to be used as dietary supplements or adjuvants to conventional
approved medications for the relief of inflammatory conditions.
[0002] There have been a number of mostly anecdotal reports that
the proteoglycan chondroitin sulfate, as well as glucosamine
sulfate, a product of the intestinal breakdown of proteoglycans,
may be helpful in relieving the pain of osteoarthritis:--Shute N.
Aching for an arthritis cure. US News and World Report, Feb. 10,
1997.-- Cowley G. The arthritis cure? Newsweek, Feb. 17, 1997;
Foreman J., People, and their pets, tout arthritis remedy. The
Boston Globe, Apr. 7, 1997; Tye L. Treatment gains scientific
attention. The Boston Globe, Sep. 25, 2000.
[0003] A recent meta-analysis showed potential therapeutic benefit
of chondroitin sulfate and/or glucosamine in osteoarthritis
[McAlindon et al. J Am Med Assn. 283:1469 (2000)], while a
double-blind clinical trial with glucosamine showed definite
benefits in osteoarthritis with respect to both pain and
radiographic joint appearance [Reginster et al., Lancet 337:252
(2001)]. However, less than 5% of the chondroitin sulfate in
commercially available preparations is absorbed orally, because the
size of the molecule and the degree of sulfation impede its
absorption from the gastrointestinal tract. Furthermore, such
commercial preparations use chondroitin sulfate obtained from cow
trachea, with the possible danger of contracting spongiform
encephalopathy or "mad cow disease". In fact, the European Union
has banned even cosmetics that contain bovine-derived products.
[0004] Theoharides et al. British Journal of Pharmacology 131:1039
(2000) indicated for the first time how proteoglycans such as
chondroitin sulfate may work. The paper reported that chondroitin
sulfate and, to a lesser degree, glucosamine sulfate, inhibit
activation of mast cells that are known to trigger allergy and
asthma. This discovery is the basis for Theoharides, U.S. patent
application Ser. No. 09/056,707, filed Apr. 8, 1998 and 09/773,576,
filed Feb. 2, 2001.
[0005] Mast cells are also now recognized as important causative
intermediary in many painflul inflammatory conditions[Galli, N Eng
J. Med. 328:257 (1993); Theoharides, Int J Tissue Reactions 18:1
(1996)], such as insterstitial cystitis and irritable bowel
syndrome [Theoharides, Ann NY Acad, Sci. 840:619 (1998)], as well
as in migraines and possibly multiple sclerosis [Theoharides, Persp
Biol Med. 26:672 (1983); Theoharides, Life Sci46:607 (1996)]. In
fact, glucosamine was recently considered to be prophylactic for
migraines [Russell, Med Hypoth 55:195 (2000)].
[0006] Mast cells are increasingly implicated in conditions
involving inflamed joints, such as in osteoarthritis and rheumatoid
arthritis, through activation of local mast cells by, for example,
neuropeptides, such as Substance P. Additional indirect evidence
also supports the involvement of mast cells in bone resorption: (a)
systemic mastocytosis is invariably associated with osteoporosis;
(b) inhibition of mast cell mediator release reversed lytic bone
changes; (c) depletion of mast cells inhibited bone resorption in
organ culture; (d) human synovial mast cells were shown to secrete
in response to allergic and non-immunologic stimuli; (e) human mast
cells release the cytokine IL-6 and (f) IL-6 has been definitively
linked to bone resorption and osteoporosis.
[0007] It was recently shown that chondroitin sulfate's ability to
inhibit the activation of mast cells compliments the inhibitory
effects on mast cell activation of another class of naturally
occurring compounds, the flavonoids [Middleton et al. Pharm Rev
52:1 (2000)]. Certain plant flavones (in citrus fruit pulp, seeds,
sea weed) are now recognized as anti-allergic, anti-inflammatory,
anti-oxidant and cytoprotective with possible anti-cancer
properties. Only some flavonoids that belong to the subclass of
flavones, e.g., quercetin, inhibit mast cell activation.
[0008] Quercetin inhibits secretion from human activated mast cells
[Kimata et al. Allergy 30:501(2000)], and has also been used
effectively for the treatment of chronic prostatitis [Shoskes et
al., Urology 54:960 (1999)]. However, other flavonoids may have
opposite effects. Use of the term "bioflavonoids" or "citrus
flavonoids" in certain commercial products, therefore, provides
little information, and may include molecules that have detrimental
effects; for example, soy contains isoflavones that have
estrogen-like activity that worsens inflammatory conditions.
[0009] Copending U.S. patent application Ser. No. 09/056,707, filed
Apr. 8, 1998, and divisional 09/773,576 claim the oral use of
proteoglycans, without and with flavonoids, for the treatment of
mast cell activation-induced diseases. Absorption of these
compositions from the gastrointestinal tract and synergism with
other treatment modalities were not addressed in these
applications.
[0010] Applicant has described the use of antagonists of the action
of Corticotropin Releasing Hormone (also known as Corticotropin
Releasing Factor) in inhibiting myocardial mast cell activation in
myocardial ischemia (copending U.S. patent application Ser. No.
08/858,136, filed May 18, 1997), in treating stress-induced skin
disease (U.S. Pat. No. 6,020,305) and stress-induced migraine
headaches (U.S. Pat. No. 5,855,884), the contents of which are
incorporated herein by reference. The synergistic effects of the
compositions of the present invention that include antagonists of
the actions of Corticotropin Releasing Hormone ("CRH") on mast
cells were not recognized at the time of the previous studies. The
word "antagonists" in connection with CRH is intended herein to
include any molecule that prevents the actions of CRH on target
cells, and includes, but is not limited to, anti-CRH neutralizing
antibodies or binding proteins, or molecules preventing the release
of CRH at local sites (see below for details).
[0011] Applicant has also described a method for treating patients
with mast cell derived molecules-induced interstitial cystitis with
histamine-1 receptor antagonists (U.S. Pat. No. 5,994,357).
Treatment of mast cell molecules-induced migraines with histamine-1
receptor antagonists is the subject of Theoharides U.S. Pat. No.
5,855,884. Histamine-3 receptor agonists as pharmaceutical agents
in mast cell-involved diseases are described in Theoharides U.S.
Pat. No. 5,831,259. The contents of these three patents are
incorporated herein by reference. At the time of this invention the
synergistic effects of the present compositions with such
antagonists had not yet been recognized.
[0012] An important need therefore exists for compositions for
administration to human patients being treated for mast
cell-induced inflammatory diseases by various modalities, that are
synergistic in that they have stronger effects than the sum of the
effects of the individual components, and also synergistic with
conventional clinical treatments of inflammatory conditions.
"Synergistic" is also intended to mean: "coordinated or correlated
action by two or more structures or drugs" [Stedman's Medical
Dictionary, 23rd edition, Williams & Wilkins, Baltimore, 1976].
An important need also exists for formulations that increase the
absorption from the gastrointestinal tract, nasal passages and skin
surface of the compositions of the invention. Such formulations
have been discovered, and are described below.
SUMMARY OF THE INVENTION
[0013] The invention comprises compositions for human use
containing a heavily sulfated proteoglycan, with or without an
unrefined olive kernel extract, and one or more active ingredients
selected from the group consisting of a sulfated hexosamine, a
flavonoid compound, S-adenosylmethionine ("SAM"), histamine-1
receptor antagonists, histamine-3 receptor agonists, antagonists of
the actions of CRH, caffeine, folic acid, rutin, polyunsaturated
fatty acids, and polyamines, together with appropriate excipients
and carriers, said compositions having improved absorption from the
gastrointestinal tract, skin surface, and nasal and pulmonary
surfaces, and anti-inflammatory effects synergistic with each other
and synergistic with available conventional clinical treatment
modalities.
[0014] In one embodiment, the sulfated glucosamine is D-glucosamine
sulfate, the proteoglycan is non-bovine chondroitin sulfate, and
the flavone is quercetin.
[0015] In an other embodiment, compositions may also contain
antagonists of the effects of CRH on mast cells or other target
cells of the myocardium, gastric mucosa, urinary bladder, skin,
meningeal membranes, and blood-brain barrier.
[0016] In still another embodiment, the inventive compositions are
used against superficial vasodilator flush syndromes.
[0017] In still another embodiment, the inventive compositions may
be used as coatings on medical devices, not only to protect
surrounding tissues from inflammation due to the devices, but also
to treat innate inflammation in surrounding tissues.
[0018] In another embodiment, the inventive compositions are used
against the inflammatory processes of endometriosis.
[0019] In yet another embodiment, the inventive compositions are
used against the inflammatory components of hormonally-related
cancers, such as breast, testicular, ovarian and uterine cancers,
and when supplemented with chemotherapeutic agents are used against
the cancer itself.
[0020] In still another embodiment, the inventive compositions may
be used in the treatment of multiple sclerosis.
[0021] In another embodiment, the inventive olive kernel extract is
used to improve the absorption of drugs across membrane barriers in
the body, such as those of the intestine, skin and pulmonary
alveoli.
[0022] In yet another embodiment, the inventive compositions may be
used in the treatment of fibromyalgia.
[0023] The inventive olive kernel extract may be used to increase
the absorption of difficultly-absorbable drugs across the
intestine, skin and pulmonary alveoli.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE
INVENTION
[0024] It has been discovered that a combination of a sulfated
proteoglycan, with or without a unique unrefined olive kernel
extract, with one or more of a sulfated D-hexoseamine, a flavone or
isoflavone, CRH antagonists, histamine-1 receptor antagonists,
histamine-3 receptor agonists, polyamines, rutin and caffeine has
synergistic anti-inflammatory effects when used as a dietary
supplement, a topical product or an aerosol for nasal or pulmonary
adminstration, without or with a conventional clinical treatment
for inflammatory diseases. Within the present context, such
inflammatory diseases result from the activation, degranulation and
consequent secretion of inflammatory biochemicals from mast cells,
and the resultant inflammatory diseases include the group
consisting of: allergic inflammation, arthritis (to include
osteoarthritis and rheumatoid arthritis), fibromyalgia,
inflammatory bowel disease, interstitial cystitis, irritable bowel
syndrome, migraines, atherosclerosis, coronary inflammation,
ischemia, chronic prostatitis, eczema, multiple sclerosis,
psoriasis, sun burn, periodontal disease of the gums, superficial
vasodilator flush syndromes, hormonally-dependent cancers,
endometriosis and medical devices. The olive kernel extract alone
may be used to improve the transmembrane transport of
difficultly-absorbable drugs in the intestine, skin and pulmonary
alveoli.
[0025] In a highly preferred embodiment, the sulfated proteoglycan
is non-bovine chondroitin sulfate, preferably from shark cartilage,
which blocks mast cell activation, degranulation and consequent
secretion of inflammatory biochemicals from the mast cells. Other
natural sulfated proteoglycans suitable for practicing this
invention include keratan sulfate, dermatan sulfate and hyaluronic
acid sodium salt (sodium hyaluronate). The preferred biological
source of the chondroitin sulfate is shark cartilage which is
more-highly sulfated than the common commercial chondroitin sulfate
isolated from cow trachea; the shark cartilage source also avoids
the potential dangers associated with bovine sources.
[0026] The highly preferred flavone is quercetin which inhibits
secretion of inflammatory molecules from mast cells by affecting
moesin, a unique 78 kDa mast cell protein [Theoharides et al. J
Pharm Exp Therap 294:810 (2000)]. In addition to quercetin, other
flavones suitable in carrying out the invention include the
quercetin glycoside rutin, myricetin, genistein, kaempferol, the
isoflavone phenoxodiol, and the kaempferol glycoside
astrazaline.
[0027] The olive kernel extract product component of the inventive
compositions is preferably an unrefined (first pressing, filtered,
oleic acid-related acidity <3%, water content <1%) extract
product produced, for one source, on the island of Crete in Greece.
This kernel extract product is especially prepared by applicant's
process consisting essentially of: (1) harvesting first collection
ripe olives, preferably in December; (2) compressing the oil from
the flesh of the ripe olives; (3) washing the kernels remaining
after step (2) with water to remove debris; (4) drying the washed
kernels with a stream of hot air; (5) crushing the dried kernels to
produce an extract; (6) extracting the extract from step (5) with
an organic solvent (e.g., hexane, heptane, octane) plus steam; (7)
removing particulate matter from the organic extract by
centrifugation or microfiltering through 1-2 micron pore size
filters; (8) evaporating the organic solvent and water from the
clarified extract of step (7) by maintaining the extract at 86-100
degrees C. while percolating helium (to avoid oxidation) through
the fluid, which process reduces the water content to <1%, the
acidity (as oleic acid) to <3%; and, the organic solvent to
<1%; and (8) storing the final kernel extract product in the
absence of air.
[0028] The inventive olive kernel extract surprisingly has the
unique property of increasing absorption of the other components of
the anti-inflammatory compositions through the intestinal mucosa or
skin, and also adds its own content of important anti-oxidants,
such as omega fatty acids (e.g., eicosapentanoic acid) and alpha
tocopherol. The polyphenols found in such olive kernel extracts
also have anti-inflammatory effects in, for example, arthritis
[Martinez-Dominguez et al., Inflamm. Res. 50:102 (2001)]. E.B.E.K.,
Inc., Commercial, Industrial Enterprises of Crete, 118 Ethnikis
Antistasecos, Heraklion, Crete, 71306, Greece, will prepare the
extract product according to applicant's above-described procedure
for commercial users.
[0029] In addition to its usefulness in increasing the absorption
of the inventive macromolecular compositions across the intestinal
wall and the skin, the inventive olive kernel extract product is
useful in aiding the the dissolution of other drugs prior to
administration to a patient, and is useful in promoting the
absorption of other difficultly-absorbable drugs, e.g., the
HDL-increasing drug torcetrapib (DeNinno et al. U.S. Pat. No.
6,586,448), across intestinal mucosa, oral mucosl, nasal mucosa,
and skin of patients.
[0030] Supplementation of the compositions described above with the
methylation reagent S-adenosylmethionine ("SAM") adds antioxidant,
anti-inflammatory and cytoprotective properties, particularly in
inflammatory joint diseases. Addition of SAM also accelerates
metabolism of homocysteine, which amino acid has been implicated in
coronary disease, to cysteine, which is harmless. Folic acid may be
added to certain of the present formulations for similar
reasons.
[0031] Another supplement to the basic compositions of the
invention is a histamine-1 receptor antagonist, such as
hydroxyzine, merelastine, azelastine, azatadine and cyproheptadine.
Other histamine-1 receptor antagonists are described in Table 25-1
in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics,
9.sup.th ed., New York, 1996. Histamine-3 receptor agonists are
described in the Theoharides patents listed above.
[0032] Inhibitors of mast cell activation and secretion of
inflammatory biochemicals may be used in the treatment of
inflammatory processes such as superficial vasodilator syndrome,
such as occurs in menopausal-associated flush, carcinoid flush,
MSG-associated flush, and niacin-associated flush.
[0033] Hormone-dependent cancers, including the estrogen/progestin
linked ovarian, uterine, breast, and endometrial cancers, and the
androgen-linked testicular cancers, are associated with tissue
inflammation. These inflammations can be treated with chondroitin
sulfate, quercetin, genestein, phenoxodiol isoflavone, olive kernel
oil/extract, and, optionally, chemotherapeutic agents such as
tomoxifen or raloxifen.
[0034] Pelvic inflammatory conditions, such as presents in
endometriosis, can also be treated with the inventive compositions.
Particularly useful in this regard are compositions delivering
50-300 mg/day of chondroitin sulfate, quercetin or myricetin, and
hydroxyzine.
[0035] The inventive compositions may also be used as coatings on
implanted medical devices, which devices may lead to or be
associated with inflammation of surrounding tissues, in order to
provide protection against such inflammations. Not only can the
coating of such medical devices inhibit or protect against
inflammation caused by the device itself, but the coated devices
can also be used to deliver the inventive compositions to innately
inflamed tissues due to other causes. Such medical devices include
artificial skins (scaffolding such as naturally occurring polymers,
e.g., collagen; man-made polymers, e.g., PTFE, Dacron, PET or
polyethylene; self-degrading man-made polymers, e.g., PLA or PGA;
biopolymer matrices from animal tissues including fetal and
neonatal tissues to be used as tissue engineering scaffolds (cf.
Bell et al., U.S. patent application Pub. No. 20020146393)),
artificial joints, band-aids, stents for blood vessels, artificial
blood vessels, pacemakers, stents for abdominal support in hernia
repair, tissue transplants, prostheses, breast implants, etc.
Particularly useful in this regard are compositions containing
heavily sulfated, non-bovine proteoglycans (e.g., chondroitin
sulfate) and flavonoids (e.g., quercetin, myricetin,
gentistein).
[0036] Sources of CRH antagonists include, in addition to the
Theoharides patents listed in the Background section above:
Neurocrine Biochem. Inc.'s D-Phe 12 Nle Ala32,21,38hCRH(12-41)NH2,
cat no. 1P-36-41; Pfizer non-peptide CP-154,526-1; Sigma Chem., St.
Louis anti-CRH polyclonal antiserum; and Pfizer, NY patents and
applications: U.S. Pat. No. 6,211,195, U.S. Pat. No. 5,795,905,
PCT/IB95/00573, PCT/IB95/00439, U.S. Ser. No. 08/448,539, U.S. Ser.
No. 08/481,413, U.S. Ser. No. 09/735,841, and in Owens et al.
Pharm. Rev. 43:425 (1991).
[0037] The preferred concentration range of the proteoglycan,
hexosamine sulfate and flavone components of the oral formulations
are 10-3,000 mg per tablet or capsule. The preferred concentration
range for SAM is 3-1,000 mg per capsule or tablet. Generally, where
present, the amounts of the unrefined kernel extract are at least
three times those of the other active ingredients, preferably
300-1200 mg. The number of capsules or tablets to be taken per day
is determined by the nature and severity of the medical condition,
and is readily determinable by the patient's health provider. Other
representative formulations are described in the examples
below.
[0038] The compositions of the invention may be formulated in any
standard means of introducing pharmaceuticals into a patient, e.g.,
by means of tablets or capsules. The compositions of the invention
include ointments and creams for skin conditions, mouth washes and
toothpaste for periodontal diseases, and solutions for nasal
aerosols. Standard excipients and carriers for the active
ingredients of the inventive compositions are described in
Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,
Pa.
[0039] Although not bound by any particular mechanism of action of
the components of the claimed compositions, the inventor
contemplates that the proteoglycan inhibits the activation and
degranulation of the relevant mast cells, while the flavone
inhibits the secretion of inflammatory biomolecules from these mast
cells. "Activation" and "degranulation" of mast cells are defined
herein as is standard and well known in this art, that is, to mean
synthesis and secretion from the activated mast cell of any type of
molecule(s) that alone or in combination triggers inflammatory
processes.
EXAMPLES
Example 1
[0040] Table 1 compares chondroitin sulfate-containing commercial
products to the present compositions.
1TABLE 1 Comparison of Chondroitin Sulfate-Containing Products to
Present Invention Most Available Product Compositions Present
Invention Main ingredient Mixture of Non-bovine chondroitin
chondroitins sulfate, preferably the C type Source Cow trachea
Shark cartilage Amount per 100-300 10-3000 mg capsule or tablet
Degree of sulfation Low, if any High Absorption from g.i. <5%
>15% tract Target Unknown Mast cells, inflammatory cells Other
ingredients Vitamins, fish oils Flavones, unrefined (some
preparations) kernel olive oil, SAM, histamine-1 receptor
antagonists, histamine-3 receptor agonists, CRH antagonists,
polyamines, caffeine, folic acid Advantages None known
Anti-allergic, anti- inflammatory, anti- oxidant, cytoprotective
Adverse effects Risk of mad cow None known disease, spongiform
encephalopathy, stomach upset, allergy to fish products Relevant
conditions Osteoarthritis Allergic inflammation angina, asthma
coronary artery disease, arthritis (osteoarthritis or rheumatoid
arthritis), chronic prostatitis, eczema, fibromyalgia, interstitial
cystitis, irritable bowel syndrome, inflammatory bowel disease,
migraines, multiple sclerosis, psoriasis, periodontal disease,
flush syndrome, cancer (including hormonally-dependent forms).
Scientific publications None found Theoharides et al. Br J Pharm
131: 1039 (2000) Middleton et al. Pharm Rev 52: 673 (2000)
[0041] In all examples, chondroitin sulfate is to assumed to be of
a non-bovine variety.
Example 2
Composition For Protecting Against Inflammatory Diseases
[0042] Two capsules to be taken orally 2-3 times daily, at least
one hour before meals
2 Ingredients, per capsule. mg: Chondroitin sulfate 150-300
D-Glucosamine sulfate 150-300 Quercetin 150-300 Olive kernel
extract 350-1200
Example 3
Composition For Protecting Against Arthritis
[0043]
3 Ingredients per capsule, mg: D-Glucosamine sulfate 150-300
Chondroitin sulfate 150-300 Sodium hyaluronate 100-200 Quercetin
150-300 Olive kernel extract 350-1200
Example 4
Topical Composition For Protecting Against Arthritis
[0044] Skin ointment or cream. Apply three times per day to
affected areas.
4 Ingients % by weight D-glucosamine sulfate 5 Condroitin sulfate 5
Sodium hyaluronate 0.5 Bitter willow bark extract 5 Quercetin 3
Aloe vera 10 Olive kernel extract 5
Example 5
Composition For Protecting Against Cardiovascular Disease
[0045]
5 mg/capsule: Chondroitin sulfate 50 Kaempferol 100
S-adenosylmethionine 50 Niacin 0.01 Olive kernel extract 350-1200
Bitter willow bark extract 5% by weight Polyunsaturated fatty
acids(DHA, DPA) 100-600
Example 6
Composition For Protecting Against Periodontal Disease
[0046]
6 Mouthwash: Chondroitin sulfate 0.4 M Quercetin 0.4 M ln a
standard mouthwash vehicle
Example 7
Toothpaste Composition
[0047]
7 Toothpaste, mg %: Chondroitin sulfate 5 Quercetin 3 D-glucosamine
sulfate 5 Olive kernel extract 1 ln a standard toothpaste
vehicle
Example 8
Sunscreen Composition
[0048]
8 Ingredients % by weight Chondroitin sulfate 5 D-glucosamine
sulfate 5 Quercetin 3 Aloe vera 10 Olive kernel extract 5 Sun
screen (e.g., TiO.sub.2) 5
Example 9
Composition For Protecting Against Migraine Headaches
[0049]
9 Ingredients. mg: Chondroitin sulfate 50 Quercetin 100 Azatadine 4
Optionally, a CRH-receptor antagonist 5-300
Example 10
Oral Composition For Protecting Against Inflammatory Processes in
Relapsing Multiple Sclerosis
[0050]
10 Ingredients, mg/day Chondroitin sulfate 50-300 Quercetin or
myricetin 50-300 Hydroxyzine 50-300 Optionally, olive kernel
extract 350-1200 Optionally, interferon-beta 8 million IU Betaferon
(Schering), S.C., on alternate days or 30 .mu.g (Avonex, Biogen)
i.m. once weekly Optionally, a CRH receptor antagonist 5
Example 11
Composition For Protecting Against Cystitis And Prostatitis
[0051]
11 Ingredients, mg/capsule or tablet: D-glucosamine sulfate 50
Chondroitin sulfate 100-300 Sodium hyaluronate 200 Quercetin
100-400 Olive kernel extract 350-1200
Example 12
Composition For Protecting Against "Flush"
[0052]
12 Ingredients, per capsule: Chondroitin sulfate 50 mg Quercetin
150-350 mg Optionally, olive kernel extract 100-750 mg Bitter
willow bark extract 5% by weight Optionally, cyproheptadine or 4 mg
azatadine
Example 13
Cream Composition For Protecting Against Skin Allergy
[0053]
13 Ingredients: % by weight Aloe vera 5 Non-bovine chondroitin
sulfate 5 Myricetin 5 Alpha-tocopherol 5 Olive kernel extract 5
Aloe vera 10 Optionally, azelastine or hydroxyzine 5
Example 14
Composition For Protecting Against Allergies and Allergic
Asthma
[0054]
14 Ingredients, mg/tablet Myricetin 500 Chondroitin sulfate 200
Optionally, azelastine 4 Rutin 500 Optionally, hydroxyzine 25
Example 15
Composition For Protecting Against Hormonally-Dependent Cancers
[0055]
15 Ingredients, mg/day Chondroitin sulfate 50-300 Quercetin 25-250
Genestein 50-300 Phenoxodiol isoflavone 500-1000 Olive kernel
extract 350-1200 Optionally, tomoxifen or raloxifen About 10
Example 16
Composition For Protecting Against Allergic Conjunctivitis
[0056]
16 Ingredients: Quercetin 0.05% Chondroitin sulfate 2.0% Optionally
azelastine 0.05%
Example 17
Effect of Olive Kernel Extract on Absorption of a Proteoglycan
Sulfate In Vivo
[0057] Chondroitin sulfate was tritiated by New England Nuclear
Corp. to a specific activity of 4.3 mCi/ml.
[0058] Unlabeled chondroitin sulfate was dissolved in olive kernel
extract at a ratio of about 55 w/v chondroitin sulfate powder to
about 450 w/v of olive kernel extract (2.9% acidity as oleic acid,
1.03% water, 0.08% hexane). To this solution was added 20.2
microcuries of the labeled chondroitin sulfate. AAA gelatin
capsules were filled with the resulting solution using an aluminum
template molding device.
[0059] The laboratory animals (250 g male Sprague-Dawley rats) were
kept overnight without food but with free access to water. One
capsule containg the above-described chondroitin sulfate-olive
kernel extract solution was given to each rat per os. Control
animals were given the equivalent amount of chondroitin, but
without olive kernel extract. The animals were then given free
access to food. Serum radioactivity was measured 8 hours thereafter
in a beta scintillation counter.
[0060] The results showed that, in control animals, about
3.9%+/-0.4% (n=3) of the dose of labeled chondroitin sulfate
reached the circulation. In sharp contrast, in animals given the
olive kernel extract along with the labeled chondroitin sulfate,
about 14.3%+/-0.7% (n=4) of the dose was absorbed into the general
circulation.
[0061] These results demonstrate that olive kernel extract
increased by almost 400% the absorption of a proteoglycan from the
intestine into the general circulation.
[0062] Parallel experiments with codfish oil, corn oil and olive
oil (from the flesh of the olive) were comtemplated, but
chondroitin sulfate solubility in these oils was insufficient to
meet the requirements of the experiment.
Example 18
Composition for Protecting Against Endometriosis
[0063]
17 Ingredients mg/tablet Rutin 500 Chondroitin sulfate 500
* * * * *